─ Characteristic feature: Hair shafts (often fragmented) within inflamed tissue, abscesses, or sinus tracts, inciting foreign body giant cell reaction

─ Fibrosis common in chronic lesions

─ Cyst lining, if present, is usually granulation tissue or stratified squamous epithelium, not a true developmental cyst

DDx

─ Folliculitis/Furuncle (less chronic sinus tracts, fewer free hair shafts)

─ Hidradenitis suppurativa (different location, involves apocrine glands/follicles)

─ Ruptured epidermoid or dermoid cyst (true epithelial lining usually identifiable, lacks prominent free hairs in sinus tracts)

─ Anal fistula (connection to anorectal canal)

Prognosis ─ Benign, but prone to recurrence and chronic inflammation if hair/tracts not completely removed

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Proliferating Pilar Cyst (Proliferating Trichilemmal Cyst/Tumor)

Pilar cyst variant with prominent epithelial proliferation, mostly benign, rare malignant potential

Clinical

─ Typically larger, often lobulated subcutaneous nodule, sometimes >5 cm

─ Usually scalp of elderly women

─ May grow rapidly, can ulcerate

Micro

─ Areas of typical pilar cyst lining blend with marked epithelial proliferation forming complex, convoluted lobules

─ Proliferating squamous epithelium often shows trichilemmal keratinization (abrupt, no granular layer)

─ Cells generally bland, eosinophilic cytoplasm, peripheral palisading common

─ Variable cytologic atypia and mitotic activity usually low grade in benign lesions

─ Calcification and cholesterol clefts common in cyst contents

─ Look for well-demarcated "pushing" borders, not infiltrative growth

DDx

─ Pilar cyst (lacks significant epithelial proliferation)

─ Squamous cell carcinoma (invasive growth, significant atypia/mitoses, typical keratin pearls, usually lacks trichilemmal keratinization)

─ Trichilemmal carcinoma (overtly malignant cytology, infiltrative growth)

Prognosis ─ Mostly benign, curable by complete excision, higher recurrence than simple pilar cysts, rare malignant transformation

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Bronchogenic Cyst (Cutaneous)

Congenital cyst from anomalous budding of ventral foregut (tracheobronchial tree)

Clinical

─ Cutaneous presentation uncommon

─ Usually solitary nodule or draining sinus tract, present since birth/early childhood

─ Typical location suprasternal notch, manubrium, anterior neck

Micro

─ Lined by pseudostratified ciliated columnar epithelium (respiratory type), often with goblet cells

─ Wall characteristically contains smooth muscle bundles

─ May contain seromucous glands and/or hyaline cartilage in fibrous wall

─ Lymphoid aggregates possible, usually less organized than branchial cleft cyst

DDx

─ Thyroglossal duct cyst (midline, thyroid follicles)

─ Branchial cleft cyst (lateral neck, prominent lymphoid aggregates +/- germinal centers)

─ Cutaneous ciliated cyst (lower limbs of women, Müllerian-type lining, may lack cartilage/glands)

─ Epidermoid/Dermoid cyst (different lining/wall structures)

Prognosis ─ Benign

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Dermoid Cyst

Developmental cyst (choristoma) lined by epidermis-like epithelium with mature adnexal structures in wall

Clinical

─ Firm, non-tender, subcutaneous nodule, usually present at birth/early childhood

─ Typically located along embryonic fusion lines

─ Most common site lateral upper eyelid/eyebrow, also forehead, scalp, neck, midline nose/back (midline lesions raise concern for deeper tract/CNS connection)

Micro

─ Lined by mature stratified squamous epithelium with granular layer (like epidermoid cyst)

─ Characteristic presence of mature adnexal structures in fibrous wall (eg, hair follicles often entering lumen, sebaceous glands, +/- eccrine/apocrine glands, smooth muscle)

─ Lumen contains laminated keratin, often numerous hair shafts, sometimes sebum

DDx

─ Epidermoid cyst (lacks adnexal structures in wall)

─ Teratoma (contains elements from all three germ layers, eg, cartilage, bone, neural tissue, respiratory/GI epithelium, usually deeper)

─ Trichofolliculoma (more organized rudimentary follicles radiating from central pore/cyst)

Prognosis ─ Benign

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Hidrocystoma (Eccrine or Apocrine)

Benign cyst derived from sweat duct epithelium

Clinical

─ Translucent, skin-colored or bluish papule or nodule, often solitary (apocrine) or multiple (eccrine)

─ Typically periorbital (especially eccrine), also head, neck, trunk

─ May fluctuate in size, especially eccrine type with heat/humidity

Micro

─ Eccrine Hidrocystoma: Unilocular or multilocular cyst, usually in dermis, lined by two layers of small cuboidal epithelial cells, no decapitation secretion, minimal stroma

─ Apocrine Hidrocystoma: Usually unilocular, larger cyst, lined by columnar cells showing decapitation secretion (apical snouts), often with underlying myoepithelial layer, papillary projections into lumen common

DDx

─ Epidermoid cyst (squamous lining with granular layer)

─ Cutaneous ciliated cyst (ciliated lining, often lower extremities)

─ Steatocystoma (sebaceous glands in wall, eosinophilic cuticle)

Prognosis ─ Benign

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Apocrine WSI WSI

Eccrine WSI WSI

Thymic Cyst (Cutaneous)

Rare developmental cyst derived from remnants of the thymopharyngeal duct

Clinical

─ Usually presents in childhood as asymptomatic, slow-growing mass

─ Typically located in lateral neck, often supraclavicular or suprasternal area

Micro

─ Cyst lining variable, can be squamous, cuboidal, columnar, pseudostratified ciliated (respiratory), or transitional epithelium

─ Characteristic feature: Presence of thymic tissue (Hassall's corpuscles, lymphocytes, epithelial reticular cells) within the cyst wall or fibrous stroma

─ May contain cholesterol clefts, lymphoid aggregates (often without well-formed germinal centers)

DDx

─ Branchial cleft cyst (more prominent lymphoid tissue with germinal centers, location often higher/more anterior neck)

─ Thyroglossal duct cyst (midline location, thyroid follicles in wall)

─ Dermoid cyst (adnexal structures in wall)

─ Bronchogenic cyst (may have cartilage, smooth muscle, respiratory glands, location often suprasternal)

Prognosis ─ Benign

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Thyroglossal Duct Cyst

Developmental cyst arising from remnants of the thyroglossal duct tract

Clinical

─ Midline neck mass, usually infrahyoid, smooth, mobile, non-tender

─ Typically presents in childhood or young adulthood

─ Moves upward with swallowing or tongue protrusion

Micro

─ Cyst lining variable, often pseudostratified ciliated columnar (respiratory), squamous, or cuboidal epithelium, may show inflammation-induced changes

─ Characteristic feature: Presence of thyroid follicles (containing colloid) within the cyst wall or adjacent fibrous tissue

─ Salivary gland tissue may also be present in the wall

─ Lymphoid aggregates common, but usually less prominent/organized than branchial cleft cyst

DDx

─ Branchial cleft cyst (lateral neck, prominent lymphoid tissue with germinal centers)

─ Dermoid cyst (adnexal structures in wall, may occur midline)

─ Epidermoid cyst (squamous lining only, no thyroid tissue)

─ Thymic cyst (thymic tissue in wall, location often lower neck/suprasternal)

─ Bronchogenic cyst (cartilage/glands often present, location often suprasternal)

Prognosis ─ Benign, risk of infection, requires complete excision of cyst and tract (Sistrunk procedure) to prevent recurrence

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Benign epidermal neoplasms

WSI set with video and notes

Seborrheic Keratosis (SK)

Very common benign epidermal proliferation, "stuck-on" appearance, aging barnacles

Clinical

─ Tan to brown/black papules or plaques, greasy or warty surface

─ Anywhere except palms/soles, common >30 years old

─ Variants: Dermatosis papulosa nigra (small, face/neck, darker skin), stucco keratosis (small, white, lower extremities)

─ Leser-Trelat sign: sudden onset multiple SKs, associated with internal malignancy

Micro

─ Exophytic proliferation of basaloid keratinocytes

─ Hyperkeratosis, papillomatosis, acanthosis

─ Horn pseudocysts (keratin-filled invaginations) characteristic

─ Variable melanin pigmentation

─ Irritated SK: shows squamous eddies (whorls of eosinophilic keratinocytes), inflammation, more prominent dyskeratosis possible

DDx

─ Verruca vulgaris (viral cytopathic changes, koilocytes)

─ Melanocytic nevus (nevus cells)

─ Melanoma (atypical melanocytes, pagetoid spread)

─ Actinic keratosis (pigmented variant) (cytologic atypia, parakeratosis)

─ Squamous cell carcinoma in situ (Bowen's) (full-thickness atypia)

Prognosis ─ Benign

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Irritated seborrheic keratosis WSI WSI

Clonal seborrheic keratosis WSI WSI

Inverted follicular keratosis WSI WSI

Reticulated seborrheic keratosis WSI

Epidermal nevus WSI (entirely resembles SK)

Grover’s Disease (Transient Acantholytic Dermatosis)

Self-limited eruption, often pruritic papules and vesicles

Clinical

─ Sudden onset, pruritic small red papules, papulovesicles, or keratotic papules

─ Predilection for trunk, especially chest and back, middle-aged/elderly men

─ Often transient, exacerbated by heat, sweating, bed confinement

Micro

─ Focal acantholysis and dyskeratosis in small discrete foci within epidermis

─ Several patterns described, resembling:

─ Darier's disease (suprabasal acantholysis, corps ronds, grains)

─ Hailey-Hailey disease (more extensive intraepidermal acantholysis, "dilapidated brick wall")

─ Pemphigus vulgaris (suprabasal acantholysis)

─ Spongiotic pattern (spongiosis with focal acantholysis/dyskeratosis)

─ Variable superficial perivascular inflammation, sometimes with eosinophils

DDx

─ Darier's disease (more confluent changes, often familial)

─ Hailey-Hailey disease (more extensive acantholysis, often familial, different distribution)

─ Pemphigus variants (immunofluorescence positive)

─ Acantholytic actinic keratosis (sun-exposed sites, cytologic atypia)

Prognosis ─ Benign, often self-limited but can recur

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Warty Dyskeratoma

Solitary follicular adnexal neoplasm with acantholysis and dyskeratosis

Clinical

─ Solitary flesh-colored to reddish-brown papule or nodule, often umbilicated or crusted

─ Typically head, neck, or face, middle-aged or older adults

Micro

─ Cup-shaped epidermal invagination filled with keratinous material

─ Lined by hyperplastic epithelium showing suprabasal acantholysis forming lacunae

─ Prominent villi (dermal papillae lined by single basal layer) project into lacunae

─ Acantholytic and dyskeratotic cells (corps ronds, grains) within lacunae and stratum corneum

─ Often arises from a pilosebaceous follicle

DDx

─ Darier's disease (usually multiple lesions clinically, similar histology but often less cup-shaped)

─ Acantholytic actinic keratosis (sun-exposed sites, cytologic atypia)

─ Acantholytic squamous cell carcinoma (invasive growth, significant atypia)

─ Grover's disease (usually multiple clinically, more focal acantholysis/dyskeratosis)

Prognosis ─ Benign

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Acantholytic Acanthoma

Benign epidermal neoplasm characterized by acanthosis with acantholysis

Clinical

─ Usually solitary papule or nodule, often keratotic

─ Trunk or extremities common sites

Micro

─ Well-circumscribed epidermal hyperplasia (acanthosis)

─ Prominent acantholysis, often throughout thickness of hyperplastic epidermis

─ Minimal to no significant cytologic atypia or dyskeratosis

─ May have hyperkeratosis and parakeratosis

─ Sparse dermal inflammation

DDx

─ Pemphigus vulgaris (suprabasal acantholysis, DIF+)

─ Hailey-Hailey disease (full-thickness acantholysis, often familial, different clinical)

─ Grover's disease (more focal changes, often dyskeratosis)

─ Warty dyskeratoma (cup-shaped, villi, dyskeratosis)

─ Acantholytic squamous cell carcinoma (cytologic atypia, invasion)

─ Irritated seborrheic keratosis (can have focal acantholysis)

Prognosis ─ Benign

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Epidermolytic Hyperkeratosis (EHK)

Histologic pattern (granular degeneration), seen in bullous congenital ichthyosiform erythroderma, some epidermal nevi, or incidental finding, due to keratin gene mutations (KRT1, KRT10)

Clinical

─ Varies depending on associated condition

─ Bullous congenital ichthyosiform erythroderma: blistering at birth, later widespread hyperkeratosis, erythema

─ Epidermal nevus: linear verrucous plaques

─ Incidental finding: no specific clinical lesion

Micro

─ Compact hyperkeratosis

─ Prominent granular layer with large, irregular keratohyalin granules

─ Characteristic vacuolar degeneration (cytolysis) of cells in upper spinous and granular layers, clear spaces around nuclei

─ Epidermal acanthosis, papillomatosis may be present

DDx

─ Ichthyosis vulgaris (hypogranulosis)

─ X-linked ichthyosis (normal granular layer)

─ Verruca vulgaris (koilocytes, viral inclusions)

─ Seborrheic keratosis (horn pseudocysts, basaloid cells)

Prognosis ─ Benign pattern, prognosis depends on underlying condition

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Clear Cell Acanthoma (Pale Cell Acanthoma of Degos)

Uncommon benign epidermal neoplasm, likely reactive, not truly neoplastic

Clinical

─ Solitary, sharply demarcated, reddish-brown, moist or slightly crusted papule or plaque

─ Usually on lower legs of middle-aged or older adults

─ "Stuck-on" appearance, may resemble SK, pyogenic granuloma, or BCC

Micro

─ Sharply defined area of psoriasiform epidermal hyperplasia

─ Keratinocytes above basal layer distinctly pale or clear due to abundant glycogen (PAS+, diastase-sensitive)

─ Elongated, sometimes fused rete ridges

─ Surface often parakeratotic, granular layer thinned or absent

─ Characteristic migration of neutrophils through pale epidermis, sometimes forming intraepidermal or subcorneal microabscesses

─ Dilated capillaries in dermal papillae, moderate dermal lymphohistiocytic infiltrate

DDx

─ Psoriasis (Munro's microabscesses, neutrophils in stratum corneum, lacks sharp demarcation and diffuse clear cell change)

─ Seborrheic keratosis (irritated/inflamed variants, lacks diffuse clear cell change)

─ Eccrine poroma/Hidroacanthoma simplex (shows ductal differentiation)

─ Clear cell squamous cell carcinoma in situ (cytologic atypia)

─ Trichilemmoma (clear cells, peripheral palisading, thickened basement membrane, follicular origin)

Prognosis ─ Benign

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Lichen Simplex Chronicus (LSC)

Localized, thickened skin from chronic rubbing or scratching

Clinical

─ Well-demarcated, lichenified (thickened skin with accentuated skin lines) plaque

─ Often hyperpigmented, intensely pruritic

─ Common sites: nape of neck, ankles, wrists, vulva, scrotum, extensor extremities

─ Represents reaction pattern to chronic irritation

Micro

─ Marked compact hyperkeratosis

─ Irregular acanthosis with elongation and broadening of rete ridges (psoriasiform hyperplasia, sometimes irregular)

─ Hypergranulosis

─ Papillary dermal fibrosis with vertically oriented collagen bundles

─ Superficial perivascular chronic inflammation (lymphocytes, histiocytes, few eosinophils possible)

─ Nerve fiber hyperplasia sometimes seen but not required

DDx

─ Psoriasis (more regular acanthosis, Munro's microabscesses, dilated/tortuous capillaries)

─ Hypertrophic lichen planus (more lichenoid inflammation, colloid bodies)

─ Prurigo nodularis (more pronounced, dome-shaped epidermal hyperplasia)

─ Dermatophytosis (fungal elements present)

─ Allergic contact dermatitis (more spongiosis typically)

Prognosis ─ Benign, persistent if rubbing continues

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Porokeratosis

Disorder of epidermal keratinization characterized by a cornoid lamella, some forms linked to mevalonate pathway gene mutations

Clinical

─ Annular or linear plaques with distinct, thread-like, raised keratotic border

─ Well-demarcated plaques with hyperkeratotic peripheral ridge, central area often atrophic, hyper- or hypopigmented

─ Common variants include: Mibelli (large plaques), Disseminated Superficial Actinic Porokeratosis (DSAP, common, sun-exposed areas), Linear, PPPD, Punctate

Micro

─ Cornoid lamella (key feature): Slanted column of parakeratotic cells within an epidermal invagination, overlying an area of absent/reduced granular layer and often dyskeratotic cells

─ Epidermis centrally may be atrophic

─ Dermis may show mild superficial perivascular lymphocytic infiltrate

DDx

─ Actinic keratosis (lacks true cornoid lamella, different atypia pattern)

─ Hyperkeratosis lenticularis perstans (Flegel disease) (parakeratotic column but lacks distinct invagination/underlying epidermal changes of cornoid lamella)

─ Squamous cell carcinoma in situ (full-thickness epidermal atypia)

Prognosis ─ Chronic condition, carries a risk of developing squamous cell carcinoma (approx 7,5-11%)

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Large Cell Acanthoma

Benign epidermal proliferation, possibly a variant of solar lentigo or seborrheic keratosis

Clinical

─ Solitary or few, flat, tan to brown macule or thin plaque

─ Usually sun-exposed skin of elderly individuals

Micro

─ Sharply circumscribed focus of epidermal acanthosis

─ Keratinocytes (basal and spinous layers) are distinctly larger than adjacent normal keratinocytes, with enlarged nuclei and cytoplasm

─ Minimal cytologic atypia

─ Hyperkeratosis and hyperpigmentation common

─ Solar elastosis usually present in dermis

DDx

─ Solar lentigo (less prominent large cells, more regular rete ridge elongation)

─ Seborrheic keratosis (macular or reticulated variants) (may overlap significantly)

─ Bowen's disease (full-thickness atypia, more disorganization)

─ Melanoma in situ (lentigo maligna) (atypical melanocytes, not large keratinocytes)

Prognosis ─ Benign

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Melanoacanthoma

Benign epidermal neoplasm, heavily pigmented variant of seborrheic keratosis

Clinical

─ Dark brown to black papule or plaque, often warty or stuck-on appearance

─ Similar distribution to seborrheic keratosis

Micro

─ Features of acanthotic seborrheic keratosis (hyperkeratosis, papillomatosis, acanthosis, horn pseudocysts)

─ Characteristic feature: Numerous large, heavily pigmented dendritic melanocytes scattered throughout all levels of the proliferating basaloid/squamous epithelium

─ Abundant melanin within keratinocytes as well

DDx

─ Pigmented seborrheic keratosis (melanocytes confined to basal layer)

─ Melanoma (especially verrucous melanoma) (cytologic atypia, pagetoid spread of atypical melanocytes)

─ Pigmented basal cell carcinoma (basaloid nests with peripheral palisading, stromal retraction)

Prognosis ─ Benign

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Malignant tumors of the epidermis

Study set with video and notes

Basal Cell Carcinoma (BCC)

Most common cutaneous malignancy, arises from basal keratinocytes of epidermis or adnexa, locally invasive, rarely metastasizes

Clinical

─ Several variants:

─ Nodular: pearly papule/nodule, often with telangiectasias, may ulcerate (rodent ulcer)

─ Superficial: erythematous, slightly scaly patch, often with thread-like pearly border, common on trunk

─ Morpheaform/Sclerosing/Infiltrative: indurated, scar-like plaque, ill-defined borders, aggressive

─ Pigmented: contains melanin, brown/black/blue color

─ Fibroepithelioma of Pinkus: pink, firm papule/nodule, often lower back

─ Usually sun-exposed skin (head/neck > trunk > extremities), fair-skinned individuals

Micro

─ Nodular: islands/nests of basaloid cells extending into dermis, peripheral palisading of nuclei, stromal retraction artifact common, variable stromal mucin

─ Superficial: buds of basaloid cells attached to underside of epidermis, minimal dermal invasion

─ Morpheaform/Infiltrative: narrow strands/cords of basaloid cells infiltrating densely sclerotic stroma, often little palisading or retraction

─ Fibroepithelioma of Pinkus: anastomosing thin strands of basaloid cells in prominent fibrovascular stroma

─ Micronodular: small nests, may be deceptively circumscribed but often infiltrates widely

─ Keratotic/Infundibulocystic/Follicular variants show some differentiation (keratin cysts, follicular structures)

─ Basosquamous: mixed features of BCC and SCC (controversial entity)

─ Low mitotic rate, minimal pleomorphism typical (except aggressive subtypes)

DDx

─ Trichoepithelioma/Trichoblastoma (benign follicular tumors, more organized stroma, papillary mesenchymal bodies, horn cysts, no stromal retraction)

─ Sebaceous neoplasms (adenoma, carcinoma) (sebaceous differentiation)

─ Eccrine/Apocrine neoplasms (sweat gland differentiation)

─ Merkel cell carcinoma (neuroendocrine markers+, CK20+)

─ Melanoma (S100+, Melan-A+, SOX10+)

─ Squamous cell carcinoma (more eosinophilic cytoplasm, keratinization, intercellular bridges)

Prognosis ─ Excellent if completely excised, high recurrence if infiltrative/morpheaform or incompletely removed, metastasis extremely rare

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Nodular BCC WSI WSI WSI

Superficial BCC WSI

Fibroepithelioma of Pinkus WSI WSI WSI video

Infiltrative BCC WSI WSI WSI WSI

Micronodular BCC WSI WSI

Morpheaform BCC WSI WSI WSI WSI

Infundibulocystic BCC WSI WSI

Actinic Keratosis (AK)

Premalignant epidermal lesion caused by chronic sun exposure, potential to progress to SCC

Clinical

─ Rough, scaly papule or macule ("sandpaper" feel) on erythematous base

─ Often multiple lesions on sun-exposed sites (face, scalp, ears, dorsal hands/forearms)

─ Variants: hypertrophic (thickened), atrophic (thin), pigmented, lichenoid, Bowenoid (resembles SCCis), cutaneous horn formation possible

Micro

─ Atypia of basal keratinocytes (enlarged, hyperchromatic, pleomorphic nuclei, loss of polarity), often not full-thickness

─ Parakeratosis often alternating with orthokeratosis ("flag sign" over follicular ostia)

─ Epidermis may be hypertrophic, atrophic, or show acantholysis or budding

─ Solar elastosis prominent in papillary dermis

─ Superficial perivascular lymphocytic infiltrate, often with plasma cells

DDx

─ Bowen's disease/SCCis (full-thickness epidermal atypia)

─ Squamous cell carcinoma (invasive nests into dermis)

─ Seborrheic keratosis (irritated or lichenoid variants) (horn pseudocysts, less atypia)

─ Discoid lupus erythematosus (more interface change, follicular plugging, deeper infiltrate)

─ Verruca plana (viral cytopathic changes)

─ Porokeratosis (cornoid lamella)

Prognosis ─ Premalignant, small percentage (<1% to 10% per lesion per year debated) progress to invasive SCC, but majority of SCCs arise from AKs

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Hypertrophic WSI

Lichenoid WSI

Acantholytic WSI

Pigmented WSI

Atrophic WSI

Bowen's Disease / SCCis (Squamous Cell Carcinoma in situ)

Intraepidermal squamous cell carcinoma, potential for invasion

Clinical

─ Solitary or multiple, erythematous, scaly, crusted patch or plaque, often sharply demarcated

─ Can occur sun-exposed or non-sun-exposed skin

─ May be associated with arsenic exposure or HPV (especially genital/periungual)

─ Erythroplasia of Queyrat: SCCis on glans penis or inner prepuce, velvety red plaque

Micro

─ Full-thickness epidermal atypia ("windblown" appearance)

─ Keratinocytes show large, hyperchromatic, pleomorphic nuclei, loss of polarity, abnormal maturation

─ Increased and often atypical mitoses at all levels

─ May involve adnexal epithelium (follicular infundibula)

─ Hyperkeratosis and parakeratosis common

─ Intact basement membrane (by definition, no dermal invasion)

DDx

─ Actinic keratosis (AK) (typically partial thickness atypia, less disorganization, usually lacks adnexal involvement)

─ Irritated seborrheic keratosis (squamous eddies, horn pseudocysts, less atypia)

─ Psoriasis (neutrophils in stratum corneum, more regular acanthosis, lacks significant atypia)

─ Paget's disease (intraepidermal adenocarcinoma cells, glandular differentiation, mucin+)

─ Melanoma in situ (atypical melanocytes, S100/Melan-A/SOX10+)

Prognosis ─ Excellent if completely excised, small risk of progression to invasive SCC if untreated

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Squamous Cell Carcinoma (SCC)

Malignant neoplasm of keratinocytes with potential for local invasion and metastasis

Clinical

─ Variable presentation: indurated papule, plaque, or nodule, often erythematous, scaly, crusted, or ulcerated

─ Arises frequently from precursor AKs or SCCis (Bowen's disease)

─ Common on sun-exposed skin, especially head, neck, dorsal hands/forearms

─ Risk factors: chronic sun exposure, fair skin, immunosuppression, chronic inflammation/scars (Marjolin's ulcer), HPV, arsenic exposure

Micro

─ Invasive nests, strands, or sheets of atypical squamous epithelial cells originating from epidermis or adnexa and extending into dermis

─ Cells show variable degrees of atypia: enlarged, hyperchromatic, pleomorphic nuclei, prominent nucleoli, increased/abnormal mitoses

─ Variable keratinization: keratin pearls (well-differentiated), individual cell keratinization/dyskeratosis (poorly differentiated)

─ Intercellular bridges often visible (especially well-differentiated)

─ Stroma often desmoplastic or inflamed (lymphocytes, plasma cells, neutrophils, eosinophils)

─ Variants: Acantholytic (pseudoglandular spaces), Spindle cell (sarcomatoid), Verrucous (low-grade, pushing borders), Adenosquamous (glandular differentiation)

DDx

─ Keratoacanthoma (KA) (controversial, often considered well-diff SCC KA-type, symmetrical crateriform architecture)

─ Pseudoepitheliomatous hyperplasia (PEH) (reactive epidermal proliferation over inflammation/infection/tumor, lacks significant atypia)

─ Actinic keratosis/Bowen's disease (no dermal invasion)

─ Verruca vulgaris (viral cytopathic changes)

─ Other carcinomas with squamous features (eg, mucoepidermoid, adenosquamous)

Prognosis ─ Depends on size, depth, differentiation, location, perineural/lymphovascular invasion, etiology (UV vs other), immune status, metastasis relatively uncommon from typical sun-induced SCC but higher risk with other factors

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well diff WSI WSI mod diff WSI WSI poorly diff WSI WSI

KA-type SCC WSI

Acantholytic type SCC WSI WSI

Desmoplastic SCC WSI

Spindle cell SCC WSI WSI WSI

Verrucous SCC WSI

SCC in epidermoid cyst WSI

SCC in proliferating trichilemmal cyst WSI

Keratoacanthoma (KA)

Rapidly growing epithelial neoplasm, often dome-shaped with central keratin plug, debated whether benign or variant of SCC

Clinical

─ Rapid growth over weeks to months, typically forms dome-shaped nodule with central keratin-filled crater

─ Usually solitary, sun-exposed skin (face, hands), elderly individuals

─ May spontaneously involute over months leaving a scar

─ Multiple KAs associated with syndromes (Muir-Torre, Ferguson-Smith)

Micro

─ Symmetrical, cup-shaped architecture with central keratin-filled crater

─ Buttresses of relatively normal epidermis overhang crater shoulders

─ Proliferating squamous epithelium forms lobules extending into dermis with "pushing" borders

─ Cells often large, glassy eosinophilic cytoplasm, minimal atypia (can vary)

─ Intraepidermal neutrophilic microabscesses common within proliferating epithelium

─ Dermal inflammatory infiltrate (lymphocytes, histiocytes, neutrophils, eosinophils) often prominent, especially at base

DDx

─ Squamous cell carcinoma (SCC) (often indistinguishable histologically, especially on partial biopsy, SCC usually more atypical, infiltrative growth)

─ Pseudoepitheliomatous hyperplasia (reactive, underlying cause often identifiable, less glassy cytoplasm)

─ Verruca vulgaris (viral changes)

─ Prurigo nodularis (more vertical streaking of collagen)

Prognosis ─ Most regress spontaneously, but often treated as SCC due to histologic overlap and potential for aggressive behavior/metastasis in rare cases or misdiagnosis

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KA in Ferguson-Smith syndrome WSI WSI WSI

Regressed KA WSI

Regressing Keratoacanthoma

Keratoacanthoma undergoing spontaneous involution

Clinical

─ Lesion begins to flatten, central crater may extrude keratin, eventually heals with scar

Micro

─ Features of KA (crateriform shape, glassy keratinocytes) may still be present but less pronounced

─ Marked chronic inflammation (lymphocytes, histiocytes, plasma cells, eosinophils) undermining and replacing epithelial lobules

─ Fibrosis and granulation tissue replacing base of lesion

─ Remnant epithelial islands may be trapped in inflamed/fibrotic stroma, can be difficult to distinguish from invasive SCC

DDx

─ Squamous cell carcinoma undergoing regression/inflammation (difficult distinction)

─ Ruptured cyst with inflammation/granulation tissue (cyst remnants usually identifiable)

─ Inflamed/regressing verruca or seborrheic keratosis

Prognosis ─ Represents natural involution of KA, usually leads to scarring

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Verrucous Carcinoma

Low-grade variant of SCC, slow-growing, exophytic, locally destructive, rarely metastasizes

Clinical

─ Large, fungating, cauliflower-like mass

─ Common sites: oral cavity (oral florid papillomatosis), larynx, anogenital region (giant condyloma of Buschke-Löwenstein), sole of foot (epithelioma cuniculatum)

─ Associated with HPV (especially types 6, 11), chronic inflammation, poor hygiene

Micro

─ Marked epidermal hyperplasia with papillomatosis, acanthosis, hyperkeratosis

─ Bulbous rete ridges push deeply into dermis with broad, rounded "pushing" front, minimal stromal invasion

─ Cytologic atypia is minimal to absent, cells well-differentiated

─ Mitoses infrequent and basal

─ Dense chronic inflammation in stroma common

DDx

─ Verruca vulgaris/Condyloma acuminatum (viral cytopathic changes more prominent, less endophytic growth)

─ Pseudoepitheliomatous hyperplasia (reactive, often over ulcer or infection, less bulbous rete)

─ Conventional SCC (more cytologic atypia, infiltrative invasion)

Prognosis ─ Good, locally recurrent if incompletely excised, metastasis very rare

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Extramammary Paget’s Disease (EMPD)

Intraepithelial adenocarcinoma, usually of apocrine gland origin, affecting skin rich in apocrine glands

Clinical

─ Erythematous, eczematous, often crusted or weeping plaque

─ Common sites: vulva, perianal region, scrotum, axilla

─ Often pruritic or painful

─ May be primary (originating in skin) or secondary (extension from underlying anorectal or genitourinary adenocarcinoma)

Micro

─ Paget cells: large, pale-staining cells with abundant cytoplasm (may contain mucin, PAS+, diastase resistant, Alcian blue+) and large, atypical nuclei (often vesicular with prominent nucleoli)

─ Cells scattered singly or in nests within the epidermis, often concentrated along basal layer but can extend to surface

─ May involve adnexal epithelium (hair follicles, sweat ducts)

─ Underlying dermis often has chronic inflammatory infiltrate

─ Underlying invasive adenocarcinoma or adnexal carcinoma present in some cases (especially secondary EMPD)

IHC

─ Paget cells typically (+) CK7, EMA, CEA, GCDFP-15 (apocrine marker)

─ (-) CK20 (usually distinguishes from secondary spread of colorectal adenocarcinoma which is CK20+)

─ (-) S100, Melan-A (distinguishes from melanoma)

DDx

─ Pagetoid Bowen's disease (SCCis) (keratinocytic atypia, CK7-, CEA-, GCDFP-15-)

─ Melanoma in situ (pagetoid spread of atypical melanocytes, S100+, Melan-A+)

─ Clear cell acanthoma (glycogen-rich clear cells, PAS+, diastase sensitive, lacks atypia)

─ Pagetoid Spitz nevus (benign melanocytes, lacks atypia)

Prognosis ─ Primary EMPD often indolent but can recur locally, risk of underlying invasive carcinoma, Secondary EMPD prognosis depends on underlying primary tumor

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Verrucae (Warts)

Benign epidermal proliferations caused by Human Papillomavirus (HPV)

Clinical

─ Verruca vulgaris (common wart): hyperkeratotic papules/nodules, often rough surface, common on hands, fingers

─ Verruca plana (flat wart): small, flat-topped, skin-colored or light brown papules, common on face, hands

─ Verruca plantaris/palmaris (plantar/palmar wart): hyperkeratotic plaques on soles/palms, may be painful, often show thrombosed capillaries ("black dots")

─ Condyloma acuminatum (genital wart): soft, fleshy, cauliflower-like papules/plaques in anogenital region, associated with HPV types 6, 11 (low risk) or 16, 18, etc, (high risk)

Micro

─ Common features: epidermal hyperplasia (acanthosis), papillomatosis, hyperkeratosis, parakeratosis (often in columns over papillae tips)

─ Koilocytes: characteristic HPV cytopathic effect - keratinocytes with enlarged, irregular, hyperchromatic ("raisinoid") nuclei surrounded by clear perinuclear halo, most prominent in upper spinous/granular layers

─ Hypergranulosis with coarse keratohyalin granules

─ Dilated, thrombosed capillaries in dermal papillae

─ Specific types:

─ Verruca vulgaris: marked papillomatosis, acanthosis, hyperkeratosis, prominent koilocytes

─ Verruca plana: less papillomatosis, basket-weave hyperkeratosis, subtle koilocytes ("bird's eye cells") in upper layers

─ Verruca plantaris (myrmecia type): deep endophytic growth, eosinophilic intracytoplasmic inclusions

─ Condyloma acuminatum: marked papillomatosis, acanthosis, less hyperkeratosis, koilocytes often prominent

DDx

─ Seborrheic keratosis (horn pseudocysts, lacks koilocytes)

─ Actinic keratosis/Bowen's disease/SCC (cytologic atypia)

─ Lichen planus (lichenoid infiltrate, Civatte bodies)

─ Molluscum contagiosum (molluscum bodies)

─ Nevi (melanocytic proliferation)

Prognosis ─ Benign, often regress spontaneously, can recur, condylomata associated with high-risk HPV have malignant potential

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Verruca vulgaris pathoutlines WSI WSI WSI WSI video

Verruca plantaris and palmaris pathoutlines WSI WSI

Verruca plana WSI WSI WSI video

Epidermodysplasia Verruciforis video WSI WSI

Benign follicular & sebaceous neoplasms

Study set with video and notes

Sebaceous Hyperplasia

Common benign enlargement of sebaceous glands, often on face of middle-aged/older individuals

Clinical

─ Yellowish or skin-colored soft papules, often with central umbilication

─ Common on forehead, cheeks, nose

─ May resemble basal cell carcinoma or molluscum contagiosum

Micro

─ Enlarged sebaceous gland lobules grouped around a somewhat dilated central sebaceous duct

─ Lobules contain mature sebocytes with foamy cytoplasm and small central nuclei, and peripheral basaloid germinative cells

─ Overall architecture is relatively normal despite enlargement, no significant atypia

DDx

─ Sebaceous adenoma (more disorganized, >50% basaloid cells)

─ Sebaceoma (predominantly basaloid cells with scattered mature sebocytes)

─ Basal cell carcinoma (basaloid nests, peripheral palisading, stromal retraction, no true sebaceous differentiation)

─ Fordyce spot (ectopic sebaceous glands, no true hyperplasia around a central duct, mucosal location)

Prognosis ─ Benign

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Fordyce Spot (Fordyce Granules)

Ectopic sebaceous glands in mucosa or mucocutaneous junctions

Clinical

─ Small, yellowish or whitish, slightly elevated papules

─ Common on vermilion border of lips, buccal mucosa, less often on genital mucosa

─ Asymptomatic, considered a normal variant

Micro

─ Mature sebaceous gland lobules located superficially beneath the mucosal epithelium

─ Glands are usually not associated with hair follicles

─ Ducts may open directly onto the mucosal surface

─ No significant hyperplasia or atypia

DDx

─ Sebaceous hyperplasia (skin, enlarged glands around central duct)

─ Mucocele (mucous extravasation, granulation tissue)

─ Viral warts (koilocytosis, papillomatosis)

Prognosis ─ Benign, normal variant

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Sebaceous Adenoma

Benign neoplasm with prominent sebaceous differentiation and a significant basaloid component

Clinical

─ Solitary, firm, yellowish or skin-colored papule or nodule

─ Usually on head and neck, especially face and scalp, of older adults

─ May be associated with Muir-Torre syndrome (sebaceous neoplasms and internal malignancies, especially GI)

Micro

─ Well-circumscribed, often lobulated dermal tumor, may connect to epidermis

─ Composed of irregularly shaped sebaceous lobules

─ Two cell types: mature sebocytes (multivacuolated cytoplasm, scalloped nuclei) and smaller basaloid (germinative) cells

─ Basaloid cells typically constitute less than 50% of the tumor mass and are at periphery of lobules

─ Sebocytes show holocrine secretion into duct-like spaces

─ Minimal cytologic atypia, few mitoses

DDx

─ Sebaceous hyperplasia (more organized, normal architecture, fewer basaloid cells)

─ Sebaceoma (basaloid cells >50% of tumor)

─ Sebaceous carcinoma (cytologic atypia, infiltrative growth, necrosis, more mitoses)

─ Basal cell carcinoma with sebaceous differentiation (features of BCC with focal sebaceous change)

Prognosis ─ Benign, consider Muir-Torre syndrome if multiple or young patient

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Sebaceoma (Sebaceous Epithelioma)

Benign sebaceous neoplasm with a predominant basaloid cell component

Clinical

─ Yellowish or skin-colored papule or nodule

─ Usually on head and neck, especially face and scalp

─ May be associated with Muir-Torre syndrome

Micro

─ Dermal tumor composed of irregularly sized and shaped lobules/nests of basaloid cells

─ Basaloid (germinative) cells constitute more than 50% of the tumor mass

─ Scattered mature sebocytes with foamy cytoplasm are present individually or in small clusters within the basaloid nests

─ Ductal structures may be present

─ Stroma often fibrous

─ Cytologic atypia usually mild, mitoses can be present but not typically atypical or numerous

DDx

─ Sebaceous adenoma (mature sebocytes >50% of tumor)

─ Basal cell carcinoma with sebaceous differentiation (classic BCC features like peripheral palisading, stromal retraction, plus sebaceous differentiation)

─ Sebaceous carcinoma (significant cytologic atypia, infiltrative growth, necrosis)

Prognosis ─ Benign, consider Muir-Torre syndrome

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Cystic Sebaceous Adenoma

Benign sebaceous neoplasm characterized by prominent cystic change, may be associated with Muir-Torre syndrome

Clinical

─ Similar to sebaceous adenoma, yellowish papule or nodule, often head and neck

─ Presence of cystic features may or may not be clinically apparent

─ Suspicion for Muir-Torre syndrome if multiple or in a young patient

Micro

─ Features of sebaceous adenoma: well-circumscribed, lobulated, >50% mature sebocytes, <50% basaloid cells

─ Prominent cystic degeneration or ductal dilatation within the lobules

─ Cystic spaces may contain eosinophilic debris or holocrine secretions

─ Minimal cytologic atypia

DDx

─ Sebaceous adenoma (without prominent cystic change)

─ Steatocystoma (different cyst lining, eosinophilic cuticle, often multiple clinically)

─ Epidermoid or pilar cyst with sebaceous glands in wall (different primary cyst structure)

─ Sebaceous carcinoma with cystic change (cytologic atypia, infiltrative growth)

Prognosis ─ Benign, consider Muir-Torre syndrome

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Sebaceous Carcinoma

Malignant neoplasm with sebaceous differentiation, can be aggressive, especially ocular/periocular

Clinical

─ Firm, yellowish or reddish papule, nodule, or plaque, may ulcerate

─ Ocular: commonly arises from Meibomian glands or glands of Zeis of eyelid, can mimic chalazion or chronic blepharoconjunctivitis, aggressive

─ Extraocular: head and neck most common, less aggressive than ocular but still potential for recurrence and metastasis

─ May be associated with Muir-Torre syndrome

Micro

─ Infiltrative growth pattern with nests and sheets of atypical cells

─ Variable sebaceous differentiation: cells with foamy, vacuolated cytoplasm (sebocytes), scalloped nuclei

─ Basaloid cells often present, pleomorphic, hyperchromatic nuclei, prominent nucleoli, increased and atypical mitoses

─ Comedo-necrosis (central necrosis within tumor lobules) is common

─ Pagetoid spread into overlying epidermis or conjunctival epithelium can occur (especially ocular)

─ Perineural or lymphovascular invasion indicates aggressive behavior

IHC

─ (+) EMA, Androgen Receptor (AR)

─ Adipophilin or Oil Red O (on frozen tissue) highlights lipid in sebocytes

─ May be (+) CK7, CAM5,2

─ (-) S100, CEA (usually, helps distinguish from other clear cell or pagetoid tumors)

DDx

─ Basal cell carcinoma with sebaceous differentiation (less atypia, classic BCC features)

─ Squamous cell carcinoma with clear cell change (keratin pearls, intercellular bridges, lacks true sebaceous differentiation)

─ Clear cell hidradenocarcinoma (sweat gland origin, different IHC profile)

─ Metastatic renal cell carcinoma (clear cells, different IHC: PAX8+, CD10+)

─ Sebaceous adenoma/sebaceoma (less atypia, circumscribed, benign features)

Prognosis ─ Guarded, ocular lesions more aggressive, high recurrence rate, potential for regional and distant metastasis

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Pilar Sheath Acanthoma

Benign follicular neoplasm, typically a solitary lesion on the face of adults

Clinical

─ Asymptomatic, skin-colored or slightly erythematous papule or small nodule

─ Often has a central pore or comedo-like opening

─ Usually on upper lip, nose, or forehead

Micro

─ Well-circumscribed, symmetrical, exo-endophytic proliferation of squamous epithelium

─ Connects to the epidermis via a single, often dilated, keratin-filled follicular infundibulum

─ Tumor composed of broad lobules of bland squamous epithelium (pilar sheath type) extending radially into the dermis from the central cystic invagination

─ Peripheral palisading of basaloid cells and abundant pale to clear glycogenated cytoplasm in tumor cells, resembling outer root sheath

─ No significant cytologic atypia or high mitotic activity

DDx

─ Dilated pore of Winer (simple dilated follicle with atrophic epithelial lining, no significant acanthosis)

─ Trichofolliculoma (more complex, with multiple small radiating hair follicles)

─ Inverted follicular keratosis (more endophytic, squamous eddies, often irritated SK variant)

─ Trichilemmoma (more exophytic, lobular, prominent clear cells, thickened basement membrane)

─ Basal cell carcinoma (infiltrative nests, stromal retraction, atypia)

Prognosis ─ Benign

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Dilated Pore of Winer

Benign, enlarged solitary comedo-like follicular structure

Clinical

─ Solitary, prominent, open comedo ("giant blackhead") with a patulous follicular opening

─ Usually on the face, neck, or upper trunk of adults, more common in men

Micro

─ Greatly dilated, keratin-filled follicular infundibulum opening to the epidermal surface

─ Cyst wall is lined by stratified squamous epithelium that is often atrophic (thinned) centrally and acanthotic at the periphery near the opening

─ Rete ridges radiate outward from the dilated pore in a spoke-like fashion at the periphery

─ Small abortive hair follicles or sebaceous gland lobules may connect to the wall

─ Lumen contains abundant laminated keratin material

─ Minimal dermal inflammation unless ruptured

DDx

─ Pilar sheath acanthoma (more prominent epithelial proliferation extending from the pore)

─ Epidermoid cyst (true cyst, not just a dilated pore, usually lacks radiating rete)

─ Comedo (acne) (often associated with inflammation, smaller)

─ Trichofolliculoma (more complex follicular differentiation)

Prognosis ─ Benign

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Inverted Follicular Keratosis (IFK)

Benign endophytic proliferation of squamous and basaloid cells, often considered a variant of irritated seborrheic keratosis with follicular involvement

Clinical

─ Solitary, firm, skin-colored or slightly pigmented papule, sometimes verrucous

─ Usually on the face (eyelids, cheeks, upper lip) or neck of older adults

─ May resemble verruca vulgaris, seborrheic keratosis, or basal cell carcinoma

Micro

─ Sharply demarcated, endophytic, often cup-shaped proliferation of squamous epithelium connected to epidermis, often centered on a follicle

─ Prominent squamous eddies (whorls of eosinophilic, somewhat spindled keratinocytes) are characteristic

─ Variable mixture of basaloid and paler squamous cells

─ Hyperkeratosis and parakeratosis common, may fill central invagination

─ Mild inflammation in stroma

─ Minimal cytologic atypia, though squamous eddies can appear somewhat atypical

DDx

─ Irritated seborrheic keratosis (more exophytic, horn pseudocysts more typical, IFK is endophytic variant)

─ Trichilemmoma (more prominent clear cells, peripheral palisading, thickened basement membrane, usually more exophytic)

─ Verruca vulgaris (viral cytopathic changes, koilocytes, papillomatosis)

─ Squamous cell carcinoma (significant cytologic atypia, infiltrative growth)

Prognosis ─ Benign

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Trichilemmoma

Benign follicular neoplasm showing differentiation towards outer root sheath (trichilemma)

Clinical

─ Solitary or multiple, smooth or verrucous, skin-colored papule or small nodule

─ Most common on the face (nose, lips, eyelids, forehead)

─ Multiple trichilemmomas are a hallmark of Cowden syndrome (multiple hamartoma syndrome, PTEN mutations), associated with increased risk of breast, thyroid, endometrial cancers

Micro

─ Well-circumscribed, lobular, often exophytic epidermal proliferation, may connect to epidermis or hair follicle

─ Lobules composed predominantly of pale to clear cells due to abundant glycogen (PAS+, diastase sensitive)

─ Characteristic peripheral palisading of smaller, more basaloid cells at the edge of lobules

─ Prominent, thickened, eosinophilic basement membrane surrounding tumor lobules

─ Minimal cytologic atypia, scant mitoses

─ Sometimes central follicular keratinization or small horn cysts

DDx

─ Verruca vulgaris (koilocytes, papillomatosis, lacks clear cell change and thickened basement membrane)

─ Sebaceous hyperplasia/adenoma (sebaceous differentiation)

─ Basal cell carcinoma (especially keratotic or clear cell variants) (infiltrative growth, stromal retraction, atypia)

─ Clear cell acanthoma (psoriasiform hyperplasia, intraepidermal neutrophils, lacks prominent peripheral palisading/thickened BM)

─ Inverted follicular keratosis (squamous eddies, more endophytic)

Prognosis ─ Benign, consider Cowden syndrome if multiple lesions

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Tumor of Follicular Infundibulum (TFI)

Benign follicular neoplasm showing differentiation towards the follicular infundibulum

Clinical

─ Solitary, flat or slightly elevated, skin-colored or hypopigmented papule or small plaque

─ Usually on the face (especially cheeks) or neck of adults

─ Often subtle and asymptomatic

Micro

─ Superficial, plate-like proliferation of anastomosing strands and fenestrations of pale-staining epithelial cells, extending from the undersurface of the epidermis or multiple follicular infundibula

─ Epithelial strands are typically one to three cells thick, composed of bland keratinocytes with pale eosinophilic or clear cytoplasm (glycogen-rich)

─ Peripheral palisading of basaloid cells along the epithelial strands

─ Stroma between epithelial strands is often loose and slightly fibrous, may contain mucin

─ No significant atypia or mitoses

DDx

─ Superficial basal cell carcinoma (stromal retraction, peripheral palisading of tumor nests, atypia)

─ Fibroepithelioma of Pinkus (anastomosing strands of basaloid cells in prominent fibrovascular stroma, BCC variant)

─ Eccrine syringofibroadenoma (more prominent ductal structures, anastomosing cords in fibrous stroma)

─ Trichoadenoma (keratinous cysts with epithelial strands)

─ Desmoplastic trichoepithelioma (horn cysts, desmoplastic stroma, more solid basaloid islands)

Prognosis ─ Benign

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Trichoadenoma (of Nikolowski)

Benign follicular neoplasm with numerous horn cysts and epithelial strands, showing differentiation towards various parts of the hair follicle

Clinical

─ Solitary, firm, skin-colored or yellowish papule or nodule

─ Usually on the face or buttocks, can occur elsewhere

─ Slow-growing, asymptomatic

Micro

─ Well-circumscribed dermal tumor composed of numerous, variably sized keratinous cysts

─ Cysts are lined by stratified squamous epithelium with a granular layer and contain laminated keratin (infundibular-type keratinization)

─ Interspersed among the cysts are small nests and strands of basaloid or squamoid epithelial cells

─ Stroma is typically fibrous and may contain a mild chronic inflammatory infiltrate

─ No significant cytologic atypia

DDx

─ Trichoepithelioma (more prominent basaloid cell proliferation, papillary mesenchymal bodies, less numerous/dominant keratin cysts)

─ Keratotic basal cell carcinoma (basaloid atypia, stromal retraction, peripheral palisading)

─ Pilomatricoma (ghost cells, calcification, basaloid cells with abrupt keratinization)

─ Dilated pore of Winer / Pilar sheath acanthoma (connection to surface, different architecture)

Prognosis ─ Benign

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Trichofolliculoma

Benign hamartoma of the pilosebaceous follicle, usually a solitary facial papule with a central pore often extruding a tuft of vellus hairs

Clinical

─ Solitary, skin-colored, dome-shaped papule or small nodule

─ Typically on face (nose, scalp, forehead), sometimes neck or ears, in adults

─ Often has a central umbilication or pore, sometimes with a protruding white, silky hair tuft (immature vellus hairs)

Micro

─ Large, centrally located, often dilated and keratin-filled primary (mother) follicle

─ Numerous small, well-differentiated, secondary and tertiary hair follicles (vellus type) radiate from the wall of the central primary follicle

─ Follicles are embedded in a dense, well-vascularized, fibroblastic stroma

─ Sebaceous glands may be associated with some of the radiating follicles

─ No significant cytologic atypia

DDx

─ Dilated pore of Winer (simple dilated follicle, less prominent radiating structures)

─ Pilar sheath acanthoma (lobules of pilar sheath epithelium radiating from central pore, not distinct follicles)

─ Trichoepithelioma/Trichoblastoma (basaloid nests, papillary mesenchymal bodies, horn cysts, more stromal induction)

─ Basal cell carcinoma (especially keratotic/follicular variants) (atypia, stromal retraction)

Prognosis ─ Benign

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Fibrofolliculoma

Benign hamartoma of the hair follicle, characterized by proliferation of perifollicular fibrous tissue and thin epithelial strands

Clinical

─ Solitary or multiple, small, skin-colored or whitish, dome-shaped papules

─ Usually on head and neck (face, scalp, ears), upper trunk

─ Multiple lesions characteristic of Birt-Hogg-Dubé syndrome (autosomal dominant, FLCN gene mutation), associated with renal tumors (especially chromophobe renal cell carcinoma and oncocytoma), pulmonary cysts/spontaneous pneumothorax, and other skin lesions (trichodiscomas, acrochordons)

Micro

─ Well-circumscribed dermal nodule composed of one or more distorted hair follicles

─ Central follicle often slightly dilated and may contain keratin

─ Characteristic feature: Thin, anastomosing strands or cords of bland epithelial cells (follicular epithelium) extending outwards from the central follicle(s) into a prominent, specialized, loose, often mucinous perifollicular fibrous stroma

─ Epithelial strands are typically one to two cells thick, resembling mantle epithelium

─ Sebaceous glands may be present but are often atrophic or absent

DDx

─ Trichodiscoma (more vascular stroma, lacks prominent epithelial strands, often coexists in Birt-Hogg-Dubé)

─ Neurofibroma (wavy spindle cells, S100+)

─ Angiofibroma (more vascular, stellate fibroblasts)

─ Trichoepithelioma (basaloid nests, papillary mesenchymal bodies, horn cysts)

─ Tumor of follicular infundibulum (plate-like epithelial growth, less prominent specialized stroma)

Prognosis ─ Benign, consider Birt-Hogg-Dubé syndrome if multiple

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Trichodiscoma

Benign hamartoma of the Haarscheibe (hair disc), which is a specialized neurovascular tactile structure associated with some hair follicles

Clinical

─ Solitary or multiple, small, skin-colored, dome-shaped papules

─ Usually on head and neck, trunk

─ Multiple lesions may be associated with Birt-Hogg-Dubé syndrome (often coexisting with fibrofolliculomas)

Micro

─ Well-circumscribed, dome-shaped dermal lesion

─ Composed of a proliferation of fine, wavy collagen bundles in a mucinous or edematous stroma

─ Numerous dilated capillaries and small venules are characteristic

─ May contain scattered spindle-shaped or stellate fibroblasts

─ Overlying epidermis is often flattened

─ Hair follicles are usually not a central component, though a follicle may be adjacent

DDx

─ Fibrofolliculoma (prominent epithelial strands from follicles, specialized perifollicular stroma, often coexists)

─ Angiofibroma/Fibrous papule (more prominent concentric fibrosis around vessels/adnexa, more stellate fibroblasts)

─ Neurofibroma (wavy nuclei, S100+)

─ Connective tissue nevus (collagenoma/elastoma) (thicker collagen bundles, variable elastin)

Prognosis ─ Benign, consider Birt-Hogg-Dubé syndrome if multiple

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Nevus Sebaceus (of Jadassohn)

Congenital hamartomatous lesion with predominant sebaceous gland hyperplasia, also involves epidermis and other adnexal structures, evolves through stages

Clinical

─ Present at birth or appears in early childhood, usually solitary

─ Most common on scalp or face

─ Initially a flat or slightly raised, yellowish or skin-colored, hairless, often velvety or waxy plaque

─ Becomes more verrucous, papillomatous, and nodular during puberty/adulthood due to hormonal influence

─ Risk of secondary benign or malignant neoplasms developing within the nevus, especially later in life (most commonly trichoblastoma, syringocystadenoma papilliferum, basal cell carcinoma less common than previously thought)

─ Linear nevus sebaceus syndrome: extensive nevus sebaceus with extracutaneous findings (CNS, ocular, skeletal abnormalities)

Micro

─ Childhood: Epidermis may be normal or slightly acanthotic, underdeveloped/immature hair follicles, sebaceous glands often small or normal, apocrine glands may be present but immature

─ Puberty/Adulthood (classic features):

─ Epidermal hyperplasia, often papillomatous and verrucous

─ Numerous, large, mature but often abnormally shaped sebaceous glands, often high in dermis, sometimes opening directly to surface

─ Hair follicles often small, vellus-like, or absent

─ Ectopic apocrine glands frequently present and often dilated in lower dermis

─ Smooth muscle (arrector pili) may be hyperplastic

─ Secondary neoplasms can arise within the lesion

DDx

─ Epidermal nevus (lacks prominent sebaceous and apocrine hyperplasia)

─ Sebaceous hyperplasia (acquired, discrete enlarged glands around central duct, not congenital plaque)

─ Verruca vulgaris (viral cytopathic changes, koilocytes)

─ Specific secondary tumors arising in nevus sebaceus (eg, trichoblastoma, syringocystadenoma papilliferum)

Prognosis ─ Benign hamartoma, lifelong persistence, small risk of secondary neoplasms

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Cutaneous Lymphadenoma (Adamantinoid Trichoblastoma)

Rare benign adnexal neoplasm, considered a variant of trichoblastoma with prominent stromal lymphocytes

Clinical

─ Solitary, firm, skin-colored or erythematous papule or nodule

─ Usually on the head and neck (especially face) of adults

─ Slow-growing, asymptomatic

Micro

─ Well-circumscribed dermal tumor composed of lobules and islands of basaloid epithelial cells

─ Epithelial islands often have a peripheral layer of smaller, darker basaloid cells and central areas of larger, paler cells, sometimes with a vaguely "adamantinoid" (enamel organ-like) or swirled appearance

─ Characteristic feature: Dense lymphocytic infiltrate intimately admixed with and surrounding the epithelial nests, often obscuring epithelial elements

─ No significant cytologic atypia, mitoses usually sparse

─ No stromal retraction or prominent mucin as seen in BCC

DDx

─ Trichoblastoma (less prominent or intimately admixed lymphocytic component)

─ Trichoepithelioma (more differentiated follicular structures, horn cysts, papillary mesenchymal bodies)

─ Basal cell carcinoma (especially with lymphoid stroma) (atypia, stromal retraction, peripheral palisading of tumor nests)

─ Lymphoepithelioma-like carcinoma (malignant, more atypia, infiltrative, usually arises in other organs or as SCC variant)

─ Other adnexal tumors with lymphoid stroma

Prognosis ─ Benign

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Trichoblastoma

Benign neoplasm of follicular germinative cells, represents the benign counterpart of basal cell carcinoma in terms of follicular differentiation

Clinical

─ Solitary, firm, skin-colored or pigmented papule or nodule

─ Usually on head and neck, especially scalp and face, can occur on trunk

─ May arise de novo or within a nevus sebaceus

─ Several variants described (eg, giant, pigmented, subcutaneous)

Micro

─ Well-circumscribed, symmetrical dermal tumor composed of nests and lobules of basaloid cells

─ Two main patterns: large nodular (large, solid aggregations) and cribriform/retiform (anastomosing strands and nests)

─ Basaloid cells resemble those of BCC but generally show less atypia, fewer mitoses, and no significant necrosis

─ Peripheral palisading of nuclei in tumor nests is common

─ Characteristic feature: Prominent, cellular, often fibromyxoid stroma that is intimately associated with epithelial nests, often showing follicular stromal induction with papillary mesenchymal bodies (aggregates of stromal fibroblasts indenting epithelial nests)

─ Horn cysts (infundibular-type keratinization) may be present

─ No stromal retraction artifact (unlike BCC)

─ Pigmentation variable

DDx

─ Basal cell carcinoma (BCC) (stromal retraction, more atypia, less organized stroma, lacks prominent papillary mesenchymal bodies, though some overlap exists, especially with keratotic BCC)

─ Trichoepithelioma (smaller, more superficial, more numerous horn cysts and well-formed papillary mesenchymal bodies, considered by some a subtype of trichoblastoma)

─ Nevus sebaceus (may contain trichoblastoma, but also shows epidermal, sebaceous, and apocrine changes)

─ Other adnexal tumors

Prognosis ─ Benign, complete excision is curative

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Trichoepithelioma

Benign follicular neoplasm with differentiation towards hair germ structures

Clinical

─ Solitary or multiple, small, firm, skin-colored or slightly yellowish papules or nodules

─ Usually on the face, especially nose, cheeks, forehead, upper lip

─ Multiple trichoepitheliomas may be inherited (autosomal dominant, Brooke-Spiegler syndrome, CYLD gene mutations), often associated with cylindromas and spiradenomas

Micro

─ Well-circumscribed, superficial dermal tumor composed of nests and cords of basaloid epithelial cells

─ Numerous keratinous horn cysts (infundibular-type keratinization) are characteristic

─ Basaloid cell nests often show peripheral palisading

─ Papillary mesenchymal bodies (abortive hair papillae): small clusters of stromal fibroblasts indenting basaloid nests, a key feature

─ Stroma is typically cellular and fibrotic, closely associated with epithelial elements

─ Minimal cytologic atypia, few mitoses

─ No stromal retraction

DDx

─ Trichoblastoma (larger, deeper, may have fewer horn cysts, considered by some to encompass trichoepithelioma)

─ Basal cell carcinoma (keratotic type) (stromal retraction, atypia, lacks well-formed papillary mesenchymal bodies)

─ Trichoadenoma (more prominent and numerous keratin cysts, less basaloid proliferation)

─ Desmoplastic trichoepithelioma (narrow strands, desmoplastic stroma, often central dell)

Prognosis ─ Benign, consider Brooke-Spiegler syndrome if multiple

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Desmoplastic Trichoepithelioma (Sclerosing Epithelial Hamartoma)

Benign follicular neoplasm with prominent desmoplastic stroma

Clinical

─ Solitary, firm, skin-colored or slightly erythematous, annular or arcuate papule or plaque, often with a central dell or depression

─ Usually on the face (cheeks, chin, forehead) of young to middle-aged women

Micro

─ Poorly circumscribed dermal tumor, often biphasic

─ Narrow strands and small nests of bland basaloid epithelial cells embedded in a dense, sclerotic (desmoplastic) fibrous stroma

─ Small keratinous horn cysts are characteristic and often numerous

─ Calcification within horn cysts or stroma is common

─ Epithelial component shows minimal atypia

─ May show focal connection to epidermis

─ Perineural or perivascular infiltration by epithelial strands can occur but is not a sign of malignancy in this context

DDx

─ Morpheaform/Infiltrative basal cell carcinoma (more cytologic atypia, stromal retraction, peripheral palisading, mitoses, lacks numerous horn cysts, though some overlap in desmoplastic stroma)

─ Microcystic adnexal carcinoma (MAC) (more deeply infiltrative, often involves subcutis/muscle, ductal differentiation, perineural invasion more prominent and concerning)

─ Syringoma (comma-shaped ducts, tadpole-like epithelial strands, different epithelial morphology)

─ Sclerosing nevus (melanocytes, not basaloid epithelial cells)

Prognosis ─ Benign, but can recur locally if incompletely excised

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Pilomatrixoma (Pilomatricoma, Calcifying Epithelioma of Malherbe)

Benign follicular neoplasm differentiating towards hair matrix cells

Clinical

─ Solitary, firm or rock-hard, deep-seated papule or nodule, often skin-colored or slightly bluish

─ Common on head (face, scalp, neck) and upper extremities, often in children and young adults

─ May be tender, "tent sign" or "teeter-totter sign" (multiple facets on stretching skin)

─ Multiple lesions may be associated with Gardner syndrome, myotonic dystrophy, Turner syndrome, Rubinstein-Taybi syndrome

Micro

─ Well-circumscribed, often encapsulated dermal or subcutaneous tumor, sometimes with cystic areas

─ Composed of islands of epithelial cells

─ Two main cell types:

─ Basaloid cells: small, dark, round to oval nuclei, scant cytoplasm, arranged peripherally in nests, mitotically active

─ Ghost cells (shadow cells): pathognomonic, central in islands, pale eosinophilic cytoplasm, distinct cell borders, central unstained area where nucleus was (karyolysis)

─ Transition from basaloid cells to ghost cells is often abrupt

─ Foreign body giant cell reaction to keratin and ghost cells is common

─ Calcification within areas of ghost cells is very frequent (hence "calcifying epithelioma")

─ Ossification can occur

─ Stroma is often fibrous and may show inflammation

DDx

─ Basal cell carcinoma with matrical differentiation (more infiltrative, atypia, stromal retraction)

─ Proliferating pilar cyst (trichilemmal keratinization, lacks ghost cells, usually scalp)

─ Epidermoid or pilar cyst with rupture and calcification (true cyst lining elsewhere, different keratinization)

─ Cutaneous calcinosis (calcium deposits without epithelial tumor)

Prognosis ─ Benign, recurrence possible if incompletely excised

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Trichilemmal Carcinoma

Rare malignant follicular neoplasm showing differentiation towards outer root sheath (trichilemma), often arising from a trichilemmoma or trichilemmal cyst

Clinical

─ Solitary, firm, often exophytic, crusted, or ulcerated papule or nodule

─ Usually on sun-exposed skin of head and neck (face, scalp, ears) of elderly individuals

─ May resemble SCC, BCC, or KA

Micro

─ Lobular or sheet-like proliferation of atypical epithelial cells, often connecting to epidermis or pre-existing trichilemmoma/trichilemmal cyst

─ Cells often have abundant pale to clear, glycogen-rich cytoplasm (PAS+, diastase sensitive)

─ Peripheral palisading of tumor lobules and a thickened basement membrane may be present focally (features reminiscent of benign trichilemmoma)

─ Significant cytologic atypia: nuclear pleomorphism, hyperchromasia, prominent nucleoli, increased and often atypical mitoses

─ Infiltrative growth pattern may be seen at the periphery

─ Areas of trichilemmal keratinization (abrupt, without granular layer) can occur

─ Necrosis may be present

IHC

─ (+) Cytokeratins (eg, AE1/AE3, CK5/6)

─ CD34 may highlight peripheral tumor cells or stroma

─ EMA, CEA usually negative

DDx

─ Squamous cell carcinoma (SCC) (especially clear cell SCC) (more typical squamous differentiation, keratin pearls, lacks prominent clear cell change of trichilemmal type, lacks peripheral palisading/thickened BM)

─ Trichilemmoma (benign, lacks significant atypia and infiltrative growth)

─ Basal cell carcinoma with clear cell change (classic BCC features, stromal retraction)

─ Sebaceous carcinoma (sebaceous differentiation, lipid stains+)

─ Clear cell hidradenocarcinoma (sweat gland origin, ductal differentiation)

Prognosis ─ Low-grade malignancy, locally recurrent, metastasis is rare but possible

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Sweat gland tumors

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Syringoma

Benign adnexal neoplasm with eccrine ductal differentiation, typically multiple small papules

Clinical

─ Multiple, small (1-3 mm), firm, skin-colored or slightly yellowish papules

─ Most common on lower eyelids and upper cheeks (periorbital region)

─ Also occurs on chest, neck, axillae, abdomen, vulva

─ More common in women, often appears around puberty or early adulthood

─ Eruptive syringomas: generalized, sudden onset

─ Clear cell syringoma variant associated with diabetes mellitus

Micro

─ Superficial dermis contains numerous small ducts and epithelial cords embedded in a dense, fibrous stroma

─ Ducts are lined by two rows of small, bland, cuboidal epithelial cells

─ Characteristic feature: some ducts have a "tadpole" or "comma" shape due to a small tail of epithelial cells extending from one side

─ Lumina may contain eosinophilic, PAS-positive material

─ Solid epithelial strands or nests may also be present

─ No significant atypia or mitoses

DDx

─ Microcystic adnexal carcinoma (MAC) (more infiltrative, deeper extension, perineural invasion, desmoplastic stroma, more atypia, though can be subtle)

─ Desmoplastic trichoepithelioma (horn cysts, calcification, different epithelial morphology, often central dell clinically)

─ Sclerosing/Morpheaform basal cell carcinoma (basaloid atypia, stromal retraction, peripheral palisading)

─ Eccrine hidrocystoma (cystic spaces lined by two layers of cuboidal cells, usually larger, periorbital)

Prognosis ─ Benign, can be a cosmetic concern

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Clear Cell Syringoma

Variant of syringoma with prominent clear cell change in epithelial cells, often associated with diabetes mellitus

Clinical

─ Similar to classic syringoma: multiple, small, skin-colored or yellowish papules

─ Periorbital area, neck, chest common

─ Strong association with diabetes mellitus

Micro

─ Features of syringoma: small ducts, "tadpole" or "comma" shapes, epithelial cords in fibrous stroma

─ Characteristic feature: Epithelial cells lining ducts and forming cords show abundant clear cytoplasm due to glycogen accumulation (PAS+, diastase sensitive)

─ Nuclei are bland, centrally or eccentrically located

─ No significant atypia or mitoses

DDx

─ Classic syringoma (lacks prominent clear cell change)

─ Other clear cell adnexal neoplasms (eg, clear cell hidradenoma, trichilemmoma, sebaceous tumors – differ in architecture and specific differentiation)

─ Metastatic renal cell carcinoma (cytologic atypia, different IHC profile: PAX8+, CD10+)

Prognosis ─ Benign

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Microcystic Adnexal Carcinoma (MAC)

Rare, locally aggressive, deeply infiltrative sweat gland carcinoma with ductal and sometimes follicular differentiation

Clinical

─ Slow-growing, firm, indurated plaque or nodule, often skin-colored or yellowish

─ Most common on the face, especially upper lip, periorbital, and nasolabial fold areas

─ Often ill-defined borders, may mimic morpheaform BCC or desmoplastic trichoepithelioma

Micro

─ Deeply infiltrative tumor extending into reticular dermis, subcutis, and sometimes underlying muscle or bone

─ Biphasic pattern:

─ Superficial portion: keratinous cysts (horn cysts), small nests, and cords of squamoid or basaloid cells, some ductal differentiation

─ Deep portion: narrow strands and small nests of bland epithelial cells, often single-file, embedded in a dense, desmoplastic (sclerotic) stroma

─ Ductal structures (some with eosinophilic cuticle) and small keratinous cysts are characteristic throughout

─ Perineural and perivascular invasion are very common and characteristic features, even with bland cytology

─ Cytologic atypia is usually minimal, mitoses are infrequent

IHC

─ Epithelial cells (+) CK (AE1/AE3, CK7, CAM5,2), EMA, CEA

─ Ductal structures may show S100 protein positivity in some cells

─ Stromal cells (-) S100 (helps distinguish from desmoplastic melanoma)

DDx

─ Desmoplastic trichoepithelioma (more superficial, prominent horn cysts, calcification, lacks deep infiltration and prominent perineural invasion of MAC)

─ Syringoma (more superficial, classic tadpole/comma-shaped ducts, less infiltrative, no perineural invasion)

─ Morpheaform/Infiltrative basal cell carcinoma (basaloid atypia, stromal retraction, peripheral palisading, lacks ductal differentiation and horn cysts of MAC)

─ Metastatic carcinoma (especially breast) (different primary site, different IHC profile)

─ Squamous cell carcinoma, desmoplastic variant (more atypia, keratinization, lacks ductal features)

Prognosis ─ Locally aggressive with high recurrence rates due to infiltrative growth and perineural invasion, metastasis is rare but can occur

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Hidroadenoma Simplex (Hidroacanthoma Simplex, Intraepidermal Poroma)

Benign intraepidermal sweat gland tumor, considered an entirely intraepidermal variant of eccrine poroma

Clinical

─ Solitary or multiple, flat or slightly elevated, often hyperkeratotic or verrucous papule or plaque

─ May resemble seborrheic keratosis, viral wart, or Bowen's disease

─ Common on extremities, especially lower legs of older adults

Micro

─ Sharply demarcated nests and islands of small, uniform, basaloid to cuboidal "poroid" cells confined entirely within the acanthotic epidermis

─ Tumor cells are smaller than surrounding keratinocytes, with round to oval nuclei and scant eosinophilic cytoplasm

─ Small ductal lumina (lined by eosinophilic cuticle, CEA+) are often present within the tumor nests

─ Tumor nests may show a "Borst-Jadassohn" phenomenon (appearing as discrete clones within the epidermis)

─ No dermal invasion (by definition)

─ Variable hyperkeratosis, parakeratosis, and papillomatosis

DDx

─ Clonal seborrheic keratosis (basaloid cells, horn pseudocysts, lacks true ductal differentiation)

─ Bowen's disease (SCCis) (full-thickness keratinocytic atypia, "windblown" appearance, lacks ductal differentiation)

─ Eccrine poroma (shows dermal component or broad connection to dermis)

─ Paget's disease (larger pale cells, glandular atypia, mucin+)

─ Melanoma in situ (atypical melanocytes, S100/Melan-A+)

Prognosis ─ Benign

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Poroma (Eccrine Poroma)

Benign sweat gland neoplasm with differentiation towards the acrosyringium (intraepidermal sweat duct) and upper dermal duct

Clinical

─ Solitary, firm, often slightly moist or eroded, erythematous or skin-colored papule, plaque, or nodule

─ May be pedunculated or sessile

─ Most common on palms and soles, but can occur anywhere with eccrine glands

─ Usually asymptomatic, but may bleed or become tender

Micro

─ Tumor arises from the undersurface of the epidermis and extends downwards into the dermis as broad, anastomosing bands and nests of small, uniform cuboidal "poroid" cells

─ Poroid cells have round to oval, relatively monomorphic nuclei and scant to moderate eosinophilic cytoplasm, intercellular bridges often visible

─ Ductal lumina, lined by an eosinophilic cuticle (CEA+), are usually present and are a key diagnostic feature

─ Tumor cells may contain glycogen (PAS+, diastase sensitive)

─ Stroma is typically vascular and may be edematous

─ Minimal cytologic atypia, mitoses generally infrequent

─ Hidroacanthoma simplex is the intraepidermal variant, Dermal duct tumor is the entirely intradermal variant

DDx

─ Seborrheic keratosis (especially irritated or acanthotic types) (horn pseudocysts, lacks true ductal differentiation)

─ Basal cell carcinoma (basaloid atypia, peripheral palisading, stromal retraction)

─ Squamous cell carcinoma (keratinization, atypia)

─ Other adnexal tumors (eg, nodular hidradenoma, spiradenoma – different architecture/cytology)

─ Porocarcinoma (malignant counterpart, shows atypia, mitoses, infiltrative growth)

Prognosis ─ Benign

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Dermal Duct Tumor

Benign eccrine sweat gland neoplasm, considered an entirely intradermal variant of eccrine poroma

Clinical

─ Solitary, firm, skin-colored or slightly erythematous papule or nodule

─ Can occur anywhere, often on head, neck, or trunk

─ Usually asymptomatic

Micro

─ Well-circumscribed, entirely intradermal tumor composed of nests and cords of small, uniform cuboidal "poroid" cells similar to those of eccrine poroma

─ Ductal lumina, lined by an eosinophilic cuticle (CEA+), are present within the epithelial nests

─ Tumor cells have bland, monomorphic nuclei and eosinophilic cytoplasm, may contain glycogen

─ No connection to the overlying epidermis (distinguishes from eccrine poroma)

─ Stroma is often fibrous

─ Minimal cytologic atypia, infrequent mitoses

DDx

─ Eccrine poroma (shows connection to epidermis)

─ Nodular hidradenoma (eccrine acrospiroma) (often larger, more architectural diversity, may have cystic change and clear cells)

─ Metastatic carcinoma (especially breast) (more atypia, different IHC profile)

─ Syringoma (smaller ducts, tadpole shapes, more sclerotic stroma)

─ Other benign adnexal tumors

Prognosis ─ Benign

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Nodular Hidradenoma (Eccrine Acrospiroma, Solid-Cystic Hidradenoma)

Benign sweat gland neoplasm, usually eccrine, presenting as a solitary dermal or subcutaneous nodule

Clinical

─ Solitary, firm, often well-circumscribed, skin-colored, reddish, or bluish nodule

─ May be dermal or subcutaneous, can sometimes ulcerate or discharge clear fluid

─ Occurs anywhere, common on head, neck, trunk, extremities

─ Usually asymptomatic, but can be tender

Micro

─ Well-circumscribed, often lobulated dermal tumor, may or may not connect to epidermis

─ Composed of two main cell types:

─ Polygonal cells: larger, eosinophilic or amphophilic cytoplasm, vesicular nuclei

─ Basaloid (poroid) cells: smaller, darker, scant cytoplasm, often at periphery of nests

─ Tumor cells arranged in solid sheets, nests, and/or with cystic spaces (solid-cystic pattern)

─ Ductal lumina (lined by eosinophilic cuticle, CEA+) are usually present, though may be focal

─ Stroma is typically fibrous, may be hyalinized or myxoid

─ Cytologic atypia is generally minimal, mitoses usually infrequent

─ Clear cell change can occur (see Clear Cell Hidradenoma)

DDx

─ Eccrine poroma (more distinct connection to epidermis, anastomosing bands of poroid cells)

─ Spiradenoma (different cytology, often two distinct basaloid cell types, prominent lymphoid stroma)

─ Cylindroma (jigsaw puzzle nests, hyaline droplets)

─ Metastatic carcinoma (more atypia, infiltrative, different IHC)

─ Hidradenocarcinoma (malignant counterpart, shows atypia, mitoses, necrosis, infiltrative growth)

Prognosis ─ Benign, recurrence possible if incompletely excised

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Clear Cell Hidradenoma

Variant of nodular hidradenoma (eccrine acrospiroma) characterized by a predominance of clear cells

Clinical

─ Similar to nodular hidradenoma: solitary, firm papule or nodule

─ Can occur anywhere, often head, neck, trunk

─ May appear more translucent or yellowish due to clear cell component

Micro

─ Architectural features similar to nodular hidradenoma (well-circumscribed, lobulated, dermal tumor, +/- cystic change, +/- epidermal connection)

─ Predominant cell type: large polygonal cells with abundant clear cytoplasm due to glycogen accumulation (PAS+, diastase sensitive)

─ Smaller basaloid (poroid) cells and cells with eosinophilic cytoplasm are also usually present in varying proportions

─ Ductal lumina (lined by eosinophilic cuticle) are typically identifiable

─ Minimal cytologic atypia, infrequent mitoses

DDx

─ Nodular hidradenoma (less prominent or absent clear cell change)

─ Sebaceous neoplasms (true sebaceous differentiation, lipid vacuoles, different architecture)

─ Trichilemmoma (follicular origin, prominent peripheral palisading, thickened basement membrane)

─ Clear cell syringoma (smaller, more numerous ducts, tadpole shapes, often periorbital)

─ Metastatic renal cell carcinoma (more atypia, vascular stroma, different IHC: PAX8+, CD10+)

─ Balloon cell nevus/melanoma (melanocytic markers+)

Prognosis ─ Benign

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Spiradenoma (Eccrine Spiradenoma)

Benign sweat gland neoplasm, often eccrine, typically presenting as a painful dermal or subcutaneous nodule

Clinical

─ Solitary or multiple, firm, skin-colored or bluish, often tender or painful nodule

─ Usually deep dermal or subcutaneous

─ Can occur anywhere, common on ventral trunk, head, neck

─ Multiple lesions may be associated with cylindromas in Brooke-Spiegler syndrome

Micro

─ Well-circumscribed, often encapsulated, multilobular dermal tumor

─ Lobules composed of sharply demarcated nests and cords of epithelial cells in a "adenoid" or "rosette-like" pattern

─ Two main cell types are characteristic:

─ Small, dark basaloid cells with scant cytoplasm, typically at the periphery of nests and lining small ductal lumina

─ Larger, pale cells with more abundant eosinophilic cytoplasm and larger vesicular nuclei, often central in nests

─ Small ductal lumina are usually present

─ Stroma is typically scant within lobules but may be hyalinized around them

─ Prominent lymphocytic infiltrate is often present within and around tumor lobules

─ Vascular stroma

─ Minimal atypia, mitoses rare

DDx

─ Cylindroma (jigsaw puzzle nests, hyaline droplets/bands, often coexists in Brooke-Spiegler)

─ Nodular hidradenoma (different cell types, less organized rosettes, usually not painful)

─ Basal cell carcinoma (atypia, stromal retraction, peripheral palisading of tumor nests)

─ Metastatic adenocarcinoma (more atypia, infiltrative)

─ Spiradenocarcinoma (malignant counterpart, shows atypia, mitoses, necrosis, infiltrative growth)

Prognosis ─ Benign, malignant transformation (spiradenocarcinoma) is rare

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Cylindroma

Benign adnexal neoplasm, often with eccrine or apocrine differentiation, presenting as nodules, especially on scalp ("turban tumor")

Clinical

─ Solitary or multiple, firm, smooth, pinkish or reddish nodules or plaques

─ Most common on head and neck, especially scalp (can be extensive, "turban tumor")

─ Multiple lesions characteristic of Brooke-Spiegler syndrome (autosomal dominant, CYLD gene mutations), often associated with spiradenomas and trichoepitheliomas

Micro

─ Well-circumscribed dermal tumor composed of multiple, irregularly shaped nests and islands of epithelial cells fitting together like a "jigsaw puzzle"

─ Two cell types typically present:

─ Small, dark basaloid cells with scant cytoplasm, usually at periphery of nests and lining small ductal lumina

─ Larger, pale cells with more abundant eosinophilic cytoplasm and larger vesicular nuclei, often central in nests

─ Characteristic feature: Thick, eosinophilic, PAS-positive hyaline material (basement membrane-like) surrounding and sometimes within epithelial nests as droplets or bands

─ Ductal lumina are often present

─ Lymphocytes may be scattered in stroma

─ Minimal atypia, mitoses rare

DDx

─ Spiradenoma (more prominent lymphoid infiltrate within tumor, less prominent hyaline material, often coexists in Brooke-Spiegler)

─ Eccrine poroma/Nodular hidradenoma (different architecture, lacks jigsaw pattern and extensive hyaline)

─ Basal cell carcinoma (adenoid type) (atypia, stromal retraction, lacks two cell types and prominent hyaline of cylindroma)

─ Adenoid cystic carcinoma (more infiltrative, cribriform pattern, perineural invasion, true mucin)

Prognosis ─ Benign, malignant transformation (cylindrocarcinoma) is rare

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Mixed Tumor (Chondroid Syringoma)

Benign adnexal neoplasm with epithelial (usually sweat gland) and prominent stromal (often chondroid) differentiation

Clinical

─ Slow-growing, firm, usually solitary, skin-colored or slightly bluish nodule

─ Most common on head and neck (especially nose, cheeks, upper lip) of middle-aged or older adults, more common in men

─ May be dermal or subcutaneous

Micro

─ Well-circumscribed, often lobulated dermal or subcutaneous tumor

─ Biphasic tumor composed of:

─ Epithelial component: nests, tubules, ducts, and cords of cuboidal or polygonal epithelial cells, may show eccrine (small lumina, CEA+) or apocrine (decapitation secretion, GCDFP-15+) differentiation, sometimes squamous metaplasia or keratinous cysts

─ Stromal component: abundant, often myxoid, chondroid (cartilaginous), or fibrous stroma surrounding epithelial elements, chondroid matrix is characteristic but not always present

─ No significant cytologic atypia, mitoses are rare

─ Malignant mixed tumor is very rare, shows atypia, infiltrative growth, necrosis

DDx

─ Other adnexal tumors with prominent stroma (eg, spiradenoma, cylindroma – lack chondroid stroma)

─ Extraskeletal chondroma (lacks epithelial component)

─ Metastatic carcinoma with stromal reaction (atypia, known primary)

─ Myoepithelioma (predominantly myoepithelial cells, S100+, SMA+)

Prognosis ─ Benign, recurrence uncommon after complete excision

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Extramammary Paget’s Disease (EMPD)

Intraepithelial adenocarcinoma, typically of apocrine sweat gland origin or associated with underlying adnexal or visceral carcinoma

Clinical

─ Erythematous, eczematous, often crusted, weeping, or scaly plaque, may be pruritic or painful

─ Common sites: anogenital region (vulva, perianal, scrotum, penis), axilla, less often eyelids or external ear canal

─ Primary EMPD: arises in epidermis/adnexa, often associated with underlying in situ or invasive adnexal (apocrine/eccrine) carcinoma

─ Secondary EMPD: intraepidermal spread from an underlying non-cutaneous carcinoma (eg, anorectal, urothelial, cervical)

Micro

─ Paget cells: large, atypical cells with abundant pale, often vacuolated or granular eosinophilic cytoplasm and large, pleomorphic, hyperchromatic nuclei, often with prominent nucleoli

─ Cells are scattered singly ("buckshot" pattern) or in nests within the epidermis, often concentrated along the basal layer but can extend to all levels, including stratum corneum

─ Paget cells may involve follicular infundibula and eccrine/apocrine ducts

─ Overlying epidermis often hyperkeratotic, parakeratotic, acanthotic

─ Dermal chronic inflammatory infiltrate common

─ Underlying invasive adnexal or visceral carcinoma may be present

IHC

─ Paget cells typically (+) CK7, EMA, CEA, GCDFP-15 (especially in primary apocrine-related EMPD)

─ Primary cutaneous EMPD: often CK7+, GCDFP-15+, CK20-, GATA3+

─ Secondary EMPD (eg, colorectal origin): often CK20+, CDX2+, CK7-, GCDFP-15-

─ Secondary EMPD (eg, urothelial origin): often CK7+, CK20+, GATA3+, uroplakin+

─ (-) S100, Melan-A, HMB-45 (distinguishes from melanoma)

DDx

─ Pagetoid Bowen's disease (SCCis) (keratinocytic atypia, p63+, high MW CK+, CK7-, CEA-)

─ Melanoma in situ (pagetoid spread of atypical melanocytes, S100+, Melan-A+, SOX10+)

─ Clear cell acanthoma (glycogen-rich clear cells, PAS+ diastase sensitive, lacks atypia)

─ Eczematous dermatitis (spongiosis, lymphocytes, lacks Paget cells)

Prognosis ─ Primary EMPD often indolent but high local recurrence, risk of underlying invasive adnexal carcinoma, Secondary EMPD prognosis dictated by underlying primary tumor

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Primary Mucinous Carcinoma (Cutaneous Mucinous Carcinoma)

Rare, low-grade malignant sweat gland neoplasm characterized by abundant extracellular mucin

Clinical

─ Slow-growing, solitary, soft, fluctuant or gelatinous, often bluish or translucent nodule or cyst

─ Most common on head and neck (especially eyelids, scalp, face) of older adults

─ May mimic benign cyst or basal cell carcinoma

Micro

─ Well-circumscribed, often lobulated dermal tumor, occasionally subcutaneous

─ Composed of small islands, nests, and cribriform structures of bland to mildly atypical epithelial cells floating in abundant pools of pale basophilic extracellular mucin

─ Mucin is PAS+, Alcian blue+, diastase resistant

─ Epithelial cells are often cuboidal or polygonal with eosinophilic cytoplasm, round to oval nuclei, inconspicuous nucleoli

─ Ductal differentiation may be subtle or absent

─ Fibrous septa often divide mucin pools

─ Minimal stromal reaction typically

─ Important to exclude metastasis from other sites (eg, breast, GI tract, lung, salivary gland)

IHC

─ Epithelial cells (+) CK7, EMA, CEA

─ Often (+) hormone receptors (ER, PR), GCDFP-15 (suggesting breast or sweat gland origin)

─ (-) CK20, CDX2 (helps exclude GI origin)

─ (-) S100

DDx

─ Metastatic mucinous carcinoma (from breast, GI, lung, etc – clinical history and broader IHC panel crucial)

─ Myxoid neoplasms (eg, cutaneous myxoma, myxoid neurofibroma – lack epithelial nests and true mucin production by tumor cells)

─ Mixed tumor (chondroid syringoma) with extensive myxoid stroma (different epithelial component, often chondroid areas)

─ Basal cell carcinoma with mucinous stroma (BCC features, mucin is stromal not epithelial product)

Prognosis ─ Indolent, locally recurrent if incompletely excised, metastasis is rare

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Adenoid Cystic Carcinoma (Cutaneous)

Rare, slow-growing but locally aggressive malignant adnexal neoplasm, histologically similar to salivary gland counterpart

Clinical

─ Solitary, firm, often painful or tender nodule or plaque

─ Most common on head and neck (scalp, face, ear canal), can occur on trunk, extremities, breast

─ Slow but persistent growth, high propensity for local recurrence and perineural invasion

Micro

─ Dermal tumor, often poorly circumscribed and infiltrative

─ Characteristic patterns:

─ Cribriform: nests of basaloid cells with multiple, small, rounded, punched-out spaces containing hyaline eosinophilic material (PAS+, diastase resistant, basement membrane material) or basophilic mucin (Alcian blue+)

─ Tubular: small duct-like structures lined by two cell layers (inner cuboidal/eosinophilic, outer basaloid)

─ Solid: sheets of basaloid cells with minimal glandular formation

─ Two cell types: smaller, dark basaloid cells and larger cells with more eosinophilic cytoplasm (myoepithelial/ductal)

─ Perineural invasion is very common and a hallmark feature, even with bland cytology

─ Cytologic atypia often mild to moderate, mitoses usually not frequent

─ Stroma often hyalinized

IHC

─ Epithelial cells (+) CK (AE1/AE3, CK7), EMA

─ Myoepithelial cells (often surrounding nests/ducts) (+) S100, SMA, p63, Calponin

─ Hyaline material (+) Collagen IV, Laminin

─ CEA often highlights ductal lumina

DDx

─ Cylindroma (benign, more distinct jigsaw puzzle nests, thicker hyaline, lacks infiltrative growth and perineural invasion of ACC)

─ Basal cell carcinoma (adenoid type) (stromal retraction, peripheral palisading, lacks true ductal/myoepithelial differentiation and extensive hyaline of ACC)

─ Microcystic adnexal carcinoma (keratinous cysts, more squamoid differentiation superficially, different stromal quality)

─ Metastatic adenoid cystic carcinoma (from salivary gland, breast, etc – clinical history essential)

─ Syringoma (more superficial, tadpole/comma shapes, lacks cribriform pattern and perineural invasion)

Prognosis ─ High rate of local recurrence, especially with perineural invasion, distant metastasis can occur late (often to lungs)

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Syringocystadenoma Papilliferum

Benign adnexal neoplasm with ductal (apocrine or eccrine) and papillary differentiation, often arising in a nevus sebaceus

Clinical

─ Solitary papule, nodule, or plaque, often verrucous or crusted, may be eroded or discharge fluid

─ Most common on head and neck (especially scalp), often present at birth or arises in childhood within a nevus sebaceus

─ Can also occur de novo in older individuals on trunk or anogenital area

Micro

─ One or more cystic epidermal invaginations or dilated duct-like structures extending from epidermis into dermis

─ Invaginations are lined by squamous epithelium superficially and by two layers of glandular epithelium (inner columnar, outer cuboidal) deeper down

─ Characteristic feature: Numerous fibrovascular papillary projections extending into the lumina of cystic invaginations/ducts

─ Papillary cores contain a prominent plasma cell infiltrate, often dense

─ Luminal cells often show decapitation secretion (apocrine differentiation, GCDFP-15+)

─ Stroma around the lesion is often fibrous and contains chronic inflammation, especially plasma cells

─ Often associated with nevus sebaceus or trichoblastoma

DDx

─ Hidradenoma papilliferum (usually anogenital region of women, well-circumscribed dermal nodule, no epidermal connection, lacks prominent plasma cell stroma of SCAP)

─ Tubular apocrine adenoma (well-circumscribed dermal tumor, numerous small tubules, less papillary, lacks epidermal connection)

─ Papillary eccrine adenoma (dermal tumor, tubules with papillary projections, eccrine differentiation, lacks plasma cell stroma)

─ Nevus sebaceus (may be precursor, shows epidermal, sebaceous, and apocrine hyperplasia without the prominent cystic invaginations and papillary projections of SCAP)

─ Warty dyskeratoma (follicular origin, acantholytic dyskeratosis, villi, different epithelial lining)

Prognosis ─ Benign, rare malignant transformation (syringocystadenocarcinoma papilliferum)

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Hidradenoma Papilliferum

Benign adnexal neoplasm with apocrine differentiation, almost exclusively in anogenital region of adult women

Clinical

─ Solitary, well-circumscribed, asymptomatic or tender, firm or cystic nodule

─ Typically on vulva, perineum, or perianal skin of adult women

─ Rare in men (scrotum, perianal)

─ May be mistaken for Bartholin gland cyst or abscess

Micro

─ Well-circumscribed, often encapsulated, purely dermal (no epidermal connection) tumor, sometimes with cystic areas

─ Composed of complex, anastomosing tubules and papillary fronds forming glandular and cystic spaces

─ Papillary fronds have fibrovascular cores and are lined by two layers of epithelial cells:

─ Inner layer: tall columnar cells with eosinophilic cytoplasm, often showing prominent apical decapitation secretion (apocrine "snouts")

─ Outer layer: smaller, cuboidal myoepithelial cells (may be inconspicuous)

─ No significant cytologic atypia, mitoses are rare

─ Stroma is usually scant and fibrous, lacks the prominent plasma cell infiltrate seen in syringocystadenoma papilliferum

IHC

─ Luminal cells (+) CK7, EMA, GCDFP-15, Androgen Receptor

─ Myoepithelial cells (+) p63, SMA, Calponin, S100 (variable)

DDx

─ Syringocystadenoma papilliferum (epidermal connection, prominent plasma cell stroma, usually head/neck)

─ Tubular apocrine adenoma (more solidly tubular, less complex papillary architecture)

─ Endometriosis (endometrial glands and stroma, hemosiderin)

─ Metastatic adenocarcinoma (especially breast or GI) (more atypia, infiltrative, different IHC)

Prognosis ─ Benign

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Tubular Adenoma (Tubular Apocrine Adenoma)

Benign adnexal neoplasm with predominantly tubular architecture and apocrine differentiation

Clinical

─ Solitary, firm, skin-colored or reddish-brown papule or nodule

─ Can occur anywhere, common on scalp, face, axilla

─ Usually asymptomatic

Micro

─ Well-circumscribed, sometimes encapsulated, dermal tumor

─ Composed of numerous, closely packed, small to medium-sized tubules and duct-like structures

─ Tubules are lined by two layers of epithelial cells:

─ Inner layer: columnar or cuboidal cells with eosinophilic cytoplasm, often showing apical decapitation secretion (apocrine snouts)

─ Outer layer: flattened or cuboidal myoepithelial cells

─ Lumina are generally small and round, may contain eosinophilic secretions

─ Papillary projections into lumina are usually absent or minimal (distinguishes from papillary hidradenomas)

─ Stroma is typically scant and fibrous

─ Minimal cytologic atypia, mitoses rare

DDx

─ Syringoma (smaller, tadpole-shaped ducts, more sclerotic stroma, often periorbital)

─ Hidradenoma papilliferum (more complex papillary and cystic architecture, usually anogenital)

─ Papillary eccrine adenoma (prominent papillary projections, eccrine differentiation)

─ Microcystic adnexal carcinoma (infiltrative growth, perineural invasion, desmoplastic stroma, more aggressive)

─ Metastatic adenocarcinoma (atypia, infiltrative, known primary)

Prognosis ─ Benign

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Papillary Eccrine Adenoma

Benign eccrine sweat gland neoplasm characterized by tubules with intraluminal papillary projections

Clinical

─ Solitary, slow-growing, firm, skin-colored or reddish papule or nodule

─ Most common on extremities, especially distal (hands, feet, fingers, toes) of adults, can occur in Black individuals

─ Usually asymptomatic

Micro

─ Well-circumscribed dermal tumor, may be encapsulated, sometimes extends into subcutis

─ Composed of variably sized tubules and duct-like structures, often dilated

─ Characteristic feature: numerous intraluminal papillary projections with fibrovascular cores, lined by epithelial cells

─ Epithelial lining of tubules and papillae is typically two-layered:

─ Inner layer: cuboidal to low columnar cells with eosinophilic cytoplasm, lacking decapitation secretion (eccrine type)

─ Outer layer: smaller, often flattened or cuboidal myoepithelial cells

─ Lumina may contain amorphous eosinophilic material

─ Stroma is fibrous, may be hyalinized

─ No significant cytologic atypia, mitoses infrequent

DDx

─ Tubular adenoma (apocrine or eccrine) (lacks prominent papillary projections)

─ Syringocystadenoma papilliferum (epidermal connection, prominent plasma cell stroma, apocrine features)

─ Hidradenoma papilliferum (anogenital, apocrine differentiation, different papillary architecture)

─ Digital papillary adenocarcinoma (malignant counterpart, shows atypia, mitoses, infiltrative growth, necrosis)

─ Metastatic papillary carcinoma (eg, thyroid, breast, ovary – IHC and clinical history crucial)

Prognosis ─ Benign, local recurrence possible if incompletely excised

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Digital Papillary Adenocarcinoma (Aggressive Digital Papillary Adenocarcinoma)

Rare malignant sweat gland neoplasm, typically on digits, with papillary architecture and aggressive local behavior

Clinical

─ Solitary, firm nodule, often on fingers or toes, less commonly palms or soles

─ Affects adults, predominantly males

─ May be dome-shaped, sometimes ulcerated or cystic

─ High rate of local recurrence, potential for metastasis (lymph nodes, lungs)

Micro

─ Dermal tumor, may be well-circumscribed or infiltrative, often with solid and cystic areas

─ Prominent papillary structures projecting into cystic spaces or lining glandular lumina

─ Tumor cells are cuboidal to columnar, often with eosinophilic cytoplasm

─ Nuclear atypia variable, can range from bland to overtly malignant

─ Mitotic figures often present, may be numerous

─ Necrosis can be seen

─ Infiltrative growth into surrounding tissues, including bone, is common

─ Ductal differentiation (CEA+) usually evident

DDx

─ Papillary eccrine adenoma (benign counterpart, lacks significant atypia, mitoses, infiltrative growth, necrosis)

─ Metastatic papillary carcinoma (eg, thyroid, lung, breast, kidney – IHC, clinical history crucial)

─ Other adnexal carcinomas with papillary features

─ Florid eccrine papillary proliferation (often in diabetic foot ulcers, reactive, less atypia)

Prognosis ─ Locally aggressive, significant risk of recurrence and metastasis, long-term follow-up essential

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Accessory Nipple (Supernumerary Nipple, Polythelia)

Congenital hamartomatous lesion representing an ectopic nipple, usually along the embryonic milk lines

Clinical

─ Small, brownish or skin-colored macule, papule, or nodule

─ Located anywhere along the milk lines (axilla to inguinal region), most commonly on anterior chest or abdomen inferior to normal nipple

─ May be mistaken for a melanocytic nevus

─ Can enlarge or become tender with hormonal changes (eg, pregnancy, puberty)

Micro

─ Epidermis often shows mild papillomatosis and hyperpigmentation of basal layer

─ Dermis contains features resembling normal nipple/areola:

─ Increased numbers of smooth muscle bundles (arrector pili-like) oriented vertically and horizontally

─ Pilosebaceous units often present, may be well-developed or rudimentary

─ Mammary-like ducts or glandular structures (lactiferous ducts) may be present, lined by cuboidal or columnar epithelium, sometimes with apocrine-like changes

─ Stroma is often fibrous and well-vascularized

DDx

─ Melanocytic nevus (especially intradermal or compound) (nevus cells, lacks organized smooth muscle and mammary ducts)

─ Leiomyoma (more prominent smooth muscle proliferation, lacks other nipple structures)

─ Seborrheic keratosis (if biopsy is very superficial and shows only epidermal changes)

─ Neurofibroma (wavy spindle cells, S100+)

Prognosis ─ Benign, normal variant

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Nevus Lipomatosus Superficialis (of Hoffmann and Zurhelle)

Benign hamartoma characterized by ectopic mature adipose tissue in the dermis

Clinical

─ Soft, skin-colored or yellowish, cerebriform or cobblestone-like papules, nodules, or plaques

─ Two main types:

─ Classical (multiple lesions): groups of non-tender, compressible papules/nodules, often in a linear or zosteriform arrangement, typically on buttocks, lower back, thighs, present at birth or appears in childhood/adolescence

─ Solitary type: single papule or nodule, can occur anywhere, often in older adults

Micro

─ Presence of mature adipocytes (fat cells) ectopically located high in the dermis, often intermingled with dermal collagen bundles, sometimes extending into papillary dermis

─ Adipocytes are typically normal in appearance

─ Overlying epidermis is usually normal or slightly acanthotic/papillomatous

─ Dermal collagen may be thickened or normal

─ Blood vessels may be prominent in some areas

─ No encapsulation

DDx

─ Acrochordon (skin tag) with fatty change (fibrovascular core, may have some fat but different overall structure)

─ Dermal lipoma (well-circumscribed collection of fat, usually deeper, encapsulated)

─ Focal dermal hypoplasia (Goltz syndrome) (areas of dermal atrophy with herniation of subcutaneous fat, associated with other developmental anomalies)

─ Connective tissue nevus with fatty metaplasia

─ Encephalocraniocutaneous lipomatosis (rare syndrome with nevus psiloliparus, CNS abnormalities)

Prognosis ─ Benign, persistent

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Hidradenocarcinoma

Malignant counterpart of nodular hidradenoma (eccrine acrospiroma), a rare sweat gland carcinoma

Clinical

─ Solitary, firm, often rapidly enlarging nodule or plaque, may ulcerate

─ Can arise de novo or from a pre-existing benign hidradenoma

─ Occurs in adults, common on head, neck, extremities

─ Potential for local recurrence and distant metastasis

Micro

─ Dermal tumor, often with infiltrative borders, may show connection to epidermis

─ Composed of lobules, nests, and sheets of atypical epithelial cells

─ Two main cell types often recognizable, similar to benign hidradenoma but with malignant features:

─ Polygonal cells: larger, eosinophilic or amphophilic cytoplasm, pleomorphic vesicular nuclei, prominent nucleoli

─ Basaloid (poroid-like) cells: smaller, darker, higher N/C ratio, pleomorphic nuclei

─ Clear cell change (glycogen-rich) can be prominent in some areas (clear cell hidradenocarcinoma)

─ Ductal differentiation (CEA+) usually present, though may be focal or poorly formed

─ Significant cytologic atypia, nuclear pleomorphism, hyperchromasia, increased and often atypical mitotic figures, tumor necrosis are key malignant features

─ Infiltrative growth pattern, lymphovascular or perineural invasion may be seen

IHC

─ (+) Cytokeratins (AE1/AE3, CK7, CAM5,2), EMA, CEA (often highlights ducts)

─ p63 may be positive in basaloid/myoepithelial-like cells

─ Ki-67 shows increased proliferation index

DDx

─ Nodular hidradenoma (benign counterpart, lacks significant atypia, high mitoses, necrosis, infiltrative growth)

─ Metastatic carcinoma (especially squamous cell carcinoma, adenocarcinoma from breast/lung/GI – clinical history and broader IHC panel crucial)

─ Other primary adnexal carcinomas (eg, porocarcinoma, sebaceous carcinoma, trichilemmal carcinoma – differ in specific lines of differentiation and IHC)

─ Squamous cell carcinoma with clear cell features (if clear cells prominent in hidradenocarcinoma)

Prognosis ─ Aggressive tumor with significant risk of local recurrence and distant metastasis (lymph nodes, lung, bone, viscera)

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Porocarcinoma (Malignant Eccrine Poroma)

Malignant sweat gland neoplasm with differentiation towards the acrosyringium and upper dermal duct, the malignant counterpart of eccrine poroma

Clinical

─ Solitary, firm, often ulcerated, crusted, or polypoid papule, plaque, or nodule

─ May arise de novo or from a pre-existing benign eccrine poroma

─ Common on lower extremities (especially feet), head, neck, trunk of older adults

─ Can be erythematous, skin-colored, or pigmented

─ Potential for local recurrence, lymph node, and distant metastasis

Micro

─ Tumor often arises from epidermis and extends into dermis as infiltrative, irregular nests, cords, and broad anastomosing bands

─ Composed of atypical "poroid" cells: cuboidal to polygonal cells with pleomorphic, hyperchromatic nuclei, prominent nucleoli, increased and often atypical mitoses

─ Ductal differentiation (CEA+) is usually present, often with lumina lined by eosinophilic cuticle, but can be focal or poorly formed

─ Areas may resemble benign eccrine poroma, but with cytologic atypia and infiltrative growth

─ Necrosis within tumor nests (comedo-like necrosis) can be seen

─ Lymphovascular invasion is a poor prognostic sign

─ Intraepidermal (pagetoid) spread of atypical poroid cells (malignant hidroacanthoma simplex) can occur

IHC

─ (+) Cytokeratins (AE1/AE3, CK7, CAM5,2), EMA, CEA (highlights ducts)

─ p63 may be positive

─ Ki-67 shows increased proliferation index

DDx

─ Eccrine poroma (benign counterpart, lacks significant atypia, high mitoses, infiltrative growth, necrosis)

─ Squamous cell carcinoma (especially if ductal differentiation is not obvious in porocarcinoma, SCC shows more keratinization)

─ Basal cell carcinoma (different cytology, peripheral palisading, stromal retraction)

─ Other adnexal carcinomas (eg, hidradenocarcinoma – different architecture/cytology)

─ Metastatic adenocarcinoma (clinical history, broader IHC panel)

Prognosis ─ Significant risk of local recurrence (20-50%), lymph node metastasis (approx 20%), and distant metastasis (approx 10%), especially with deep invasion or lymphovascular involvement

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Benign Melanocytic

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Congenital Pattern Nevus (Congenital Melanocytic Nevus, CMN)

Melanocytic nevus present at birth or appearing within first few months, classified by size (small <1,5cm, medium 1,5-19,9cm, large/giant ≥20cm projected adult size)

Clinical

─ Variable appearance: flat macule to raised plaque or nodule, often pigmented (tan to dark brown/black), may be hairy (hypertrichosis)

─ Surface can be smooth, mammillated, verrucous, or pebbly

─ Large/giant CMN (GCMN) carry increased risk of developing melanoma (lifetime risk approx 2-5% for GCMN, lower for smaller CMN)

─ May be associated with neurocutaneous melanosis if multiple or large, especially axial/posterior midline (risk of leptomeningeal melanoma, CNS abnormalities)

Micro

─ Typically compound or intradermal nevus architecture

─ Nevus cells often extend deeper into reticular dermis and subcutis than acquired nevi

─ Characteristic "congenital pattern" features:

─ Splaying of nevus cells between collagen bundles in reticular dermis (single-file or small nests)

─ Periadnexal (around hair follicles, sweat glands, vessels) and perineural involvement by nevus cells

─ Involvement of arrector pili muscles

─ Nevus cells in deeper dermis often smaller, more mature (type C cells), and may be spindled or neuroid

─ Junctional component may be present, especially in younger lesions

─ Epidermal hyperplasia, papillomatosis common

─ Cytologic atypia usually absent or mild, mitoses rare in older lesions (can be present in neonatal CMN)

─ Proliferative nodules (benign or atypical) can occur within CMN

DDx

─ Acquired melanocytic nevus (usually smaller, less deep extension, lacks prominent periadnexal/perineural involvement)

─ Spitz nevus (different cytology, Kamino bodies, often epithelioid/spindle cells)

─ Melanoma arising in CMN (significant cytologic atypia, expansile dermal nodules, increased mitoses, loss of maturation – can be challenging to diagnose)

─ Blue nevus (dermal dendritic and spindled melanocytes, often heavily pigmented)

Prognosis ─ Mostly benign, risk of melanoma development (especially in GCMN), cosmetic concerns

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Blue Nevi

Group of benign melanocytic nevi composed of dermal dendritic and/or spindled melanocytes, typically heavily pigmented

Clinical

─ Solitary, well-demarcated, blue, blue-gray, or blue-black papule or nodule

─ Common types:

─ Common blue nevus: small (<1cm), usually on extremities (dorsal hands/feet), face, scalp, buttocks

─ Cellular blue nevus: larger (often >1cm), firm nodule, common on buttocks, sacrococcygeal area, scalp, may be lobulated

─ Usually appear in childhood or early adulthood

Micro

─ Common Blue Nevus:

─ Dermal proliferation of elongated, slender, wavy, dendritic melanocytes, often heavily pigmented with fine melanin granules

─ Cells are scattered singly and in small fascicles between dermal collagen bundles, often associated with melanophages

─ Sclerosis (fibrosis) of dermal stroma is common

─ No junctional activity

─ Cellular Blue Nevus:

─ Well-circumscribed, often dumb-bell shaped dermal tumor, may extend into subcutis

─ Composed of two main components:

─ Fascicles of heavily pigmented dendritic melanocytes (as in common blue nevus)

─ Cellular islands and fascicles of paler, plumper spindle cells with ovoid nuclei and less pigment

─ Melanophages often abundant

─ Minimal atypia, mitoses rare (can be seen in benign cellular blue nevi but should be few and typical)

─ Epithelioid blue nevus: variant with plump epithelioid melanocytes, often seen in Carney complex

─ Combined nevus: features of blue nevus with acquired melanocytic nevus components

IHC

─ Melanocytes (+) S100, Melan-A, HMB-45 (HMB-45 often strong throughout, unlike acquired nevi where it diminishes with depth)

DDx

─ Melanoma (especially metastatic melanoma or malignant blue nevus – look for atypia, mitoses, necrosis, infiltrative borders, asymmetry)

─ Pigmented dermatofibroma (Factor XIIIa+, hemosiderin, entrapped collagen, lacks dendritic melanocytes)

─ Tattoo (exogenous pigment, often perivascular, no melanocytic proliferation)

─ Spitz nevus (pigmented spindle cell variant) (junctional component, different cytology)

─ Sclerosing nevus with pseudomelanomatous features

Prognosis ─ Benign, malignant transformation (malignant blue nevus) is very rare, more often associated with cellular blue nevus

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Halo Nevus (Sutton Nevus)

Melanocytic nevus undergoing immune-Media ─ placeholder ted regression, characterized by a surrounding depigmented halo

Clinical

─ Central pigmented melanocytic nevus (often compound or intradermal) surrounded by a symmetrical ring of depigmentation (leukoderma)

─ Usually occurs in children or young adults, often on the trunk

─ Nevus may progressively lighten and disappear, leaving a depigmented macule

─ Multiple halo nevi can occur

─ May be associated with vitiligo or rarely with melanoma elsewhere (halo phenomenon around melanoma)

Micro

─ Central melanocytic nevus (can be junctional, compound, or intradermal, often with features of a common acquired nevus or sometimes a dysplastic nevus)

─ Characteristic feature: Dense, band-like lymphocytic infiltrate permeating and surrounding the nevus cells, often obscuring them

─ Lymphocytes are typically small and mature-appearing

─ Nevus cells may show signs of damage or apoptosis (pyknotic nuclei, vacuolated cytoplasm)

─ Melanophages common in dermis

─ Epidermis in the halo region shows loss of melanin pigment and melanocytes (similar to vitiligo)

─ In late stages, nevus cells may be completely absent, leaving only fibrosis and residual lymphocytic infiltrate

DDx

─ Melanoma with regression (asymmetrical, atypical melanocytes, irregular fibrosis, inflammation may be less dense or patchy, clinical history important)

─ Lichenoid keratosis (solitary lesion, epidermal changes, different inflammatory pattern)

─ Lichen planus-like drug eruption (clinical history, different epidermal changes)

─ Vitiligo (if nevus component is completely gone or not biopsied)

─ Spitz nevus with lymphocytic infiltrate

Prognosis ─ Benign, represents an immune response to nevus cells, usually leads to nevus regression

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Spitz Nevus (Spindle and Epithelioid Cell Nevus)

Benign melanocytic nevus, typically in children/young adults, composed of spindle and/or epithelioid melanocytes, can mimic melanoma

Clinical

─ Solitary, dome-shaped, pink, red, or tan/brown papule or nodule, often rapid initial growth

─ Most common on head, neck, extremities, usually in children or young adults

─ Variants: Pigmented Spitz (heavily pigmented), Desmoplastic Spitz (firm, scar-like), Agminated Spitz (multiple grouped)

─ Reed nevus: darkly pigmented spindle cell variant, often on extremities of children

Micro

─ Symmetrical, well-circumscribed, often wedge-shaped or dome-shaped compound or dermal nevus

─ Composed of large, plump spindle and/or epithelioid melanocytes with abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli

─ Cells often arranged in nests, fascicles, or sheets, may show maturation with depth (smaller cells deeper)

─ Junctional nests often vertically oriented, may show clefting from adjacent keratinocytes (retraction artifact)

─ Pagetoid spread (upward migration of melanocytes) can occur but usually focal and central, not extensive or at periphery

─ Kamino bodies: eosinophilic, PAS-positive, diastase-resistant hyaline globules at dermoepidermal junction or within epidermis, characteristic but not always present

─ Mitotic figures can be present, especially in superficial portions, but typically few and not atypical

─ Epidermal hyperplasia, hyperkeratosis, telangiectasias common

─ Minimal to moderate lymphocytic infiltrate

IHC

─ (+) S100, Melan-A, SOX10

─ HMB-45 often positive in superficial/junctional component, may be lost with depth (maturation)

─ p16 often diffusely positive (in contrast to melanoma where it's often lost or patchy)

─ Ki-67 proliferation index usually low, especially in deep component

DDx

─ Melanoma (especially spitzoid melanoma – asymmetry, poor circumscription, significant cytologic atypia, atypical mitoses, deep mitoses, lack of maturation, extensive pagetoid spread, loss of p16)

─ Cellular blue nevus (different cell types, often dumbbell shape, more pigment)

─ Pigmented spindle cell nevus of Reed (more uniformly spindled, heavily pigmented, often younger patients)

─ Leiomyoma/other spindle cell tumors (if amelanotic) (negative melanocytic markers)

Prognosis ─ Benign, complete excision often recommended due to histologic overlap with melanoma, atypical Spitz tumors (STUMP/MELTUMP) have uncertain malignant potential

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Dysplastic Nevus (Clark's Nevus, Atypical Nevus)

Melanocytic nevus with architectural disorder and cytologic atypia, considered a potential precursor and risk marker for melanoma

Clinical

─ Often larger than common nevi (>5-6 mm), irregular or indistinct borders, variable pigmentation (tan, brown, pink, black), often macular component with central papule ("fried egg" or "targetoid" appearance)

─ Occur on sun-exposed or non-sun-exposed skin, trunk and extremities common

─ May be sporadic or familial (familial atypical multiple mole melanoma [FAMMM] syndrome)

─ Presence of multiple dysplastic nevi increases risk of melanoma

Micro

─ Architectural disorder:

─ Lentiginous melanocytic proliferation (elongated rete ridges with increased single melanocytes along basal layer)

─ Irregularly sized and shaped junctional nests, often bridging/fusing adjacent rete ridges ("shoulder phenomenon" if dermal component present)

─ Lamellar fibroplasia (concentric eosinophilic fibrosis around rete ridges)

─ Papillary dermal fibrosis (more haphazard fibrosis)

─ Cytologic atypia (usually mild to moderate):

─ Enlarged, hyperchromatic, pleomorphic melanocytic nuclei, irregular nuclear contours, prominent nucleoli

─ Atypia often most prominent in junctional component

─ Dermal component (if present) usually composed of smaller, more mature-appearing nevus cells (type A, B, C)

─ Superficial dermal lymphocytic infiltrate, often patchy or lichenoid

─ Telangiectasias in papillary dermis

DDx

─ Melanoma in situ / Lentigo maligna (more severe and diffuse cytologic atypia, confluent growth, extensive pagetoid spread, adnexal involvement)

─ Common acquired nevus (lacks significant architectural disorder and cytologic atypia)

─ Spitz nevus (different cytology – large epithelioid/spindle cells, Kamino bodies)

─ Solar lentigo (lentiginous proliferation of melanocytes without nesting or significant atypia, solar elastosis)

Prognosis ─ Benign, but marker of increased melanoma risk, low risk of transformation of an individual dysplastic nevus to melanoma, management often involves surveillance or prophylactic excision for severely atypical lesions or in high-risk patients

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Recurrent Nevus (Pseudomelanoma)

Melanocytic proliferation occurring in a scar from a previously partially removed benign nevus, can mimic melanoma

Clinical

─ Irregular pigmentation (often linear or stellate) developing within a scar, usually weeks to months after incomplete removal (eg, shave biopsy) of a benign nevus

─ Confined to the area of the scar

Micro

─ Atypical junctional melanocytic proliferation overlying dermal scar tissue

─ Junctional component may show:

─ Irregularly shaped and sized nests, sometimes confluent

─ Single melanocytes, some with pagetoid upward scatter (usually central over scar)

─ Variable cytologic atypia (enlarged, hyperchromatic nuclei), can be alarming

─ Dermal component:

─ Scar tissue (fibrosis, altered collagen, neovascularization)

─ Often residual benign dermal nevus cells beneath or within the scar, showing maturation

─ Inflammation (lymphocytes, melanophages) common

─ Key feature: Atypical changes are confined to the epidermis and papillary dermis overlying the scar, should not extend into adjacent normal skin beyond scar borders

DDx

─ Melanoma (especially recurrent melanoma – atypia extends beyond scar, more extensive pagetoid spread, dermal mitoses in atypical cells, lack of clear maturation of any dermal component, original biopsy review is crucial)

─ Dysplastic nevus (if original nevus was dysplastic, recurrence may show similar features)

─ Spitz nevus (if original was Spitz, recurrence may show spitzoid features)

Prognosis ─ Benign, represents benign persistence/regrowth, but careful correlation with original biopsy and complete excision sometimes needed to rule out melanoma

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Neurotized Nevus (Neural Nevus)

Benign intradermal melanocytic nevus showing prominent neural differentiation in its deeper portions

Clinical

─ Soft, dome-shaped or polypoid, skin-colored or lightly pigmented papule or nodule

─ Usually on head and neck (especially face) or trunk, common in adults

─ Represents a late stage in the "life cycle" of a common acquired nevus

Micro

─ Entirely intradermal proliferation of nevus cells

─ Superficial portion: nests and cords of conventional type A (epithelioid) and/or type B (lymphocytoid) nevus cells, often with melanin

─ Deeper portion: gradual transition to type C (neuroid) nevus cells, which are spindled or Schwannian-like with wavy nuclei and fibrillar eosinophilic cytoplasm, arranged in fascicles or diffuse sheets, resembling neural tissue

─ Meissner-like bodies (tactile body differentiation): small, laminated, S100+ structures resembling Meissner corpuscles may be present in deeper parts

─ Melanin pigment typically sparse or absent in neurotized areas

─ Minimal to no cytologic atypia, mitoses absent or very rare

─ Stroma often loose and fibrillar in neurotized areas

DDx

─ Neurofibroma (S100+, but lacks melanocytic markers like Melan-A/MART-1, lacks superficial nevus cell nests, more uniform spindle cells)

─ Schwannoma (encapsulated, Antoni A/B areas, Verocay bodies, S100+, lacks melanocytic markers)

─ Dermatofibroma (Factor XIIIa+, entrapped collagen, different spindle cell morphology)

─ Desmoplastic melanoma (if neurotized nevus is amelanotic and very spindled – melanoma shows atypia, infiltrative growth, S100+ but often loses Melan-A/HMB-45 in desmoplastic areas)

Prognosis ─ Benign

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Balloon Cell Nevus

Benign melanocytic nevus variant characterized by large melanocytes with abundant, pale, foamy, or vacuolated cytoplasm (balloon cells)

Clinical

─ No distinct clinical appearance, usually resembles a common acquired nevus, tan to brown papule

─ Can occur at any age, any site

─ Balloon cell change can be focal or extensive within a nevus

Micro

─ Features of a common acquired nevus (junctional, compound, or intradermal) with a population of balloon cells

─ Balloon cells: large, polygonal melanocytes with abundant, pale, finely granular or multivacuolated cytoplasm, centrally or eccentrically placed small, bland nucleus

─ Balloon cells often occur in clusters or sheets, may predominate or be a minor component

─ Conventional nevus cells are usually also present

─ Minimal to no cytologic atypia, mitoses rare

─ Melanin pigment may be sparse in balloon cells themselves but present in adjacent conventional nevus cells or melanophages

IHC

─ Balloon cells (+) S100, Melan-A, SOX10, HMB-45 (often weaker or patchy compared to conventional nevus cells)

─ Cytoplasm often negative for lipid, glycogen, or mucin by special stains, though some vacuolization is due to melanosome degeneration

DDx

─ Balloon cell melanoma (malignant counterpart, shows cytologic atypia, pleomorphism, mitoses, infiltrative growth, necrosis, balloon cells also atypical)

─ Clear cell neoplasms (eg, clear cell hidradenoma, sebaceous neoplasms, metastatic renal cell carcinoma – distinguished by specific differentiation and IHC markers)

─ Xanthoma/Histiocytic lesions (if balloon cells are very foamy – distinguished by melanocytic markers)

─ Lipoma/Liposarcoma (if balloon cells resemble adipocytes – distinguished by melanocytic markers)

Prognosis ─ Benign

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Myerson’s Nevus (Halo Eczema, Sutton's Phenomenon variant)

Melanocytic nevus surrounded by an eczematous (spongiotic) dermatitis

Clinical

─ Central melanocytic nevus (junctional, compound, or intradermal, can be dysplastic)

─ Surrounded by an erythematous, scaly, often pruritic halo of eczema

─ Usually occurs in young adults, common on trunk

─ Distinct from halo nevus (Sutton's nevus) which has a depigmented halo due to lymphocytic attack on nevus cells, not eczematous change

Micro

─ Central melanocytic nevus (may be common acquired, dysplastic, or other type)

─ Overlying and surrounding epidermis shows features of acute or subacute spongiotic dermatitis:

─ Spongiosis (intercellular edema in epidermis)

─ Acanthosis, parakeratosis

─ Exocytosis of lymphocytes into epidermis

─ Eosinophils may be present in the spongiotic epidermis or dermis

─ Dermis shows superficial perivascular and interstitial lymphocytic infiltrate, often with eosinophils, corresponding to the eczematous reaction

─ Nevus cells themselves are not typically targeted by a dense lymphocytic infiltrate as in halo nevus

DDx

─ Halo nevus (depigmented halo, dense lymphocytic infiltrate directly targeting nevus cells)

─ Irritated melanocytic nevus (inflammation due to trauma, may lack prominent spongiosis)

─ Melanoma with eczematous reaction (rare, look for atypical melanocytes)

─ Allergic contact dermatitis overlying a nevus (clinical history may help)

Prognosis ─ Benign, eczematous reaction usually resolves, nevus itself persists

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Nevus of Nanta (Osteo-nevus, Nevus with Osseous Metaplasia)

Benign melanocytic nevus (usually intradermal) containing foci of mature bone (osseous metaplasia)

Clinical

─ Firm, skin-colored or pigmented papule or nodule, often on face or scalp

─ Presence of bone may give a very firm or stony hard consistency on palpation

─ Typically an incidental finding in an otherwise unremarkable nevus

Micro

─ Features of a benign intradermal melanocytic nevus (nests and cords of type A, B, and/or C nevus cells)

─ Characteristic feature: Presence of one or more foci of mature lamellar bone within the dermal component of the nevus

─ Bone may be compact or trabecular, sometimes with osteoblasts, osteoclasts, or marrow elements

─ Osseous metaplasia is thought to arise from pluripotential mesenchymal cells in the nevus stroma, possibly secondary to chronic inflammation, trauma, or calcification

─ Calcification may precede or accompany ossification

─ No cytologic atypia in the melanocytic or osseous components

DDx

─ Pilomatrixoma (ghost cells, basaloid cells, calcification common, ossification can occur, different epithelial component)

─ Osteoma cutis (primary or secondary) (bone formation without associated melanocytic nevus)

─ Calcified melanocytic nevus (calcification without true bone formation)

─ Other tumors with osseous metaplasia (rare)

Prognosis ─ Benign

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Acral Nevus

Benign melanocytic nevus occurring on palms, soles, or digits (acral skin)

Clinical

─ Pigmented macule or papule on palmar, plantar, or subungual skin

─ Often has a linear or fibrillar pigment pattern on dermoscopy due to arrangement along skin markings (dermatoglyphics)

─ Can be junctional, compound, or intradermal

─ Concern often arises due to location and potential confusion with acral lentiginous melanoma

Micro

─ Junctional, compound, or intradermal melanocytic nevus architecture

─ Nevus cells often arranged in nests along dermoepidermal junction, following contours of rete ridges and eccrine ducts

─ Characteristic acral pattern ("MANIAC" - melanocytic acral nevus with intraepidermal ascent of cells - for some variants):

─ Junctional nests may be large, irregular, sometimes confluent

─ Pagetoid (upward) spread of single melanocytes or small nests into stratum spinosum can be seen, but usually focal, central, and composed of bland cells (unlike melanoma)

─ Melanocytes may extend down eccrine ducts (adnexal involvement)

─ Dermal component (if present) shows maturation

─ Cytologic atypia typically absent or mild

─ Heavy pigmentation common, especially in stratum corneum over junctional nests

─ Thickened stratum corneum characteristic of acral skin

DDx

─ Acral lentiginous melanoma (asymmetry, poor circumscription, extensive and atypical pagetoid spread, significant cytologic atypia, dermal mitoses, lack of maturation)

─ Solar lentigo/Lentigo simplex (if predominantly macular and junctional, but acral nevi usually have more nesting)

─ Tinea nigra (fungal elements in stratum corneum)

─ Subcorneal hemorrhage/Talon noir (extravasated red blood cells, hemosiderin, no melanocytic proliferation)

Prognosis ─ Benign, but biopsy often performed to rule out melanoma due to acral location

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Talon Noir (Calcaneal Petechiae, Black Heel)

Benign traumatic lesion, common in athletes, due to shearing stress causing intraepidermal hemorrhage

Clinical

─ Asymptomatic, speckled or confluent, blue-black or dark brown macule or patch

─ Typically on posterior or posterolateral aspect of heel, less often on forefoot or toes

─ May appear as linear streaks or punctate dots

─ Often bilateral, common in young active individuals, especially those in sports like basketball, tennis, soccer

Micro

─ Intraepidermal hemorrhage, primarily within stratum corneum, sometimes extending into upper spinous layer

─ Extravasated red blood cells are seen, may appear intact or degenerated (brownish pigment)

─ No melanocytic proliferation or atypia

─ No hemosiderin deposition in dermis (pigment is intracorneal blood)

─ Epidermis otherwise usually normal, may show slight acanthosis or parakeratosis

DDx

─ Acral melanocytic nevus (melanocytic proliferation, nests)

─ Acral lentiginous melanoma (atypical melanocytic proliferation, pagetoid spread, dermal invasion in invasive lesions)

─ Tinea nigra (fungal hyphae in stratum corneum, PAS or GMS positive)

─ Exogenous pigment (eg, tar, dye – foreign material visible)

Prognosis ─ Benign, resolves spontaneously with cessation of trauma, though may recur

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Melanosis (Melanotic Macule, eg, Labial, Vulvar, Penile Melanotic Macule)

Benign focal increase in melanin pigmentation of basal epidermis/mucosal epithelium, without significant melanocytic proliferation

Clinical

─ Well-demarcated, flat, brown to black macule

─ Common on lips (labial melanotic macule), oral mucosa (oral melanotic macule), vulva, penis, conjunctiva

─ Usually solitary, but can be multiple (eg, Laugier-Hunziker syndrome – labial/oral melanotic macules with longitudinal melanonychia)

─ Asymptomatic

Micro

─ Increased melanin pigment within basal keratinocytes/epithelial cells

─ Number of melanocytes is usually normal or only slightly increased, without nesting or significant atypia

─ Melanocytes are typically confined to basal layer, may have prominent dendrites

─ Melanin incontinence (melanophages in superficial lamina propria/dermis) is common and contributes to clinical color

─ Lamina propria/dermis may show a sparse lymphocytic infiltrate

─ No architectural disorder or significant cytologic atypia of melanocytes

DDx

─ Lentigo simplex (more prominent elongation of rete ridges/epithelial papillae, increased number of melanocytes)

─ Melanocytic nevus (junctional or compound) (presence of melanocytic nests)

─ Melanoma in situ (lentigo maligna or mucosal lentiginous melanoma) (significant cytologic atypia, confluent proliferation of atypical melanocytes, pagetoid spread)

─ Amalgam tattoo (if oral, shows metallic particles)

─ Smoker's melanosis (clinical history, often more diffuse)

Prognosis ─ Benign

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Amalgam Tattoo

Common iatrogenic oral pigmentation due to traumatic implantation of dental amalgam particles

Clinical

─ Blue, gray, or black macule or slightly raised area on oral mucosa

─ Most common on gingiva, alveolar mucosa, buccal mucosa, often adjacent to restored teeth

─ Asymptomatic, usually discovered incidentally or during dental examination

─ May be visible on dental radiographs as radiopaque particles

Micro

─ Fine, dark brown to black, refractile granules and larger irregular particles of foreign material (amalgam) deposited in connective tissue of lamina propria/submucosa

─ Pigment particles often preferentially stain and encase reticulin and elastic fibers of connective tissue and blood vessel walls

─ Variable chronic inflammatory response, often with lymphocytes, plasma cells, and macrophages (melanophages may be present if there's associated melanin)

─ Foreign body giant cell reaction can occur around larger particles

─ Overlying epithelium is usually normal

DDx

─ Melanotic macule (increased melanin in basal layer, melanophages, no metallic particles)

─ Blue nevus (dermal dendritic melanocytes, S100+)

─ Melanoma (atypical melanocytes, S100+, Melan-A+)

─ Graphite tattoo (carbon particles, often less refractile and less associated with elastic fibers)

Prognosis ─ Benign, persistent unless excised

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Solar Lentigo (Lentigo Senilis, Age Spot, Liver Spot)

Common benign hyperpigmented macule on chronically sun-exposed skin of older individuals

Clinical

─ Well-demarcated, tan to dark brown, flat (macular) or slightly raised (thin plaque) lesion, variable size (mm to >1 cm)

─ Common on face, dorsal hands, forearms, upper trunk (sun-exposed areas)

─ Often multiple, increases in number and size with age and continued sun exposure

Micro

─ Elongated, often club-shaped or bud-like rete ridges extending into papillary dermis

─ Increased melanin pigmentation in basal keratinocytes

─ Increased number of melanocytes along basal layer, but typically without significant nesting or atypia (melanocytes are regularly spaced)

─ Overlying epidermis may show hyperkeratosis and mild acanthosis

─ Solar elastosis (basophilic degeneration of collagen) prominent in papillary dermis

─ No significant cytologic atypia of melanocytes or architectural disorder seen in dysplastic nevi or melanoma in situ

DDx

─ Lentigo simplex (occurs at any age, not necessarily sun-exposed, less prominent rete elongation, no solar elastosis)

─ Ephelis (freckle) (darkens with sun exposure, fades without, normal number of melanocytes, no rete elongation)

─ Pigmented actinic keratosis (keratinocytic atypia, parakeratosis)

─ Lentigo maligna (melanoma in situ on sun-damaged skin) (atypical melanocytes, often confluent proliferation, pagetoid spread, adnexal involvement, epidermal atrophy)

─ Seborrheic keratosis (especially flat/macular variant) (horn pseudocysts, papillomatosis, basaloid cell proliferation)

─ Junctional dysplastic nevus (cytologic atypia, architectural disorder, lamellar fibroplasia)

Prognosis ─ Benign, but marker of chronic sun damage and increased risk for other sun-induced skin cancers (AK, BCC, SCC, melanoma)

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Malignant Melanocytic

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Lentigo Maligna Melanoma (LMM)

Melanoma in situ (lentigo maligna, LM) or invasive melanoma arising in chronically sun-damaged skin, typically on head/neck of elderly

Clinical

─ LM: Slow-growing, large, flat, tan to brown/black macule with irregular borders and variable pigmentation, on sun-damaged skin

─ LMM (invasive): Development of papule/nodule, or darker/thicker area within pre-existing LM

─ Usually elderly individuals, face (cheeks, nose, temples), neck, forearms

Micro

─ LM (in situ phase):

─ Atypical melanocytes proliferating predominantly as single cells along dermoepidermal junction, often confluent ("lentiginous" proliferation)

─ Melanocytes show nuclear atypia (enlarged, hyperchromatic, irregular), may be spindled

─ Epidermis often atrophic, rete ridges effaced

─ Extension of atypical melanocytes down follicular epithelium (adnexal involvement) is characteristic

─ Pagetoid spread (upward migration) may be present but often less prominent than in superficial spreading melanoma

─ Prominent solar elastosis in dermis, often with lymphocytic infiltrate and melanophages

─ LMM (invasive phase):

─ Features of LM in situ in adjacent epidermis

─ Invasive component in dermis, often spindled melanocytes, may be desmoplastic or neurotropic

─ Depth of invasion (Breslow thickness), ulceration, mitotic rate are key prognostic factors

IHC

─ Melanocytes (+) S100, SOX10, Melan-A, HMB-45 (HMB-45 may be weaker or lost in invasive spindle cell areas)

DDx

─ Solar lentigo (no significant atypia, regular rete elongation)

─ Pigmented actinic keratosis (keratinocytic atypia, parakeratosis, lacks confluent atypical melanocytic proliferation)

─ Dysplastic nevus (especially on sun-damaged skin) (architectural disorder, focal atypia, often younger patients, different overall pattern)

─ Lichenoid keratosis (lichenoid infiltrate, regressing lentigo features, lacks atypical melanocytic proliferation)

─ Desmoplastic nevus (if LMM is desmoplastic and amelanotic) (benign spindle cells, S100+, often MART-1 negative)

Prognosis ─ LM (in situ) has excellent prognosis if completely excised, LMM prognosis depends on Breslow thickness and other staging factors, desmoplastic/neurotropic variants have higher local recurrence

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Superficial Spreading Melanoma (SSM)

Most common type of invasive melanoma, characterized by a significant intraepidermal (radial) growth phase before dermal invasion

Clinical

─ Irregularly pigmented (variegated tan, brown, black, pink, blue, white) macule or plaque with irregular borders, often >6mm

─ Asymmetry, Border irregularity, Color variegation, Diameter >6mm, Evolving (ABCDE criteria)

─ Can occur anywhere, common on trunk (especially men) and lower legs (especially women)

─ Usually arises de novo, but can occur in pre-existing nevus (common or dysplastic)

Micro

─ Radial growth phase (in situ or microinvasive):

─ Asymmetrical proliferation of atypical melanocytes within epidermis

─ Melanocytes are large, epithelioid, or mixed, with pleomorphic, hyperchromatic nuclei, prominent nucleoli

─ Prominent pagetoid spread (upward migration of single and nested atypical melanocytes throughout epidermis, often to stratum corneum)

─ Irregularly sized and shaped junctional nests, often confluent and poorly demarcated

─ Consumption of epidermis (thinning over nests) may occur

─ Vertical growth phase (invasive component):

─ Nests, fascicles, or sheets of atypical melanocytes invading dermis

─ Cells in dermal component often similar to or more atypical than intraepidermal cells

─ Lack of maturation with depth (deeper cells remain large and atypical)

─ Dermal mitoses, often atypical

─ Lymphocytic host response common at base of invasive component

─ Breslow thickness, ulceration, mitotic rate are key prognostic factors

IHC

─ (+) S100, SOX10, Melan-A, HMB-45

DDx

─ Dysplastic nevus (lesser degree of atypia and architectural disorder, maturation in dermal component, lacks extensive/atypical pagetoid spread)

─ Spitz nevus (spindle/epithelioid cells, Kamino bodies, symmetry, often younger patients, p16 diffuse)

─ Paget's disease/Pagetoid Bowen's disease (adenocarcinoma cells or atypical keratinocytes, respectively, negative for melanocytic markers)

─ Recurrent nevus (history of prior biopsy, atypia confined over scar)

Prognosis ─ Depends on Breslow thickness, ulceration, mitotic rate, sentinel lymph node status, etc, good if thin and non-ulcerated

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Nodular Melanoma

Invasive melanoma characterized by predominantly vertical growth phase with absent or minimal radial growth phase

Clinical

─ Rapidly growing, often darkly pigmented (blue-black or dark brown, can be amelanotic/pink-red) papule or nodule

─ May ulcerate or bleed early

─ Can occur anywhere, common on trunk, head, neck

─ Often arises de novo, less commonly from pre-existing nevus

─ Tends to be thicker and have worse prognosis at diagnosis due to rapid vertical growth

Micro

─ Predominantly dermal invasive tumor with little or no intraepidermal component beyond the margins of the dermal tumor (radial growth phase absent or limited to <3 rete ridges beyond dermal component)

─ Tumor cells are often epithelioid, spindled, or mixed, with significant cytologic atypia (large, pleomorphic, hyperchromatic nuclei, prominent nucleoli)

─ Numerous mitoses, often atypical, frequently present throughout tumor thickness

─ Expansile dermal nodules, often pushing or infiltrative borders

─ Ulceration common

─ Lack of maturation with depth

─ Lymphocytic infiltrate may be present or absent (brisk, non-brisk, or absent)

─ Breslow thickness, ulceration, mitotic rate are key prognostic factors

IHC

─ (+) S100, SOX10, Melan-A, HMB-45

DDx

─ Spitz nevus (especially polypoid or nodular variants) (symmetry, Kamino bodies, younger age, specific cytology, p16 diffuse)

─ Cellular blue nevus (different cytology, often dumbbell shape, biphasic pattern)

─ Metastatic melanoma (usually no epidermal connection, multiple lesions clinically, known primary)

─ Other poorly differentiated carcinomas or sarcomas (if amelanotic – IHC panel crucial)

─ Pyogenic granuloma (if amelanotic and ulcerated) (vascular proliferation, lacks atypical melanocytes)

Prognosis ─ Generally worse than SSM of similar thickness due to inherent vertical growth, prognosis depends on Breslow thickness, ulceration, mitotic rate, etc

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Metastatic Melanoma

Melanoma that has spread from a primary site to skin or other organs

Clinical

─ Skin metastases: firm, dome-shaped or subcutaneous nodules, often multiple, can be pigmented or amelanotic

─ May occur anywhere, common near primary site (in-transit/satellite metastases) or distant sites

─ Can be first sign of melanoma recurrence or progression

─ Internal organ metastases common (lung, liver, brain, bone, lymph nodes)

Micro

─ Dermal and/or subcutaneous nodules, sheets, or infiltrative patterns of atypical melanocytes

─ Cells often epithelioid, spindled, or pleomorphic, resembling primary melanoma cells but can be variable

─ Cytologic atypia, mitoses (often atypical), necrosis common

─ Epidermal involvement (epidermotropism) is rare in cutaneous metastases, but can occur (epidermotropic metastatic melanoma)

─ Lymphovascular invasion often present

─ Usually lacks features of a primary melanoma's radial growth phase (eg, extensive junctional activity, pagetoid spread clearly arising from epidermis)

─ Inflammation variable, often sparse

IHC

─ (+) S100, SOX10, Melan-A, HMB-45 (though HMB-45/Melan-A can be lost in some metastases, especially desmoplastic or spindle cell)

─ Ki-67 often high

DDx

─ Primary nodular melanoma (may have some overlying epidermal involvement or ulceration, difficult to distinguish from solitary metastasis without clinical history)

─ Cellular blue nevus (if pigmented and cellular) (lacks significant atypia/mitoses of metastasis)

─ Other metastatic carcinomas or sarcomas (IHC panel crucial)

─ Lymphoma/Leukemia cutis (lymphoid markers+)

─ Spitz nevus/Atypical Spitz tumor (if metastasis is spitzoid) (clinical context, prior history)

Prognosis ─ Poor, indicates systemic disease (Stage IV), though some patients with limited skin/nodal metastases may respond to systemic therapies or surgical resection

Ancient Change (in Melanocytic Nevi)

Degenerative changes in long-standing benign nevi, leading to cytologic atypia that can mimic melanoma, "ancient nevus"

Clinical

─ Usually in older intradermal nevi, no specific clinical features distinct from a common nevus

─ May appear as a long-standing, stable, often dome-shaped, skin-colored or lightly pigmented papule

Micro

─ Features of a benign intradermal nevus (often neurotized or sclerotic)

─ Degenerative nuclear atypia: enlarged, hyperchromatic, often smudgy or pleomorphic nuclei in some nevus cells, particularly in deeper portions or associated with sclerosis/vascular changes

─ Cytoplasm of atypical cells may be scant or prominent

─ No significant increase in mitotic activity, no atypical mitoses

─ No expansile growth, no sheets of atypical cells, no pagetoid spread in overlying epidermis (if present)

─ Other features: stromal fibrosis/sclerosis, vascular ectasia, edema, hyalinization of vessel walls, pseudovascular spaces, focal hemorrhage, hemosiderin, and sometimes a sparse lymphocytic infiltrate

─ Overall architecture remains benign and symmetrical

DDx

─ Melanoma (especially nevoid melanoma or melanoma arising in a nevus) (more significant and diffuse atypia, atypical mitoses, expansile growth, lack of maturation, pagetoid spread if junctional component involved)

─ Dysplastic nevus (junctional architectural disorder and atypia, lamellar fibroplasia)

─ Recurrent nevus (history of prior biopsy, atypia often junctional over scar)

─ Spitz nevus (different cytology – large epithelioid/spindle cells, Kamino bodies)

Prognosis ─ Benign, represents degenerative atypia, not malignant transformation

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BAPoma (BAP1-inactivated Melanocytic Tumor)

Melanocytic neoplasms characterized by loss of BAP1 (BRCA1 associated protein-1) expression, often with spitzoid or epithelioid cytology

Clinical

─ May present as dome-shaped, pink or tan papules, often multiple

─ Can be sporadic or part of a tumor predisposition syndrome (BAP1-TPDS) associated with uveal melanoma, mesothelioma, renal cell carcinoma, etc

─ Lesions in BAP1-TPDS often appear in childhood or early adulthood

Micro

─ Typically compound melanocytic proliferation, often well-circumscribed and symmetrical

─ Composed predominantly of large epithelioid melanocytes with abundant eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli (spitzoid-like)

─ May show some degree of cytologic atypia, but often lacks high-grade features of conventional melanoma

─ Mitotic activity usually low

─ Lymphocytic infiltrate common

─ Some lesions may resemble atypical Spitz tumors or "MELTUMP" (melanocytic tumor of uncertain malignant potential)

─ BAP1 IHC shows loss of nuclear staining in tumor cells (internal control in normal cells should be positive)

IHC

─ Tumor cells (+) S100, SOX10, Melan-A

─ Characteristic loss of nuclear BAP1 staining in tumor cells

─ p16 often retained (can be variable)

DDx

─ Spitz nevus (BAP1 intact, often diffuse p16 positive)

─ Atypical Spitz tumor (may show BAP1 loss, careful assessment needed)

─ Melanoma (especially spitzoid melanoma or epithelioid cell melanoma – BAP1 usually intact, other features of melanoma like high mitotic rate, necrosis, severe atypia)

─ Common acquired or dysplastic nevus (BAP1 intact)

Prognosis ─ Spectrum of behavior, some considered borderline/interMedia ─ placeholder te, risk of internal malignancies in BAP1-TPDS, complete excision recommended

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Desmoplastic Melanoma

Rare, aggressive variant of invasive melanoma characterized by spindled melanocytes and prominent desmoplastic (sclerotic) stroma

Clinical

─ Firm, indurated, often scar-like papule, plaque, or nodule, may be skin-colored, pink, or lightly pigmented, sometimes amelanotic

─ Usually on chronically sun-exposed skin of head and neck in elderly individuals

─ Often arises in association with lentigo maligna

─ High propensity for local recurrence and neurotropism

Micro

─ Infiltrative proliferation of atypical spindle cells in dermis, often extending into subcutis

─ Spindle cells are often elongated, with hyperchromatic, pleomorphic nuclei, may be widely spaced

─ Prominent desmoplastic stroma: dense collagen deposition, fibrosis, may resemble scar or fibromatosis

─ "Pure" desmoplastic melanoma: >90% of tumor has desmoplastic stroma and spindled cells

─ "Mixed" desmoplastic melanoma: <90% desmoplastic component, with areas of conventional melanoma (epithelioid/nevoid cells)

─ Neurotropism (invasion of nerves by tumor cells) is common and characteristic, associated with increased recurrence

─ Lymphocytic aggregates often present, sometimes forming peritumoral cuffs

─ Overlying epidermis may show lentigo maligna (atypical melanocytic proliferation along basal layer, adnexal extension)

─ Cytologic atypia can be subtle in some cases ("bland" desmoplastic melanoma)

─ Mitoses may be infrequent

IHC

─ Spindle cells (+) S100, SOX10 (often strong and diffuse)

─ Melan-A and HMB-45 are often negative or only focally positive in the desmoplastic component (can be positive in non-desmoplastic areas of mixed lesions)

─ p75 (NGFR) may be positive

DDx

─ Scar/Fibromatosis/Sclerotic dermatofibroma (lack atypical spindle cells, S100-/SOX10-)

─ Atypical fibroxanthoma (pleomorphic cells, different IHC: CD10+, procollagen-1+, S100-)

─ Spindle cell squamous cell carcinoma (keratin+, S100-)

─ Leiomyosarcoma (SMA+, desmin+, S100-)

─ Malignant peripheral nerve sheath tumor (MPNST) (S100+ but often patchy, SOX10+, lacks epidermal LM component, clinical context)

─ Desmoplastic Spitz nevus (benign, lacks significant atypia, younger age, often p16 diffuse)

─ Sclerosing blue nevus (different spindle cells, pigment, lacks atypia of DM)

Prognosis ─ High rate of local recurrence, especially with neurotropism, metastatic potential similar to conventional melanoma of comparable thickness, but often diagnosed at greater thickness

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Melanoma in situ – Lentigo Maligna (LM)

Melanoma confined to the epidermis and adnexal epithelium, occurring on chronically sun-damaged skin, precursor to LMM

Clinical

─ Slow-growing, flat, tan to brown/black macule with irregular borders and variable pigmentation

─ Usually on sun-exposed skin of elderly individuals, especially face (cheeks, nose, temples), neck

─ Can be large (several cm) due to prolonged radial growth

Micro

─ Atypical melanocytes proliferating predominantly as single cells along the dermoepidermal junction, often forming a confluent or near-confluent layer ("lentiginous" proliferation)

─ Melanocytes show nuclear atypia (enlarged, hyperchromatic, irregular shapes, pleomorphism), cells may be spindled or epithelioid

─ Epidermis is typically atrophic with effacement of rete ridges due to solar damage

─ Characteristic extension of atypical melanocytes down the outer root sheath of hair follicles and sometimes eccrine ducts (adnexal involvement)

─ Pagetoid spread (upward migration of single atypical melanocytes into spinous layer) may be present but often focal and less extensive than in superficial spreading melanoma in situ

─ Dermis shows prominent solar elastosis (basophilic degeneration of collagen)

─ Superficial dermal lymphocytic infiltrate and melanophages are common

─ No dermal invasion of atypical melanocytes (by definition of in situ)

IHC

─ Atypical melanocytes (+) S100, SOX10, Melan-A, HMB-45 (MART-1/Melan-A often highlights density of melanocytes well)

DDx

─ Solar lentigo (increased number of melanocytes but no significant atypia, regular rete elongation, "dirty feet" appearance of rete)

─ Pigmented actinic keratosis (keratinocytic atypia, parakeratosis, atypical melanocytes not confluent or extending down adnexa to same degree)

─ Dysplastic nevus on sun-damaged skin (architectural disorder, often nested proliferation, focal atypia, lamellar fibroplasia, lacks diffuse confluent atypical melanocytic proliferation of LM)

─ Lichenoid keratosis (regressing lentigo) (lichenoid infiltrate, apoptotic keratinocytes, often lacks prominent atypical melanocytic proliferation)

Prognosis ─ Excellent if completely excised, risk of progression to invasive lentigo maligna melanoma if untreated or incompletely excised (estimated 5% lifetime risk for an individual LM lesion to invade)

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Lentigo Maligna with Lichenoid Reaction

Lentigo maligna (melanoma in situ on sun-damaged skin) associated with a prominent band-like lymphocytic infiltrate that can obscure the dermoepidermal junction

Clinical

─ Similar to classic lentigo maligna: flat, irregularly pigmented macule on sun-damaged skin of elderly

─ May appear more inflamed or erythematous due to the lichenoid reaction

─ Can sometimes lead to partial regression or altered pigmentation clinically

Micro

─ Features of lentigo maligna: atypical melanocytes (often spindled) proliferating as single cells and in small nests along an atrophic epidermis, with adnexal extension, on background of solar elastosis

─ Characteristic feature: Dense, band-like lymphocytic infiltrate in the upper dermis, closely abutting and often obscuring the dermoepidermal junction (lichenoid infiltrate)

─ Vacuolar alteration of the basal layer and Civatte (colloid) bodies may be present

─ Melanophages common in the dermis

─ The lichenoid infiltrate can sometimes make assessment of invasion difficult or mimic regression

DDx

─ Lichenoid keratosis (benign lichenoid keratosis) (often solitary, may represent regressing solar lentigo or seborrheic keratosis, lacks confluent atypical melanocytic proliferation of LM)

─ Lichenoid actinic keratosis (keratinocytic atypia is primary, melanocytic atypia absent or reactive)

─ Lichenoid drug eruption (clinical history, may lack prominent atypical melanocytes)

─ Lichen planus (lacks atypical melanocytic proliferation, other classic LP features)

─ Regressing melanoma (areas of tumor destruction, fibrosis, melanosis, inflammation, but LM with lichenoid reaction is specifically about the inflammatory pattern with in situ disease)

Prognosis ─ Similar to lentigo maligna without prominent lichenoid reaction, excellent if completely excised and truly in situ, lichenoid reaction itself doesn't necessarily change prognosis but can complicate diagnosis

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Metastatic Melanoma

Melanoma that has spread from a primary site to skin or other organs (reiteration from Set 22 as per list)

Clinical

─ Skin metastases: firm, dome-shaped or subcutaneous nodules, often multiple, can be pigmented or amelanotic

─ May occur anywhere, common near primary site (in-transit/satellite metastases) or distant sites

─ Can be first sign of melanoma recurrence or progression

Micro

─ Dermal and/or subcutaneous nodules, sheets, or infiltrative patterns of atypical melanocytes

─ Cells often epithelioid, spindled, or pleomorphic, resembling primary melanoma cells but can be variable

─ Cytologic atypia, mitoses (often atypical), necrosis common

─ Epidermal involvement (epidermotropism) is rare in cutaneous metastases but can occur

─ Lymphovascular invasion often present

─ Usually lacks features of a primary melanoma's radial growth phase

IHC

─ (+) S100, SOX10, Melan-A, HMB-45 (Melan-A/HMB-45 can be lost in some metastases)

─ Ki-67 often high

DDx

─ Primary nodular melanoma (may have some overlying epidermal involvement, difficult to distinguish solitary metastasis without history)

─ Cellular blue nevus (lacks significant atypia/mitoses)

─ Other metastatic carcinomas or sarcomas (IHC panel crucial)

─ Lymphoma/Leukemia cutis (lymphoid markers+)

Prognosis ─ Poor, indicates systemic disease (Stage IV)

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Regressing Melanoma

Melanoma (in situ or invasive) undergoing immune-Media ─ placeholder ted partial or complete destruction

Clinical

─ Area of pigment loss (white, gray, or blue areas), scarring, or inflammation within a known or suspected melanoma

─ May have irregular borders, variable pigmentation with areas of fading or depigmentation

─ Regression does not necessarily indicate a better prognosis, and can make staging (eg, Breslow thickness assessment) difficult if extensive

Micro

─ Areas of tumor cell loss replaced by:

─ Fibrosis in the dermis, often with new collagen deposition (scar-like)

─ Melanosis (abundant melanophages in the dermis)

─ Dense lymphocytic infiltrate, often band-like or patchy, sometimes with plasma cells

─ Vascular proliferation and ectasia

─ Residual atypical melanocytes (in situ or invasive) are usually present at periphery or focally within regressed area, essential for diagnosis

─ Epidermis overlying regressed areas may be thinned or ulcerated

─ Complete regression: no identifiable residual melanoma cells, only dermal changes (fibrosis, melanosis, inflammation), diagnosis often relies on clinical history and prior biopsies

DDx

─ Halo nevus (dense lymphocytic infiltrate targeting benign nevus cells, symmetrical depigmented halo clinically)

─ Lichenoid keratosis (regressing solar lentigo/SK) (lacks atypical melanocytes)

─ Scar (if regression is complete and no prior biopsy)

─ Inflamed or irritated nevus (inflammation usually less destructive, lacks extensive fibrosis/melanosis of true regression)

─ Lentigo maligna with lichenoid reaction (prominent inflammation but primarily in situ disease)

Prognosis ─ Controversial, extensive regression may obscure true tumor thickness leading to understaging, some studies suggest extensive regression might be associated with better immune response, others with worse outcome or no difference, presence of regression should be noted in pathology report

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Interface dermatitis

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Lichen Planus (LP)

Idiopathic inflammatory disorder affecting skin, mucous membranes, hair follicles, and nails, characterized by "4 Ps": pruritic, purple, polygonal papules and plaques

Clinical

─ Skin: violaceous, flat-topped (lichenoid) papules and plaques, often with fine white lines (Wickham's striae), intensely pruritic, common on flexor wrists, forearms, ankles, lumbar back, shins

─ Oral: reticular white plaques (Wickham's striae), erosive, or atrophic lesions on buccal mucosa, tongue, gingiva

─ Nails: thinning, ridging, pterygium formation, shedding

─ Scalp (Lichen Planopilaris): scarring alopecia with perifollicular erythema/scale

─ Variants: hypertrophic, atrophic, bullous, actinic, annular, linear, ulcerative

Micro

─ Classic features of interface dermatitis (lichenoid pattern):

─ Hyperkeratosis (often compact orthokeratosis)

─ Irregular acanthosis with "sawtooth" or pointed rete ridges

─ Hypergranulosis (often wedge-shaped or thickened)

─ Liquefaction degeneration (vacuolar alteration) of the basal cell layer

─ Band-like lymphocytic infiltrate in the superficial dermis, closely abutting and often obscuring the dermoepidermal junction

─ Civatte bodies (colloid bodies, hyaline bodies): eosinophilic, PAS-positive globules representing apoptotic basal keratinocytes, found at DE junction or in upper dermis

─ Melanin incontinence (melanophages in papillary dermis) common

─ No significant eosinophils or plasma cells (typically)

DDx

─ Lichenoid drug eruption (often has eosinophils, parakeratosis, deeper infiltrate, clinical history)

─ Lichenoid keratosis (benign lichenoid keratosis) (usually solitary, may have parakeratosis, often regressing lentigo/SK)

─ Lupus erythematosus (especially DLE) (follicular plugging, basement membrane thickening, deeper perivascular/periadnexal infiltrate, positive DIF for lupus band)

─ Graft-versus-host disease (clinical history, often more prominent apoptosis/satellite cell necrosis)

─ Secondary syphilis (plasma cells in infiltrate, endothelial swelling, positive spirochete stain)

─ Pityriasis lichenoides chronica (parakeratosis, RBC extravasation, less "sawtoothing")

─ Mycosis fungoides (patch/plaque stage) (atypical lymphocytes, epidermotropism, Pautrier's microabscesses)

Prognosis ─ Benign, but can be chronic and recurrent, oral LP has small risk of SCC development

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Lichen Nitidus

Chronic inflammatory disease characterized by tiny, discrete, skin-colored or slightly erythematous, shiny (nitid) papules

Clinical

─ Numerous, pinpoint to pinhead-sized (1-2 mm), shiny, flat-topped papules

─ Often grouped, can be linear (Koebner phenomenon)

─ Common sites: flexor aspects of upper extremities, trunk, genitalia (especially penis), less often palms/soles or mucous membranes

─ Usually asymptomatic or mildly pruritic, more common in children and young adults

Micro

─ Well-circumscribed, dense, lymphohistiocytic infiltrate in a widened dermal papilla, typically "clutching" or indenting the overlying epidermis ("ball and claw" configuration)

─ Epidermis overlying the infiltrate is often thinned or effaced, with loss of rete ridges

─ Parakeratosis is often present over the center of the papule

─ Basal layer may show vacuolar alteration

─ Epidermal collarettes (downward growth of epidermis at edges of papilla) embrace the infiltrate

─ Infiltrate composed mainly of lymphocytes and histiocytes (often epithelioid), sometimes with giant cells

─ Minimal to no significant hyperkeratosis or hypergranulosis (unlike lichen planus)

DDx

─ Lichen planus (larger papules, Wickham's striae, sawtooth rete, more prominent hypergranulosis/hyperkeratosis, denser band-like infiltrate not confined to single papillae)

─ Sarcoidosis (especially micropapular) (naked granulomas, diascopy positive, different infiltrate composition)

─ Secondary syphilis (plasma cells, endothelial swelling, spirochetes)

─ Verruca plana (viral cytopathic changes, koilocytes)

─ Lichen scrofulosorum (tuberculid, often associated with TB, different granulomatous pattern)

Prognosis ─ Benign, often self-limited over months to years, but can be persistent

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Lichenoid Drug Eruption

Cutaneous reaction to a medication, mimicking lichen planus clinically and/or histologically

Clinical

─ Eruption can be widespread, often more morbilliform or eczematous initially than classic LP, may become more violaceous and lichenoid over time

─ Can involve skin, oral mucosa

─ Pruritus is common

─ Onset usually weeks to months after starting offending drug (eg, ACE inhibitors, thiazides, antimalarials, NSAIDs, beta-blockers, gold, penicillamine)

Micro

─ Interface dermatitis with features overlapping with lichen planus:

─ Band-like lymphocytic infiltrate in upper dermis, often obscuring DE junction

─ Vacuolar alteration of basal layer, Civatte bodies

─ Irregular acanthosis, hypergranulosis, hyperkeratosis (may be less regular than classic LP)

─ Features more suggestive of drug eruption than classic LP:

─ Presence of eosinophils in the infiltrate (often a key clue)

─ Parakeratosis (less typical for classic LP skin lesions)

─ Deeper perivascular and interstitial lymphocytic infiltrate, in addition to superficial band

─ More prominent dermal edema

─ More numerous necrotic keratinocytes scattered at all levels of epidermis (not just basal)

DDx

─ Lichen planus (typically lacks eosinophils and prominent parakeratosis in skin lesions)

─ Graft-versus-host disease (clinical history, often more apoptosis/satellite cell necrosis)

─ Lupus erythematosus (follicular plugging, thickened basement membrane, deeper perivascular/periadnexal infiltrate, DIF findings)

─ Mycosis fungoides (atypical lymphocytes, epidermotropism, Pautrier's)

─ Viral exanthem (different clinical, often more superficial perivascular infiltrate)

Prognosis ─ Usually resolves upon withdrawal of offending drug, may take weeks to months, post-inflammatory hyperpigmentation common

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Benign Lichenoid Keratosis (Lichen Planus-like Keratosis, LPLK, Solitary Lichen Planus)

Common, solitary, benign inflammatory lesion, often representing an involuting solar lentigo or seborrheic keratosis

Clinical

─ Solitary, small (<1 cm), pink, erythematous, violaceous, or brownish papule or thin plaque

─ Often on sun-exposed skin of trunk (especially chest, back), upper extremities, face of middle-aged or older adults

─ May be slightly scaly or crusted, usually asymptomatic or mildly pruritic

─ Can mimic basal cell carcinoma, actinic keratosis, or melanoma clinically

Micro

─ Interface dermatitis with a dense, band-like lymphocytic infiltrate in superficial dermis, obscuring DE junction

─ Features often indistinguishable from or very similar to lichen planus:

─ Vacuolar alteration of basal layer, Civatte bodies

─ Irregular acanthosis, hypergranulosis (often wedge-shaped), hyperkeratosis

─ Features that may suggest LPLK over classic LP:

─ Presence of parakeratosis (more common in LPLK)

─ Eosinophils or plasma cells may be present in infiltrate (less typical for LP)

─ Remnants of a pre-existing lesion (eg, solar lentigo with elongated rete, or seborrheic keratosis with horn pseudocysts) may be seen at periphery or within the lesion

─ More prominent melanin incontinence and melanophages

─ Solar elastosis often present in underlying dermis

DDx

─ Lichen planus (usually multiple lesions clinically, LPLK is solitary by definition)

─ Lichenoid drug eruption (clinical history, often more eosinophils, may be more widespread)

─ Lichenoid actinic keratosis (keratinocytic atypia, parakeratosis, solar elastosis)

─ Lupus erythematosus (DLE) (follicular plugging, thickened basement membrane, deeper infiltrate)

─ Melanoma with lichenoid regression (atypical melanocytes usually identifiable, especially with IHC)

Prognosis ─ Benign, represents an inflammatory response, often leads to lesion resolution

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Lichenoid Actinic Keratosis

Actinic keratosis with a prominent lichenoid (band-like) lymphocytic inflammatory infiltrate

Clinical

─ Similar to classic actinic keratosis: rough, scaly papule or macule on sun-exposed skin

─ May appear more erythematous or indurated due to the inflammation

─ Can be solitary or multiple

Micro

─ Features of actinic keratosis:

─ Atypia of basal keratinocytes (enlarged, hyperchromatic, pleomorphic nuclei, loss of polarity), often not full-thickness

─ Parakeratosis, often alternating with orthokeratosis

─ Epidermis may be hypertrophic or atrophic

─ Prominent band-like lymphocytic infiltrate in the superficial dermis, closely abutting and often obscuring the dermoepidermal junction (lichenoid infiltrate)

─ Vacuolar alteration of the basal layer and Civatte bodies often present

─ Solar elastosis prominent in papillary dermis

─ Plasma cells may be present in the infiltrate

DDx

─ Bowen's disease/SCCis with lichenoid inflammation (full-thickness epidermal atypia)

─ Benign lichenoid keratosis (LPLK) (lacks significant keratinocytic atypia of AK, often remnants of lentigo/SK)

─ Lichen planus (lacks keratinocytic atypia of AK, different clinical context)

─ Lichenoid drug eruption (clinical history, may have eosinophils, lacks consistent AK atypia)

─ Discoid lupus erythematosus (follicular plugging, thickened basement membrane, deeper infiltrate, lacks AK atypia)

Prognosis ─ Premalignant, similar to other AKs, potential to progress to invasive SCC

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Hypertrophic LP (Hypertrophic Lichen Planus)

Chronic variant of lichen planus, characterized by very thick, warty plaques, often on lower extremities

Clinical

─ Extremely pruritic, thick, hyperkeratotic, verrucous (warty) plaques

─ Most common on shins, ankles, dorsal feet

─ Lesions are often persistent and resistant to treatment

─ May arise in areas of previous classic LP or de novo

Micro

─ Marked epidermal hyperplasia, often irregular and pseudoepitheliomatous, with significant hyperkeratosis and hypergranulosis (unlike classic LP which has more regular acanthosis or even atrophy)

─ Other features of lichen planus are present:

─ Band-like lymphocytic infiltrate in superficial dermis, hugging and obscuring the DE junction

─ Vacuolar alteration of the basal cell layer

─ Civatte bodies (apoptotic keratinocytes)

─ Dermal papillae often fibrotic and widened

─ No significant eosinophils typically

DDx

─ Prurigo nodularis/Lichen simplex chronicus (marked epidermal hyperplasia, but typically lacks dense lichenoid infiltrate and prominent basal vacuolar change of HLP)

─ Verrucous carcinoma/Squamous cell carcinoma (cytologic atypia, invasive growth, though HLP can have pseudoepitheliomatous hyperplasia that mimics SCC)

─ Verruca vulgaris (viral cytopathic changes, koilocytes, papillomatosis)

─ Chromoblastomycosis/Deep fungal infections (pseudoepitheliomatous hyperplasia with neutrophils, granulomas, organisms visible with special stains)

Prognosis ─ Benign, but chronic, persistent, and often very pruritic, small risk of SCC development in long-standing hypertrophic oral or cutaneous LP lesions

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Secondary Syphilis

Systemic manifestations of infection with Treponema pallidum, occurring weeks to months after primary chancre

Clinical

─ Variable rash: macular, papular, papulosquamous, pustular, annular, nodular, often widespread

─ "Great imitator" – can mimic many dermatoses

─ Papulosquamous lesions common, often coppery-red or brownish, may involve palms and soles (characteristic)

─ Condylomata lata: moist, flat-topped papules/plaques in intertriginous areas (anogenital, axillae)

─ Mucous patches in oral cavity

─ Generalized lymphadenopathy, fever, malaise common

Micro

─ Variable epidermal changes:

─ Psoriasiform hyperplasia common in papulosquamous lesions

─ May show spongiosis, parakeratosis, or interface changes (lichenoid or vacuolar)

─ Dermal infiltrate typically superficial and deep, perivascular, and often interstitial

─ Characteristic (but not always present) features:

─ Prominent plasma cell component in the infiltrate (a key clue)

─ Endothelial swelling and proliferation in small blood vessels

─ Lymphocytes and histiocytes also present in infiltrate, neutrophils less common unless pustular lesions

─ Granulomas (non-caseating) may be seen in some lesions (nodular syphilis)

─ Spirochetes (T, pallidum) can be demonstrated with special stains (eg, Warthin-Starry, Steiner silver stain) or immunohistochemistry, but often difficult to find in secondary lesions

DDx

─ Pityriasis rosea (epidermal collarette of scale, different infiltrate, lacks plasma cells and endothelial swelling)

─ Lichen planus (if lichenoid pattern, but syphilis often has plasma cells and deeper infiltrate)

─ Psoriasis (if psoriasiform, but syphilis has plasma cells, endothelial swelling)

─ Drug eruption (can be lichenoid or psoriasiform, may have eosinophils, history of drug)

─ Mycosis fungoides (atypical lymphocytes, epidermotropism)

─ Pityriasis lichenoides (more RBC extravasation, necrotic keratinocytes)

Prognosis ─ Curable with appropriate antibiotic treatment (penicillin), untreated can progress to tertiary syphilis

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PLEVA (Pityriasis Lichenoides et Varioliformis Acuta)

Acute form of pityriasis lichenoides, characterized by recurrent crops of papules that may vesiculate, ulcerate, and heal with scarring

Clinical

─ Abrupt onset of small (few mm to 1 cm), erythematous or purpuric papules, often rapidly evolving to become vesicular, pustular, hemorrhagic, crusted, or necrotic (varioliform = smallpox-like)

─ Lesions in different stages of evolution often present simultaneously

─ Common on trunk, flexor extremities, buttocks, more common in children and young adults

─ May be associated with mild fever, malaise

─ Usually self-limited over weeks to months, but can recur or transition to pityriasis lichenoides chronica (PLC)

Micro

─ Interface dermatitis, often wedge-shaped infiltrate

─ Epidermal changes:

─ Parakeratosis, often confluent and crusted if ulcerated

─ Spongiosis, intraepidermal vesiculation, or necrosis/ulceration

─ Necrotic keratinocytes (apoptotic bodies) common, may be scattered or confluent

─ Exocytosis of lymphocytes, often with admixed neutrophils and red blood cells into epidermis

─ Dermal changes:

─ Superficial and often deep perivascular lymphocytic infiltrate, sometimes lichenoid

─ Lymphocytes often appear somewhat atypical (enlarged, hyperchromatic, irregular – "active" appearance) but not usually overtly malignant

─ Extravasation of red blood cells into papillary dermis is a characteristic feature

─ Endothelial swelling may be present

─ Dermal edema common in papillary dermis

DDx

─ Lymphomatoid papulosis (LyP) (clinically similar recurrent papulonodular lesions, but LyP has large atypical CD30+ lymphocytes, PLEVA is CD30-)

─ Viral exanthem (eg, varicella – different clinical, ballooning degeneration, multinucleated giant cells)

─ Arthropod bite reaction (often more eosinophils, less epidermal necrosis, clinical history)

─ Vasculitis (leukocytoclastic) (fibrinoid necrosis of vessel walls, more neutrophils, karyorrhexis)

─ Guttate psoriasis (if lesions are more papulosquamous, psoriasis shows Munro's, regular acanthosis)

─ Drug eruption (clinical history, may have eosinophils)

Prognosis ─ Benign, self-limited, but can be chronic or recurrent, may leave post-inflammatory pigmentary changes or small scars

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Mycosis Fungoides (MF) (Patch/Plaque Stage – Interface Pattern)

Most common form of cutaneous T-cell lymphoma (CTCL), typically indolent, chronic, progressing through patch, plaque, and tumor stages

Clinical

─ Patch stage: erythematous, often slightly scaly, thin patches, may be pruritic, often ill-defined, variable size/shape, common on non-sun-exposed areas (buttocks, trunk, thighs), can mimic eczema or psoriasis

─ Plaque stage: infiltrated, indurated, erythematous to violaceous plaques, often annular or arcuate, more pruritic

Micro (Patch/Early Plaque Stage – Interface Features):

─ Epidermal changes:

─ Often mild acanthosis, may have focal parakeratosis or spongiosis (can mimic eczema)

─ Epidermotropism: characteristic feature – atypical lymphocytes infiltrating epidermis, often singly or in small clusters along basal layer or scattered in spinous layer, without significant spongiosis ("too many lymphocytes for the degree of spongiosis")

─ Lymphocytes are often small to medium-sized, with hyperconvoluted (cerebriform) nuclei (Lutzner cells), though atypia can be subtle in early lesions

─ Pautrier's microabscesses: collections of atypical lymphocytes within epidermis (more specific but less common in early MF)

─ Dermal changes:

─ Superficial, band-like or patchy lymphocytic infiltrate in papillary dermis, often hugging the epidermis (interface pattern)

─ Lymphocytes may appear bland or show subtle atypia (cerebriform nuclei)

─ "Wiry" or "ropy" collagen: thickened, eosinophilic collagen bundles in papillary dermis often seen

─ Fibrosis of papillary dermis

─ Eosinophils and plasma cells usually sparse or absent in early MF (presence may suggest other conditions)

IHC

─ Atypical lymphocytes are mature T-helper cells: CD3+, CD4+, CD8-, CD45RO+

─ Loss of pan-T-cell antigens (eg, CD5, CD7) can be a clue to MF

─ TCR gene rearrangement studies can demonstrate clonality (supports MF but not diagnostic alone, can be seen in some benign lichenoid infiltrates)

DDx

─ Chronic spongiotic dermatitis (eg, eczema, contact dermatitis) (more prominent spongiosis, lymphocytes usually not atypical or as epidermotropic in a non-spongiotic way)

─ Psoriasis (neutrophils in stratum corneum/epidermis, regular acanthosis, dilated papillary dermal vessels, lacks atypical lymphocytes)

─ Lichen planus/Lichenoid drug eruption (more prominent basal vacuolar change, Civatte bodies, infiltrate usually not as atypical, drug eruption may have eosinophils)

─ Parapsoriasis (small plaque/large plaque) (histologic overlap, some consider large plaque parapsoriasis early MF or precursor)

─ Lymphomatoid drug eruption/contact dermatitis (may show atypical lymphocytes, history crucial)

Prognosis ─ Generally indolent in patch/plaque stage, slow progression over years or decades, risk of progression to tumor stage and systemic involvement is higher with more extensive skin involvement and thicker plaques

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Lymphomatoid Papulosis Type B (MF-like)

Part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders, histologically resembles mycosis fungoides

Clinical

─ Chronic, recurrent, self-healing papules and nodules, may ulcerate

─ Lesions typically last weeks to months, then regress spontaneously, often without scarring (unlike some other LyP types)

─ Trunk and extremities common sites

─ Histologic types A (histiocytic), B (MF-like), C (anaplastic large cell lymphoma-like), D (epidermotropic CD8+), E (angioinvasive), F (follicular) exist, Type B is less common

Micro (Type B)

─ Dense, band-like or patchy lymphocytic infiltrate in superficial dermis, often with epidermotropism

─ Lymphocytes are often small to medium-sized with cerebriform (convoluted) nuclei, mimicking Mycosis Fungoides (MF)

─ Unlike classic MF patch/plaque stage, LyP Type B may have fewer large atypical CD30+ cells, or they may be inconspicuous (CD30+ cells are hallmark of LyP Type A and C)

─ Epidermal changes can include acanthosis, parakeratosis, spongiosis, or interface changes

─ Eosinophils and plasma cells may be present but usually not prominent in Type B

─ Important to correlate with clinical picture of waxing/waning lesions

IHC

─ Lymphocytes are T-cells (CD3+)

─ In Type B, the epidermotropic cells are typically CD4+ T-cells, similar to MF

─ CD30 expression is variable in Type B, often sparse or negative in the MF-like cells (unlike Type A/C where large atypical cells are strongly CD30+)

─ Loss of pan-T-cell antigens (eg, CD7) can occur

DDx

─ Mycosis fungoides (MF) (clinical correlation essential, MF is persistent/progressive, LyP is recurrent/regressing, TCR clonality may be present in both)

─ PLEVA (more epidermal necrosis, RBC extravasation, less consistently atypical infiltrate)

─ Pityriasis lichenoides chronica (PLC) (less atypia, more parakeratosis, often milder epidermotropism)

─ Lichenoid drug eruption (may have eosinophils, history of drug, less consistent atypia)

─ Secondary syphilis (plasma cells, endothelial swelling, spirochetes)

Prognosis ─ Generally excellent, chronic relapsing course, small risk (10-20%) of associated lymphoma (MF, Hodgkin, ALCL) over many years, so long-term follow-up advised

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Pigmented Purpuric Eruption (Pigmented Purpuric Dermatosis, PPD, Capillaritis)

Group of chronic, benign skin conditions characterized by petechial and purpuric macules/patches, often with golden-brown pigmentation due to hemosiderin

Clinical

─ Several variants:

─ Schamberg's disease (progressive pigmentary dermatosis): most common, "cayenne pepper" spots, usually lower legs of adults, asymptomatic or mildly pruritic

─ Purpura annularis telangiectodes (Majocchi's disease): annular or polycyclic patches with telangiectasias and atrophy, often younger individuals

─ Lichen aureus (lichen purpuricus): solitary or few, persistent, golden-brown or rust-colored lichenoid papules/plaques, often on lower legs

─ Eczematid-like purpura of Doucas and Kapetanakis: scaly, eczematous component with purpura

─ Itching purpura of Lowenthal: more pruritic variant

─ Usually lower extremities, can be more widespread

Micro

─ Superficial perivascular lymphocytic infiltrate in papillary dermis, often "hugging" capillaries

─ Endothelial cell swelling of capillaries in papillary dermis

─ Characteristic extravasation of red blood cells into papillary dermis

─ Hemosiderin deposition (free and within macrophages/siderophages) in papillary dermis, responsible for clinical pigmentation

─ Epidermis usually normal or mildly acanthotic, may show focal spongiosis or parakeratosis in eczematid variants

─ No true vasculitis (no fibrinoid necrosis of vessel walls, no significant neutrophils/karyorrhexis)

DDx

─ Leukocytoclastic vasculitis (palpable purpura, fibrinoid necrosis of vessel walls, neutrophils, karyorrhexis)

─ Stasis dermatitis (more edema, venous changes, epidermal spongiosis/acanthosis, fibrosis in later stages)

─ Drug eruption (may be purpuric, history of drug, may have eosinophils)

─ Thrombocytopenic purpura (clinical/lab findings, histology may just show hemorrhage)

─ Mycosis fungoides (especially purpuric variants) (atypical lymphocytes, epidermotropism)

Prognosis ─ Benign, chronic, often persistent or recurrent, primarily a cosmetic concern

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Fixed Drug Eruption (FDE)

Adverse cutaneous reaction to a drug, characterized by recurrent lesions at the same site(s) upon re-exposure to the offending drug

Clinical

─ One or few, sharply demarcated, round or oval, erythematous or dusky-violaceous plaques

─ May become edematous, bullous, or eroded

─ Common sites: lips, genitalia, extremities, trunk

─ Lesions recur in exactly the same location(s) with each drug exposure, often with increasing intensity

─ Pruritus or burning common

─ Heals with prominent post-inflammatory hyperpigmentation

─ Common offending drugs: NSAIDs, sulfonamides, tetracyclines, barbiturates, carbamazepine

Micro

─ Interface dermatitis with vacuolar alteration of basal cell layer

─ Numerous necrotic (apoptotic) keratinocytes, often scattered throughout all levels of epidermis, or confluent full-thickness epidermal necrosis in bullous lesions

─ Superficial and often deep perivascular and interstitial mixed inflammatory infiltrate

─ Lymphocytes are prominent, eosinophils and neutrophils may be present, especially in bullous or older lesions

─ Dermal edema, especially papillary dermis

─ Subepidermal blister formation can occur due to severe basal cell damage

─ Prominent melanin incontinence (melanophages in dermis) in healing or resolved lesions (corresponds to clinical hyperpigmentation)

DDx

─ Erythema multiforme (often targetoid lesions clinically, more widespread, histologically similar interface changes but inflammation often less dense/deep, triggers often HSV or Mycoplasma)

─ Lichenoid drug eruption (more band-like infiltrate, often more acanthosis/hypergranulosis, less prominent individual cell necrosis usually)

─ Bullous pemphigoid (if bullous FDE – DIF shows linear IgG/C3 at BMZ in BP, usually negative or non-specific in FDE)

─ Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) (more widespread, severe mucosal involvement, extensive full-thickness epidermal necrosis, often sparser dermal infiltrate than typical FDE)

─ Lupus erythematosus (different clinical, other LE features, DIF findings)

Prognosis ─ Benign upon drug withdrawal, lesions resolve but hyperpigmentation can persist for months/years

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Erythema Multiforme (EM)

Acute, self-limited, often recurrent hypersensitivity reaction commonly triggered by infections (especially Herpes simplex virus, Mycoplasma pneumoniae) or drugs

Clinical

─ Abrupt onset of symmetrical eruption

─ Characteristic target lesions (iris lesions): dusky central area or blister, surrounded by pale edematous ring, and an erythematous peripheral ring

─ Papules, macules, plaques, vesicles, bullae may also occur

─ Common on extensor extremities (especially hands/feet), palms/soles, face, neck, less often trunk

─ Mucosal involvement (oral, genital, ocular) common in EM major (can overlap with SJS)

─ EM minor: typical targets, minimal or no mucosal involvement

─ EM major: typical targets, prominent mucosal involvement, systemic symptoms (fever, malaise)

Micro

─ Interface dermatitis with vacuolar alteration of basal cell layer

─ Scattered necrotic (apoptotic) keratinocytes at all levels of epidermis, often more prominent in basal/suprabasal layers ("satellite cell necrosis" – lymphocytes adjacent to necrotic keratinocytes)

─ Superficial perivascular lymphocytic infiltrate, often with some lymphocytes migrating into epidermis

─ Papillary dermal edema is often prominent, can lead to subepidermal blister formation

─ Intraepidermal vesiculation can occur due to extensive keratinocyte necrosis

─ Eosinophils usually sparse or absent (presence suggests drug-induced EM or other diagnoses)

─ Full-thickness epidermal necrosis with subepidermal split in severe/bullous lesions (can overlap with SJS)

DDx

─ Fixed drug eruption (recurs at same site, often more pigment incontinence, may have more eosinophils/neutrophils)

─ Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) (more widespread, severe mucosal involvement, extensive full-thickness epidermal necrosis, often sparser dermal infiltrate)

─ Bullous pemphigoid (urticarial plaques with tense bullae, DIF shows linear IgG/C3 at BMZ)

─ Viral exanthem (morbilliform, lacks true target lesions, less interface change/necrosis)

─ Urticaria (transient wheals, dermal edema without significant interface change or necrosis)

─ Sweet's syndrome (neutrophilic infiltrate, dermal edema, no significant interface change/necrosis)

Prognosis ─ EM minor usually self-limited in 2-4 weeks, recurrences common (especially HSV-associated), EM major more severe, may require supportive care, resolves in weeks

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SJS/TEN (Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis)

Severe, life-threatening mucocutaneous reactions, usually drug-induced, characterized by widespread blistering and epidermal detachment

Clinical

─ Spectrum of severity: SJS <10% body surface area (BSA) detachment, SJS/TEN overlap 10-30% BSA, TEN >30% BSA

─ Acute onset of fever, malaise, followed by painful, dusky red or purpuric macules, rapidly progressing to flaccid blisters and extensive epidermal detachment (Nikolsky sign +)

─ Severe mucosal involvement (oral, ocular, genital) is characteristic and often precedes skin lesions

─ Common offending drugs: allopurinol, sulfonamides, anticonvulsants (carbamazepine, lamotrigine, phenytoin, phenobarbital), NSAIDs (oxicam type), nevirapine

─ Infections (Mycoplasma pneumoniae, CMV) less common triggers

Micro

─ Full-thickness or near full-thickness epidermal necrosis with subepidermal blister formation

─ Epidermal roof of blister is necrotic

─ Basal cell layer shows extensive vacuolar alteration and necrosis

─ Dermal inflammatory infiltrate is often surprisingly sparse, composed mainly of lymphocytes, may have few eosinophils or neutrophils

─ Minimal dermal edema compared to EM in some cases

─ Apoptotic keratinocytes prominent throughout epidermis

DDx

─ Erythema multiforme major (can overlap, EM usually has more typical target lesions, often less extensive/confluent necrosis, more prominent dermal inflammation/edema)

─ Staphylococcal scalded skin syndrome (SSSS) (superficial intraepidermal (subcorneal/granular layer) split, no full-thickness necrosis, usually infants/young children, Nikolsky sign +)

─ Fixed drug eruption (bullous variant) (lesions recur at same sites, often more pigment incontinence and eosinophils, less widespread)

─ Graft-versus-host disease (acute) (clinical history of transplant, can be histologically very similar)

─ Pemphigus/Pemphigoid (DIF usually diagnostic, different blister level/inflammatory pattern typically)

Prognosis ─ High mortality (10-30% or higher for TEN) due to sepsis, fluid/electrolyte imbalance, organ failure, requires intensive supportive care, often in burn unit

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Subacute Lupus Erythematosus (Subacute Cutaneous Lupus Erythematosus, SCLE)

Photosensitive, non-scarring form of cutaneous lupus, often associated with anti-Ro/SSA antibodies

Clinical

─ Annular or polycyclic erythematous plaques with central clearing, or papulosquamous (psoriasiform) plaques

─ Predominantly on sun-exposed areas (upper trunk, shoulders, extensor arms, neck, face – often spares central face)

─ Non-scarring, non-atrophic (unlike DLE)

─ May be drug-induced (eg, HCTZ, terbinafine, PPIs, TNF-alpha inhibitors)

─ High association with anti-Ro/SSA antibodies, often anti-La/SSB also

─ Patients may meet criteria for systemic lupus erythematosus (SLE), but often milder systemic disease

Micro

─ Interface dermatitis with vacuolar alteration of basal cell layer

─ Superficial, and sometimes deeper, perivascular and often periadnexal lymphocytic infiltrate

─ Epidermis may be normal, slightly atrophic, or slightly acanthotic, often with focal hyperkeratosis or parakeratosis

─ Scattered necrotic (apoptotic) keratinocytes (Civatte bodies) in basal layer and lower epidermis

─ Papillary dermal edema common

─ Melanin incontinence variable

─ Follicular plugging and significant basement membrane thickening are less prominent than in DLE

─ Direct immunofluorescence (DIF) of lesional skin: granular deposits of IgG, IgM, C3 along DE junction (lupus band test), often positive

DDx

─ Discoid lupus erythematosus (DLE) (more follicular plugging, epidermal atrophy, thickened basement membrane, scarring alopecia, often more intense/deeper infiltrate)

─ Dermatomyositis (similar interface changes, but clinically different rash – heliotrope, Gottron's papules, often more dermal mucin)

─ Lichen planus (more sawtooth rete, wedge-shaped hypergranulosis, denser band-like infiltrate, less periadnexal inflammation)

─ Psoriasis (if papulosquamous SCLE – psoriasis has neutrophils in stratum corneum/epidermis, regular acanthosis, lacks significant interface change)

─ Erythema annulare centrifugum (superficial and deep perivascular lymphocytic infiltrate, "coat-sleeve" pattern, lacks interface changes of SCLE)

Prognosis ─ Generally good, skin lesions often respond to sun protection and topical/systemic therapies, risk of developing SLE varies

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Dermatomyositis

Idiopathic inflammatory myopathy with characteristic cutaneous manifestations, may be associated with internal malignancy in adults

Clinical

─ Skin findings can precede, accompany, or follow muscle weakness

─ Pathognomonic skin signs:

─ Heliotrope rash: violaceous erythema and edema of eyelids

─ Gottron's papules: violaceous, flat-topped papules over knuckles and other extensor joint surfaces (elbows, knees)

─ Other characteristic findings: photosensitive poikilodermatous eruption (V-neck, shawl sign, holster sign), periungual telangiectasias, cuticular hypertrophy/hemorrhages, calcinosis cutis (especially juvenile DM)

─ Muscle weakness (proximal), myalgias, elevated muscle enzymes (CK, aldolase)

─ Increased risk of internal malignancy in adults (especially ovarian, lung, GI, breast, lymphoma)

─ Amyopathic dermatomyositis: characteristic skin findings without clinical muscle weakness for ≥6 months

Micro

─ Interface dermatitis with vacuolar alteration of basal cell layer, often subtle

─ Epidermis usually atrophic or thinned, may have slight hyperkeratosis

─ Scattered necrotic (apoptotic) keratinocytes in basal layer

─ Superficial perivascular lymphocytic infiltrate, usually sparse to moderate

─ Papillary dermal edema and increased dermal mucin (Alcian blue+) are often prominent features

─ Melanin incontinence may be present

─ Follicular plugging and significant basement membrane thickening less common/prominent than in DLE

─ DIF of lesional skin may show granular deposits (IgG, IgM, C3) at DE junction, but often less consistently than in LE

DDx

─ Lupus erythematosus (especially SCLE or acute LE) (histology can be very similar, LE often has more prominent epidermal atrophy/hyperkeratosis, follicular plugging, or deeper/denser infiltrate, DIF more consistently positive in LE, clinical correlation and serology crucial)

─ Polymorphous light eruption (more dermal edema, often denser perivascular infiltrate, lacks consistent interface changes/mucin of DM)

─ Lichen planus (sawtooth rete, wedge hypergranulosis, denser band-like infiltrate, lacks prominent mucin)

─ Viral exanthem (different clinical, often less interface change)

Prognosis ─ Varies, depends on muscle involvement severity and presence/type of associated malignancy in adults, juvenile DM often has better prognosis regarding malignancy but can have significant morbidity from calcinosis/contractures

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Graft Versus Host Disease (GVHD)

Complication of allogeneic hematopoietic stem cell transplantation (or rarely solid organ transplant/transfusion) where donor T-lymphocytes attack recipient tissues

Clinical

─ Acute GVHD (usually within first 100 days post-transplant):

─ Skin: maculopapular erythematous rash, often starting on palms/soles, ears, face, may become confluent, bullous, or lead to desquamation similar to TEN in severe cases

─ Liver (jaundice, elevated LFTs) and GI tract (diarrhea, abdominal pain) also commonly affected

─ Chronic GVHD (usually >100 days post-transplant, can arise de novo or follow acute GVHD):

─ Skin: protean manifestations, lichenoid (lichen planus-like), sclerodermoid (morphea-like or systemic sclerosis-like), poikilodermatous, eczematous, keratosis pilaris-like

─ Oral (lichenoid, xerostomia), ocular (sicca), liver, lung, joint involvement common

Micro (Acute Cutaneous GVHD):

─ Interface dermatitis with vacuolar alteration of basal cell layer

─ Lymphocytic exocytosis and satellitosis (lymphocytes apposed to necrotic keratinocytes)

─ Necrotic (apoptotic) keratinocytes are a hallmark, often numerous, scattered at all levels of epidermis, especially basal layer

─ Superficial perivascular lymphocytic infiltrate, usually mild to moderate, lymphocytes may appear somewhat "activated"

─ Epidermal changes can range from mild interface changes (Grade I) to subepidermal blister formation due to extensive basal cell necrosis (Grade IV, similar to TEN)

─ Dermal edema may be present

Micro (Chronic Cutaneous GVHD):

─ Lichenoid pattern: similar to lichen planus (hyperkeratosis, acanthosis, hypergranulosis, sawtooth rete, band-like lymphocytic infiltrate, basal vacuolar change, Civatte bodies)

─ Sclerodermoid pattern: dermal sclerosis with thickened, hyalinized collagen bundles, loss of adnexae, entrapped eccrine glands, overlying epidermal atrophy, sparse inflammation (similar to scleroderma/morphea)

─ Poikilodermatous pattern: epidermal atrophy, basal vacuolar change, melanin incontinence, telangiectasias, dermal fibrosis

DDx

─ Acute GVHD: Erythema multiforme/SJS/TEN (clinical history crucial, EM may have more dermal edema/less prominent satellitosis, SJS/TEN often sparser dermal infiltrate), Drug eruption (can be very similar, may have eosinophils), Viral exanthem

─ Chronic GVHD (Lichenoid): Lichen planus, Lichenoid drug eruption

─ Chronic GVHD (Sclerodermoid): Scleroderma/Morphea (clinical history)

Prognosis ─ Variable, depends on severity and organs involved, significant cause of morbidity/mortality post-transplant

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Discoid Lupus (Erythematosus) (DLE)

Most common form of chronic cutaneous lupus erythematosus, characterized by well-demarcated, scarring plaques, often in sun-exposed areas

Clinical

─ Well-demarcated, erythematous or violaceous, indurated plaques with adherent scale, follicular plugging ("carpet tack" sign), and atrophy

─ Lesions heal with scarring, alopecia (if scalp involved), and dyspigmentation (central hypopigmentation, peripheral hyperpigmentation)

─ Common on sun-exposed areas: face (malar, ears, scalp), V-area of neck, extensor arms

─ Hypertrophic DLE: thick, warty plaques, often on extensor arms or face

─ Small percentage (5-10%) of DLE patients may develop systemic lupus erythematosus (SLE)

Micro

─ Interface dermatitis with prominent vacuolar alteration of basal cell layer

─ Epidermal atrophy (thinning) or sometimes acanthosis (especially in hypertrophic DLE)

─ Hyperkeratosis, often with prominent follicular plugging (keratin-filled dilated follicular ostia)

─ Thickened, eosinophilic basement membrane (PAS+) is a characteristic feature

─ Superficial and deep, perivascular and periadnexal lymphocytic infiltrate, often dense

─ Lymphocytes may extend into overlying atrophic epidermis (epidermotropism)

─ Necrotic (apoptotic) keratinocytes (Civatte bodies) common in basal layer and lower epidermis

─ Dermal mucin deposition (Alcian blue+) often increased in reticular dermis

─ Melanin incontinence common

─ Direct immunofluorescence (DIF) of lesional skin: granular deposits of IgG, IgM, C3 along DE junction (lupus band test), usually positive

DDx

─ Lichen planus (sawtooth rete, wedge hypergranulosis, denser band-like infiltrate, less follicular plugging/BM thickening, less deep/periadnexal infiltrate)

─ Subacute cutaneous lupus erythematosus (SCLE) (less follicular plugging, atrophy, scarring, BM thickening, often more superficial infiltrate)

─ Dermatomyositis (can be histologically similar, but DLE has more prominent follicular plugging/BM thickening, DM often more mucin, different clinical presentation)

─ Lichenoid drug eruption (may have eosinophils, parakeratosis, history of drug)

─ Lymphocytic infiltrate of Jessner (no significant epidermal changes, lacks interface features/follicular plugging/BM thickening)

─ Polymorphous light eruption (more dermal edema, often denser perivascular infiltrate, lacks consistent interface changes/follicular plugging/BM thickening of DLE)

Prognosis ─ Chronic, scarring, disfiguring, small risk of SLE development, slightly increased risk of SCC in old DLE scars

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Lichen Striatus

Uncommon, self-limited, linear inflammatory dermatosis, usually in children, following Lines of Blaschko

Clinical

─ Abrupt onset of small, flat-topped, skin-colored, pink, or slightly hypopigmented papules

─ Papules coalesce to form a linear band, typically 1-2 cm wide, extending along an extremity or trunk, following Lines of Blaschko

─ Usually unilateral, common in children (peak age 5-15 years), can occur in adults

─ Asymptomatic or mildly pruritic

─ Spontaneous resolution usually within 3-12 months, may leave transient hypopigmentation or hyperpigmentation

Micro

─ Interface dermatitis, often lichenoid or sometimes more spongiotic or psoriasiform

─ Band-like or patchy lymphocytic infiltrate in superficial dermis, often hugging epidermis

─ Vacuolar alteration of basal layer, necrotic (apoptotic) keratinocytes (Civatte bodies)

─ Epidermis may show acanthosis, hyperkeratosis, parakeratosis, and sometimes spongiosis

─ Lymphocytic infiltrate may extend around adnexal structures (especially eccrine ducts and hair follicles – "periadnexitis")

─ Eosinophils are generally absent

─ Melanin incontinence may be present

DDx

─ Linear lichen planus (clinically similar, LP histology usually more classic sawtooth rete, wedge hypergranulosis, denser band-like infiltrate)

─ Inflammatory linear verrucous epidermal nevus (ILVEN) (present at birth or early infancy, more persistent, often more psoriasiform/eczematous histology with alternating ortho/parakeratosis)

─ Linear psoriasis (psoriatic features – Munro's, regular acanthosis, dilated papillary dermal vessels)

─ Blaschkitis (adult counterpart, often more eczematous/spongiotic)

─ Incontinentia pigmenti (linear lesions in stages, different histology depending on stage)

Prognosis ─ Benign, self-limited

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Pernio (Chilblains)

Localized inflammatory vascular reaction to cold, damp, non-freezing conditions

Clinical

─ Erythematous to violaceous, edematous, often pruritic or painful papules, plaques, or nodules

─ Occur on acral sites (fingers, toes, heels, nose, ears) after exposure to cold, damp conditions

─ May blister or ulcerate in severe cases

─ More common in women, young adults, individuals with peripheral vascular disease or connective tissue disease (eg, lupus pernio in sarcoidosis, or chilblain lupus)

Micro

─ Superficial and deep, dense perivascular lymphocytic infiltrate

─ Marked papillary dermal edema is characteristic, can lead to subepidermal blister formation

─ Endothelial cell swelling in small vessels, vessel walls may appear thickened or hyalinized

─ Lymphocytes may extend into lower epidermis causing vacuolar interface change and necrotic keratinocytes

─ Extravasated red blood cells common

─ No true fibrinoid necrosis of vessel walls (distinguishes from leukocytoclastic vasculitis)

─ Dermal perieccrine lymphocytic inflammation can be prominent

DDx

─ Lupus erythematosus (especially chilblain lupus – DIF positive for lupus band, other LE features, serology)

─ Leukocytoclastic vasculitis (palpable purpura, fibrinoid necrosis of vessel walls, neutrophils, karyorrhexis)

─ Erythema multiforme (target lesions, different epidermal changes)

─ Cold panniculitis (involves subcutis primarily, fat necrosis)

─ Raynaud's phenomenon (vasospastic, often lacks significant inflammation unless secondary changes)

─ Acrocyanosis (persistent cyanosis, less inflammation)

Prognosis ─ Benign, lesions usually resolve in 1-3 weeks with warming, recurrences common with re-exposure to cold

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Tumid Lupus (Erythematosus)

Uncommon variant of cutaneous lupus erythematosus, characterized by succulent, erythematous, non-scarring plaques, minimal epidermal change

Clinical

─ Indurated, erythematous or violaceous, edematous, "juicy" plaques or nodules, often annular or arcuate

─ Typically on face, neck, upper trunk (sun-exposed areas)

─ Surface is smooth, lacks scale, follicular plugging, or atrophy (key distinction from DLE)

─ Non-scarring

─ Photosensitive

─ Usually not associated with systemic lupus erythematosus (SLE) or specific autoantibodies (ANA often negative or low titer)

Micro

─ Epidermis is typically normal or shows only minimal, focal interface changes (eg, slight basal vacuolization), no significant atrophy, hyperkeratosis, or follicular plugging (hallmark of tumid LE)

─ Characteristic feature: Abundant interstitial mucin deposition (Alcian blue+, colloidal iron+) throughout reticular dermis, separating collagen bundles

─ Dense, superficial and deep, perivascular and often periadnexal lymphocytic infiltrate

─ Lymphocytes may be arranged in nodular aggregates

─ Plasma cells may be present but usually not prominent

─ No significant vasculitis

─ DIF of lesional skin may be negative or show sparse granular deposits at DE junction

DDx

─ Jessner's lymphocytic infiltrate (histologically very similar or identical, some consider them part of same spectrum, Jessner's lacks mucin or has less, no photosensitivity, no association with LE)

─ Polymorphous light eruption (papular/plaque type) (more prominent papillary dermal edema, often denser perivascular infiltrate, lacks abundant mucin of tumid LE)

─ Reticular erythematous mucinosis (REM) (net-like erythematous eruption on chest/back, histologically similar with mucin and perivascular lymphocytes)

─ Pseudolymphoma (B-cell lymphoid hyperplasia) (denser, more nodular infiltrate, may have germinal centers, lacks prominent mucin)

─ Urticaria (transient wheals, more edema, less dense/deep infiltrate, no mucin)

─ Scleromyxedema (if mucin prominent, but scleromyxedema has fibroblast proliferation, fibrosis, paraproteinemia)

Prognosis ─ Benign, chronic, recurrent, skin lesions often respond well to antimalarials or topical/intralesional steroids, low risk of progression to SLE

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Polymorphous Light Eruption (PMLE)

Common, acquired, idiopathic photodermatosis, characterized by recurrent, delayed, abnormal reactions to sunlight

Clinical

─ Pruritic, erythematous papules, vesicles, plaques, or eczematous lesions on sun-exposed skin (face, neck, V-area of chest, extensor arms, dorsal hands)

─ Typically occurs hours to days after sun exposure, especially first significant exposures of spring/early summer ("hardening" phenomenon – tolerance increases with repeated exposure)

─ Lesions are non-scarring, resolve in days to weeks if further sun exposure avoided

─ More common in young adult women, fair-skinned individuals, temperate climates

Micro

─ Superficial and often deep, dense, perivascular lymphocytic infiltrate

─ Marked papillary dermal edema is a prominent and characteristic feature, may lead to subepidermal vesiculation in papulovesicular variants

─ Endothelial cell swelling may be present

─ Epidermis often shows spongiosis, acanthosis, and parakeratosis, especially in papular/eczematous types

─ Interface changes (vacuolar alteration, necrotic keratinocytes) can be present but usually less intense than in LE or EM

─ Eosinophils are usually absent or sparse

DDx

─ Lupus erythematosus (especially SCLE or tumid LE) (LE often has more prominent interface changes, follicular plugging, dermal mucin, positive DIF for lupus band, serology)

─ Jessner's lymphocytic infiltrate (lacks significant epidermal changes and prominent papillary dermal edema of PMLE, often no photosensitivity)

─ Solar urticaria (wheals appear within minutes of sun exposure, transient, different histology – dermal edema with sparse perivascular infiltrate)

─ Drug-induced photosensitivity (phototoxic/photoallergic) (clinical history of drug, may have more eosinophils or different inflammatory pattern)

─ Erythema multiforme (target lesions, more prominent keratinocyte necrosis)

─ Contact dermatitis (if eczematous PMLE, history and distribution may differ)

Prognosis ─ Benign, recurrent with sun exposure, tends to improve with age or continued sun exposure during summer

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Erythema Annulare Centrifugum (EAC)

Reactive erythema characterized by annular or polycyclic, slowly enlarging erythematous lesions with trailing scale

Clinical

─ Annular, arcuate, or polycyclic, erythematous, slightly raised plaques

─ Lesions enlarge peripherally with central clearing, often with a characteristic delicate scale trailing just inside the advancing border ("trailing scale")

─ Common on trunk, buttocks, thighs, usually asymptomatic or mildly pruritic

─ May be associated with underlying infections (fungal, bacterial, viral), drugs, neoplasms, or idiopathic

─ Two main types: superficial (more scaling, common) and deep (more indurated, less scale, rare)

Micro

─ Superficial EAC:

─ Superficial perivascular lymphocytic infiltrate, often in a "coat-sleeve" or "cuffed" arrangement around vessels in papillary and upper reticular dermis

─ Epidermis may show mild acanthosis, focal parakeratosis (corresponding to trailing scale), and slight spongiosis

─ Papillary dermal edema may be present

─ No significant interface change, vasculitis, or deep dermal involvement

─ Deep EAC:

─ Denser, superficial and deep perivascular lymphocytic infiltrate, often extending into mid-reticular dermis

─ Epidermal changes usually minimal or absent

─ "Coat-sleeve" perivascular infiltrate may be more prominent

DDx

─ Tinea corporis (fungal elements demonstrable with PAS/GMS, often more epidermal change/vesiculation)

─ Urticaria (annular variant) (transient wheals, more dermal edema, sparser infiltrate, no scale)

─ Granuloma annulare (annular plaques, but dermal palisading granulomas with mucin, no significant epidermal change/scale)

─ Psoriasis (annular variants) (more silvery scale, Munro's microabscesses, neutrophilic Psoriasiform hyperplasia)

─ Subacute cutaneous lupus erythematosus (SCLE) (annular lesions, but photosensitive, interface dermatitis, positive DIF/serology)

─ Mycosis fungoides (annular plaque stage) (atypical lymphocytes, epidermotropism)

─ Pityriasis rosea (herald patch, "Christmas tree" distribution, different scale pattern)

Prognosis ─ Benign, often chronic or recurrent, may resolve if underlying cause identified and treated

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Arthropod Bite Reaction (Insect Bite Reaction)

Localized inflammatory skin reaction to salivary proteins or venom injected by arthropods (insects, arachnids, etc)

Clinical

─ Pruritic, erythematous papules, wheals, vesicles, bullae, or nodules at site(s) of bite(s)

─ May have central punctum

─ Common sites: exposed areas, but can be anywhere

─ Reaction severity varies (imMedia ─ placeholder te wheal-and-flare, delayed papular reaction, persistent nodular reaction)

─ Papular urticaria: recurrent crops of pruritic papules in children, often hypersensitivity to flea/mosquito bites

Micro

─ Superficial and deep, often wedge-shaped (pointing towards bite site), mixed inflammatory cell infiltrate in dermis

─ Lymphocytes and histiocytes are usually prominent

─ Eosinophils are characteristic and often numerous, both perivascularly and interstitially, sometimes forming "flame figures" (eosinophilic debris on collagen)

─ Neutrophils may be present, especially if excoriated or secondarily infected, or with certain arthropods (eg, fire ants)

─ Epidermal changes: spongiosis, acanthosis, parakeratosis, intraepidermal vesiculation (if bullous), ulceration (if excoriated or necrotic bite)

─ Endothelial cell swelling, vascular ectasia, dermal edema common

─ Remnants of arthropod mouthparts rarely seen

─ Pseudolymphomatous reactions can occur with persistent bites (dense lymphoid infiltrates, sometimes with germinal center-like structures)

DDx

─ Urticaria (more transient, less dense/deep infiltrate, usually fewer eosinophils unless urticarial vasculitis)

─ Allergic contact dermatitis (more prominent spongiosis, less deep infiltrate, often lacks numerous eosinophils unless specific allergen)

─ Bullous pemphigoid (if bullous bite – DIF for BP usually positive, BP often has more eosinophils in blister cavity/DE junction)

─ Prurigo nodularis/Lichen simplex chronicus (if chronic/nodular bite – more epidermal hyperplasia, fibrosis, nerve hyperplasia)

─ Lymphoma/Pseudolymphoma (dense atypical lymphoid infiltrate, IHC/clonality studies may be needed for pseudolymphomatous bites)

─ Wells syndrome (eosinophilic cellulitis) (more diffuse dermal eosinophilic infiltrate, flame figures, lacks clinical bite history)

Prognosis ─ Benign, usually self-limited, but can be intensely pruritic, persistent nodular reactions ("bugomas") can occur

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Psoriasis & Spongiosis

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Psoriasis

Chronic, immune-Media ─ placeholder ted inflammatory disease characterized by well-demarcated, erythematous plaques with silvery scale

Clinical

─ Well-demarcated, erythematous plaques with thick, silvery-white scale

─ Common sites: elbows, knees, scalp, lumbosacral area, glans penis, nails (pitting, onycholysis, oil spots, subungual hyperkeratosis)

─ Auspitz sign: pinpoint bleeding when scale is removed

─ Koebner phenomenon: new lesions at sites of trauma

─ Variants:

─ Psoriasis vulgaris (plaque psoriasis): most common

─ Guttate psoriasis: small, drop-like papules/plaques, often after streptococcal infection

─ Pustular psoriasis (von Zumbusch, palmoplantar, acrodermatitis continua of Hallopeau): sterile pustules

─ Erythrodermic psoriasis: generalized erythema and scaling

─ Inverse psoriasis: involves intertriginous areas, less scale

─ Psoriatic arthritis affects up to 30% of patients

Micro (Classic Plaque Psoriasis):

─ Epidermal changes:

─ Confluent parakeratosis (retained nuclei in stratum corneum)

─ Hypogranulosis or absent granular layer beneath parakeratosis

─ Acanthosis with regular elongation of rete ridges, often club-shaped or "test tube" like, with thinning of suprapapillary epidermal plates

─ Munro's microabscesses: collections of neutrophils in stratum corneum (characteristic but not always present)

─ Spongiform pustules of Kogoj: collections of neutrophils within superficial spinous layer (characteristic of pustular psoriasis, can be seen in plaque psoriasis)

─ Mild spongiosis may be present, especially in early or guttate lesions

─ Dermal changes:

─ Dilated, tortuous capillaries within elongated dermal papillae, often extending close to epidermal surface

─ Superficial perivascular lymphocytic infiltrate, may have some neutrophils

─ Papillary dermal edema

DDx

─ Lichen simplex chronicus/Prurigo nodularis (more irregular acanthosis, hypergranulosis, lacks Munro's/Kogoj, less prominent vascular changes)

─ Seborrheic dermatitis (often more spongiosis, parakeratosis often around follicular ostia ("shoulder parakeratosis"), less regular acanthosis, fewer neutrophils in SC)

─ Pityriasis rubra pilaris (alternating ortho- and parakeratosis, follicular plugging, broader rete ridges, lacks Munro's)

─ Dermatophytosis (fungal elements in stratum corneum, neutrophils in SC can mimic Munro's, "sandwich sign")

─ Eczematous dermatitis (chronic) (more spongiosis, irregular acanthosis, lacks Munro's/Kogoj)

─ Secondary syphilis (papulosquamous) (plasma cells in infiltrate, endothelial swelling, spirochetes)

─ Reiter's disease (keratoderma blenorrhagicum) (histologically very similar or identical to pustular psoriasis)

─ Pityriasis rosea (more spongiosis, focal parakeratosis, different clinical)

Prognosis ─ Chronic, relapsing-remitting course, associated with psoriatic arthritis and metabolic syndrome

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Clear Cell Acanthoma (Pale Cell Acanthoma of Degos)

Uncommon benign epidermal neoplasm, likely reactive, sharply demarcated, often on lower legs (Reiteration from Set 4)

Clinical

─ Solitary, reddish-brown, moist or slightly crusted papule/plaque, "stuck-on" appearance

─ Usually lower legs of middle-aged or older adults

Micro

─ Sharply defined area of psoriasiform epidermal hyperplasia

─ Keratinocytes above basal layer distinctly pale or clear due to abundant glycogen (PAS+, diastase-sensitive)

─ Elongated, sometimes fused rete ridges, surface often parakeratotic, granular layer thinned/absent

─ Characteristic migration of neutrophils through pale epidermis, sometimes forming intraepidermal/subcorneal microabscesses

─ Dilated capillaries in dermal papillae, moderate dermal lymphohistiocytic infiltrate

DDx

─ Psoriasis (Munro's microabscesses, but lacks sharp demarcation and diffuse clear cell change)

─ Seborrheic keratosis (irritated/inflamed) (lacks diffuse clear cell change)

─ Eccrine poroma/Hidroacanthoma simplex (ductal differentiation)

─ Clear cell squamous cell carcinoma in situ (cytologic atypia)

─ Trichilemmoma (clear cells, peripheral palisading, thickened basement membrane)

Prognosis ─ Benign

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Inflamed Linear Verrucous Epidermal Nevus (ILVEN)

Variant of epidermal nevus, characterized by persistent linear, erythematous, pruritic, verrucous plaques, often with psoriasiform or eczematous features

Clinical

─ Linear, erythematous, often intensely pruritic, verrucous or psoriasiform plaques

─ Usually present at birth or appears in early childhood, follows Lines of Blaschko

─ Often on lower extremities, can be resistant to treatment

Micro

─ Alternating bands of orthokeratosis and parakeratosis in stratum corneum

─ Epidermis shows alternating areas of acanthosis with hypergranulosis (under orthokeratosis) and acanthosis with hypogranulosis/spongiosis (under parakeratosis) - this alternating pattern is characteristic

─ Psoriasiform hyperplasia of rete ridges

─ Superficial perivascular lymphocytic infiltrate in dermis, may have some spongiosis

─ Dermal papillae may be edematous with dilated capillaries

DDx

─ Linear psoriasis (histologically can be very similar, psoriasis often lacks consistent alternating ortho/parakeratosis pattern of ILVEN, clinical correlation important)

─ Lichen striatus (more prominent lichenoid interface component, often periadnexal inflammation, self-limited)

─ Epidermal nevus (non-inflamed) (lacks significant inflammation and alternating parakeratosis)

─ Chronic eczematous dermatitis (linearized) (more prominent spongiosis throughout, less regular acanthosis)

Prognosis ─ Benign, but chronic, persistent, and often very pruritic

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Lichen Simplex Chronicus (LSC) / Prurigo Nodule

Localized, thickened skin (LSC) or discrete, intensely pruritic nodules (Prurigo Nodularis, PN) resulting from chronic rubbing, scratching, or picking

Clinical

─ LSC: Well-demarcated, lichenified (thickened skin with accentuated skin lines) plaque, often hyperpigmented, intensely pruritic, common on nape of neck, ankles, wrists, vulva, scrotum

─ PN: Firm, dome-shaped or warty papules/nodules, often excoriated, intensely pruritic, typically multiple on extensor extremities, trunk

Micro

─ Both show marked compact hyperkeratosis and irregular acanthosis

─ Rete ridges are elongated, broadened, sometimes irregular or pseudoepitheliomatous (especially PN)

─ Hypergranulosis

─ Papillary dermal fibrosis with vertically oriented collagen bundles is characteristic

─ Superficial perivascular chronic inflammatory infiltrate (lymphocytes, histiocytes, few eosinophils possible)

─ Nerve fiber hyperplasia in dermis may be seen, especially in PN

─ Prurigo Nodularis often shows more pronounced, dome-shaped epidermal hyperplasia and may have ulceration/crusting from excoriation

DDx

─ Psoriasis (more regular acanthosis, Munro's microabscesses, dilated/tortuous capillaries, less prominent fibrosis)

─ Hypertrophic lichen planus (more lichenoid inflammation, Civatte bodies, basal vacuolar change)

─ Verruca vulgaris (viral cytopathic changes, koilocytes, papillomatosis)

─ Keratoacanthoma/SCC (if pseudoepitheliomatous hyperplasia prominent – look for atypia in SCC/KA)

─ Arthropod bite reaction (persistent nodular) (often more eosinophils, history of bite)

Prognosis ─ Benign, persistent if rubbing/scratching continues, difficult to treat due to itch-scratch cycle

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Nutritional Deficiency (Cutaneous Manifestations)

Various skin changes can result from deficiencies of vitamins, minerals, or essential fatty acids, some mimicking psoriasiform or spongiotic dermatitis

Clinical

─ Highly variable depending on specific deficiency

─ Eg, Pellagra (niacin deficiency): photosensitive dermatitis ("Casal's necklace"), diarrhea, dementia

─ Eg, Acrodermatitis enteropathica (zinc deficiency): periorificial and acral erythematous, vesiculobullous, pustular, or psoriasiform plaques, alopecia, diarrhea

─ Eg, Scurvy (vitamin C deficiency): perifollicular hemorrhage, corkscrew hairs, gingival bleeding

─ Eg, Essential fatty acid deficiency: dry, scaly, eczematous dermatitis

Micro

─ Histologic patterns are often non-specific, can overlap with psoriasis or spongiotic dermatitis

─ Pellagra: may show epidermal pallor (especially upper layers), parakeratosis, acanthosis, variable dermal inflammation, can resemble necrolytic migratory erythema

─ Acrodermatitis enteropathica: confluent parakeratosis, psoriasiform epidermal hyperplasia, pallor of superficial keratinocytes, decreased or absent granular layer, superficial dermal inflammation

─ Scurvy: perifollicular hemorrhage, hyperkeratosis, follicular plugging

─ Essential fatty acid deficiency: acanthosis, parakeratosis, hyperkeratosis, dermal perivascular infiltrate

─ Diagnosis often relies on clinical suspicion, dietary history, and specific laboratory tests for the suspected deficiency

DDx

─ Psoriasis (specific features like Munro's, regular acanthosis)

─ Seborrheic dermatitis (shoulder parakeratosis, more spongiosis)

─ Atopic/Contact dermatitis (more prominent spongiosis, specific clinical context)

─ Necrolytic migratory erythema (glucagonoma syndrome) (histologically similar to pellagra/acrodermatitis enteropathica)

─ Drug eruptions

Prognosis ─ Depends on specific deficiency and ability to correct it, skin changes usually reversible with appropriate supplementation

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Pityriasis Rubra Pilaris (PRP)

Uncommon chronic papulosquamous disorder characterized by follicular keratotic papules, salmon-colored plaques, and palmoplantar keratoderma

Clinical

─ Reddish-orange or salmon-colored scaly plaques, often with characteristic "islands of sparing" (uninvolved skin within or at edge of plaques)

─ Follicular hyperkeratotic papules, especially on dorsal fingers ("nutmeg grater" feel)

─ Palmoplantar keratoderma: thick, yellowish, waxy hyperkeratosis of palms and soles, often with fissures

─ May progress to erythroderma

─ Six clinical types described (Griffiths classification), classical adult onset (Type I) is most common

─ Nail changes: thickening, discoloration, subungual hyperkeratosis

Micro

─ Alternating orthokeratosis and parakeratosis in both horizontal and vertical directions ("checkerboard" or "chessboard" pattern) is a helpful clue but not always present

─ Follicular plugging with perifollicular parakeratosis ("shoulder parakeratosis")

─ Irregular acanthosis, often with broad, club-shaped, or "stubby" rete ridges

─ Focal areas of hypogranulosis or absent granular layer under parakeratosis, hypergranulosis under orthokeratosis

─ Superficial perivascular lymphocytic infiltrate, may have few histiocytes

─ Dermal papillae often edematous with dilated capillaries

─ Acantholysis and significant spongiosis are usually absent or minimal (though some spongiosis can be seen)

DDx

─ Psoriasis (more regular acanthosis, Munro's microabscesses, spongiform pustules, more prominent neutrophilic component, less follicular plugging)

─ Chronic eczematous dermatitis/Lichen simplex chronicus (more spongiosis, irregular acanthosis, LSC has more vertical papillary dermal fibrosis)

─ Seborrheic dermatitis (shoulder parakeratosis can be similar, but often more spongiosis, less prominent palmoplantar/follicular features clinically)

─ Ichthyosiform dermatoses (different clinical onset/features, different keratinization patterns)

─ Mycosis fungoides (patch/plaque stage) (atypical lymphocytes, epidermotropism, Pautrier's)

Prognosis ─ Variable, classical adult type may resolve in years, other types can be more chronic and persistent

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Guttate Psoriasis

Acute eruption of small, drop-like, scaly papules, often triggered by streptococcal pharyngitis

Clinical

─ Sudden onset of multiple, small (2-10 mm), erythematous, scaly papules and plaques ("drop-like")

─ Primarily on trunk and proximal extremities

─ Often follows an acute streptococcal infection (eg, pharyngitis, perianal strep) by 1-3 weeks, especially in children and young adults

─ May be first presentation of psoriasis or occur in patients with chronic plaque psoriasis

Micro

─ Features are often less well-developed than classic plaque psoriasis, may show more overlap with spongiotic or pityriasiform patterns

─ Focal parakeratosis, often in mounds, sometimes with neutrophils (early Munro's microabscesses)

─ Hypogranulosis beneath parakeratosis

─ Mild to moderate acanthosis, rete ridges may be less elongated/clubbed than in chronic plaque psoriasis

─ Spongiosis can be present, sometimes prominent, especially in early lesions

─ Superficial perivascular lymphocytic infiltrate in dermis

─ Dilated and tortuous capillaries in dermal papillae, but may be less striking than in chronic plaque psoriasis

─ Neutrophils may be seen migrating into epidermis

DDx

─ Pityriasis rosea (herald patch, "Christmas tree" distribution, collarette of scale, often more spongiosis, fewer neutrophils)

─ Secondary syphilis (papulosquamous) (plasma cells in infiltrate, endothelial swelling, spirochetes)

─ Viral exanthem (morbilliform, less scale, different epidermal changes)

─ Pityriasis lichenoides chronica (PLC) (more vacuolar interface change, RBC extravasation)

─ Nummular eczema (more spongiosis, vesicles, crusting, fewer neutrophils in SC)

Prognosis ─ Often self-limited, resolving in weeks to months, but can persist or evolve into chronic plaque psoriasis in some individuals

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Pityriasis Rosea

Common, acute, self-limited exanthematous disease, often preceded by a "herald patch"

Clinical

─ Starts with a "herald patch" (single, larger, oval, erythematous, scaly plaque) in 50-90% of cases, usually on trunk

─ Followed 1-2 weeks later by a generalized eruption of smaller, oval, erythematous or tan, slightly raised, scaly papules and plaques

─ Lesions typically arranged along skin cleavage lines on trunk and proximal extremities in a "Christmas tree" or "fir tree" pattern

─ Collarette of scale (fine scale attached at periphery, free edge pointing inwards) is characteristic

─ Mild pruritus common, usually affects adolescents and young adults, more common in spring/fall

─ Possible association with reactivation of human herpesviruses 6 and 7 (HHV-6, HHV-7)

Micro

─ Superficial perivascular lymphocytic infiltrate, often with some histiocytes and occasionally few eosinophils

─ Papillary dermal edema

─ Epidermal changes:

─ Focal parakeratosis, often in mounds or forming a collarette at periphery of lesion

─ Mild to moderate acanthosis

─ Spongiosis, usually mild to moderate, can be focal

─ Exocytosis of lymphocytes into epidermis

─ Extravasation of red blood cells into papillary dermis and sometimes epidermis is a helpful feature but not always present

─ Dyskeratotic/necrotic keratinocytes are usually not prominent (unlike pityriasis lichenoides)

DDx

─ Guttate psoriasis (often more silvery scale, Munro's microabscesses, more regular acanthosis, history of strep infection)

─ Secondary syphilis (papulosquamous) (plasma cells in infiltrate, endothelial swelling, spirochetes, palmar/plantar involvement common)

─ Tinea corporis (annular lesions, leading scaly edge, fungal elements on PAS/GMS)

─ Nummular eczema (coin-shaped plaques, often more vesicular/crusted, more intense spongiosis)

─ Drug eruption (morbilliform or pityriasiform) (history of drug, may have more eosinophils)

─ Pityriasis versicolor (hypo- or hyperpigmented macules, fine scale, yeast/hyphae in SC)

Prognosis ─ Benign, self-limited, usually resolves spontaneously in 6-8 weeks without scarring, recurrences rare

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Spongiotic Dermatitis (Eczematous Dermatitis)

Histologic pattern characterized by intercellular edema in the epidermis (spongiosis), common to various forms of eczema/dermatitis

Clinical

─ Acute: Erythema, edema, vesicles, bullae, weeping, crusting, intense pruritus (eg, acute allergic contact dermatitis, dyshidrotic eczema)

─ Subacute: Erythema, scaling, papules, mild vesiculation, pruritus

─ Chronic: Lichenification (thickened skin, accentuated skin lines), scaling, fissuring, hyperpigmentation, pruritus (eg, atopic dermatitis, lichen simplex chronicus, chronic contact dermatitis)

─ Causes include atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, seborrheic dermatitis, nummular eczema, stasis dermatitis, asteatotic eczema, id reaction

Micro

─ Spongiosis: intercellular edema in epidermis, widening intercellular spaces, stretching of desmosomes (keratinocytes appear "spiky")

─ Acute: prominent spongiosis, formation of intraepidermal vesicles (spongiotic vesicles), exocytosis of lymphocytes (and sometimes eosinophils or neutrophils) into epidermis, papillary dermal edema, superficial perivascular mixed inflammatory infiltrate (lymphocytes, histiocytes, often eosinophils in allergic reactions)

─ Subacute: moderate spongiosis, acanthosis, parakeratosis, lymphocytic exocytosis, superficial perivascular infiltrate

─ Chronic: less spongiosis, marked acanthosis (often irregular), hyperkeratosis, parakeratosis, hypergranulosis, dermal fibrosis, persistent superficial perivascular chronic inflammation

─ Eosinophils suggest allergic contact dermatitis, atopic dermatitis, id reaction, or drug reaction

─ Neutrophils suggest dermatophytosis, impetigo, or pustular dermatoses if prominent

DDx

─ Psoriasiform dermatitides (eg, psoriasis – less spongiosis, more regular acanthosis, Munro's, Kogoj pustules)

─ Pityriasis rosea (often has focal spongiosis but also RBC extravasation, collarette of parakeratosis)

─ Viral exanthems (may have focal spongiosis, but often more interface change or specific viral cytopathic effects)

─ Early bullous pemphigoid (urticarial phase) (eosinophilic spongiosis, dermal eosinophils, DIF for BP)

─ Mycosis fungoides (patch stage) (can have spongiosis, but look for atypical lymphocytes, epidermotropism out of proportion to spongiosis)

─ Dermatophytosis (fungal elements in stratum corneum, neutrophils in SC)

Prognosis ─ Depends on underlying cause and ability to manage it

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Eosinophilic Spongiosis

Histologic pattern of spongiosis with prominent eosinophilic exocytosis, not a specific disease but a clue to certain conditions

Clinical

─ Variable, depends on underlying cause (eg, allergic contact dermatitis, atopic dermatitis, drug eruption, pemphigoid, incontinentia pigmenti, arthropod bite)

─ Often pruritic, erythematous, papulovesicular, or bullous lesions

Micro

─ Spongiosis (intercellular edema in epidermis)

─ Prominent exocytosis of eosinophils into the epidermis, often forming intraepidermal eosinophilic microvesicles or pustules

─ Dermal infiltrate usually contains lymphocytes, histiocytes, and prominent eosinophils, often perivascular

─ Papillary dermal edema may be present

DDx

─ Allergic contact dermatitis (often shows eosinophilic spongiosis)

─ Atopic dermatitis (can have eosinophilic spongiosis, especially in acute/subacute phases)

─ Pemphigoid gestationis (herpes gestationis) (eosinophilic spongiosis in pre-bullous phase, DIF for C3)

─ Bullous pemphigoid (urticarial or pre-bullous phase) (eosinophilic spongiosis, dermal eosinophils, DIF for IgG/C3)

─ Incontinentia pigmenti (vesicular stage) (linear vesicles in neonates, later stages different, X-linked dominant)

─ Arthropod bite reaction (can have marked eosinophilic spongiosis and dermal eosinophilia)

─ Drug eruption (allergic type)

─ Eosinophilic pustular folliculitis (Ofuji's disease) (eosinophilic spongiosis involving follicular epithelium)

Prognosis ─ Depends on underlying cause

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Dyshidrotic Eczema (Pompholyx, Acute Palmoplantar Eczema)

Recurrent vesicular eruption primarily affecting palms, soles, and lateral aspects of fingers/toes

Clinical

─ Sudden onset of intensely pruritic, deep-seated vesicles ("tapioca-like" appearance) on palms, soles, lateral fingers/toes

─ Vesicles may coalesce to form bullae

─ Later stages show scaling, fissuring, lichenification if chronic

─ Often associated with atopic dermatitis, contact dermatitis (nickel), id reaction (dermatophytid), hyperhidrosis, stress

Micro

─ Acute: Marked intraepidermal spongiosis leading to formation of large, multilocular spongiotic vesicles (often in stratum spinosum)

─ Lymphocytic exocytosis into epidermis and vesicles

─ Superficial perivascular lymphocytic infiltrate in dermis, may have eosinophils

─ Papillary dermal edema

─ Chronic: Acanthosis, hyperkeratosis, parakeratosis, less prominent spongiosis

DDx

─ Allergic contact dermatitis (can be identical, patch testing may help identify allergen)

─ Id reaction (dermatophytid) (fungal infection elsewhere, eg, tinea pedis)

─ Bullous tinea (fungal elements on PAS/GMS)

─ Pustular psoriasis of palms/soles (more neutrophilic, less spongiosis, other psoriasis features)

─ Herpetic infection (acral) (viral cytopathic changes, multinucleated giant cells)

Prognosis ─ Benign, but often recurrent and chronic, can be very symptomatic

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Tinea Pedis (Athlete's Foot)

Common superficial fungal infection of the feet, especially soles, interdigital spaces

Clinical

─ Variable:

─ Interdigital type: scaling, maceration, erythema, fissuring, often between 4th-5th toes

─ Moccasin type (chronic hyperkeratotic): diffuse, fine, silvery scaling with variable erythema, often involving entire sole and sides of foot

─ Vesiculobullous type (inflammatory): pruritic vesicles or bullae, often on instep or digits

─ Pruritus common, can have secondary bacterial infection

Micro

─ Fungal hyphae (septate, branching) and sometimes arthrospores within stratum corneum

─ Best visualized with PAS or GMS stain, hyphae often run parallel to skin surface

─ Epidermal changes variable depending on clinical type and host reaction:

─ Minimal change or compact orthokeratosis/hyperkeratosis

─ Spongiosis, acanthosis, parakeratosis (eczematous pattern)

─ Psoriasiform hyperplasia

─ Intraepidermal or subcorneal pustules (with neutrophils) if inflammatory/vesiculobullous

─ Dermal inflammatory infiltrate usually superficial perivascular, mixed (lymphocytes, histiocytes, neutrophils, eosinophils), intensity varies

─ "Sandwich sign": fungal elements between layers of orthokeratosis and parakeratosis, or within compact orthokeratosis

DDx

─ Contact dermatitis (allergic or irritant) (no fungi, may have more eosinophils if allergic)

─ Dyshidrotic eczema (if vesiculobullous tinea, no fungi)

─ Psoriasis (palmoplantar) (more regular acanthosis, Munro's, Kogoj, no fungi)

─ Pitted keratolysis (bacterial infection, crateriform pits in stratum corneum)

─ Juvenile plantar dermatosis (chronic eczematous changes, often atopic background)

Prognosis ─ Benign, but often chronic or recurrent if not adequately treated

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Seborrheic Dermatitis

Common chronic inflammatory dermatosis affecting areas rich in sebaceous glands (scalp, face, chest, intertriginous areas)

Clinical

─ Greasy, yellowish or erythematous, scaling patches and plaques

─ Scalp: dandruff (mildest form), or more inflamed, crusted plaques

─ Face: eyebrows, glabella, nasolabial folds, retroauricular areas

─ Chest: presternal or interscapular "petaloid" or annular lesions

─ Intertriginous areas: axillae, groin, inframammary, often more erythematous and moist

─ Pruritus variable

─ Associated with Malassezia yeast, more common/severe in HIV/AIDS, Parkinson's disease

Micro

─ Histologic pattern often overlaps with psoriasis ("sebopsoriasis") or spongiotic dermatitis

─ Acanthosis, often with some irregularity of rete ridges

─ Spongiosis, usually mild to moderate, can be focal

─ Parakeratosis, characteristically around follicular ostia ("shoulder parakeratosis" or "sputtering parakeratosis") and sometimes containing neutrophils (early Munro-like microabscesses)

─ Superficial perivascular lymphocytic infiltrate in dermis, may have few neutrophils

─ Dilated capillaries in dermal papillae

─ Yeast forms of Malassezia may be seen in stratum corneum or follicular ostia, especially with PAS stain, but not always numerous or specific

DDx

─ Psoriasis (more regular acanthosis, clubbed rete, Munro's/Kogoj more prominent, less spongiosis typically)

─ Atopic/Contact dermatitis (often more prominent spongiosis, may have more eosinophils)

─ Tinea capitis/faciei (fungal hyphae on PAS/GMS)

─ Langerhans cell histiocytosis (infants, crusted scalp/intertriginous lesions, atypical Langerhans cells on IHC)

─ Pityriasis rosea (different distribution, collarette of scale, often more RBC extravasation)

─ Lupus erythematosus (DLE/SCLE) (interface changes, follicular plugging, deeper infiltrate, DIF+)

Prognosis ─ Benign, chronic, relapsing course

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IgA Pemphigus

Rare autoimmune blistering disease characterized by intraepidermal IgA deposits and neutrophilic infiltrates

Clinical

─ Two main types:

─ Subcorneal pustular dermatosis (SCPD) type: annular or circinate plaques with superficial pustules, often on trunk and intertriginous areas, resembles Sneddon-Wilkinson disease

─ Intraepidermal neutrophilic (IEN) type: flaccid vesicles or pustules, often on erythematous base, may be more widespread

─ Pruritus common, chronic relapsing course

─ May be associated with monoclonal IgA gammopathy, myeloma, inflammatory bowel disease

Micro

─ Intraepidermal blister, often subcorneal or within upper spinous layer

─ Acantholysis may be present but often less prominent than in classic pemphigus

─ Characteristic dense neutrophilic infiltrate within epidermis and blister cavity, forming pustules

─ Eosinophils may also be present

─ Superficial dermal perivascular infiltrate of neutrophils, lymphocytes, and sometimes eosinophils

─ Direct immunofluorescence (DIF) shows intercellular IgA deposits in epidermis (often upper layers in SCPD type, throughout in IEN type)

DDx

─ Pemphigus foliaceus (subcorneal acantholysis, DIF shows IgG)

─ Sneddon-Wilkinson disease (subcorneal pustular dermatosis) (histologically identical to SCPD type of IgA pemphigus, DIF for IgA negative or weak)

─ Acute generalized exanthematous pustulosis (AGEP) (drug-induced, more spongiosis, eosinophils, edema, different DIF)

─ Pustular psoriasis (spongiform pustules of Kogoj, psoriasiform hyperplasia, Munro's microabscesses)

─ Dermatitis herpetiformis (subepidermal blisters with neutrophils in dermal papillae, granular IgA at DE junction on DIF)

Prognosis ─ Chronic, relapsing, generally benign but can be resistant to treatment

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Stasis Dermatitis

Common eczematous dermatitis of lower legs due to chronic venous insufficiency

Clinical

─ Erythema, scaling, pruritus, edema, and often brownish discoloration (hemosiderin deposition) on lower legs, especially Media ─ placeholder l ankle

─ May have weeping, crusting in acute phases, lichenification in chronic phases

─ Associated with varicose veins, venous incompetence, history of DVT

─ Complications: ulceration (stasis ulcers), lipodermatosclerosis, atrophie blanche, secondary infection, allergic contact dermatitis (to topical agents)

Micro

─ Epidermal changes:

─ Spongiosis (acute/subacute), acanthosis (chronic), hyperkeratosis, parakeratosis

─ Dermal changes:

─ Papillary dermal edema

─ Proliferation of small blood vessels (capillaries, venules) in superficial dermis, often thickened, hyalinized walls, and prominent endothelial cells

─ Extravasation of red blood cells and hemosiderin deposition (within macrophages/siderophages and free) are characteristic

─ Superficial perivascular lymphocytic infiltrate, may have plasma cells or eosinophils

─ Dermal fibrosis and sclerosis in long-standing lesions (lipodermatosclerosis)

─ Lobular panniculitis may be present in lipodermatosclerosis

DDx

─ Allergic contact dermatitis (may have more eosinophils, different distribution unless superimposed on stasis)

─ Nummular eczema (coin-shaped plaques, often less prominent vascular changes/hemosiderin unless stasis underlying)

─ Asteatotic eczema (dry, cracked skin, often elderly, less edema/hemosiderin)

─ Cellulitis/Erysipelas (more acute inflammation, neutrophils, systemic symptoms)

─ Pigmented purpuric dermatoses (capillaritis) (less epidermal change, primary capillaritis features)

─ Vasculitis (palpable purpura, fibrinoid necrosis of vessels, more neutrophils)

Prognosis ─ Chronic, depends on management of underlying venous insufficiency

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Granular Parakeratosis

Uncommon condition characterized by retention of keratohyalin granules within a parakeratotic stratum corneum, typically in intertriginous areas

Clinical

─ Erythematous or brownish, hyperkeratotic, sometimes macerated or verrucous papules and plaques

─ Most commonly in axillae, also inguinal folds, inframammary areas, umbilicus

─ May be pruritic or asymptomatic

─ Has been associated with use of certain deodorants/antiperspirants or excessive washing, but etiology unclear, likely a disorder of keratinization

Micro

─ Compact parakeratosis (retained nuclei in stratum corneum)

─ Characteristic feature: Retention of basophilic keratohyalin granules within the parakeratotic stratum corneum (normally granules are lost as keratinocytes cornify)

─ Epidermis may be acanthotic, papillomatous, or normal thickness

─ Spongiosis usually absent or minimal

─ Superficial perivascular lymphocytic infiltrate in dermis, usually mild

─ Fungal stains are negative (distinguishes from tinea with parakeratosis)

DDx

─ Hailey-Hailey disease (acantholysis, dilapidated brick wall appearance, different clinical)

─ Darier's disease (acantholytic dyskeratosis, corps ronds, grains, different clinical)

─ Pemphigus vegetans (intraepidermal eosinophilic/neutrophilic abscesses, acantholysis)

─ Confluent and reticulated papillomatosis (CARP) (papillomatosis, acanthosis, hyperkeratosis, often yeast forms visible, different clinical)

─ Acanthosis nigricans (papillomatosis, hyperkeratosis, dermal undulations, less parakeratosis, no retained granules in SC)

─ Tinea cruris/axillaris (fungal hyphae in SC)

Prognosis ─ Benign, may be persistent or recurrent

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Sweet’s Syndrome (Acute Febrile Neutrophilic Dermatosis)

Reactive dermatosis characterized by abrupt onset of tender erythematous plaques/nodules, fever, leukocytosis, and dense neutrophilic dermal infiltrate

Clinical

─ Sudden onset of tender, painful, erythematous or violaceous, edematous, sharply demarcated papules, plaques, or nodules, often with a pseudovesicular or "juicy" appearance

─ Common on face, neck, upper extremities, trunk

─ Fever, malaise, arthralgias, leukocytosis (neutrophilia) common

─ May be associated with:

─ Hematologic malignancy (especially acute myelogenous leukemia, AML) – paraneoplastic Sweet's

─ Solid tumors (less common)

─ Infections (especially upper respiratory, GI)

─ Inflammatory bowel disease

─ Drugs (eg, G-CSF, all-trans-retinoic acid, antibiotics)

─ Pregnancy

─ Idiopathic (most common)

Micro

─ Dense, diffuse neutrophilic infiltrate throughout the dermis, often concentrated in papillary and upper reticular dermis

─ Neutrophils are mature, typically without significant atypia

─ Marked papillary dermal edema is characteristic, may lead to subepidermal blister formation (pseudovesiculation)

─ Endothelial cell swelling common, but no true fibrinoid necrosis of vessel walls or significant leukocytoclasis (karyorrhexis) to suggest true vasculitis (though some "vasculitis-like" changes can occur)

─ Lymphocytes and histiocytes usually present in smaller numbers, eosinophils may be seen

─ Epidermis is usually spared or shows only mild spongiosis or exocytosis of neutrophils

DDx

─ Leukocytoclastic vasculitis (palpable purpura, fibrinoid necrosis of vessel walls, prominent karyorrhexis)

─ Cellulitis/Erysipelas (more diffuse dermal involvement, often bacteria identifiable, systemic signs of infection)

─ Erythema multiforme (target lesions, prominent interface dermatitis with keratinocyte necrosis)

─ Pyoderma gangrenosum (ulcerative lesions, different clinical evolution, often more mixed infiltrate with necrosis)

─ Arthropod bite reaction (if very neutrophilic, but usually more eosinophils, clinical history)

─ Behçet's disease (pustular or nodular lesions, often true vasculitis, other systemic features)

Prognosis ─ Usually responds rapidly to systemic corticosteroids, recurrences possible, prognosis may depend on underlying associated condition (especially malignancy)

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Blistering disorders

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Pemphigus Foliaceus

Autoimmune blistering disease, autoantibodies against desmoglein 1, causing superficial intraepidermal (subcorneal or granular layer) acantholysis

Clinical

─ Scaly, crusted, superficial erosions or flaccid blisters on an erythematous base, often in seborrheic distribution (face, scalp, upper trunk)

─ "Cornflake" scale/crust

─ Mucous membranes usually spared (unlike pemphigus vulgaris)

─ Variants:

─ Endemic pemphigus foliaceus (Fogo Selvagem): in rural South America, associated with black fly bites

─ Pemphigus erythematosus (Senear-Usher syndrome): overlap with lupus erythematosus, malar rash, ANA+, DIF shows intercellular IgG and granular IgG/C3 at DE junction

─ Drug-induced pemphigus foliaceus can occur (eg, penicillamine, captopril)

Micro

─ Subcorneal or intragranular acantholytic blister formation

─ Acantholytic cells (rounded keratinocytes) present within blister cavity or along blister base/roof

─ Epidermis beneath blister may show minimal change or some acanthosis

─ Superficial dermal inflammatory infiltrate, often with lymphocytes and eosinophils, neutrophils may be present in older/crusted lesions

─ Dyskeratotic cells usually not prominent

─ Direct immunofluorescence (DIF) shows intercellular IgG (and often C3) deposits in epidermis, typically more intense in superficial layers

DDx

─ Bullous impetigo (subcorneal pustules with neutrophils, Gram+ cocci often visible, DIF negative for intercellular IgG)

─ Staphylococcal scalded skin syndrome (SSSS) (subcorneal/granular layer split, often minimal inflammation, no acantholysis, Nikolsky sign+, usually infants/young children)

─ IgA pemphigus (SCPD type) (subcorneal pustules with neutrophils, DIF shows intercellular IgA)

─ Dermatophytosis (if pustular/vesicular) (fungal elements in stratum corneum, PAS/GMS+)

─ Subcorneal pustular dermatosis (Sneddon-Wilkinson) (subcorneal pustules with neutrophils, DIF negative or non-specific)

Prognosis ─ Generally more benign course than pemphigus vulgaris, can be chronic and relapsing

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Staph Scalded Skin (Syndrome) (SSSS, Ritter's Disease)

Toxin-Media ─ placeholder ted (exfoliative toxins A and B from Staphylococcus aureus) epidermal cleavage disorder, primarily affecting infants and young children

Clinical

─ Abrupt onset of diffuse, tender erythema, often starting periorificially or in flexures

─ Rapid progression to formation of large, flaccid blisters and widespread superficial epidermal peeling/desquamation (Nikolsky sign +)

─ Mucous membranes are typically NOT involved (important distinction from SJS/TEN)

─ Fever, irritability common

─ Usually in infants and young children (<5 years), rarely in immunocompromised adults or those with renal failure

Micro

─ Superficial intraepidermal split, typically at level of stratum granulosum or just beneath stratum corneum

─ Cleavage occurs due to toxin-Media ─ placeholder ted disruption of desmoglein 1

─ Minimal to no acantholysis (cells separate but don't round up significantly)

─ Epidermal roof of blister is stratum corneum +/- granular layer, floor is spinous layer

─ Inflammatory infiltrate in dermis is usually sparse or absent, especially in early lesions

─ No significant keratinocyte necrosis (unlike SJS/TEN or EM)

─ Organisms are usually not seen in the skin lesion itself (toxin is blood-borne from distant site of infection, eg, nasopharynx, umbilicus)

DDx

─ Bullous impetigo (localized SSSS, staphylococci present in blister, more inflammation)

─ Toxic epidermal necrolysis (TEN) (full-thickness epidermal necrosis, subepidermal blister, prominent mucosal involvement, usually drug-induced, different age group)

─ Pemphigus foliaceus (acantholysis, DIF shows intercellular IgG)

─ Epidermolysis bullosa (hereditary, different blister levels depending on type)

─ Severe sunburn/Thermal burn (different history, often deeper necrosis)

Prognosis ─ Generally good with supportive care and antibiotics for underlying staph infection, mortality low in children, higher in adults

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Bullous Impetigo

Localized form of staphylococcal scalded skin syndrome, caused by exfoliative toxin-producing Staphylococcus aureus acting locally at site of infection

Clinical

─ Flaccid vesicles and bullae, often on an erythematous base, rupture easily leaving crusted erosions ("honey-colored crust" less typical than in non-bullous impetigo)

─ Common in neonates and young children, can occur in adults

─ Face, trunk, extremities, intertriginous areas are common sites

─ Lesions may be few or multiple, Nikolsky sign usually negative or only locally positive

Micro

─ Subcorneal or intragranular acantholytic blister/pustule

─ Blister cavity contains neutrophils, acantholytic keratinocytes, and often clusters of Gram-positive cocci (Staphylococci)

─ Epidermis beneath blister may show some spongiosis or acanthosis

─ Superficial dermal inflammatory infiltrate with neutrophils and lymphocytes

─ Direct immunofluorescence (DIF) is negative for autoantibodies

DDx

─ Staphylococcal scalded skin syndrome (SSSS) (widespread peeling, mucous membranes spared, organisms not in skin lesion, toxin systemic)

─ Pemphigus foliaceus (acantholysis, DIF shows intercellular IgG, no bacteria in blister typically)

─ IgA pemphigus (SCPD type) (neutrophilic pustules, DIF shows intercellular IgA)

─ Subcorneal pustular dermatosis (Sneddon-Wilkinson) (sterile pustules, DIF negative)

─ Candidiasis (pustular variant) (yeast/pseudohyphae on PAS/GMS)

─ Viral vesicles (eg, herpes, varicella – viral cytopathic changes)

Prognosis ─ Good with appropriate antibiotic treatment

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AGEP (Acute Generalized Exanthematous Pustulosis)

Severe, acute drug reaction characterized by widespread, non-follicular, sterile pustules on an erythematous background, often with fever and leukocytosis

Clinical

─ Rapid onset (usually within days of drug exposure) of numerous, small (<5 mm), non-follicular, sterile pustules on a background of widespread, edematous erythema

─ Often starts in intertriginous areas (axillae, groin) or face, then generalizes

─ Fever (>38°C) and peripheral blood leukocytosis (often neutrophilia, sometimes eosinophilia) are common

─ Pruritus or burning may occur

─ Mucosal involvement (oral, genital) in about 20% of cases

─ Resolves rapidly (within 1-2 weeks) upon drug withdrawal, often with superficial desquamation

─ Common offending drugs: beta-lactam antibiotics, macrolides, quinolones, calcium channel blockers, antimalarials, terbinafine, carbamazepine, less commonly viral infections

Micro

─ Subcorneal and/or intraepidermal pustules filled with neutrophils

─ Spongiosis, often prominent, especially beneath and around pustules

─ Papillary dermal edema is usually marked

─ Superficial and sometimes mid-dermal perivascular and interstitial inflammatory infiltrate

─ Infiltrate is mixed, often with prominent neutrophils and eosinophils, as well as lymphocytes

─ Scattered necrotic keratinocytes may be present

─ Leukocytoclastic vasculitis is usually absent, though some vessel wall changes can be seen due to edema/inflammation

DDx

─ Pustular psoriasis (von Zumbusch type) (history of psoriasis, spongiform pustules of Kogoj more typical, less edema/eosinophils usually, different clinical evolution)

─ Sneddon-Wilkinson disease (subcorneal pustular dermatosis) (chronic relapsing course, lacks fever/leukocytosis, less edema/eosinophils)

─ IgA pemphigus (SCPD type) (DIF shows intercellular IgA)

─ Drug hypersensitivity syndrome (DRESS/DIHS) (different clinical – morbilliform rash, facial edema, lymphadenopathy, systemic involvement, often longer latency)

─ Sweet's syndrome (plaques/nodules, dense dermal neutrophilia, less prominent pustulation/spongiosis)

─ Bullous impetigo/SSSS (bacterial toxins, different blister level/cytology)

Prognosis ─ Generally good, rapid resolution after drug withdrawal, mortality rare

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Pustular Psoriasis

Group of psoriasis variants characterized by macroscopic sterile pustules, can be localized or generalized

Clinical

─ Generalized (von Zumbusch): acute, widespread erythema, followed by crops of numerous, small, sterile pustules that coalesce ("lakes of pus"), fever, malaise, leukocytosis, can be life-threatening

─ Palmoplantar pustulosis: chronic, recurrent eruption of sterile pustules on palms and soles, often associated with pain and fissuring

─ Acrodermatitis continua of Hallopeau: chronic, pustular eruption of distal digits, nails, may lead to nail destruction and osteolysis

─ Pustules in plaque psoriasis: can occur within typical psoriatic plaques

Micro

─ Epidermal changes:

─ Spongiform pustules of Kogoj: characteristic large, multilocular pustules in upper spinous layer/stratum granulosum, formed by accumulation of neutrophils within degenerating keratinocytes

─ Munro's microabscesses: collections of neutrophils in stratum corneum

─ Parakeratosis, often extensive

─ Acanthosis with elongated rete ridges (may be less regular than classic plaque psoriasis)

─ Epidermal edema (spongiosis) may be present

─ Dermal changes:

─ Superficial perivascular infiltrate of lymphocytes and neutrophils

─ Dilated, tortuous capillaries in dermal papillae

─ Papillary dermal edema

DDx

─ Acute generalized exanthematous pustulosis (AGEP) (drug-induced, often more eosinophils and dermal edema, non-follicular pustules on erythematous background)

─ Subcorneal pustular dermatosis (Sneddon-Wilkinson) (subcorneal pustules, often annular lesions, DIF negative)

─ IgA pemphigus (SCPD type) (subcorneal pustules, DIF shows intercellular IgA)

─ Bullous impetigo (subcorneal pustules, Gram+ cocci, acantholysis)

─ Candidiasis (pustular) (yeast/pseudohyphae in SC, PAS/GMS+)

─ Reactive arthritis (Reiter's syndrome) (keratoderma blenorrhagicum can be histologically identical)

Prognosis ─ Variable, generalized form can be severe/life-threatening, localized forms often chronic and relapsing

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Tinea (with Blistering/Pustular Features)

Superficial fungal infection (dermatophytosis) that elicits a significant inflammatory response leading to vesicle, bulla, or pustule formation

Clinical

─ Inflammatory tinea (eg, tinea corporis, tinea pedis, tinea capitis – kerion) can present with vesicles, bullae, or pustules on an erythematous, often annular or arcuate, base

─ Bullous tinea pedis: vesicles/bullae on soles or instep

─ Kerion (tinea capitis): boggy, inflammatory, pustular scalp mass

─ Majocchi's granuloma: perifollicular granulomatous inflammation due to dermatophyte invasion of hair follicle, often pustular

Micro

─ Fungal hyphae (septate, branching) and/or arthrospores within stratum corneum, hair follicles, or rarely dermis (Majocchi's) – PAS or GMS stain essential

─ Epidermal changes:

─ Intraepidermal or subcorneal vesicles or pustules containing neutrophils and/or eosinophils

─ Spongiosis, acanthosis, parakeratosis

─ Acantholysis can occur in some pustular tineas

─ Dermal changes:

─ Superficial and sometimes deep perivascular and interstitial mixed inflammatory infiltrate (lymphocytes, histiocytes, neutrophils, eosinophils)

─ Papillary dermal edema

─ In Majocchi's granuloma: perifollicular granulomatous inflammation (epithelioid histiocytes, giant cells) with neutrophils, fungal elements within follicle or free in dermis

DDx

─ Dyshidrotic eczema (if tinea pedis/manuum – no fungi)

─ Allergic contact dermatitis (no fungi, often more prominent eosinophilic spongiosis)

─ Bullous impetigo (Gram+ cocci, acantholysis, no fungi)

─ Pustular psoriasis (Munro's, Kogoj, no fungi)

─ Bacterial folliculitis/Furuncle (if Majocchi's – bacteria, different granulomatous reaction if any)

─ Pemphigus foliaceus/IgA pemphigus (if acantholytic/pustular tinea – DIF for autoantibodies)

Prognosis ─ Good with appropriate antifungal treatment, though inflammatory reactions can be severe

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Dermatitis Herpetiformis (DH, Duhring's Disease)

Chronic, intensely pruritic, autoimmune blistering disease strongly associated with gluten sensitivity (celiac disease)

Clinical

─ Symmetrical eruption of intensely pruritic, grouped (herpetiform) vesicles, papules, and urticarial plaques

─ Common on extensor surfaces (elbows, knees), buttocks, scalp, posterior neck/shoulders

─ Lesions are often excoriated due to severe pruritus

─ Oral lesions rare

─ Strong association with gluten-sensitive enteropathy (celiac disease), though GI symptoms may be absent

Micro

─ Subepidermal blister formation

─ Characteristic feature: Neutrophilic microabscesses within dermal papillae (at tips of papillae), often associated with fibrin deposition

─ Blister forms at DE junction above these neutrophilic collections, due to destruction of anchoring fibrils

─ Papillary dermal edema

─ Superficial perivascular infiltrate of neutrophils, lymphocytes, and often numerous eosinophils in dermis

─ Epidermis overlying early lesions may be intact, later forms roof of blister

─ Direct immunofluorescence (DIF) of perilesional skin is diagnostic: granular deposits of IgA (and often C3) in dermal papillae and/or along DE junction

DDx

─ Bullous pemphigoid (tense bullae, DIF shows linear IgG/C3 along BMZ, eosinophils often more prominent in blister cavity)

─ Linear IgA bullous dermatosis (LABD) (linear IgA deposits along BMZ on DIF, clinically may have annular "string of pearls" lesions)

─ Epidermolysis bullosa acquisita (EBA) (mechanobullous, trauma-prone sites, DIF shows linear IgG/C3 on dermal side of salt-split skin)

─ Pemphigus (intraepidermal blisters, acantholysis, different DIF)

─ Arthropod bite reaction (if vesicular/papular, but usually more random distribution, lacks consistent papillary microabscesses/DIF)

─ Scabies (burrows, mites, different distribution, lacks specific DIF)

Prognosis ─ Chronic, relapsing course, skin lesions respond to dapsone and gluten-free diet, gluten-free diet manages associated enteropathy

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Bullous Pemphigoid (BP)

Most common autoimmune subepidermal blistering disease, primarily affecting elderly, autoantibodies against hemidesmosomal proteins BPAG1 (BP230) and BPAG2 (BP180, type XVII collagen)

Clinical

─ Prodromal phase: pruritic, urticarial plaques or eczematous lesions, may last weeks to months

─ Bullous phase: large, tense blisters on erythematous, urticarial, or normal-appearing skin

─ Common on trunk, flexor aspects of extremities, intertriginous areas

─ Oral mucosal involvement in 10-30% of cases, usually non-scarring

─ Intense pruritus is common

─ Primarily affects elderly (>60 years), but can occur at any age

Micro

─ Subepidermal blister with a cell-poor or cell-rich inflammatory infiltrate

─ Blister roof is intact epidermis, floor is dermis

─ Blister cavity may contain fibrin, lymphocytes, and often numerous eosinophils

─ Dermal infiltrate: superficial perivascular and interstitial lymphocytes, histiocytes, and prominent eosinophils (characteristic, but can be absent in cell-poor variant)

─ Eosinophilic spongiosis (eosinophils in epidermis with spongiosis) may be seen in urticarial/pre-bullous lesions

─ Papillary dermal edema common

─ No significant acantholysis or keratinocyte necrosis

─ Direct immunofluorescence (DIF) of perilesional skin is diagnostic: linear deposits of IgG (mainly IgG4) and/or C3 along the dermoepidermal junction (basement membrane zone)

─ Salt-split skin DIF: deposits localize to epidermal side (roof) of split (lamina lucida)

DDx

─ Epidermolysis bullosa acquisita (EBA) (mechanobullous, trauma-prone sites, DIF localizes to dermal side of salt-split skin)

─ Dermatitis herpetiformis (grouped vesicles, neutrophilic papillary microabscesses, granular IgA at DE junction on DIF)

─ Linear IgA bullous dermatosis (LABD) (linear IgA at DE junction on DIF)

─ Pemphigus vulgaris (intraepidermal blisters, acantholysis, intercellular IgG on DIF)

─ Bullous fixed drug eruption (history of drug, recurs at same site, often more pigment incontinence)

─ Bullous arthropod bite reaction (clinical history, often more random, may lack linear DIF)

─ Cicatricial pemphigoid (mucous membrane predominant, scarring, DIF similar to BP)

Prognosis ─ Chronic, relapsing course, can be associated with significant morbidity in elderly, usually responds to topical/systemic corticosteroids or immunosuppressants

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Pemphigus Vulgaris

Serious autoimmune blistering disease, autoantibodies against desmoglein 3 (and often desmoglein 1), causing intraepidermal, suprabasal acantholysis

Clinical

─ Flaccid blisters and painful erosions on skin and mucous membranes

─ Oral mucosa is often first site involved, and may be only site in some cases

─ Skin lesions rupture easily, leaving denuded areas (Nikolsky sign +)

─ Common on scalp, face, trunk, intertriginous areas, pressure points

─ Variants: Pemphigus vegetans (verrucous, vegetating plaques in intertriginous areas)

─ Typically affects middle-aged to older adults

Micro

─ Suprabasal acantholytic blister: separation occurs just above the basal cell layer

─ Basal keratinocytes remain attached to dermis ("row of tombstones" appearance)

─ Acantholytic (rounded) keratinocytes (Tzanck cells) are present within blister cavity

─ Epidermal roof of blister is intact but may be thin

─ Superficial dermal inflammatory infiltrate, often with lymphocytes and eosinophils, neutrophils may be present, especially in older or vegetating lesions

─ Hair follicles (outer root sheath) may show similar suprabasal acantholysis

─ Pemphigus vegetans: marked pseudoepitheliomatous hyperplasia with intraepidermal eosinophilic/neutrophilic abscesses and suprabasal acantholysis

─ Direct immunofluorescence (DIF) is diagnostic: intercellular IgG (mainly IgG4) and often C3 deposits throughout epidermis ("chicken wire" or "fishnet" pattern)

DDx

─ Hailey-Hailey disease (benign familial pemphigus) (full-thickness acantholysis, "dilapidated brick wall," intertriginous, familial, DIF negative)

─ Darier's disease (keratosis follicularis) (acantholytic dyskeratosis, corps ronds, grains, follicular papules, DIF negative)

─ Pemphigus foliaceus (more superficial, subcorneal/granular layer acantholysis, mucous membranes usually spared, targets desmoglein 1)

─ Bullous pemphigoid/other subepidermal blistering diseases (subepidermal blister, different DIF)

─ Erythema multiforme/SJS/TEN (interface dermatitis, keratinocyte necrosis, different DIF)

─ Grover's disease (transient acantholytic dermatosis) (focal acantholysis/dyskeratosis, often Darier-like or Hailey-Hailey-like foci, different clinical)

Prognosis ─ Serious, potentially fatal if untreated, prognosis significantly improved with systemic corticosteroids and immunosuppressants

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Hailey Hailey (Disease) (Benign Familial Pemphigus)

Autosomal dominant genodermatosis (ATP2C1 gene mutation affecting calcium pump), characterized by recurrent vesicles and erosions in intertriginous areas due to acantholysis

Clinical

─ Recurrent eruption of flaccid vesicles and bullae that rupture easily, leading to crusted erosions, fissures, and vegetating plaques

─ Primarily affects intertriginous areas: axillae, groin, inframammary folds, neck

─ Pruritus, burning, pain common, lesions often malodorous due to secondary bacterial infection

─ Exacerbated by heat, sweating, friction

─ Onset usually in adolescence or early adulthood, chronic relapsing course

Micro

─ Extensive intraepidermal acantholysis throughout all or most of the thickness of the epidermis, creating a "dilapidated brick wall" appearance

─ Suprabasal clefts and lacunae formation

─ Acantholytic keratinocytes are present but generally show less rounding and atypia than in pemphigus vulgaris

─ Dyskeratosis is usually minimal or absent (unlike Darier's disease)

─ Overlying stratum corneum often shows parakeratosis and crusting

─ Epidermis may show acanthosis and papillomatosis, especially in vegetating lesions

─ Superficial dermal inflammatory infiltrate, usually lymphocytic, may have neutrophils if secondarily infected

─ Direct immunofluorescence (DIF) is negative for autoantibodies

DDx

─ Pemphigus vulgaris/vegetans (suprabasal acantholysis, but DIF shows intercellular IgG, often more prominent oral involvement)

─ Darier's disease (acantholytic dyskeratosis, corps ronds, grains, follicular papules, different gene mutation)

─ Grover's disease (focal acantholysis, often multiple histologic patterns, transient)

─ Warty dyskeratoma (solitary lesion, cup-shaped invagination, prominent dyskeratosis)

─ Intertrigo/Candidiasis/Bacterial infection (clinical overlap, but lack primary acantholysis, organisms may be present)

Prognosis ─ Benign, but chronic, relapsing, can cause significant discomfort and morbidity

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Dariers (Disease) (Keratosis Follicularis)

Autosomal dominant genodermatosis (ATP2A2 gene mutation affecting calcium pump SERCA2), characterized by keratotic papules, acantholysis, and dyskeratosis

Clinical

─ Greasy, crusted, firm, skin-colored or yellowish-brown, keratotic papules, often coalescing into warty plaques

─ Predilection for seborrheic areas (scalp, face, chest, back, flexures)

─ Nail changes: longitudinal red/white streaks, subungual hyperkeratosis, V-nicking of distal nail plate

─ Palmar pits or keratoses, oral mucosal cobblestone papules

─ Pruritus common, lesions may be malodorous, exacerbated by heat, sweating, sun exposure

─ Onset usually in adolescence or early adulthood

Micro

─ Focal acantholytic dyskeratosis:

─ Suprabasal clefts or lacunae containing acantholytic keratinocytes

─ Dyskeratosis is prominent:

─ Corps ronds: large, rounded dyskeratotic cells in spinous/granular layers, with dark pyknotic nucleus surrounded by clear halo and eosinophilic cytoplasm

─ Grains: small, elongated, parakeratotic-like dyskeratotic cells in stratum corneum or upper lacunae, with flattened dark nuclei

─ Overlying hyperkeratosis and parakeratosis, often forming a central plug within a follicular or epidermal invagination

─ Acanthosis and papillomatosis (villi) with upward proliferation of dermal papillae lined by single basal layer into lacunae

─ Superficial dermal lymphocytic infiltrate

─ Direct immunofluorescence (DIF) is negative

DDx

─ Grover's disease (transient acantholytic dermatosis) (histologically can be identical with Darier-like foci, but Grover's is transient, often truncal, lacks familial history/nail changes)

─ Warty dyskeratoma (solitary lesion, often larger cup-shaped invagination, histologically very similar, some consider it localized Darier's)

─ Hailey-Hailey disease (more extensive acantholysis, "dilapidated brick wall," less dyskeratosis, intertriginous, different gene)

─ Pemphigus vulgaris (suprabasal acantholysis, but DIF shows intercellular IgG, less dyskeratosis)

─ Seborrheic keratosis (irritated) (can have squamous eddies, but lacks consistent acantholytic dyskeratosis of Darier's)

Prognosis ─ Benign, but chronic, persistent, can be disfiguring and symptomatic

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Warty Dyskeratoma

Solitary follicular adnexal neoplasm with prominent acantholysis and dyskeratosis, resembling localized Darier's disease (Reiteration from Set 3)

Clinical

─ Solitary, flesh-colored to reddish-brown papule or nodule, often umbilicated or crusted, with central keratinous plug

─ Typically head (face, scalp), neck of middle-aged or older adults

Micro

─ Cup-shaped epidermal and/or follicular infundibular invagination filled with keratinous material

─ Lined by hyperplastic epithelium showing:

─ Suprabasal acantholysis forming lacunae

─ Prominent villi (dermal papillae lined by single basal layer) projecting into lacunae

─ Acantholytic and dyskeratotic cells (corps ronds, grains) within lacunae and stratum corneum, similar to Darier's disease

─ Often arises from or shows differentiation towards a pilosebaceous follicle

DDx

─ Darier's disease (usually multiple lesions clinically, histologically very similar but Darier's is generalized genodermatosis, WD is solitary)

─ Acantholytic actinic keratosis (sun-exposed sites, keratinocytic atypia of AK)

─ Acantholytic squamous cell carcinoma (invasive growth, significant cytologic atypia)

─ Grover's disease (usually multiple clinically, more focal/superficial acantholysis/dyskeratosis)

─ Inverted follicular keratosis (squamous eddies, less prominent acantholysis/dyskeratosis)

Prognosis ─ Benign

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Grovers Disease (Transient Acantholytic Dermatosis)

Self-limited eruption, often pruritic papules and vesicles, with focal acantholysis and dyskeratosis (Reiteration from Set 3)

Clinical

─ Sudden onset, pruritic small red papules, papulovesicles, or keratotic papules

─ Predilection for trunk (chest, back), middle-aged/elderly men

─ Often transient, exacerbated by heat, sweating, bed confinement

Micro

─ Focal acantholysis and dyskeratosis in small discrete foci within epidermis

─ Several patterns described, resembling:

─ Darier's disease (suprabasal acantholysis, corps ronds, grains)

─ Hailey-Hailey disease (more extensive intraepidermal acantholysis, "dilapidated brick wall")

─ Pemphigus vulgaris (suprabasal acantholysis)

─ Spongiotic pattern (spongiosis with focal acantholysis/dyskeratosis)

─ Variable superficial perivascular inflammation, sometimes with eosinophils

DDx

─ Darier's disease (more confluent, often familial, nail/mucosal changes)

─ Hailey-Hailey disease (more extensive acantholysis, intertriginous, familial, lacks dyskeratosis)

─ Pemphigus variants (DIF positive for intercellular IgG)

─ Acantholytic actinic keratosis (sun-exposed sites, keratinocytic atypia of AK)

─ Warty dyskeratoma (solitary, cup-shaped, prominent dyskeratosis)

Prognosis ─ Benign, often self-limited but can recur or be persistent

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Porphyria Cutanea Tarda (PCT)

Most common type of porphyria, due to deficient uroporphyrinogen decarboxylase (UROD) activity, leading to photosensitivity and skin fragility

Clinical

─ Tense vesicles and bullae on sun-exposed skin, especially dorsal hands, forearms, face, ears

─ Skin fragility, easy bruising, milia formation (especially on dorsal hands)

─ Heals with scarring and hypopigmentation/hyperpigmentation

─ Hypertrichosis (especially malar/temporal areas), sclerodermoid changes may occur

─ Associated with liver disease (hepatitis C, alcohol, hemochromatosis), estrogens, iron overload, HIV, certain drugs, smoking

─ Elevated uroporphyrins in urine (urine may fluoresce pink under Wood's lamp)

Micro

─ Subepidermal blister, often cell-poor (minimal inflammation)

─ Festooning of dermal papillae: dermal papillae retain their shape and protrude upwards into blister cavity (characteristic)

─ Thickened, hyalinized blood vessel walls in papillary dermis (PAS+, diastase resistant)

─ "Caterpillar bodies": linear, segmented, eosinophilic material in roof of blister (degenerating basement membrane/keratinocytes), not always present

─ Minimal dermal inflammation, usually sparse perivascular lymphocytes

─ Solar elastosis common in sun-exposed sites

─ Direct immunofluorescence (DIF) of lesional/perilesional skin: linear deposits of IgG, C3, and sometimes IgA/IgM around superficial dermal blood vessels and often along DE junction

DDx

─ Epidermolysis bullosa acquisita (EBA) (mechanobullous, trauma-prone sites, DIF shows linear IgG on dermal side of salt-split skin, targets type VII collagen)

─ Pseudoporphyria (drug-induced, eg, NSAIDs, tetracyclines, diuretics – clinically and histologically similar to PCT, but porphyrin levels normal, DIF often negative or less intense)

─ Bullous pemphigoid (tense bullae, but often more inflammation with eosinophils, DIF shows linear IgG/C3 along BMZ roof pattern on salt-split)

─ Other subepidermal blistering diseases with scant inflammation (eg, bullosis diabeticorum, burns – clinical context different)

Prognosis ─ Chronic, depends on managing underlying triggers/associated conditions, phlebotomy or low-dose antimalarials can induce remission

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Pemphigus Vegetans

Rare variant of pemphigus vulgaris, characterized by vegetating, papillomatous plaques in intertriginous areas

Clinical

─ Two main types:

─ Neumann type: more common, starts with flaccid blisters like pemphigus vulgaris that evolve into hypertrophic, verrucous, vegetating plaques, often with pustules, in intertriginous areas (axillae, groin, inframammary), oral mucosa often involved

─ Hallopeau type (pyodermite végétante of Hallopeau): milder, starts with pustules that coalesce into vegetating plaques, less mucosal involvement, better prognosis

─ Lesions are often malodorous and painful

Micro

─ Marked pseudoepitheliomatous hyperplasia (acanthosis, papillomatosis) of epidermis

─ Suprabasal acantholysis and clefting, similar to pemphigus vulgaris, though may be less obvious due to hyperplasia

─ Intraepidermal abscesses containing numerous eosinophils (characteristic) and/or neutrophils are a key feature, often within the hyperplastic rete ridges

─ Acantholytic cells may be seen within abscesses or clefts

─ Dense dermal inflammatory infiltrate with lymphocytes, histiocytes, numerous eosinophils, and often plasma cells

─ Direct immunofluorescence (DIF) shows intercellular IgG (and often C3) deposits in epidermis, same as pemphigus vulgaris

DDx

─ Hailey-Hailey disease (vegetating lesions in intertrigo, but full-thickness acantholysis, "dilapidated brick wall," DIF negative)

─ Pyoderma vegetans (associated with inflammatory bowel disease, similar vegetating plaques with pustules, but lacks primary acantholysis and intercellular IgG on DIF)

─ Blastomycosis-like pyoderma (bacterial infection causing pseudoepitheliomatous hyperplasia and neutrophilic abscesses, organisms may be seen)

─ Deep fungal infections (eg, chromoblastomycosis, blastomycosis – pseudoepitheliomatous hyperplasia, granulomas, organisms on special stains)

─ Halogenoderma (eg, bromoderma, iododerma – pseudoepitheliomatous hyperplasia, eosinophils, neutrophils, history of exposure)

─ Verrucous carcinoma/SCC (cytologic atypia, invasion, lacks acantholysis/eosinophilic abscesses)

Prognosis ─ Chronic course, similar to pemphigus vulgaris but Neumann type can be more resistant to therapy, Hallopeau type generally milder

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Herpes Simplex (Virus Infection, HSV)

Common viral infection causing mucocutaneous vesicles, caused by Herpes simplex virus type 1 (HSV-1, usually orofacial) or type 2 (HSV-2, usually genital)

Clinical

─ Primary infection: often asymptomatic or mild, can cause gingivostomatitis (HSV-1) or painful genital vesicles (HSV-2), fever, malaise, lymphadenopathy

─ Recurrent infection: grouped vesicles on an erythematous base, often at same site (lips – herpes labialis/cold sore, genitalia, buttocks, fingers – herpetic whitlow)

─ Vesicles rupture to form crusted erosions, heal without scarring typically

─ Triggers for recurrence: stress, sun exposure, fever, menses, trauma

─ Eczema herpeticum (Kaposi's varicelliform eruption): widespread HSV infection in patients with pre-existing skin disease (eg, atopic dermatitis)

Micro

─ Intraepidermal vesicle formation due to keratinocyte damage

─ Characteristic viral cytopathic changes:

─ Acantholysis (separation of keratinocytes)

─ Ballooning degeneration: keratinocytes become swollen, pale, lose intercellular connections

─ Reticular degeneration: intracellular edema leading to cell rupture and multilocular vesicles

─ Multinucleated epithelial giant cells (Tzanck cells): formed by fusion of infected keratinocytes, often with molded, overlapping nuclei (ground-glass appearance or marginated chromatin)

─ Intranuclear viral inclusion bodies (Cowdry type A): eosinophilic inclusions surrounded by clear halo, marginated chromatin (less commonly seen in skin biopsies than in other organs)

─ Epidermal necrosis may be present

─ Dermal inflammatory infiltrate: lymphocytes, neutrophils, extravasated RBCs, edema

─ Vasculitis can occasionally be seen

─ IHC for HSV-1/HSV-2 or PCR can confirm diagnosis

DDx

─ Varicella-Zoster Virus (VZV) infection (chickenpox, shingles) (histologically identical, clinical correlation or specific IHC/PCR needed for distinction)

─ Pemphigus vulgaris (if acantholysis prominent, but PV has suprabasal split, "tombstoning," lacks viral cytopathic changes, DIF shows intercellular IgG)

─ Other viral exanthems with vesicles (eg, Coxsackie – hand-foot-mouth, herpangina – often less ballooning/multinucleation)

─ Acute spongiotic dermatitis with vesiculation (eg, contact dermatitis, dyshidrotic eczema – prominent spongiosis, lacks viral cytopathic changes)

─ Bullous impetigo (subcorneal pustules, Gram+ cocci, less acantholysis/ballooning)

Prognosis ─ Benign, self-limited in immunocompetent, but recurrent, can be severe or disseminated in immunocompromised or neonates

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Bullous Lichen Sclerosus

Variant of lichen sclerosus (LS), characterized by blister formation within typical LS lesions, usually anogenital

Clinical

─ White, atrophic, often "cigarette paper" or crinkled plaques, with areas of purpura, erosions, or bullae

─ Most common in anogenital region (vulva, perineum, perianal, glans penis – balanitis xerotica obliterans)

─ Can cause pruritus, pain, dyspareunia, phimosis, urinary obstruction

─ Extragenital lesions less common (trunk, neck, oral mucosa)

─ Bullae may be hemorrhagic, can be painful

Micro

─ Features of lichen sclerosus:

─ Epidermal atrophy (thinning), often with effacement of rete ridges

─ Hyperkeratosis, often compact

─ Follicular plugging may be present

─ Vacuolar alteration of basal cell layer

─ Characteristic dermal changes: broad zone of subepidermal edema and homogenization/sclerosis of papillary dermal collagen (appears pale, eosinophilic, and acellular or hypocellular)

─ Band-like or patchy lymphocytic infiltrate beneath the sclerotic zone

─ Dilated lymphatic vessels may be seen

─ Superimposed subepidermal blister formation within the edematous/sclerotic papillary dermis

─ Blister cavity may contain serous fluid, fibrin, few inflammatory cells

─ No significant acantholysis

DDx

─ Lichen planus (bullous variant) (sawtooth rete, wedge hypergranulosis, denser band-like infiltrate directly at DE junction, less dermal sclerosis, different DIF)

─ Bullous pemphigoid (tense bullae, DIF shows linear IgG/C3 at BMZ, eosinophils often prominent, lacks LS sclerosis)

─ Porphyria cutanea tarda (sun-exposed sites, festooning, thickened vessel walls, caterpillar bodies, different DIF)

─ Epidermolysis bullosa acquisita (mechanobullous, trauma-prone sites, DIF on dermal side of salt-split skin)

─ Localized scleroderma (morphea) (dermal sclerosis involves reticular dermis more prominently, less epidermal atrophy/interface change typically, rarely bullous)

Prognosis ─ Benign, but chronic, can cause significant scarring and functional impairment, small increased risk of SCC in long-standing anogenital LS

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Granulomatous & Histiocytic

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Ruptured Epidermoid Cyst (Inflamed Epidermoid Cyst)

Common benign cyst with secondary inflammation and granulomatous reaction due to rupture and extrusion of keratin contents

Clinical

─ Tender, erythematous, fluctuant or firm nodule, often with history of pre-existing non-inflamed cyst

─ May discharge cheesy, malodorous keratin material

─ Can occur anywhere epidermoid cysts are found (face, neck, trunk, scrotum)

─ Often mimics bacterial abscess clinically

Micro

─ Remnants of epidermoid cyst wall (stratified squamous epithelium with granular layer) may be identifiable, at least focally

─ Extruded keratin flakes (lamellar, anucleated) into dermis

─ Intense inflammatory response to keratin:

─ Acute phase: numerous neutrophils, forming abscesses around keratin

─ Chronic phase: prominent foreign body giant cell reaction (multinucleated histiocytes engulfing keratin flakes), lymphocytes, plasma cells, histiocytes, forming keratin granulomas

─ Fibrosis and granulation tissue in later stages

─ Cholesterol clefts may be present within inflamed areas

─ No evidence of malignancy (eg, atypia in any remaining epithelial lining to suggest SCC arising in cyst)

DDx

─ Pilar cyst, ruptured (trichilemmal keratinization in cyst wall remnants, different keratin type – dense, eosinophilic)

─ Dermoid cyst, ruptured (adnexal structures in wall remnants)

─ Acne conglobata/Hidradenitis suppurativa (if in typical locations, often more extensive sinus tracts and scarring, involves pilosebaceous units/apocrine glands)

─ Deep fungal or bacterial infection with granulomatous inflammation (organisms may be visible with special stains)

─ Foreign body granuloma (to other material if cyst wall not identified)

─ Squamous cell carcinoma arising in a cyst (atypical epithelial proliferation, invasion)

Prognosis ─ Benign inflammatory reaction, often resolves with scarring, cyst may recur if epithelial lining not completely removed/destroyed

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Gel Foam (Absorbable Gelatin Sponge Reaction)

Foreign body granulomatous reaction to Gelfoam, a hemostatic agent used in surgical procedures

Clinical

─ Papule or nodule at site of previous surgery or biopsy where Gelfoam was used

─ May appear weeks to months post-procedure

─ Usually asymptomatic or mildly tender

Micro

─ Foreign body granulomatous reaction in dermis or subcutis

─ Characteristic Gelfoam material: amorphous, glassy, eosinophilic to slightly basophilic, often fragmented or fibrillar, with a somewhat "crinkled" or "wavy" appearance, may show angulated or "sickle-shaped" wisps

─ Material is surrounded by histiocytes, foreign body giant cells, lymphocytes, and often eosinophils

─ Fibrosis and neovascularization (granulation tissue) common

─ Gelfoam is birefringent with polarized light, but often weakly or variably so

DDx

─ Suture granuloma (suture material visible, often polarizable with distinct characteristics depending on suture type)

─ Keratin granuloma (from ruptured cyst/follicle) (keratin flakes visible)

─ Other foreign body granulomas (eg, to talc, silica, wood – material identifiable, often strongly polarizable)

─ Palisading granuloma (eg, granuloma annulare, necrobiosis lipoidica – different architecture, central necrobiosis/mucin, lacks Gelfoam)

─ Myxoid neoplasms (if Gelfoam appears very pale/basophilic – but Gelfoam is acellular, surrounded by granulomatous reaction)

Prognosis ─ Benign, reactive process

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Mucocele (Mucous Extravasation Cyst, Mucous Retention Cyst)

Common lesion of oral mucosa (or rarely skin) due to rupture or obstruction of a minor salivary gland duct, leading to mucin spillage or retention

Clinical

─ Soft, fluctuant, dome-shaped, translucent or bluish vesicle, papule, or nodule

─ Most common on lower lip (oral mucocele), also buccal mucosa, floor of mouth (ranula if large), ventral tongue

─ Cutaneous mucoceles are rare, can occur on face or other sites with ectopic salivary tissue or sweat glands

─ Often history of trauma (eg, lip biting)

─ Can fluctuate in size, may rupture and discharge mucoid fluid

Micro

─ Two main types based on presence or absence of epithelial lining:

─ Mucous extravasation phenomenon (most common):

─ Cyst-like space in lamina propria/submucosa or dermis, filled with pooled mucin (pale, basophilic, foamy, or stringy on H&E, Alcian blue+, PAS+)

─ Lacks a true epithelial lining

─ Wall is composed of granulation tissue, compressed connective tissue, and inflammatory cells, especially foamy macrophages (muciphages) engulfing mucin

─ Lymphocytes, plasma cells, neutrophils may be present

─ Ruptured or adjacent minor salivary gland ducts/acini often seen nearby

─ Mucous retention cyst (less common):

─ True cyst lined by ductal epithelium (cuboidal, columnar, or squamous metaplastic)

─ Lumen contains mucin

─ Caused by ductal obstruction

─ Superficial mucoceles: mucin pool very close to or abutting overlying epithelium, which may be thinned or ulcerated

DDx

─ Lymphangioma (dilated lymphatic channels lined by endothelium, contain lymph not mucin)

─ Hemangioma (blood-filled vascular channels)

─ Hidrocystoma (sweat gland origin, different lining if true cyst, usually skin not mucosa)

─ Soft tissue myxoma (neoplastic spindle/stellate cells in myxoid stroma, no true mucin pools or salivary tissue)

─ Other cystic lesions (eg, epidermoid cyst, dermoid cyst – different lining and contents)

Prognosis ─ Benign, may recur if associated salivary gland tissue not removed or ductal obstruction persists

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Coccidioidomycosis

Fungal infection caused by Coccidioides immitis or C, posadasii, endemic in southwestern US, Mexico, Central/South America, can cause cutaneous lesions via primary inoculation or dissemination

Clinical

─ Primary cutaneous: chancre-like nodule, ulcer, or plaque at inoculation site, often with lymphangitis, regional lymphadenopathy

─ Disseminated (secondary cutaneous): more common, especially in immunocompromised, variable lesions – papules, pustules, nodules, abscesses, verrucous plaques, granulomas, ulcers, sinus tracts, often on face

─ Erythema nodosum or erythema multiforme ("valley fever" complex) can occur as reactive phenomena during primary pulmonary infection

Micro

─ Pseudoepitheliomatous hyperplasia of epidermis often prominent, may have intraepidermal neutrophilic microabscesses

─ Dermal infiltrate is typically mixed suppurative and granulomatous:

─ Neutrophils, often forming abscesses

─ Granulomas composed of epithelioid histiocytes, lymphocytes, plasma cells, and multinucleated giant cells (Langhans or foreign body type)

─ Characteristic feature: Large, thick-walled spherules (sporangia) of Coccidioides, 20-80 µm (up to 200 µm) in diameter

─ Spherules contain numerous small (2-5 µm) endospores

─ Ruptured spherules release endospores, inciting more inflammation

─ Organisms often visible on H&E, best seen with GMS or PAS stains

─ Caseation necrosis may be present within granulomas

DDx

─ Blastomycosis (broad-based budding yeast, smaller organisms usually, different geographic distribution)

─ Paracoccidioidomycosis (multiple budding yeast – "mariner's wheel," smaller parent yeast)

─ Cryptococcosis (encapsulated yeast, mucicarmine+ capsule, often less granulomatous/more gelatinous)

─ Rhinosporidiosis (very large sporangia with endospores, but different morphology/location)

─ Tuberculosis/Atypical mycobacterial infection (acid-fast bacilli, different granuloma type often, no spherules)

─ Other deep fungal infections (eg, histoplasmosis, sporotrichosis – different morphology of organisms)

─ Squamous cell carcinoma (if pseudoepitheliomatous hyperplasia is marked and organisms not seen – special stains crucial)

Prognosis ─ Variable, primary cutaneous often self-limited in immunocompetent, disseminated disease can be severe/fatal, especially in immunocompromised

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Necrobiosis Lipoidica (NL, Necrobiosis Lipoidica Diabeticorum)

Chronic granulomatous disease of dermis, often associated with diabetes mellitus, characterized by atrophic, yellowish plaques, usually on shins

Clinical

─ Well-demarcated, indurated plaques with an atrophic, yellowish, waxy, often telangiectatic center and an erythematous or violaceous, slightly raised border

─ Most common on anterior shins, often bilateral

─ May ulcerate, especially after trauma

─ Strongly associated with diabetes mellitus (NL diabeticorum), but can occur in non-diabetics

─ More common in women

Micro

─ "Layer cake" or "tiered" pattern of inflammation and necrobiosis involving full thickness of dermis, often extending into septa of subcutis

─ Palisading granulomas: histiocytes and multinucleated giant cells arranged in a palisade around areas of altered (necrobiotic) collagen

─ Necrobiosis: collagen bundles appear swollen, homogenized, eosinophilic, or pale and degenerated, with loss of cellular detail, often with associated mucin or fibrin

─ Lymphocytes and plasma cells are usually prominent in the inflammatory infiltrate, especially around blood vessels and at periphery of necrobiotic foci

─ Blood vessel walls often thickened and hyalinized, may show endothelial swelling

─ Epidermis is usually atrophic, with loss of rete ridges

─ Lipid deposition (extracellular cholesterol clefts) may be seen within necrobiotic areas, especially in older lesions (hence "lipoidica"), but not required for diagnosis

DDx

─ Granuloma annulare (GA) (more superficial usually, more prominent mucin in center of palisades, less plasma cells, less vascular change, no epidermal atrophy typically, NL has more "horizontally layered" or "tiered" granulomas)

─ Rheumatoid nodule (deeper, often subcutaneous, more central fibrinoid necrosis, different clinical context)

─ Sarcoidosis (naked epithelioid granulomas, no significant necrobiosis or mucin)

─ Necrobiotic xanthogranuloma (NXG) (more prominent xanthomatous cells, cholesterol clefts, Touton giant cells, often paraproteinemia, different clinical – often periorbital, ulcerating plaques)

─ Morphea/Scleroderma (dermal sclerosis, but lacks granulomas and necrobiosis of NL)

Prognosis ─ Chronic, persistent, difficult to treat, ulceration can be problematic

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Necrobiotic Xanthogranuloma (NXG)

Rare chronic granulomatous disorder characterized by yellowish, indurated plaques/nodules that often ulcerate, strongly associated with paraproteinemia (usually IgG monoclonal gammopathy)

Clinical

─ Yellowish to reddish-brown or violaceous, indurated plaques or nodules, often with central atrophy, telangiectasias, and a tendency to ulcerate

─ Most common in periorbital region (eyelids, cheeks), also trunk, extremities, flexures

─ Lesions are often asymptomatic but can be tender or painful, especially if ulcerated

─ Strong association (80-90%) with paraproteinemia (monoclonal gammopathy, usually IgG kappa or lambda), multiple myeloma, or other lymphoproliferative disorders

─ May have extracutaneous involvement (eg, internal organs, bone marrow)

Micro

─ Diffuse, often "bottom-heavy" granulomatous infiltrate throughout dermis, frequently extending into subcutis

─ Broad zones of necrobiosis (altered, hyalinized, or degenerated collagen) are characteristic

─ Palisading granulomas with histiocytes and numerous multinucleated giant cells (often Touton type and foreign body type) surrounding necrobiotic areas

─ Abundant cholesterol clefts (empty, needle-shaped spaces) within necrobiotic zones and among giant cells are a hallmark feature

─ Xanthoma cells (foamy histiocytes) are usually present, though can be focal

─ Lymphocytes and plasma cells are prominent in the infiltrate

─ Blood vessels may show thickened walls or mild inflammation, but true vasculitis usually absent

─ Epidermis may be atrophic or ulcerated

IHC

─ Histiocytes (+) CD68

─ Plasma cells show monoclonality in some cases if underlying myeloma/plasmacytoma

DDx

─ Necrobiosis lipoidica (NL) (less prominent xanthoma cells/cholesterol clefts/Touton cells, more tiered granulomas, often shin location, association with diabetes)

─ Granuloma annulare (GA) (more mucin, less cholesterol/xanthoma cells, different clinical)

─ Xanthomas (eruptive, tuberous, tendinous) (sheets of foam cells, lack prominent necrobiosis and palisading granulomas of NXG, different clinical context/lipid profiles)

─ Juvenile xanthogranuloma (JXG) (younger patients, Touton giant cells but lacks extensive necrobiosis/cholesterol clefts of NXG)

─ Reticulohistiocytoma (large epithelioid histiocytes with "ground glass" cytoplasm, different IHC, may be associated with arthritis mutilans)

─ Other palisading granulomas

Prognosis ─ Chronic, progressive, often resistant to treatment, prognosis related to associated hematologic disorder, requires workup for paraproteinemia/myeloma

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Reticulohistiocytoma (Solitary vs Multicentric Reticulohistiocytosis)

Rare histiocytic proliferation, solitary form is benign, multicentric form is systemic disease with skin lesions and destructive arthritis

Clinical

─ Solitary Reticulohistiocytoma: firm, skin-colored, reddish-brown, or yellowish papule or nodule, usually on head, neck, or upper trunk, asymptomatic, benign

─ Multicentric Reticulohistiocytosis (MRH):

─ Multiple cutaneous papules/nodules, often periungual ("coral beads"), ears, face, extensor surfaces

─ Severe, symmetrical, deforming, erosive polyarthritis (arthritis mutilans), especially affecting interphalangeal joints of hands

─ Mucosal lesions, fever, weight loss, internal organ involvement can occur

─ May be associated with underlying malignancy (paraneoplastic MRH in ~25%) or autoimmune disease

─ More common in middle-aged women

Micro

─ Well-circumscribed (solitary) or diffuse (multicentric) dermal infiltrate of histiocytes

─ Characteristic cells: large, polygonal to rounded histiocytes with abundant, finely granular, eosinophilic "ground glass" or "glassy" cytoplasm

─ Nuclei are often large, vesicular, sometimes multiple (multinucleated giant cells of reticulohistiocytic type), can be pleomorphic but usually not overtly malignant

─ Touton-type giant cells are typically absent or rare

─ Lymphocytes and plasma cells may be present in infiltrate

─ Minimal to no lipidization (foam cells) or necrobiosis

─ Stroma may be fibrous

IHC

─ Histiocytes (+) CD68, CD163, Factor XIIIa (variable)

─ (-) S100, CD1a (distinguishes from Langerhans cell histiocytosis and melanocytic lesions)

─ PAS stain highlights granular cytoplasm, diastase resistant

DDx

─ Juvenile xanthogranuloma (JXG) (younger patients, Touton giant cells prominent, lacks "ground glass" cytoplasm, CD163+, Factor XIIIa often negative)

─ Xanthomas (foam cells prominent, different clinical/lipid profile)

─ Granuloma annulare/Necrobiosis lipoidica (palisading granulomas, necrobiosis, mucin)

─ Langerhans cell histiocytosis (LCH) (folded/grooved nuclei, CD1a+, S100+, Birbeck granules on EM)

─ Dermatofibroma (cellular variant) (spindle cells, storiform pattern, Factor XIIIa+, CD163+)

─ Melanoma/Spitz nevus (if epithelioid cells prominent – S100+, melanocytic markers+)

─ Epithelioid sarcoma (more atypia, necrosis, CK+, EMA+, CD34 variable)

Prognosis ─ Solitary reticulohistiocytoma is benign, Multicentric reticulohistiocytosis is chronic, progressive, arthritis can be debilitating, prognosis may be influenced by associated malignancy

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Xanthogranuloma (XG, Juvenile Xanthogranuloma, JXG)

Common benign histiocytic proliferation, usually in infants/young children (JXG), can occur in adults (XG), typically self-healing

Clinical

─ JXG: Solitary or multiple, firm, dome-shaped, yellowish-red or tan-brown papules or nodules, usually <1 cm

─ Most common on head, neck, upper trunk of infants and young children (often appears in first year of life)

─ Usually asymptomatic, spontaneously regresses over months to years

─ Ocular involvement (iris, ciliary body) can occur, may lead to glaucoma, hyphema (rare)

─ Systemic JXG (rare) can involve liver, lung, spleen, CNS

─ Association with neurofibromatosis type 1 (NF1) and juvenile myelomonocytic leukemia (JMML) in children with multiple JXG

─ Adult XG: less common, similar lesions, may be larger, more persistent

Micro

─ Well-circumscribed, dense, dermal (sometimes extending to subcutis) infiltrate of histiocytes, often with admixed inflammatory cells

─ Early lesions: predominantly monomorphous infiltrate of plump histiocytes with vesicular nuclei, eosinophilic cytoplasm, few lipid vacuoles

─ Mature lesions (classic JXG):

─ Mixed infiltrate of foamy histiocytes (lipid-laden macrophages), spindle cells, lymphocytes, eosinophils

─ Touton giant cells are characteristic (but not always present): multinucleated giant cells with a peripheral wreath of nuclei, central eosinophilic cytoplasm, and peripheral foamy (lipidized) cytoplasm

─ Lymphocytes and eosinophils often present, plasma cells less common

─ No significant necrobiosis (unlike NXG)

─ Epidermis usually normal or slightly flattened, rarely ulcerated

IHC

─ Histiocytes (+) CD68, CD163, Factor XIIIa (often), Fascin

─ Touton giant cells share this profile

─ (-) CD1a, S100 (distinguishes from Langerhans cell histiocytosis and melanocytic lesions)

DDx

─ Reticulohistiocytoma (large histiocytes with "ground glass" cytoplasm, different IHC, often associated with arthritis in adults)

─ Langerhans cell histiocytosis (LCH) (folded/grooved nuclei, CD1a+, S100+, Birbeck granules on EM, often epidermotropism)

─ Dermatofibroma (spindle cells, storiform pattern, entrapped collagen, Factor XIIIa+, CD163+, but lacks Touton cells and prominent foam cells of JXG)

─ Benign cephalic histiocytosis (clinically similar papules on face/neck of infants, histologically more monomorphous histiocytes, lacks Touton cells/significant foam cells)

─ Xanthomas (eruptive, tuberous) (sheets of foam cells, associated with hyperlipidemia, different clinical context)

─ Spitz nevus/Melanoma (if epithelioid cells prominent – S100+, melanocytic markers+)

Prognosis ─ JXG usually benign and self-resolving, adult XG may be more persistent, monitor for NF1/JMML if multiple JXG in children, ocular JXG needs ophthalmologic management

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Rosai Dorfman Disease (RDD, Sinus Histiocytosis with Massive Lymphadenopathy)

Rare benign histiocytic proliferative disorder, primarily affecting lymph nodes, but cutaneous involvement occurs in ~10% (purely cutaneous RDD is rarer)

Clinical

─ Systemic RDD: massive, painless, bilateral cervical lymphadenopathy, fever, leukocytosis, elevated ESR, polyclonal hypergammaglobulinemia

─ Cutaneous RDD (with or without systemic disease): variable lesions – yellowish-brown or erythematous papules, nodules, plaques, or infiltrative masses, can occur anywhere, head/neck common

─ Usually children or young adults, can affect any age

Micro

─ Dense, diffuse or nodular dermal infiltrate, may extend into subcutis

─ Characteristic cells: very large histiocytes (Rosai-Dorfman cells) with abundant pale eosinophilic or clear cytoplasm and large, vesicular, often round to oval nuclei with prominent nucleoli

─ Emperipolesis is the hallmark feature: intact lymphocytes, plasma cells, neutrophils, or red blood cells seen within the cytoplasm of the large histiocytes (not phagocytosed, but passing through)

─ Background infiltrate of lymphocytes and numerous plasma cells is typical

─ Fibrosis (stromal sclerosis) may be prominent, especially in older lesions

─ Foamy histiocytes and Touton giant cells are usually absent

─ Epidermis usually normal or acanthotic, rarely ulcerated

IHC

─ Large histiocytes (Rosai-Dorfman cells) (+) S100 (strong nuclear and cytoplasmic), CD68, CD163, Fascin

─ (-) CD1a (distinguishes from Langerhans cell histiocytosis)

─ Emperipoletic cells retain their respective markers (eg, CD3/CD20 for lymphocytes, CD138 for plasma cells)

DDx

─ Langerhans cell histiocytosis (LCH) (CD1a+, S100+, grooved nuclei, Birbeck granules, lacks emperipolesis by large S100+ histiocytes)

─ Juvenile xanthogranuloma (JXG)/Xanthomas (Touton giant cells, foam cells, S100-, CD1a-)

─ Reticulohistiocytoma ("ground glass" cytoplasm, S100-, CD1a-, often more giant cells without classic emperipolesis)

─ Malignant melanoma (if large epithelioid cells – S100+ but also Melan-A+, SOX10+, lacks emperipolesis)

─ Other histiocytic proliferations/granulomatous disorders (careful attention to cytology and emperipolesis)

─ Lymphoma (especially Hodgkin or large cell lymphoma if infiltrate is very dense – specific lymphoid markers)

Prognosis ─ Systemic RDD often self-limited but can be chronic or rarely fatal if vital organs compromised, purely cutaneous RDD generally has good prognosis, may regress spontaneously or respond to local/systemic therapies

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Granuloma Annulare (GA)

Common, benign, self-limited inflammatory dermatosis characterized by annular or arcuate plaques, due to dermal collagen degeneration and palisading granulomatous inflammation

Clinical

─ Annular or arcuate, skin-colored, erythematous, or violaceous, firm papules or plaques with a raised border and often central clearing

─ Common on dorsal hands, feet, fingers, elbows, knees (acral sites)

─ Usually asymptomatic or mildly pruritic

─ Variants:

─ Localized GA: most common, few annular lesions

─ Generalized GA: widespread papules/plaques, often in older adults, may be associated with diabetes mellitus, thyroid disease, or malignancy (rarely)

─ Subcutaneous GA (deep GA, pseudorheumatoid nodule): firm, deep dermal or subcutaneous nodules, often on scalp, shins, buttocks, hands, feet, especially in children

─ Perforating GA: umbilicated papules with central crust/plug, transepidermal elimination of altered collagen

─ Patch GA: flat, macular, erythematous or brownish patches, often on trunk

Micro

─ Palisading granuloma: histiocytes (epithelioid cells) and lymphocytes arranged in a palisade around a central area of altered (necrobiotic or degenerated) collagen and increased mucin (Alcian blue+)

─ Collagen in center appears swollen, eosinophilic, fibrillar, or pale and smudgy, with decreased cellularity

─ Mucin deposition in center of palisade is characteristic

─ Interstitial pattern: histiocytes and lymphocytes scattered interstitially between dermal collagen bundles, often with perivascular accentuation, mucin often present (may be more common than classic palisading)

─ Mixed pattern (palisading and interstitial)

─ Multinucleated giant cells may be present

─ Lymphocytes, and sometimes few eosinophils or plasma cells, in infiltrate

─ Blood vessels usually normal, no significant vasculitis

─ Epidermis typically normal, or slight acanthosis in papular lesions

─ Perforating GA: shows transepidermal elimination of necrobiotic collagen and mucin

DDx

─ Necrobiosis lipoidica (NL) (more "tiered" or layered granulomas involving full dermis/septa, more plasma cells, prominent vascular changes, epidermal atrophy, often shin location, association with diabetes)

─ Rheumatoid nodule (deeper, often subcutaneous, more central fibrinoid necrosis, lacks prominent mucin, different clinical context)

─ Epithelioid sarcoma (malignant spindle/epithelioid cells forming pseudogranulomatous nodules, atypia, necrosis, CK+/EMA+)

─ Interstitial granulomatous dermatitis (often associated with arthritis/autoimmune disease, different clinical, may have more "floating granulomas" or "busy dermis" appearance)

─ Sarcoidosis (naked epithelioid granulomas, no significant necrobiosis or mucin)

─ Fungal/Mycobacterial granulomas (organisms on special stains, often suppurative component)

─ Annular elastolytic giant cell granuloma (loss of elastic fibers in center of granuloma, phagocytosis of elastin by giant cells, sun-exposed sites)

Prognosis ─ Benign, often self-limited, localized lesions usually resolve in months to 2 years, generalized GA can be more persistent

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Rheumatoid Nodule

Subcutaneous or deep dermal granulomatous nodule, occurring in patients with rheumatoid arthritis (RA), or rarely other conditions

Clinical

─ Firm, non-tender, subcutaneous nodules, 0,5-5 cm in diameter

─ Typically over pressure points or juxta-articular sites: elbows, fingers (extensor aspect), forearms, occiput, sacrum, Achilles tendon

─ Occur in ~20-30% of patients with RA, usually seropositive (RF+) and with more severe, erosive arthritis

─ Pseudorheumatoid nodules: histologically similar nodules in children without RA (often scalp, pretibial, feet), usually solitary, self-limited

─ Granuloma annulare (deep/subcutaneous variant) can be histologically identical to pseudorheumatoid nodule

Micro

─ Well-circumscribed, deep dermal or subcutaneous nodule

─ Central zone of prominent fibrinoid necrosis (intensely eosinophilic, acellular, smudgy material composed of fibrin, degenerated collagen, cellular debris)

─ Surrounding palisade of histiocytes (epithelioid cells) and fibroblasts, radially arranged around the necrotic center

─ Outer layer of chronic inflammatory cells (lymphocytes, plasma cells) and fibrosis

─ Vasculitis may be present in small vessels at periphery of nodule in some cases

─ Mucin is typically absent or minimal in the necrotic center (unlike GA)

DDx

─ Granuloma annulare (deep/subcutaneous variant) (more prominent mucin in center, less fibrinoid necrosis, lacks association with RA, often histologically indistinguishable from pseudorheumatoid nodule)

─ Necrobiosis lipoidica (more tiered/layered granulomas, plasma cells, vascular changes, epidermal atrophy, shin location, diabetes association)

─ Epithelioid sarcoma (malignant, cytologic atypia, CK+/EMA+)

─ Gouty tophus (urate crystals – birefringent needles, amorphous material, different giant cell reaction)

─ Calcinosis cutis (calcium deposits, different type of necrosis/inflammation)

─ Infectious granuloma (eg, deep fungal, mycobacterial – organisms on special stains, often suppuration or caseation)

Prognosis ─ Benign lesion itself, reflects underlying RA activity, may persist or regress, can ulcerate or become infected

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Epithelioid Sarcoma

Rare, aggressive soft tissue sarcoma, often in young adults, typically on distal extremities, can mimic granulomatous inflammation or carcinoma

Clinical

─ Slow-growing, firm, often ulcerated nodule or plaque, may be tender

─ Most common on distal extremities (fingers, hands, forearms, feet, lower legs), can occur on trunk, head/neck

─ Often young adults (10-40 years), more common in males

─ High propensity for local recurrence, regional lymph node, and distant metastasis (especially lungs)

─ Two main types:

─ Conventional (distal) type: as described above

─ Proximal-type (large cell epithelioid sarcoma): more aggressive, often axial (trunk, perineum, pelvis), larger cells, worse prognosis

Micro

─ Nodular or infiltrative growth pattern in dermis and/or subcutis

─ Composed of plump epithelioid and spindle cells, often arranged in a pseudogranulomatous or pseudo-carcinomatous pattern

─ Cells have abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, significant cytologic atypia

─ Central necrosis within tumor nodules is common and characteristic, often with surrounding palisading of tumor cells (mimicking rheumatoid nodule or GA)

─ Mitotic figures, including atypical forms, are usually present

─ Infiltrative growth along fascial planes, tendons, neurovascular bundles common

─ Lymphovascular invasion may be seen

IHC

─ Tumor cells characteristically (+) Cytokeratins (AE1/AE3, CAM5,2, CK7, CK19), EMA, Vimentin (coexpression is typical)

─ (+) CD34 in ~50% of cases (especially conventional type)

─ Loss of INI1 (SMARCB1/BAF47) expression is a hallmark feature in >90% of cases (nuclear staining lost in tumor cells, retained in background normal cells)

─ (-) S100, Melan-A, Desmin, Myogenin (helps exclude melanoma, MPNST, rhabdomyosarcoma)

─ ERG or other vascular markers usually negative (helps exclude epithelioid vascular tumors)

DDx

─ Granulomatous inflammation (eg, rheumatoid nodule, GA, deep fungal/mycobacterial) (lacks significant atypia and CK/EMA positivity of epithelioid sarcoma, INI1 retained)

─ Squamous cell carcinoma (poorly differentiated or spindle cell) (usually more obvious epidermal connection or squamous differentiation, INI1 retained, different CK profile sometimes)

─ Melanoma (especially epithelioid or desmoplastic) (S100+, SOX10+, Melan-A/HMB-45+, INI1 retained)

─ Synovial sarcoma (biphasic or monophasic spindle cell, TLE1+, often SS18-SSX fusion)

─ Other epithelioid soft tissue sarcomas (eg, epithelioid angiosarcoma, epithelioid MPNST – specific markers)

Prognosis ─ Aggressive, high rates of local recurrence (up to 70%) and distant metastasis (30-50%), proximal type generally worse prognosis than conventional distal type

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Sarcoidosis

Multisystem granulomatous disease of unknown etiology, characterized by non-caseating epithelioid granulomas in affected organs, skin involvement common

Clinical

─ Cutaneous lesions in ~25-35% of patients, highly variable ("great imitator"):

─ Papular sarcoidosis: small, reddish-brown or violaceous papules, often on face (eyelids, periorbital, nasolabial folds), neck, upper trunk

─ Plaque sarcoidosis: larger, indurated, annular or polycyclic plaques, often violaceous or brownish, common on trunk, extremities, buttocks, face

─ Nodular sarcoidosis: firm, subcutaneous or dermal nodules

─ Lupus pernio: violaceous, indurated plaques/nodules on nose, cheeks, ears, lips, fingers (associated with chronic fibrotic lung disease, bone cysts)

─ Scar sarcoidosis: infiltration of old scars or tattoos

─ Subcutaneous sarcoidosis (Darier-Roussy): deep, firm nodules without epidermal change

─ Ichthyosiform, ulcerative, hypopigmented, angiolupoid variants also occur

─ Systemic involvement common: lungs (bilateral hilar lymphadenopathy, pulmonary infiltrates/fibrosis), eyes (uveitis, sicca), liver, spleen, lymph nodes, heart, CNS

─ Löfgren's syndrome: acute presentation with fever, bilateral hilar adenopathy, erythema nodosum, polyarthralgias (good prognosis)

─ Heerfordt's syndrome (uveoparotid fever): uveitis, parotid enlargement, facial palsy, fever

Micro

─ Well-formed, discrete, non-caseating epithelioid cell granulomas in dermis, sometimes extending into subcutis

─ Granulomas composed of tightly clustered epithelioid histiocytes (plump cells with abundant eosinophilic cytoplasm, indistinct cell borders, vesicular nuclei)

─ Multinucleated giant cells (Langhans or foreign body type) often present within granulomas

─ Characteristic feature: "Naked" granulomas – surrounded by sparse or no lymphocytic infiltrate (though some lymphocytes are usually present)

─ No significant central necrosis (caseation) or prominent inflammation (eg, neutrophils, plasma cells) within granulomas

─ Inclusions within giant cells/histiocytes (not specific, can be seen in other granulomas):

─ Schaumann bodies: laminated, calcified concretions

─ Asteroid bodies: star-shaped eosinophilic structures

─ Epidermis usually normal or slightly atrophic, rarely ulcerated

─ Fungal and mycobacterial stains should be negative

DDx

─ Tuberculoid granulomas (eg, tuberculosis, atypical mycobacteria, deep fungi – often show some caseation necrosis, more prominent lymphocytic cuffing, organisms on special stains)

─ Granuloma annulare/Necrobiosis lipoidica (palisading granulomas, central mucin or necrobiosis, different clinical)

─ Foreign body granuloma (foreign material often visible or polarizable, different giant cells)

─ Crohn's disease (cutaneous) (non-caseating granulomas, but often perivascular/periadnexal, history of IBD)

─ Rosacea (granulomatous variant) (perifollicular granulomas, often with Demodex, different clinical)

─ Interstitial granulomatous dermatitis (different pattern, often lacks well-formed naked granulomas)

─ Beryllium disease (histologically identical, history of exposure)

Prognosis ─ Variable, many have spontaneous remission, some have chronic progressive disease, depends on extent and severity of organ involvement, Löfgren's usually good prognosis

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Langerhans Cell Histiocytosis (LCH)

Clonal proliferation of Langerhans cells, part of a spectrum of disorders previously known as histiocytosis X (Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma)

Clinical

─ Highly variable, depends on age and extent of organ involvement

─ Cutaneous lesions:

─ Infants/young children (Letterer-Siwe type, often multisystem): seborrheic dermatitis-like rash (scalp, face, intertriginous), scaly or crusted papules, vesicles, pustules, petechiae, purpura, nodules, ulcers, often widespread

─ Older children/adults (Hand-Schüller-Christian type or localized eosinophilic granuloma): more localized skin lesions, or bone lesions (lytic skull lesions, diabetes insipidus, exophthalmos – classic triad), lung, liver, spleen, lymph node involvement

─ Congenital self-healing reticulohistiocytosis (Hashimoto-Pritzker): solitary or multiple reddish-brown nodules at birth or neonatal, spontaneously regress

Micro

─ Diffuse or nodular dermal infiltrate, often with epidermotropism (infiltration of epidermis by Langerhans cells)

─ Characteristic cells: Langerhans cells – medium to large cells with abundant, pale eosinophilic cytoplasm, indistinct cell borders, and characteristic folded, grooved, or reniform (kidney-bean shaped) nuclei, nucleoli usually inconspicuous

─ Mitotic activity can be present but usually not atypical

─ Admixed inflammatory cells often present: numerous eosinophils (characteristic), lymphocytes, neutrophils, plasma cells, histiocytes

─ Epidermal changes: acanthosis, spongiosis, parakeratosis, ulceration, Pautrier-like microabscesses (collections of Langerhans cells in epidermis)

─ Hemorrhage common

─ Electron microscopy (EM): Birbeck granules (tennis-racket shaped intracytoplasmic organelles) in Langerhans cells (diagnostic but rarely needed)

IHC

─ Langerhans cells (+) CD1a (strong membranous staining, most specific), S100 protein (nuclear and cytoplasmic), Langerin (CD207)

─ (+) CD68 (variable), Vimentin

─ Ki-67 proliferation index variable

DDx

─ Juvenile xanthogranuloma (JXG) (Touton giant cells, foam cells, CD1a-, S100 often negative in histiocytes)

─ Reticulohistiocytoma ("ground glass" cytoplasm, S100-, CD1a-)

─ Mycosis fungoides (epidermotropism of atypical T-lymphocytes, CD3+, CD4+, CD1a-)

─ Spongiotic dermatitis with eosinophils (eg, allergic contact, atopic – lacks atypical Langerhans cells, CD1a-)

─ Other histiocytic disorders (eg, Rosai-Dorfman – emperipolesis, S100+, CD1a-)

─ Mastocytosis (mast cells, Giemsa/toluidine blue/CD117+)

Prognosis ─ Highly variable: congenital self-healing form excellent, localized LCH (eg, single bone lesion) often good, multisystem LCH (Letterer-Siwe type) can be aggressive and fatal, especially with organ dysfunction, BRAF V600E mutation found in ~50%, may have prognostic/therapeutic implications

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Cutaneous Crohns (Disease)

Specific granulomatous skin lesions occurring in patients with Crohn's disease (inflammatory bowel disease), distinct from reactive erythemas or nutritional deficiencies associated with IBD

Clinical

─ Variable presentations:

─ Perianal/peristomal: fissures, fistulas, ulcers, edematous skin tags, vegetating plaques

─ Genital: edema, ulceration, verrucous plaques (vulva, penis, scrotum)

─ Metastatic Crohn's: erythematous or violaceous plaques, nodules, ulcers at sites distant from GI tract (eg, extremities, trunk, face), often in skin folds or areas of lymphedema

─ Lesions may precede, accompany, or follow GI manifestations of Crohn's disease

Micro

─ Non-caseating epithelioid cell granulomas in dermis and/or subcutis, often multiple and discrete

─ Granulomas composed of epithelioid histiocytes, lymphocytes, and sometimes multinucleated giant cells

─ Granulomas are often perivascular, periadnexal (around follicles/sweat glands), or interstitial

─ Lymphangiectasia and lymphedema common in affected dermis

─ Variable superficial and deep perivascular lymphocytic infiltrate, may have plasma cells or eosinophils

─ No significant necrobiosis, mucin, or prominent vasculitis usually

─ Epidermis may be normal, acanthotic, ulcerated, or show pseudoepitheliomatous hyperplasia (especially in vegetating lesions)

─ Special stains for organisms (fungi, mycobacteria) are negative

DDx

─ Sarcoidosis (naked granulomas, less periadnexal/perivascular focus, different clinical context, though can be histologically very similar)

─ Foreign body granuloma (foreign material identifiable)

─ Infectious granulomas (eg, tuberculosis, deep fungal – organisms on special stains, may have caseation or suppuration)

─ Cheilitis granulomatosa/Melkersson-Rosenthal syndrome (if orofacial Crohn's – similar granulomas, lymphedema)

─ Hidradenitis suppurativa (if intertriginous/perianal – involves follicular occlusion, sinus tracts, plasma cells, lacks discrete granulomas of Crohn's usually)

─ Lymphoma (Hodgkin or T-cell with granulomatous reaction – atypical lymphoid cells)

Prognosis ─ Chronic, reflects activity of underlying Crohn's disease, skin lesions can be difficult to manage

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Lupus Miliaris Disseminatus Faciei (LMDF, Acne Agminata, FIGURE)

Chronic inflammatory dermatosis of unknown etiology, characterized by reddish-brown or yellowish papules on the face, especially central face and eyelids

Clinical

─ Multiple, discrete, small (1-5 mm), dome-shaped, reddish-brown, yellowish, or skin-colored papules

─ Typically on central face, especially eyelids (often lower), periorbital area, cheeks, nose, upper lip, chin

─ Lesions are usually asymptomatic, may be slightly pruritic

─ Can heal with small, pitted scars

─ Considered by some a variant of granulomatous rosacea or a tuberculid, but etiology remains unclear, "FIGURE" (Facial Idiopathic GRanulomas with Regressive Evolution) is a newer term

Micro

─ Well-formed epithelioid cell granulomas in the dermis, often centered around hair follicles or adnexal structures

─ Granulomas are typically tuberculoid type (epithelioid histiocytes, lymphocytes, multinucleated giant cells of Langhans type)

─ Characteristic feature: Central caseation necrosis within the granulomas is common and a key diagnostic pointer for LMDF (distinguishes from sarcoidosis and most rosacea)

─ Lymphocytic infiltrate surrounds granulomas, may have few plasma cells

─ No significant vasculitis, no prominent mucin or necrobiosis (as in GA/NL)

─ Special stains for acid-fast bacilli (AFB) and fungi (GMS, PAS) are negative

─ Epidermis usually normal or slightly acanthotic, may show follicular plugging if granuloma involves follicle

DDx

─ Granulomatous rosacea (perifollicular granulomas, but usually lacks prominent caseation necrosis, often has Demodex, other rosacea features like telangiectasias, flushing)

─ Sarcoidosis (papular facial) (naked epithelioid granulomas, no caseation necrosis, systemic involvement possible)

─ Tuberculosis (lupus vulgaris) (tuberculoid granulomas, may have caseation, AFB may be positive or PCR for MTB)

─ Atypical mycobacterial infection (granulomas, may have suppuration or caseation, AFB positive)

─ Deep fungal infection (eg, cutaneous blastomycosis, coccidioidomycosis – organisms visible, different granuloma type)

─ Syphilis (secondary or tertiary) (plasma cells prominent, spirochetes on special stain/IHC)

─ Perioral dermatitis (granulomatous variant) (perifollicular/perivascular inflammation, granulomas, but usually less caseation, different clinical)

─ Foreign body granuloma (foreign material, different giant cells)

Prognosis ─ Benign, chronic course, lesions often resolve spontaneously over 1-3 years, but may leave residual scarring

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Xanthelasma (Palpebrarum)

Most common type of xanthoma, characterized by yellowish, soft plaques on eyelids, often associated with hyperlipidemia but can be normolipemic

Clinical

─ Soft, velvety, yellowish or orange, flat or slightly elevated plaques

─ Typically located symmetrically on Media ─ placeholder l aspects of upper and/or lower eyelids

─ Usually asymptomatic, primarily a cosmetic concern

─ Can occur in normolipemic individuals (especially older adults) or be associated with primary or secondary hyperlipidemia (especially elevated LDL cholesterol, Type IIa or IIb hyperlipoproteinemia)

─ May be associated with increased risk of atherosclerosis if hyperlipidemia present

Micro

─ Dermal infiltrate of numerous foamy histiocytes (xanthoma cells) in superficial and mid-dermis

─ Xanthoma cells: large macrophages with abundant, pale, multivacuolated (foamy) cytoplasm (due to lipid accumulation) and small, often eccentric nuclei

─ Cells are typically arranged in loose sheets or clusters, often around small blood vessels

─ Minimal to no associated fibrosis, inflammation, or giant cells (unlike other xanthoma types or NXG)

─ Lipid is dissolved during processing, leaving clear vacuoles (can be demonstrated with Oil Red O or Sudan black on frozen sections)

─ Epidermis is usually normal or slightly atrophic, rete ridges may be effaced

IHC

─ Foam cells (+) CD68, CD163

DDx

─ Syringoma (small ducts, tadpole shapes, fibrous stroma, periorbital but different appearance)

─ Sebaceous hyperplasia/adenoma (sebaceous differentiation, different cell morphology, usually not eyelid plaques)

─ Necrobiotic xanthogranuloma (periorbital, but indurated, ulcerating, necrobiosis, cholesterol clefts, giant cells, paraproteinemia)

─ Juvenile xanthogranuloma (children, different locations usually, Touton giant cells)

─ Erdheim-Chester disease (rare systemic histiocytosis, can have xanthelasma-like lesions, but also bone pain, systemic involvement, different histiocyte morphology/IHC – CD68+, CD1a-, S100 variable, often BRAF V600E+)

Prognosis ─ Benign skin lesions, but may indicate underlying hyperlipidemia and cardiovascular risk

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Eruptive Xanthoma

Sudden onset of multiple, small, yellowish papules with an erythematous halo, typically associated with markedly elevated triglycerides (hypertriglyceridemia)

Clinical

─ Crops of small (1-5 mm), firm, yellowish or reddish-yellow papules, often with an erythematous halo

─ Common on extensor surfaces (elbows, knees), buttocks, back, may be widespread

─ Often pruritic or tender

─ Characteristic sign of severe hypertriglyceridemia (especially chylomicronemia, Type I, IV, or V hyperlipoproteinemia), often seen in uncontrolled diabetes mellitus, pancreatitis, obesity, alcoholism, certain drugs

Micro

─ Dermal infiltrate of numerous foamy histiocytes (xanthoma cells) mixed with lymphocytes, neutrophils, and sometimes eosinophils

─ Infiltrate is often perivascular and interstitial, can be quite dense

─ Extracellular lipid droplets ("milk-like" appearance in capillaries if chylomicronemia severe) may be seen in early lesions before prominent foam cell formation

─ Neutrophils can be prominent, especially in very acute lesions

─ No significant fibrosis or Touton giant cells usually (unlike tuberous or tendinous xanthomas)

─ Epidermis usually normal

DDx

─ Juvenile xanthogranuloma (children, often solitary or few, Touton giant cells)

─ Generalized eruptive histiocytoma (rare, monomorphous histiocytes, no foam cells/lipid, different clinical)

─ Langerhans cell histiocytosis (papular variant) (CD1a+, S100+, grooved nuclei)

─ Urticaria papulosa (arthropod bites) (more eosinophils, less foam cells, clinical history)

─ Disseminated granuloma annulare (annular lesions, palisading granulomas with mucin)

Prognosis ─ Skin lesions resolve with control of underlying hypertriglyceridemia, marker of severe metabolic disturbance

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Tuberous Xanthoma

Firm, yellowish or reddish, painless nodules and plaques, often over joints and pressure areas, associated with hypercholesterolemia

Clinical

─ Firm, non-tender, yellowish, pinkish, or reddish-brown papules, nodules, or plaques, can be quite large and lobulated

─ Typically located over pressure areas and extensor surfaces, especially elbows, knees, knuckles, buttocks, heels

─ Associated with severe hypercholesterolemia (especially familial hypercholesterolemia, Type IIa, or Type III hyperlipoproteinemia)

Micro

─ Dense dermal (often extending to subcutis) infiltrate composed predominantly of sheets of foamy histiocytes (xanthoma cells)

─ Variable numbers of lymphocytes, neutrophils, and fibroblasts may be present

─ Multinucleated giant cells, including Touton type, can be seen but often less prominent than in JXG or NXG

─ Cholesterol clefts may be present within the infiltrate

─ Fibrosis (stromal collagen deposition) is common, especially in older lesions, can be extensive

─ Epidermis usually normal or acanthotic

DDx

─ Tendinous xanthoma (histologically similar, but located within tendons, associated with severe hypercholesterolemia)

─ Eruptive xanthoma (smaller, more acute, more inflammatory, associated with hypertriglyceridemia)

─ Juvenile xanthogranuloma (children, often solitary, Touton cells more consistently prominent)

─ Reticulohistiocytoma ("ground glass" cytoplasm, different IHC, often arthritis)

─ Dermatofibroma (cellular or lipidized variant) (spindle cells, storiform pattern, Factor XIIIa+, lacks extensive sheets of foam cells)

─ Necrobiotic xanthogranuloma (periorbital, ulcerating, prominent necrobiosis, paraproteinemia)

Prognosis ─ Skin lesions are benign but indicate significant underlying hypercholesterolemia and high cardiovascular risk

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Verruciform Xanthoma

Uncommon benign lesion, usually of oral mucosa, less often skin or anogenital mucosa, characterized by papillomatous epithelial hyperplasia with lipid-laden foam cells in dermal papillae

Clinical

─ Solitary, sessile or pedunculated, warty or cauliflower-like papule or plaque

─ Usually <2 cm, often pink, reddish, yellowish, or gray-white

─ Most common on oral mucosa (gingiva, alveolar ridge, palate), can occur on anogenital skin (vulva, penis, scrotum) or other cutaneous sites

─ Usually asymptomatic, may be associated with chronic inflammation, lymphedema, or certain genodermatoses (eg, CHILD syndrome)

Micro

─ Verrucous or papillomatous epidermal/mucosal epithelial hyperplasia with acanthosis, hyperkeratosis, and often parakeratosis

─ Elongated rete ridges, often with bridging

─ Characteristic feature: Numerous foamy histiocytes (xanthoma cells) filling the dermal papillae and superficial lamina propria, between the elongated rete

─ Xanthoma cells: large macrophages with abundant, pale, multivacuolated cytoplasm and small nuclei

─ Superficial dermal inflammatory infiltrate, often with lymphocytes, plasma cells, and neutrophils, may be present

─ No significant cytologic atypia in epithelial cells or foam cells

─ Lipid in foam cells can be stained with Oil Red O on frozen sections

DDx

─ Verruca vulgaris/Condyloma acuminatum (viral cytopathic changes – koilocytes, lacks prominent foam cells in papillae)

─ Squamous cell carcinoma (verrucous variant) (cytologic atypia, invasive growth, lacks foam cells in papillae)

─ Oral florid papillomatosis (extensive papillomatosis, but lacks xanthoma cells)

─ Other xanthomas (eg, eruptive, tuberous – different clinical presentation, foam cells not confined to papillae of a verrucous lesion)

─ Granular cell tumor (if oral/cutaneous nodule – large cells with granular eosinophilic cytoplasm, S100+, pseudoepitheliomatous hyperplasia overlying, but different cells)

Prognosis ─ Benign, recurrence possible if incompletely excised

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Vaculitis

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Giant Cell Arteritis (Temporal Arteritis, Cranial Arteritis)

Systemic vasculitis of large and medium-sized arteries, characteristically involving temporal artery, often associated with polymyalgia rheumatica

Clinical

─ New onset headache (often temporal), scalp tenderness, jaw claudication, visual disturbances (amaurosis fugax, diplopia, blindness due to ophthalmic artery involvement – medical emergency)

─ Systemic symptoms: fever, malaise, weight loss, fatigue

─ Temporal artery may be thickened, tender, nodular, with reduced or absent pulse

─ Strongly associated with polymyalgia rheumatica (PMR – pain/stiffness in neck, shoulders, hips)

─ Usually affects individuals >50 years old, more common in women, Northern European descent

─ Elevated ESR and C-reactive protein common

─ Skin lesions rare: scalp necrosis, ulceration, purpura, nodules over affected arteries

Micro (Temporal Artery Biopsy):

─ Panarteritis: inflammatory infiltrate involving all layers of arterial wall (intima, Media ─ placeholder , adventitia)

─ Characteristic granulomatous inflammation: epithelioid histiocytes and multinucleated giant cells (Langhans or foreign body type) within arterial wall, often concentrated near fragmented internal elastic lamina

─ Lymphocytes and plasma cells also present in infiltrate, eosinophils less common

─ Fragmentation, reduplication, or destruction of internal elastic lamina (best seen with elastic stain, eg, Verhoeff-van Gieson) is a key feature

─ Intimal thickening and proliferation, leading to luminal narrowing or occlusion

─ Thrombosis may occur

─ "Skip lesions": inflammation may be focal, requiring adequate biopsy length (≥1-2 cm) and multiple sections

─ Healed phase: fibrosis, scarring, chronic inflammation, neovascularization

DDx

─ Polyarteritis nodosa (PAN) (usually affects medium-sized arteries at bifurcations, often involves skin/kidney/GI, different granulomatous features, often associated with Hepatitis B)

─ Other large vessel vasculitides (eg, Takayasu arteritis – younger patients, aortic arch/branches)

─ Thromboangiitis obliterans (Buerger's disease) (smokers, distal extremities, occlusive thrombi with inflammation)

─ Non-inflammatory arterial disease (eg, atherosclerosis – different pathology)

─ Infectious arteritis (rare, organisms may be identifiable)

Prognosis ─ Good with prompt corticosteroid treatment (prevents blindness), but relapses can occur, PMR often coexists and responds to steroids

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Polyarteritis Nodosa (PAN)

Systemic necrotizing vasculitis of small and medium-sized muscular arteries, can involve multiple organs, cutaneous involvement common

Clinical

─ Systemic PAN: fever, weight loss, myalgias, arthralgias, neuropathy (mononeuritis multiplex), hypertension, renal involvement (glomerulonephritis rare, more infarcts/ischemia), GI (pain, bleeding, infarction), cardiac

─ Cutaneous PAN (limited to skin, or part of systemic):

─ Tender subcutaneous nodules, often along course of arteries, especially on lower legs, thighs

─ Livedo reticularis or racemosa

─ Palpable purpura, ulcerations, digital gangrene, infarcts

─ May be idiopathic or associated with Hepatitis B virus infection (~10-30%), Hepatitis C, HIV, hairy cell leukemia, other autoimmune diseases

Micro

─ Segmental, necrotizing vasculitis of medium-sized or small muscular arteries in deep dermis or subcutaneous tissue (arterioles/venules usually spared, unlike LCV)

─ Fibrinoid necrosis of vessel wall (intensely eosinophilic, smudgy material)

─ Inflammatory infiltrate involving full thickness of vessel wall and perivascular area

─ Acute lesions: predominantly neutrophils, with karyorrhexis (leukocytoclasis), eosinophils may be present

─ Chronic lesions: lymphocytes, histiocytes, plasma cells, may have granulomatous features or fibrosis

─ Luminal thrombosis common, leading to ischemic changes in overlying skin (ulceration, necrosis)

─ Aneurysmal dilatation of affected vessels can occur

─ Internal elastic lamina may be fragmented or destroyed

─ Changes often focal, affecting segments of arteries

DDx

─ Leukocytoclastic vasculitis (LCV) (affects smaller vessels – postcapillary venules, more superficial usually, different clinical – palpable purpura)

─ Giant cell arteritis (larger arteries, granulomatous inflammation, different clinical)

─ Thromboangiitis obliterans (Buerger's disease) (smokers, distal extremities, occlusive thrombi with inflammation, less fibrinoid necrosis)

─ Nodular vasculitis/Erythema induratum (lobular panniculitis with vasculitis of small/medium vessels, often granulomatous, associated with TB)

─ Septic vasculitis/Emboli (organisms may be present, different clinical context)

─ Antiphospholipid syndrome/Other thrombotic vasculopathies (thrombosis prominent, less primary vessel wall inflammation/necrosis)

Prognosis ─ Systemic PAN can be serious/fatal if untreated, prognosis improved with corticosteroids/immunosuppressants, cutaneous PAN has better prognosis but can be chronic/recurrent

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Thrombophlebitis

Inflammation of a vein associated with thrombus formation, usually superficial veins (superficial thrombophlebitis)

Clinical

─ Superficial thrombophlebitis: tender, erythematous, indurated, linear or cord-like lesion along course of a superficial vein, often on legs

─ May be associated with varicose veins, trauma, IV cannulation, infection, hypercoagulable states, pregnancy, OCPs

─ Migratory superficial thrombophlebitis (Trousseau's syndrome) can be a sign of underlying malignancy (especially pancreatic, lung, GI) or Behçet's disease

─ Deep vein thrombosis (DVT): involves deep veins, often leg swelling, pain, erythema, risk of pulmonary embolism

Micro

─ Vein (superficial or deep dermis/subcutis) shows:

─ Occlusive or partially occlusive thrombus within lumen (composed of fibrin, platelets, red blood cells, inflammatory cells)

─ Inflammatory infiltrate within and around vein wall, composed of neutrophils (acute), lymphocytes, histiocytes (chronic), sometimes eosinophils or giant cells

─ Endothelial cell damage or proliferation

─ Edema and fibrosis of vein wall and perivenular tissue

─ Organization of thrombus (ingrowth of fibroblasts, capillaries) and recanalization in older lesions

─ No significant fibrinoid necrosis of vessel wall (distinguishes from true vasculitis involving veins)

─ Superficial thrombophlebitis often involves septa of subcutaneous fat (septal panniculitis pattern)

DDx

─ Vasculitis (eg, PAN, LCV – involves arteries or smaller venules respectively, shows fibrinoid necrosis of vessel wall)

─ Cellulitis/Erysipelas (more diffuse dermal inflammation, bacterial infection, lacks primary venous thrombosis/inflammation)

─ Erythema nodosum (septal panniculitis, but usually no primary venous thrombosis, often Miescher's radial granulomas)

─ Panniculitis (other types) (inflammation centered in fat lobules or septa without primary venous involvement)

─ Lymphangitis (inflammation of lymphatic vessels, red streaks clinically, different histology)

Prognosis ─ Superficial thrombophlebitis usually benign and self-limited, DVT carries risk of PE, migratory thrombophlebitis warrants investigation for underlying cause

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Leukocytoclastic Vasculitis (LCV, Hypersensitivity Vasculitis, Allergic Vasculitis)

Small vessel vasculitis characterized by neutrophilic inflammation, fibrinoid necrosis of vessel walls, and nuclear dust (leukocytoclasis)

Clinical

─ Palpable purpura (classic lesion): non-blanching, reddish-purple papules, most common on lower legs and dependent areas

─ Can also present as macules, petechiae, vesicles, bullae, pustules, ulcers, or necrotic lesions

─ May be associated with systemic symptoms (fever, arthralgias, myalgias) and internal organ involvement (kidney, GI, joints, lung, CNS)

─ Triggers: infections (strep, hepatitis B/C, HIV), drugs (penicillins, sulfonamides, NSAIDs, diuretics), autoimmune diseases (SLE, RA, Sjögren's), malignancy (especially hematologic), idiopathic (~50%)

─ Henoch-Schönlein purpura (IgA vasculitis): specific LCV subtype with palpable purpura, arthritis, abdominal pain, renal disease, IgA deposition in vessels

Micro

─ Necrotizing vasculitis affecting postcapillary venules (and sometimes capillaries/arterioles) in superficial and mid-dermis

─ Key features:

─ Fibrinoid necrosis: eosinophilic, smudgy fibrin deposition within and around vessel walls

─ Neutrophilic infiltrate: numerous neutrophils within vessel walls and perivascularly

─ Leukocytoclasis: nuclear dust from fragmented neutrophils (karyorrhexis)

─ Extravasation of red blood cells (purpura)

─ Endothelial cell swelling and damage

─ Luminal thrombi may be present

─ Eosinophils may be admixed, especially in drug-induced LCV

─ Older lesions: more lymphocytes, histiocytes, fibrosis

─ Direct immunofluorescence (DIF) of early lesional skin (within 24-48h): granular deposits of IgM, IgG, C3 (and IgA in HSP) in superficial dermal vessel walls

DDx

─ Septic vasculitis/Emboli (organisms in vessel walls or lumina, often more necrosis, different clinical context)

─ Polyarteritis nodosa (PAN) (affects medium-sized muscular arteries, deeper in dermis/subcutis, different clinical)

─ Urticarial vasculitis (urticarial plaques lasting >24h, LCV histology, often hypocomplementemia, systemic associations)

─ Sweet's syndrome (dense neutrophilic infiltrate, but usually no true fibrinoid necrosis or prominent leukocytoclasis, marked papillary dermal edema)

─ Arthropod bite reaction (if very neutrophilic, but usually more eosinophils, lacks true vasculitis)

─ Pigmented purpuric dermatoses (capillaritis) (lymphocytic infiltrate, RBC extravasation, hemosiderin, no fibrinoid necrosis/neutrophils)

─ Antiphospholipid syndrome/Other thrombotic vasculopathies (thrombosis prominent, less primary vessel wall inflammation/necrosis)

Prognosis ─ Usually self-limited if trigger identified and removed (eg, drug, infection), can be recurrent or chronic, systemic involvement dictates overall prognosis

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Granuloma Faciale (GF)

Uncommon, chronic, benign inflammatory dermatosis characterized by reddish-brown plaques or nodules, usually on the face, with a characteristic histologic pattern

Clinical

─ Solitary or multiple, well-demarcated, soft to firm, reddish-brown, violaceous, or skin-colored papules, plaques, or nodules

─ Most common on the face (cheeks, nose, forehead, ears), rarely extrafacial

─ Surface may be smooth, slightly elevated, with prominent follicular orifices

─ Usually asymptomatic, slow-growing, persistent

─ Primarily affects middle-aged adults, more common in men

Micro

─ Dense, diffuse, often nodular, mixed inflammatory cell infiltrate in superficial and mid-dermis

─ Characteristic feature: Grenz zone – a narrow band of uninvolved papillary dermis separating the infiltrate from an often normal or slightly acanthotic epidermis

─ Infiltrate composed of numerous neutrophils and eosinophils, admixed with lymphocytes, histiocytes, and plasma cells

─ Leukocytoclastic vasculitis involving small vessels (postcapillary venules) is often present, especially in early or active lesions (fibrinoid necrosis, neutrophils in vessel walls, karyorrhexis, RBC extravasation)

─ Fibrosis (stromal sclerosis) and hemosiderin deposition are common in older/chronic lesions

─ No true granuloma formation (despite the name "granuloma" faciale)

─ Follicular structures may be dilated or surrounded by infiltrate

DDx

─ Erythema elevatum diutinum (EED) (clinically different – extensor surfaces, often symmetrical, histologically similar LCV with fibrosis, but EED often more perivascular "onion-skin" fibrosis and cholesterol clefts in late lesions)

─ Mycosis fungoides (especially granulomatous MF or MF with eosinophils – atypical lymphocytes, epidermotropism, different IHC)

─ Lymphoma cutis (other types) (monomorphous atypical infiltrate, specific markers)

─ Pseudolymphoma (B-cell lymphoid hyperplasia) (may have germinal centers, lacks prominent neutrophils/eosinophils/LCV of GF)

─ Sweet's syndrome (more acute, fever, marked papillary dermal edema, predominantly neutrophils, lacks chronic fibrosis/hemosiderin of GF)

─ Deep fungal/mycobacterial infection (organisms on special stains, true granulomas)

Prognosis ─ Benign, but chronic, persistent, often resistant to treatment, primarily a cosmetic concern

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Erythema Elevatum Diutinum (EED)

Rare, chronic form of leukocytoclastic vasculitis characterized by persistent, firm, violaceous or yellowish-brown papules, plaques, and nodules, typically on extensor surfaces

Clinical

─ Symmetrical, firm, persistent, erythematous, violaceous, purplish, or yellowish-brown papules, plaques, or nodules

─ Most common on extensor surfaces of joints (hands, elbows, knees, ankles, feet), also buttocks, ears

─ Lesions may be painful or tender, can ulcerate

─ Associated with various conditions: chronic infections (streptococcal, HIV, hepatitis), autoimmune diseases (RA, SLE, IBD), hematologic disorders (especially IgA monoclonal gammopathy), celiac disease, or idiopathic

─ Usually affects middle-aged adults

Micro

─ Early lesions: Leukocytoclastic vasculitis (LCV) affecting small vessels in superficial and mid-dermis

─ Fibrinoid necrosis of vessel walls

─ Predominantly neutrophilic infiltrate in and around vessel walls, with leukocytoclasis (nuclear dust)

─ Eosinophils may be present

─ Extravasated red blood cells

─ Late (chronic) lesions:

─ Less active vasculitis, fewer neutrophils

─ Prominent fibrosis, often with concentric "onion-skin" perivascular fibrosis

─ Cholesterol clefts (extracellular lipid deposition) within areas of fibrosis and inflammation (characteristic of late EED)

─ Mixed inflammatory infiltrate with lymphocytes, histiocytes, plasma cells, foamy macrophages

─ Epidermis may be normal, acanthotic, or ulcerated

DDx

─ Granuloma faciale (GF) (usually facial, GF has more prominent Grenz zone, often lacks extensive fibrosis/cholesterol of late EED, though early EED and GF can show LCV)

─ Other forms of chronic LCV (eg, urticarial vasculitis – different clinical)

─ Xanthomas (tuberous, eruptive) (sheets of foam cells, different clinical/metabolic context, lack LCV)

─ Dermatofibroma (spindle cells, storiform pattern, Factor XIIIa+, lacks LCV)

─ Multicentric reticulohistiocytosis (different histiocytes with "ground glass" cytoplasm, associated arthritis mutilans)

─ Sweet's syndrome (more acute, fever, marked papillary dermal edema, dense neutrophilia without prominent LCV usually)

Prognosis ─ Benign, but very chronic and persistent, often resistant to treatment, may resolve spontaneously after many years, treatment of underlying condition (if any) may help

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Solar Purpura (Actinic Purpura, Senile Purpura, Bateman's Purpura)

Common benign condition of elderly individuals, characterized by easy bruising and ecchymoses on chronically sun-damaged skin, due to dermal atrophy and vascular fragility

Clinical

─ Irregularly shaped, dark purple or violaceous macules and patches (ecchymoses)

─ Occur on chronically sun-exposed skin, especially dorsal forearms and hands, after minor trauma or spontaneously

─ Skin is often thin, atrophic, and lax

─ Lesions are non-palpable, non-inflammatory, resolve slowly over days to weeks, often leaving residual brownish hemosiderin staining or stellate white pseudoscars

─ Usually asymptomatic

Micro

─ Extravasation of red blood cells into the dermis, often extensive, without significant inflammation or evidence of vasculitis

─ Dermis shows prominent solar elastosis (basophilic degeneration of collagen and elastic fibers)

─ Epidermis is usually atrophic, with flattening of rete ridges

─ Blood vessel walls in dermis may appear thin or normal, no fibrinoid necrosis or significant inflammatory infiltrate

─ Hemosiderin deposition (within macrophages and free) in dermis in resolving lesions

─ No significant inflammatory infiltrate, no evidence of vasculitis (no vessel wall damage, fibrin, neutrophils, or leukocytoclasis)

DDx

─ Traumatic purpura (not necessarily on sun-damaged skin, may have more associated inflammation/hematoma if severe trauma)

─ Steroid-induced purpura (history of topical or systemic steroid use, skin atrophy, similar histology)

─ Scurvy (vitamin C deficiency) (perifollicular hemorrhage, corkscrew hairs, gingival bleeding, different clinical context)

─ Amyloidosis (primary systemic or localized cutaneous) (can have purpura, amyloid deposits in vessel walls and dermis, Congo red+)

─ Thrombocytopenic purpura/Coagulation disorders (systemic cause, normal skin histology apart from hemorrhage)

─ Leukocytoclastic vasculitis (palpable purpura, inflammatory signs, LCV histology)

─ Pigmented purpuric dermatoses (capillaritis) (more "cayenne pepper" petechiae, lymphocytic capillaritis, hemosiderin)

Prognosis ─ Benign, cosmetic concern, reflects underlying dermal damage from chronic sun exposure and aging

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Wells Syndrome (Eosinophilic Cellulitis)

Uncommon inflammatory dermatosis characterized by recurrent, erythematous, edematous plaques resembling cellulitis, with prominent tissue and often blood eosinophilia

Clinical

─ Recurrent, tender, erythematous or violaceous, indurated plaques or nodules, often with edema, resembling bacterial cellulitis or urticaria

─ Lesions may be solitary or multiple, can be large, sometimes with annular or arcuate configuration

─ Common on extremities, trunk, face

─ Pruritus or burning may occur, systemic symptoms (fever, malaise, arthralgias) uncommon

─ Peripheral blood eosinophilia is common

─ May be idiopathic or associated with various triggers (arthropod bites, infections, drugs, hematologic disorders, myeloproliferative neoplasms)

Micro

─ Diffuse, dense inflammatory infiltrate throughout dermis, often extending into subcutis

─ Eosinophils are the predominant cell type, often numerous and degranulating

─ Characteristic "flame figures": eosinophilic major basic protein and other granular contents coating collagen bundles, surrounded by histiocytes and giant cells (not always present or specific)

─ Lymphocytes and histiocytes also present, neutrophils usually sparse

─ Papillary dermal edema often prominent

─ No true vasculitis (vessel walls intact, no fibrinoid necrosis), though endothelial swelling and perivascular eosinophils common

─ Epidermis usually normal or may show spongiosis or subepidermal vesiculation due to intense dermal edema

DDx

─ Arthropod bite reaction (can have marked eosinophilia and flame figures, but usually more focal, wedge-shaped, clinical history of bite)

─ Eosinophilic fasciitis (Shulman syndrome) (deeper involvement, thickened fascia, peripheral eosinophilia, sclerodermoid changes)

─ Allergic contact dermatitis (if very eosinophilic and edematous, but usually more epidermal spongiosis/vesiculation)

─ Bullous pemphigoid (urticarial phase) (pruritic plaques, eosinophils, DIF shows linear IgG/C3 at BMZ)

─ Drug eruption with eosinophilia (DRESS/DIHS) (more systemic involvement, often morbilliform rash, different histology usually)

─ Churg-Strauss syndrome (eosinophilic vasculitis, asthma, systemic involvement)

─ Hypereosinophilic syndrome (persistent blood eosinophilia, organ involvement)

─ Cellulitis (bacterial) (more neutrophils, fever, leukocytosis, bacteria may be identifiable)

Prognosis ─ Benign, recurrent course, lesions usually resolve spontaneously in weeks to months, often leaving greenish or slate-gray discoloration, may respond to corticosteroids

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Cholesterol Emboli (Atheroembolism)

Occlusion of small arteries or arterioles by cholesterol crystals dislodged from ulcerated atherosclerotic plaques, often after vascular procedures or anticoagulation

Clinical

─ Variable manifestations depending on site and extent of embolization

─ Skin: Livedo reticularis or racemosa (often lower extremities, buttocks), purpura, cyanosis ("blue toe syndrome"), digital necrosis/gangrene, ulcerations, nodules, splinter hemorrhages

─ Often painful

─ Systemic involvement common: kidney (renal failure), GI tract (pain, bleeding, infarction), CNS (stroke, TIA), eyes (Hollenhorst plaques)

─ Typically in older adults with severe atherosclerosis, often precipitated by angiography, vascular surgery, anticoagulation, or thrombolytic therapy

Micro

─ Characteristic feature: Biconvex, needle-shaped clefts (empty spaces where cholesterol crystals were dissolved during processing) within lumina of small arteries, arterioles, or occasionally capillaries in dermis or subcutis

─ Clefts are often surrounded by fibrin, thrombus material, and sometimes a foreign body giant cell reaction or minimal inflammation

─ Ischemic changes in tissue supplied by occluded vessel: epidermal necrosis, dermal hemorrhage, ulceration, necrosis of adnexal structures or fat

─ Inflammatory infiltrate around affected vessels variable, may be sparse or contain lymphocytes, histiocytes, neutrophils, eosinophils

─ Vessel walls themselves usually show underlying arteriosclerosis but not typically acute vasculitis (though reactive changes can occur)

DDx

─ Leukocytoclastic vasculitis/Polyarteritis nodosa (true necrotizing vasculitis, fibrinoid necrosis, prominent neutrophilic infiltrate, lacks cholesterol clefts)

─ Other embolic phenomena (eg, septic emboli – organisms, calciphylaxis – calcium in vessel walls, oxalate crystals – different crystal morphology)

─ Thrombotic vasculopathy (eg, antiphospholipid syndrome, cryoglobulinemia, DIC – thrombosis without cholesterol clefts)

─ Atrophie blanche/Livedoid vasculopathy (hyalinized vessels, thrombosis, ulceration, lacks cholesterol clefts)

Prognosis ─ Depends on extent of embolization and organ involvement, can be serious with significant morbidity/mortality if major organs affected or extensive skin necrosis

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Urticaria (Hives, Wheals)

Common vascular reaction pattern characterized by transient, pruritic, edematous plaques (wheals)

Clinical

─ Wheals: well-demarcated, erythematous or pale, edematous, raised plaques, often with central pallor and surrounding erythema (flare)

─ Intensely pruritic, lesions are transient (individual wheals usually last <24 hours, often only a few hours)

─ Can occur anywhere on skin, variable size and shape, may be annular or polycyclic

─ Acute urticaria (<6 weeks duration): often due to allergic reactions (foods, drugs, insect stings), infections

─ Chronic urticaria (>6 weeks duration): often idiopathic (chronic spontaneous urticaria), can be autoimmune, or related to physical stimuli (dermographism, cold, heat, pressure, solar, cholinergic, aquagenic)

─ Angioedema: deeper dermal and subcutaneous/submucosal swelling, often involves face, lips, tongue, larynx (can be life-threatening if airway compromised)

Micro

─ Papillary dermal edema is the most prominent and characteristic feature, causing separation of collagen bundles

─ Dilation of superficial dermal blood vessels (capillaries, venules) and lymphatic vessels

─ Sparse, superficial, perivascular inflammatory infiltrate, composed mainly of lymphocytes and histiocytes

─ Eosinophils may be present in variable numbers, sometimes prominent, especially in drug-related or allergic urticaria

─ Neutrophils may be seen, especially in some physical urticarias or early lesions, but usually not numerous or showing leukocytoclasis (unless urticarial vasculitis)

─ Epidermis is typically normal, no significant interface change or spongiosis

DDx

─ Urticarial vasculitis (wheals last >24 hours, often painful/burning, may leave purpura/pigmentation, histology shows LCV)

─ Arthropod bite reaction (often more persistent papules, central punctum, denser/deeper infiltrate with more eosinophils)

─ Bullous pemphigoid (urticarial/pre-bullous phase) (persistent pruritic plaques, eosinophils, DIF shows linear IgG/C3 at BMZ)

─ Sweet's syndrome (tender plaques/nodules, fever, dense neutrophilic infiltrate, marked papillary dermal edema but different overall pattern)

─ Polymorphous light eruption (papular/plaque type) (photosensitive, denser lymphocytic infiltrate, often some interface change)

─ Mastocytosis (urticaria pigmentosa) (Darier's sign positive, increased mast cells in dermis)

Prognosis ─ Acute urticaria usually self-limited, chronic urticaria can be persistent and significantly impact quality of life, angioedema with laryngeal involvement is a medical emergency

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Urticarial Vasculitis

Clinicopathologic entity characterized by urticarial lesions that persist >24 hours, often with burning/pain, and histologic evidence of leukocytoclastic vasculitis

Clinical

─ Urticarial plaques (wheals) that are often painful or burning rather than purely pruritic

─ Individual lesions persist for >24 hours (key clinical feature distinguishing from common urticaria), may resolve with purpura or hyperpigmentation

─ Can occur anywhere, may be associated with systemic symptoms (arthralgias, fever, abdominal pain, renal involvement)

─ Associated with:

─ Hypocomplementemia (hypocomplementemic urticarial vasculitis syndrome, HUVS – often anti-C1q antibodies, more severe systemic involvement, SLE-like features)

─ Normocomplementemic urticarial vasculitis (milder, often idiopathic or drug/infection related)

─ Connective tissue diseases (SLE, Sjögren's), infections, drugs, malignancy (rarely)

Micro

─ Leukocytoclastic vasculitis (LCV) affecting small vessels (postcapillary venules) in superficial and mid-dermis (see LCV for detailed features)

─ Fibrinoid necrosis of vessel walls

─ Neutrophilic infiltrate in and around vessel walls, with leukocytoclasis (nuclear dust)

─ Extravasation of red blood cells

─ Endothelial cell swelling

─ Eosinophils may be present in variable numbers, often numerous

─ Papillary dermal edema usually present, but may be less striking than in common urticaria

─ Direct immunofluorescence (DIF) of early lesional skin: granular deposits of IgM, IgG, C3 (and sometimes IgA) in superficial dermal vessel walls, similar to LCV

DDx

─ Common urticaria (lesions transient <24h, lacks histologic LCV, DIF usually negative or non-specific perivascular fibrin)

─ Leukocytoclastic vasculitis (non-urticarial) (clinically palpable purpura more typical, but histology is the same)

─ Sweet's syndrome (dense neutrophilic infiltrate without true vasculitis, marked papillary edema, fever, leukocytosis)

─ Bullous pemphigoid (urticarial phase) (pruritic plaques, DIF shows linear IgG/C3 at BMZ)

─ Erythema multiforme (target lesions, prominent interface dermatitis with keratinocyte necrosis)

Prognosis ─ Variable, depends on presence/absence of hypocomplementemia and systemic involvement, normocomplementemic UV often self-limited or responds to treatment of trigger, HUVS can be chronic and associated with significant morbidity

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Degos Disease (Malignant Atrophic Papulosis)

Rare, often fatal, thrombo-occlusive vasculopathy affecting skin, GI tract, and CNS

Clinical

─ Characteristic skin lesions: crops of small, pink or erythematous papules that develop central porcelain-white atrophy and a surrounding erythematous, telangiectatic rim

─ Lesions heal with atrophic, porcelain-white scars

─ Common on trunk, extremities, spares face, palms, soles usually

─ Systemic involvement (GI tract – infarction, perforation, hemorrhage, CNS – strokes, neuropathy) is common in malignant (systemic) form and often leads to death

─ Benign cutaneous form: skin lesions only, better prognosis, though some may later develop systemic signs

─ Etiology unknown, ?endothelial cell dysfunction, ?coagulopathy

Micro

─ Wedge-shaped area of dermal ischemic necrosis (infarction) beneath an atrophic or ulcerated epidermis

─ Occlusion of small arteries and arterioles in deep dermis or subcutis by intraluminal thrombosis (fibrin thrombi)

─ Vessel walls show endothelial swelling, intimal proliferation, and sometimes minimal lymphocytic inflammation, but usually no true necrotizing vasculitis (no fibrinoid necrosis or significant leukocytoclasis)

─ Dermal changes:

─ Superficial dermis: edema, telangiectasias, slight perivascular lymphocytic infiltrate (corresponding to erythematous rim)

─ Central area: acellular, sclerotic collagen, loss of adnexae (corresponding to porcelain-white scar)

─ Mucin deposition (Alcian blue+) may be seen in dermis, especially at periphery of infarct

─ Epidermis overlying infarct is atrophic, ulcerated, or shows squamoid hyperplasia at edge of ulcer

DDx

─ Antiphospholipid syndrome/Livedoid vasculopathy (thrombotic vasculopathy, often lower legs, different clinical context, may lack wedge-shaped infarcts of Degos)

─ Leukocytoclastic vasculitis (true necrotizing vasculitis, palpable purpura, different histology)

─ Polyarteritis nodosa (medium vessel vasculitis, deeper, often nodules/ulcers)

─ Atrophie blanche (scarring from livedoid vasculopathy, hyalinized vessels)

─ Other causes of cutaneous infarction (eg, cryoglobulinemia, septic emboli, calciphylaxis – different underlying pathology)

Prognosis ─ Benign cutaneous form has good prognosis, malignant (systemic) form often fatal within few years due to GI/CNS complications

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Calciphylaxis (Calcific Uremic Arteriolopathy)

Life-threatening condition characterized by progressive cutaneous necrosis due to calcification and occlusion of small and medium-sized vessels in dermis and subcutis, primarily in patients with end-stage renal disease

Clinical

─ Extremely painful, indurated, violaceous plaques or nodules, often with a retiform or livedoid pattern, progressing to ischemic necrosis, eschar formation, and deep, non-healing ulcers

─ Common on areas with abundant adipose tissue: abdomen, thighs, buttocks, breasts, penis

─ Usually in patients with end-stage renal disease on dialysis, often with hyperparathyroidism, hyperphosphatemia, elevated calcium-phosphate product

─ Can occur in non-uremic patients (eg, primary hyperparathyroidism, malignancy, connective tissue disease, warfarin use, protein C/S deficiency)

─ High mortality due to sepsis from ulcerated lesions

Micro

─ Calcification of small and medium-sized arteries, arterioles, and sometimes venules in deep dermis and subcutaneous fat (septa and lobules)

─ Calcium deposits (dark purple on H&E, von Kossa+) in Media ─ placeholder ─ and sometimes intima of vessel walls, often circumferential

─ Intimal proliferation, fibrosis, and luminal narrowing or occlusion by thrombi (fibrin, platelets)

─ Ischemic necrosis of surrounding tissue: dermal collagen, adnexal structures, subcutaneous fat (ghost-like necrotic adipocytes, calcification of fat)

─ Inflammatory infiltrate variable, may be sparse or contain neutrophils, lymphocytes, histiocytes, giant cells around calcified vessels or necrotic tissue

─ Extravasation of red blood cells common

─ Epidermal ulceration and necrosis overlying ischemic areas

DDx

─ Cholesterol emboli (cholesterol clefts in vessels, different clinical context)

─ Vasculitis (eg, PAN, LCV – fibrinoid necrosis, neutrophilic infiltrate, lacks extensive vascular calcification)

─ Warfarin-induced skin necrosis (thrombosis in venules/capillaries, often early in therapy, lacks vascular calcification)

─ Antiphospholipid syndrome/Other thrombotic vasculopathies (thrombosis without prominent vascular calcification)

─ Necrotizing soft tissue infections (eg, necrotizing fasciitis – bacterial infection, extensive tissue necrosis, different inflammatory pattern)

─ Oxalosis (calcium oxalate crystals in vessel walls/interstitium, polarizable, different crystal morphology)

Prognosis ─ Very poor, high mortality (often >50%) due to sepsis, pain, non-healing ulcers, requires multidisciplinary management

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Collagen, Elastin, and Radiation

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Chronic Radiation Dermatitis

Cutaneous changes occurring months to years after exposure to ionizing radiation

Clinical

─ Atrophy, telangiectasias, dyspigmentation (hypo- and hyperpigmentation – "poikiloderma"), dryness, hair loss in irradiated area

─ Skin may be indurated, fibrotic, with reduced pliability

─ Chronic ulcers (radiation ulcers) may develop, often painful, slow to heal

─ Increased risk of developing secondary skin cancers (BCC, SCC, atypical fibroxanthoma, angiosarcoma) within irradiated field, often after long latency (years to decades)

Micro

─ Epidermal atrophy with flattening of rete ridges, or sometimes acanthosis/hyperkeratosis

─ Atypical keratinocytes (radiation atypia) may be present in epidermis (enlarged, hyperchromatic, pleomorphic nuclei), can be difficult to distinguish from actinic keratosis or SCCis

─ Dermal changes:

─ Sclerosis and hyalinization of dermal collagen (thickened, eosinophilic collagen bundles)

─ Atypical fibroblasts (radiation fibroblasts): large, stellate or spindled cells with enlarged, hyperchromatic, often bizarrely shaped nuclei, scattered in sclerotic dermis (important diagnostic clue)

─ Vascular changes: telangiectasias, thickened hyalinized vessel walls, endothelial atypia, luminal narrowing or occlusion, fibrin thrombi

─ Loss of adnexal structures (hair follicles, sebaceous glands)

─ Elastosis may be present but often less prominent than solar elastosis

─ Chronic ulcers show granulation tissue, inflammation, and features of radiation dermatitis at edges

DDx

─ Morphea/Scleroderma (dermal sclerosis, but lacks radiation fibroblasts and prominent vascular atypia of radiation dermatitis, different clinical history)

─ Lichen sclerosus (papillary dermal edema/sclerosis, epidermal atrophy, but lacks radiation fibroblasts/vascular changes, different clinical)

─ Chronic sun damage (solar elastosis, epidermal atrophy/AKs, but radiation fibroblasts less typical/prominent)

─ Scar (fibrosis, but lacks specific radiation-induced atypia in fibroblasts/endothelium)

─ If atypical keratinocytes prominent: Actinic keratosis, Bowen's disease, SCC (may arise in radiation dermatitis)

─ If atypical spindle cells prominent: Atypical fibroxanthoma, angiosarcoma, other sarcomas (may arise in radiation dermatitis, IHC helpful)

Prognosis ─ Chronic, progressive changes, risk of ulceration, infection, and secondary malignancy

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Lichen Sclerosus (LS, Lichen Sclerosus et Atrophicus)

Chronic inflammatory dermatosis characterized by white, atrophic plaques, primarily affecting anogenital skin, can cause scarring and functional impairment

Clinical

─ White, ivory-colored, atrophic, often "cigarette paper" or crinkled plaques or papules

─ Anogenital region most common: vulva ("figure-of-eight" or "hourglass" pattern around vulva/perineum), perianal skin, glans penis/prepuce (balanitis xerotica obliterans)

─ Pruritus, soreness, pain, dyspareunia, phimosis, urinary obstruction common

─ Extragenital LS: less common (15-20%), often on upper trunk (back, shoulders, neck), breasts, flexor wrists, oral mucosa (rare), usually asymptomatic whitish plaques

─ Purpura, erosions, fissures, and bullae (bullous LS) can occur

─ Primarily affects prepubertal girls, postmenopausal women, and adult men, but can occur at any age

Micro

─ Epidermal atrophy (thinning), often with effacement of rete ridges

─ Hyperkeratosis, often compact orthokeratosis

─ Follicular plugging may be present, especially in early or extragenital lesions

─ Characteristic feature: Vacuolar alteration (liquefaction degeneration) of basal cell layer

─ Papillary dermis shows marked edema and homogenization/sclerosis of collagen, appearing pale, eosinophilic, and acellular or hypocellular (this zone of sclerosis is key)

─ Beneath the sclerotic zone, a band-like or patchy lymphocytic infiltrate is typically present in mid/upper reticular dermis

─ Dilated lymphatic vessels may be seen within the edematous/sclerotic papillary dermis

─ Melanin incontinence common

─ Elastic fibers often reduced or absent in sclerotic zone

─ Bullous LS: subepidermal blister formation within the edematous/sclerotic papillary dermis

DDx

─ Morphea/Localized scleroderma (dermal sclerosis involves reticular dermis more prominently, less epidermal atrophy/interface change, lacks prominent papillary dermal edema/homogenization of LS, different clinical)

─ Chronic radiation dermatitis (radiation fibroblasts, atypical vascular changes, history of radiation)

─ Vitiligo (depigmentation, loss of melanocytes, lacks sclerosis/inflammation of LS)

─ Lichen planus (especially atrophic or erosive oral/genital) (sawtooth rete, wedge hypergranulosis, denser band-like infiltrate directly at DE junction, less dermal sclerosis)

─ Cicatricial pemphigoid (if bullous/erosive genital LS – DIF for linear IgG/C3 at BMZ in pemphigoid)

Prognosis ─ Chronic, progressive, can lead to significant scarring, phimosis, stenosis, sexual dysfunction, small but definite increased risk of squamous cell carcinoma (SCC) development in long-standing anogenital LS (especially vulvar)

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Morphea & Linear Scleroderma

Localized forms of scleroderma characterized by fibrosis (sclerosis) of the skin, can be circumscribed (morphea) or linear

Clinical

─ Morphea:

─ Circumscribed, indurated, firm, waxy plaques with an ivory-colored center and often a violaceous (lilac) inflammatory border in active lesions

─ Skin becomes bound down, smooth, shiny, hairless, sweating may be lost

─ Common on trunk, extremities, can be solitary or multiple (generalized morphea if widespread)

─ Variants: guttate (small, drop-like), bullous, deep morphea (involves deep dermis/subcutis/fascia – morphea profunda), pansclerotic (involves full thickness skin, fascia, muscle, bone)

─ Linear Scleroderma:

─ Band-like, indurated, sclerotic plaques, often following lines of Blaschko or along an extremity

─ Can cause significant atrophy of underlying structures (muscle, bone), leading to limb length discrepancy, joint contractures, functional impairment

─ "En coup de sabre": linear scleroderma on forehead/scalp, may cause linear depression, alopecia

─ Parry-Romberg syndrome (progressive hemifacial atrophy): may be related, involves atrophy of one side of face

─ Unlike systemic sclerosis, usually no Raynaud's phenomenon, sclerodactyly, or significant internal organ involvement (though some overlap can occur, especially with generalized or linear forms)

Micro

─ Early (inflammatory) lesions:

─ Perivascular and interstitial lymphocytic infiltrate, often with plasma cells and eosinophils, in dermis and sometimes subcutis

─ Collagen bundles may appear swollen and eosinophilic

─ Endothelial cell swelling

─ Late (sclerotic) lesions:

─ Marked dermal sclerosis: thickened, hyalinized, closely packed collagen bundles replacing normal reticular dermis, often extending to papillary dermis and subcutis

─ Collagen bundles often oriented parallel to epidermis

─ Loss of periadnexal fat (eccrine glands appear "trapped" or "hanging" in dense collagen)

─ Atrophy or loss of adnexal structures (hair follicles, sebaceous glands)

─ Scant inflammatory infiltrate, or may be absent

─ Epidermis often atrophic, with loss of rete ridges

─ Subcutaneous involvement (sclerosis of fat septa, lipomembranous change) in deep morphea/linear scleroderma

DDx

─ Lichen sclerosus (LS) (more prominent papillary dermal edema/homogenization, epidermal atrophy, interface change, less deep dermal sclerosis than morphea, different clinical – anogenital common in LS)

─ Chronic radiation dermatitis (radiation fibroblasts, atypical vascular changes, history of radiation)

─ Scleredema (marked dermal thickening due to mucin deposition between collagen bundles, not true sclerosis, associated with diabetes/monoclonal gammopathy/post-infection)

─ Scleromyxedema (diffuse dermal mucin, fibroblast proliferation, fibrosis, associated with paraproteinemia)

─ Nephrogenic systemic fibrosis (history of renal failure/gadolinium, dermal spindle cell proliferation, clefts, elastic fiber changes, mucin)

─ Eosinophilic fasciitis (sclerosis primarily of fascia and deep subcutis, peripheral eosinophilia, often spares dermis initially)

─ Scar (history of trauma/surgery, different collagen arrangement – more haphazard initially, then more parallel but lacks adnexal loss/trapping of morphea)

Prognosis ─ Variable, morphea often self-limited or responds to treatment, linear scleroderma can cause significant cosmetic/functional morbidity, generalized morphea can be extensive

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Hypertrophic Scar

Raised, firm, erythematous scar that remains within the boundaries of the original wound, often developing after trauma, surgery, or burns

Clinical

─ Firm, raised, often erythematous or pink, pruritic or sometimes painful lesion

─ Confined to the site of original injury, does not extend beyond its borders (key distinction from keloid)

─ Tends to develop within weeks of injury, may partially regress over time (months to years)

─ Common after burns, surgery, trauma, especially in areas of skin tension or if healing is prolonged/complicated

Micro

─ Proliferation of fibroblasts and myofibroblasts in dermis

─ Increased deposition of collagen, but collagen bundles are typically finer, more wavy, and arranged more parallel to the epidermal surface compared to keloid

─ Blood vessels are numerous and often oriented vertically, perpendicular to epidermis

─ Epidermis overlying may be normal, flattened, or slightly acanthotic

─ Inflammatory cells (lymphocytes, mast cells) may be present, especially in early/active lesions

─ No the thick, glassy, hyalinized collagen bundles ("keloidal collagen") characteristic of keloids

─ Elastic fibers are usually present but may be fragmented or reduced

DDx

─ Keloid (extends beyond original wound boundaries, histologically has thick, glassy, hyalinized collagen bundles, fewer fibroblasts/vessels in mature keloids)

─ Dermatofibroma (spindle cell proliferation, storiform pattern, entrapped collagen at periphery, Factor XIIIa+)

─ Scar (normal mature scar) (flatter, less cellular, less vascular, collagen more organized and parallel to surface)

─ Nodular fasciitis (more cellular, myxoid stroma, "tissue culture" appearance of fibroblasts, mitoses common, rapid growth, deeper location usually)

─ Fibromatosis (more infiltrative, less vascular, different clinical context)

Prognosis ─ Benign, may improve spontaneously over time, can be a cosmetic and symptomatic concern, responds variably to treatments (intralesional steroids, silicone sheeting, pressure)

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Keloid

Exuberant scar formation that extends beyond the boundaries of the original wound, due to excessive collagen deposition

Clinical

─ Firm, rubbery, often pruritic or painful, raised lesion that grows beyond the confines of the original injury

─ Surface is often smooth, shiny, pink, violaceous, or hyperpigmented

─ Common sites: earlobes (after piercing), presternal chest, shoulders, upper back, jawline

─ More common in individuals with darker skin pigmentation, genetic predisposition

─ Rarely regress spontaneously, tend to recur after excision if not combined with adjuvant therapy

Micro

─ Dermal proliferation of fibroblasts and myofibroblasts

─ Characteristic feature: Thick, broad, glassy, brightly eosinophilic, hyalinized collagen bundles ("keloidal collagen") arranged in haphazard whorls or nodules

─ These thick collagen bundles are the hallmark and distinguish from hypertrophic scar

─ Fibroblasts are often present but may be relatively sparse in mature, hyalinized areas

─ Blood vessels usually less prominent than in hypertrophic scars

─ Epidermis overlying is often flattened or atrophic

─ Minimal to no inflammatory infiltrate in mature lesions

─ Elastic fibers are usually absent or sparse within the keloidal collagen

DDx

─ Hypertrophic scar (remains within wound boundaries, finer collagen bundles arranged more parallel to epidermis, more vascularity/cellularity usually)

─ Dermatofibroma (spindle cells, storiform pattern, entrapped collagen, Factor XIIIa+)

─ Scar (normal mature scar) (flatter, less collagen deposition, collagen more organized)

─ Fibromatosis (more infiltrative, different cell type, different clinical context)

─ Scleroderma/Morphea (different clinical, squared-off collagen bundles, adnexal trapping/loss)

Prognosis ─ Benign, but significant cosmetic concern, difficult to treat, high recurrence rate

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Metabolic & Depositional

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Scrotal Calcinosis (Idiopathic Scrotal Calcinosis)

Uncommon benign condition characterized by multiple, asymptomatic, calcified nodules in the scrotal skin

Clinical

─ Multiple, firm, yellowish-white or skin-colored papules and nodules within scrotal skin

─ Lesions are usually asymptomatic, may slowly enlarge or extrude chalky material

─ Typically occurs in young to middle-aged men

─ Etiology debated:

─ Idiopathic dystrophic calcification of dermal structures

─ Dystrophic calcification within pre-existing epidermoid cysts or other adnexal structures (some studies suggest this is common origin)

─ True idiopathic calcinosis without identifiable precursor lesion

─ Serum calcium and phosphorus levels are normal (distinguishes from metastatic calcification)

Micro

─ Large, irregular, amorphous deposits of calcium (dark purple/basophilic on H&E, von Kossa+) within the dermis of the scrotum

─ Calcium deposits are often surrounded by a foreign body giant cell reaction (multinucleated histiocytes) and variable lymphohistiocytic infiltrate

─ Fibrosis (sclerosis) around calcium deposits is common

─ Remnants of epithelial cyst linings (epidermoid or pilar type) may be seen adjacent to or surrounding some calcium deposits in many cases, suggesting origin from dystrophic calcification of cysts

─ Smooth muscle bundles characteristic of scrotal dermis are present in surrounding stroma

─ Epidermis usually normal or may show acanthosis or ulceration if calcium extrudes

DDx

─ Epidermoid cysts with calcification (if cyst lining prominent and calcium secondary)

─ Pilomatrixoma with extensive calcification (ghost cells, basaloid cells usually identifiable)

─ Metastatic calcinosis cutis (abnormal serum calcium/phosphorus, other sites often involved, different clinical context)

─ Dystrophic calcinosis cutis (secondary to trauma, inflammation, or connective tissue disease – occurs in sites of prior damage, not usually isolated to scrotum without cause)

─ Osteoma cutis (true bone formation, not just calcium deposits)

Prognosis ─ Benign, lesions may be surgically excised for cosmetic reasons or if symptomatic

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Calciphylaxis (Calcific Uremic Arteriolopathy)

Life-threatening condition with progressive cutaneous necrosis due to calcification and occlusion of small/medium vessels in dermis/subcutis, primarily in end-stage renal disease (Reiteration from Set 47)

Clinical

─ Extremely painful, indurated, violaceous plaques/nodules, often retiform/livedoid, progressing to ischemic necrosis, eschar, deep non-healing ulcers

─ Common on adipose areas: abdomen, thighs, buttocks

─ Usually in end-stage renal disease on dialysis, often with hyperparathyroidism, hyperphosphatemia

─ Can occur in non-uremic patients (eg, primary hyperparathyroidism, malignancy, warfarin)

─ High mortality due to sepsis

Micro

─ Calcification (dark purple on H&E, von Kossa+) of small/medium arteries, arterioles, +/- venules in deep dermis and subcutaneous fat (Media ─ placeholder ─ and/or intima)

─ Intimal proliferation, fibrosis, luminal narrowing or occlusion by thrombi

─ Ischemic necrosis of surrounding tissue (dermis, adnexa, fat – ghost-like necrotic adipocytes, fat calcification)

─ Inflammatory infiltrate variable, may be sparse or mixed around calcified vessels/necrotic tissue

─ Extravasated RBCs common, epidermal ulceration overlying

DDx

─ Cholesterol emboli (cholesterol clefts in vessels)

─ Vasculitis (eg, PAN, LCV – fibrinoid necrosis, neutrophilic infiltrate, lacks extensive vascular calcification)

─ Warfarin-induced skin necrosis (thrombosis in venules/capillaries, lacks vascular calcification)

─ Oxalosis (calcium oxalate crystals in vessel walls/interstitium, polarizable)

─ Necrotizing soft tissue infections (bacterial infection, different inflammatory pattern)

Prognosis ─ Very poor, high mortality, requires multidisciplinary management

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Gout (Cutaneous Tophus)

Metabolic disorder due to hyperuricemia leading to deposition of monosodium urate (MSU) crystals in joints, soft tissues, and skin (tophi)

Clinical

─ Tophi: firm, skin-colored, yellowish, or erythematous papules or nodules, may extrude chalky white material (urate crystals)

─ Common sites: helix/antihelix of ear, olecranon bursa, fingers, toes, Achilles tendon, other periarticular areas

─ Acute gouty arthritis: recurrent attacks of severe joint inflammation

─ Chronic tophaceous gout: destructive arthropathy, chronic kidney disease

─ Associated with hyperuricemia (due to overproduction or underexcretion of uric acid)

Micro

─ Dermal or subcutaneous deposits of amorphous, feathery, or fibrillar, slightly basophilic or amphophilic material (urate crystals)

─ Urate crystals are water-soluble and often dissolved during routine formalin fixation and processing, leaving empty clefts or pale, smudgy areas

─ Alcohol fixation preserves crystals better (appear as needle-shaped, negatively birefringent crystals with polarized light)

─ Characteristic foreign body giant cell reaction surrounding urate deposits, with palisading histiocytes and lymphocytes (tophaceous granuloma)

─ Neutrophils may be present in acute gouty attacks

─ Fibrosis and calcification can occur in chronic tophi

─ Overlying epidermis may be normal, atrophic, or ulcerated with extrusion of urate material

DDx

─ Calcinosis cutis (calcium deposits – purple on H&E, von Kossa+, not birefringent needles like urate)

─ Rheumatoid nodule (fibrinoid necrosis, palisading histiocytes, different clinical context, no urate crystals)

─ Xanthoma (foam cells, cholesterol clefts, different crystals if any)

─ Foreign body granuloma (to other material – different material, different crystal properties if crystalline)

─ Sarcoidosis/Other granulomatous diseases (different granuloma type, no urate)

Prognosis ─ Skin lesions benign, reflect systemic urate burden, management focuses on lowering uric acid levels to prevent joint/kidney damage

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Colloid Milium

Rare degenerative condition with deposition of amorphous eosinophilic colloid material in papillary dermis, forming translucent papules on sun-exposed skin

Clinical

─ Multiple, small (1-5 mm), dome-shaped, translucent, skin-colored, yellowish, or slightly amber papules, often grouped

─ Common on sun-exposed areas: face (especially periorbital, nose, cheeks), ears, neck, dorsal hands

─ Lesions have a "cobblestone" or "tapioca-grain" appearance

─ Usually asymptomatic

─ Types:

─ Adult colloid milium: most common, in older adults with chronic sun exposure, colloid derived from degenerated elastic fibers/fibroblasts

─ Juvenile colloid milium: rare, onset in childhood/adolescence, may be familial, not clearly related to sun exposure, colloid possibly keratin-derived (controversial)

─ Nodular colloid degeneration (paracolloid): larger, solitary or few, plaque-like lesions

Micro

─ Well-demarcated, amorphous, homogeneous or slightly fissured, pale eosinophilic to slightly basophilic colloid material deposited in expanded dermal papillae, often forming large globules

─ Colloid material is PAS+, diastase resistant, weakly positive or negative with Congo red (may show faint green birefringence if positive, but not true amyloid usually)

─ Thioflavin T may show fluorescence

─ Epidermis overlying colloid deposits is often flattened or atrophic, may show hyperkeratosis

─ Grenz zone of normal collagen often separates colloid from epidermis

─ Fibroblasts and capillaries may be scattered within or around colloid masses

─ Minimal to no inflammatory infiltrate

─ Solar elastosis often prominent in adjacent dermis in adult colloid milium

DDx

─ Amyloidosis (macular, lichen, nodular) (amyloid stains strongly with Congo red showing apple-green birefringence, different clinical, amyloid often more fibrillar)

─ Lipoid proteinosis (hyaline material around vessels/adnexa and diffusely in dermis, PAS+, different clinical – hoarseness, beaded eyelid papules)

─ Basal cell carcinoma (nodular, cystic) (basaloid tumor nests, stromal retraction)

─ Syringoma (small ducts, tadpole shapes, fibrous stroma, periorbital)

─ Trichoepithelioma (horn cysts, basaloid nests, papillary mesenchymal bodies)

Prognosis ─ Benign, persistent, primarily a cosmetic concern

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Lichen Amyloidosis / Macular Amyloidosis (Primary Localized Cutaneous Amyloidosis, PLCA)

Two most common forms of PLCA, characterized by deposition of keratin-derived amyloid in papillary dermis, often pruritic

Clinical

─ Lichen Amyloidosis: intensely pruritic, firm, hyperkeratotic, brownish papules, often grouped or coalescing into plaques, typically on shins, extensor forearms, upper back ("ripple pattern" hyperpigmentation common)

─ Macular Amyloidosis: pruritic, grayish-brown or dusky, flat macules with a reticulated or "rippled" pattern of hyperpigmentation, most common on upper back (interscapular area), chest, extremities

─ Notalgia paresthetica (sensory neuropathy of mid-back) may be associated with macular amyloidosis in that location

─ Friction/rubbing are thought to play a role in pathogenesis (keratinocyte damage leading to amyloid formation)

─ Usually no systemic amyloidosis or underlying plasma cell dyscrasia

Micro

─ Both show deposition of amorphous, eosinophilic, hyaline material (amyloid) within expanded dermal papillae, often forming small globules or larger confluent masses

─ Amyloid is derived from degenerated keratin filaments (cytokeratins) from apoptotic epidermal keratinocytes

─ Amyloid stains (+) with Congo red (salmon-pink, shows apple-green birefringence with polarized light), Crystal violet (metachromatic pink-purple), Thioflavin T (fluorescence)

─ Epidermal changes:

─ Lichen amyloidosis: marked hyperkeratosis, acanthosis, papillomatosis (can be verrucous), hypergranulosis (reflects chronic rubbing/lichenification)

─ Macular amyloidosis: epidermis often normal or slightly atrophic, may show mild hyperkeratosis, basal layer hyperpigmentation, and melanin incontinence

─ Melanophages common in papillary dermis, contributing to clinical pigmentation

─ Superficial perivascular lymphocytic infiltrate usually sparse

─ No significant plasma cell infiltrate (unlike nodular amyloidosis)

DDx

─ Lichen simplex chronicus (if lichen amyloidosis – LSC lacks amyloid deposits, more prominent fibrosis)

─ Hypertrophic lichen planus (if lichen amyloidosis – HLP has more prominent lichenoid infiltrate, sawtooth rete, Civatte bodies, lacks extensive amyloid)

─ Post-inflammatory hyperpigmentation (if macular amyloidosis – melanin incontinence without amyloid)

─ Nodular amyloidosis (deeper dermal/subcutaneous amyloid deposits, often AL-type amyloid, plasma cells prominent, may have systemic association)

─ Colloid milium (colloid material less fibrillar, different staining properties usually, sun-exposed sites)

─ Lipoid proteinosis (different hyaline material, perivascular/periadnexal, PAS+, different clinical)

Prognosis ─ Benign, but chronic, often very pruritic (especially lichen amyloidosis), difficult to treat effectively

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Nodular Amyloidosis (Primary Localized Cutaneous Nodular Amyloidosis)

Rare form of primary localized cutaneous amyloidosis, characterized by waxy nodules or plaques, amyloid is AL type (immunoglobulin light chains), may have underlying plasma cell dyscrasia

Clinical

─ Solitary or multiple, firm, waxy, yellowish, pink, or skin-colored papules, nodules, or plaques

─ May show purpura ("pinch purpura") after minor trauma

─ Common sites: face, scalp, trunk, extremities, anogenital area, can occur on mucous membranes

─ Usually asymptomatic

─ Unlike lichen/macular amyloidosis, amyloid is AL type (immunoglobulin light chains, usually lambda), produced by local plasma cells

─ Small risk (~7-15%) of progression to or association with systemic amyloidosis or multiple myeloma, so systemic workup often recommended

Micro

─ Large, amorphous, acellular, eosinophilic to slightly basophilic amyloid deposits throughout the dermis, often extending into subcutis

─ Amyloid deposits often surround blood vessels, adnexal structures, and nerves, and may form large confluent masses

─ Epidermis is usually normal or atrophic, may be ulcerated

─ Characteristic feature: Presence of numerous plasma cells, often in clusters or sheets, within and around amyloid deposits, these plasma cells are producing the AL amyloid

─ Lymphocytes and histiocytes also present in infiltrate

─ Foreign body giant cells may be seen reacting to amyloid

─ Amyloid stains (+) with Congo red (salmon-pink, shows apple-green birefringence with polarized light), Crystal violet (metachromatic), Thioflavin T (fluorescence)

─ IHC for kappa and lambda light chains can demonstrate monoclonality of plasma cells and amyloid (amyloid stains with same light chain as monoclonal plasma cells)

DDx

─ Lichen amyloidosis/Macular amyloidosis (amyloid confined to papillary dermis, keratin-derived, lacks prominent plasma cells)

─ Colloid milium (colloid material in papillary dermis, different staining, sun-exposed sites, lacks plasma cells)

─ Lipoid proteinosis (hyaline material around vessels/adnexa, PAS+, different clinical – hoarseness, beaded eyelids)

─ Scleromyxedema/Papular mucinosis (mucin deposition, fibroblast proliferation, associated with paraproteinemia but different histology)

─ Other dermal deposition diseases (eg, gout, calcinosis – different material)

─ Cutaneous B-cell lymphoma/Plasmacytoma (if plasma cell infiltrate is dense and sheet-like – amyloid may be minimal or absent, cytologic atypia of plasma cells more overt in plasmacytoma)

Prognosis ─ Lesions are benign but persistent, can be locally destructive, monitor for systemic amyloidosis or plasma cell dyscrasia

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Lipoid Proteinosis (Urbach-Wiethe Disease, Hyalinosis Cutis et Mucosae)

Rare autosomal recessive genodermatosis (ECM1 gene mutation), characterized by deposition of hyaline-like material in skin, mucous membranes, and internal organs

Clinical

─ Onset usually in infancy or early childhood

─ Hoarseness of voice (due to laryngeal infiltration) is often first sign, may be present from birth

─ Skin lesions:

─ Waxy, yellowish, thickened plaques and papules, especially on face, eyelids ("beaded" papules along eyelid margins – moniliform blepharosis), elbows, knees, hands

─ Skin fragility, easy bruising, poor wound healing, varioliform or acneiform scarring

─ Verrucous (warty) plaques on extensor surfaces or pressure points

─ Oral mucosa: thickened, yellowish, cobblestone appearance of tongue, lips, buccal mucosa, reduced tongue mobility

─ Other: intracranial calcifications (hippocampus – "bean-shaped" on CT, may lead to seizures, neuropsychiatric issues), alopecia, dental anomalies

Micro

─ Deposition of amorphous, eosinophilic, hyaline-like material in dermis and around adnexal structures

─ Characteristic feature: Thick, concentric, "onion-skin" or "targetoid" rings of hyaline material surrounding small blood vessels (capillaries, venules) and eccrine sweat glands/ducts in papillary and reticular dermis

─ Hyaline material also deposited more diffusely between collagen bundles in dermis

─ Material is PAS+, diastase resistant, Alcian blue negative or weakly positive, Congo red negative (not amyloid)

─ Collagen bundles may appear thickened and hyalinized

─ Epidermis often hyperkeratotic, may be atrophic or acanthotic

─ Fibroblast numbers may be increased in dermis

─ Elastic fibers often reduced or fragmented

─ Minimal inflammatory infiltrate usually

DDx

─ Amyloidosis (nodular or systemic) (amyloid stains with Congo red, different distribution of deposits, often plasma cells)

─ Colloid milium (colloid in papillary dermis, sun-exposed sites, different staining)

─ Erythropoietic protoporphyria (EPP) (hyaline material around superficial vessels in sun-exposed skin, but different clinical – photosensitivity, burning, porphyrin abnormalities)

─ Porphyria cutanea tarda (PCT) (subepidermal blisters, festooning, thickened vessel walls, but different clinical/biochemical)

─ Scleroderma/Morphea (dermal sclerosis, but different collagen appearance, lacks extensive perivascular/periadnexal hyaline rings)

─ Myxedema (mucin deposition, not hyaline material, different clinical)

Prognosis ─ Benign, chronic, no cure, management is symptomatic, hoarseness and skin lesions persist, lifespan usually normal unless severe laryngeal or CNS complications

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Erythropoietic Protoporphyria (EPP)

Inherited disorder of heme biosynthesis (usually autosomal dominant, ferrochelatase deficiency), leading to accumulation of protoporphyrin in erythrocytes, plasma, liver, skin, causing acute photosensitivity

Clinical

─ Acute, painful photosensitivity starting in childhood (burning, stinging, itching, edema, erythema within minutes to hours of sun exposure)

─ Common on sun-exposed areas: face, dorsal hands, ears

─ Chronic skin changes: waxy thickening, superficial scarring ("cobblestone" or "aged knuckle" appearance), shallow linear or pitted scars ("varioliform" scars), perioral rhagades, nail changes

─ Vesicles or bullae are uncommon (unlike PCT)

─ Gallstones (protoporphyrin-rich) and liver disease (cholestasis, cirrhosis, liver failure – rare but serious) can occur

─ Red fluorescence of erythrocytes under UV light, elevated free erythrocyte protoporphyrin, normal urinary porphyrins

Micro

─ Acute lesions (rarely biopsied): dermal edema, endothelial cell swelling, sparse perivascular lymphocytic infiltrate

─ Chronic lesions (more characteristic):

─ Deposition of amorphous, eosinophilic, hyaline material in papillary dermis, characteristically forming thick, concentric rings or mantles around superficial dermal blood vessels (capillaries, venules)

─ Hyaline material is PAS+, diastase resistant, may show faint red fluorescence with UV light on unstained sections

─ Material is thought to be reduplicated basement membrane material (type IV collagen) and other plasma proteins

─ Epidermis usually normal or slightly acanthotic, may show hyperkeratosis

─ Solar elastosis may be present in background

─ Minimal inflammatory infiltrate

DDx

─ Porphyria cutanea tarda (PCT) (subepidermal blisters, festooning, caterpillar bodies, different porphyrin profile – uroporphyrins in urine)

─ Lipoid proteinosis (hyaline material around vessels/adnexa, but also diffuse dermal, different clinical – hoarseness, beaded eyelids, ECM1 mutation)

─ Colloid milium (colloid in papillary dermis, but different appearance/distribution, lacks prominent perivascular hyaline rings of EPP)

─ Amyloidosis (amyloid stains with Congo red, different distribution)

─ Hyalinizing vasculopathy (as in atrophie blanche – hyalinized vessels, thrombosis, ulceration, different clinical)

Prognosis ─ Lifelong photosensitivity, risk of cholelithiasis and potentially severe liver disease, management involves sun protection, beta-carotene, afamelanotide

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Ochronosis (Alkaptonuria)

Rare autosomal recessive disorder of tyrosine metabolism due to deficient homogentisate 1,2-dioxygenase, leading to accumulation of homogentisic acid (HGA) and its oxidized polymers in connective tissues

Clinical

─ Three main features:

─ Homogentisic aciduria: urine darkens on standing or alkalinization (often noted in infancy)

─ Ochronotic arthropathy: progressive, degenerative arthritis, especially spine, large joints (knees, hips, shoulders), often starting in 3rd-4th decade, can be debilitating

─ Ochronotic pigmentation: bluish-black or grayish discoloration of cartilage, sclera, skin

─ Skin: diffuse or mottled grayish-blue or black pigmentation, especially over cartilage (ears – "paddle sign" on transillumination, nose), malar areas, axillae, groin, sclerae (often triangular patches), tendons (Achilles, knuckles)

─ Sweat may be dark, cerumen dark

─ Cardiovascular involvement (calcification of heart valves, aorta), renal stones can occur

Micro

─ Deposition of characteristic ochronotic pigment in dermis, cartilage, and other connective tissues

─ Pigment appears as ochre (yellowish-brown), golden-brown, or black, often finely granular or amorphous, sometimes forming larger globules or banana-shaped fibers

─ Pigment is found free in connective tissue, within fibroblasts, macrophages, endothelial cells, and chondrocytes, and encrusting collagen and elastic fibers

─ Collagen bundles may appear swollen, homogenized, and fragmented where pigment is deposited

─ Dermal papillae and reticular dermis involved, often around sweat glands and blood vessels

─ Foreign body giant cell reaction to pigment may occur

─ Epidermis usually normal, may show increased basal melanin or pigment incontinence

─ Pigment does not stain with iron, melanin, or calcium stains, may stain black with cresyl violet or methylene blue

DDx

─ Argyria (silver deposition – gray-blue skin, pigment granules in dermis around sweat glands/vessels, darkfield microscopy helpful, history of silver exposure)

─ Minocycline pigmentation (blue-gray or muddy brown, pigment in macrophages, perivascular, often iron present with melanin)

─ Amalgam tattoo (oral, black/gray metallic particles)

─ Melanosis/Melanocytic lesions (melanin pigment, Fontana-Masson+, S100+ for melanocytes)

─ Hemochromatosis (iron deposition, Perls Prussian blue+)

─ Carcinoid syndrome with cutaneous pigmentation (different pigment type/distribution)

Prognosis ─ Progressive arthropathy is major morbidity, cardiac/renal complications can occur, lifespan usually not significantly shortened, management involves symptomatic treatment, dietary restriction (low tyrosine/phenylalanine) of limited benefit, nitisinone (inhibits HGA production) is investigational

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Follicular disorders

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Trichotillomania

Androgenic alopecia

Lichenplanopilaris (LPP)

Discoid Lupus

Central Centrifugal Cicatricial Alopecia (CCCA)

Acne Keloidalis

Folliculitis decalvans

Hidradenitis suppurativa

Pilonidal sinus

Tinea Capitis

Follicular mucinosis

Neutrophilic eccrine hidradenitis

Panniculitis

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Erythema Nodosum (EN)

Polyarteritis Nodosa (PAN)

Eosinophilic Fasciitis

Lipodermatosclerosis

Lupus Panniculitis

Erythema Induratum/Nodular Vasculitis

Eosinophilic Panniculitis

Subcutaneous Panniculitis-Like T Cell Lymphoma

Subcutaneous Fat Necrosis of the Newborn

Pancreatic Panniculitis

Encapsulated Fat Necrosis

Lipoatrophy

Infectious

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