Cytopathology

🤱Breast

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🤱Breast

Predominantly Small Cohesive Epithelial Tissue Fragments with Myoepithelial Cells and Bare Bipolar Nuclei (Breast Pattern 1)

— Predominantly large epithelial tissue fragments with ME cells and bipolar nuclei, variable number of cohesive smaller epithelial tissue fragments, and few dispersed epithelial cells

Cytology

— Low cellularity, 3D tissue fragments representing TDLUs / small ducts

— Composed of small epithelial cells with some overlapping of small, regular nuclei

— ME cells present on tissue fragments, gives a bimodal appearance

— Smaller flat epithelial sheets with ME cells also seen

— Background contains BBN in a clear field (ie stripped ME cell nuclei)

— Occasional fat fragments and intact lobules

DDx

— Normal breast

— Undersampled or sclerotic papillomas

— —Distinctive meshwork, stellate, or true papillary tissue fragments

— —Large hyperplastic ductal cells, apocrine sheets, siderophages, histiocytes, and a proteinaceous background

— —If infarcted: scattered, rounded-up tissue fragments of degenerate, atypical ductal, apocrine, or squamous cells in a bloody background with siderophages

— Undersampled or Sclerotic Fibroadenomas

— —Distinctive stromal tissue fragments and plentiful BBN

— —Normally feature large, cohesive, 3D branching tissue fragments ("chicken drumstick" or "staghorn" shapes)

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Proteinaceous Background (Breast Pattern 2)

— Proteinaceous background

Cytology

— Granular, thin to thick background

— Variable number of histiocytes, some multinucleated

— Siderophages, cholesterol crystals, and debris common

— Best seen on pap smears (washed off in air-dried giemsaa)

— Can be thin or thick and obscuring, finely granular, or colloidal

— May contain cholesterol crystals, laminated round bodies (Liesegang rings), and calcific debris

Note

— If a nodule is suspected, cyst contents is considered inadequate.

DDx

— Cysts

— —May see only a proteinaceous background with histiocytes

— —Can show apocrine cells in sheets

— —Will show complete drainage

— Fibrocystic change

— —Proteinaceous background with apocrine sheets and small cohesive tissue fragments of ductal epithelial cells with ME cells

— Galactocele

— —Proteinaceous background that varies from cyst fluid to milk, with fat globules in thin proteinaceous material and scattered histiocytes

— Inflamed cysts

— —Large number of neutrophils

— Lactating breast

— —Milky, proteinaceous background containing microglobules of fat in a thin casein

— Epithelial Hyperplasia with Fibrocystic Change

— Radial Scars

— Papillomas

— Granular Cell Tumors

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Predominantly Large Epithelial Tissue Fragments With Myoepithelial Cells and Bare Bipolar Nuclei, a Variable Number of Cohesive Smaller Epithelial Tissue Fragments, and Few Dispersed Epithelial Cells (Breast Pattern 3)

Cytology

— High cellularity

— Large, cohesive, hyperplastic ductal epithelial fragments

— Nuclear overlapping, haphazard arrangement, and streaming

— Irregular or slit-like secondary lumina

— Plenty of ME cells / BBN in background

— Collagenous spherulosis may be present

DDx

— Epithelial Hyperplasia

— —Large hyperplastic fragments, streaming nuclei, secondary lumina, BBN, no stroma

— Fibrocystic Change with Epithelial Hyperplasia

— —Proteinaceous background, histiocytes, apocrine sheets

— Intraductal Papilloma

— —Meshwork, stellate, or true papillary fragments; apocrine cells, siderophages, histiocytes

— Fibroadenoma

— —Branched "staghorn" epithelial fragments, plentiful BBN, stromal fragments

— Phyllodes Tumor

— —Fibroadenoma-like pattern but with hypercellular stroma and spindle cell atypia

— Gynecomastia

— —Hyperplastic ductal cells, can have marked atypia, scarce BBN

— Low-Grade DCIS

— —Scant/absent ME cells and BBN, cribriform/micropapillary architecture

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Predominantly Large Epithelial Tissue Fragments, a Variable Number of Discohesive Smaller Epithelial Tissue Fragments, and Plentiful Dispersed Epithelial Cells (Breast Pattern 4)

Cytology

— High cellularity

— Large, complex 3D epithelial fragments with crowded, atypical nuclei

— Variable discohesive smaller fragments and plentiful dispersed single cells

— Architecture is key: micropapillary, cribriform, or rigid arrays

— Scant or absent ME cells / BBN

— Mild to moderate nuclear atypia

— Occasional psammomatous calcifications

Note

— Absence of ME cells / BBN is the most important feature

— Diagnosis relies on architecture more than the degree of nuclear atypia

— Cribriform fragments may appear "pockmarked" or "cratered"

— Micropapillary fragments have bulbous tips and lack fibrovascular cores

DDx

— Low- to Intermediate-Grade DCIS

— —Stereotypical lesion for this pattern, defined by its architecture

— Epithelial Hyperplasia

— —Presence of prominent ME cells / BBN

— Intraductal Papilloma

— —Has ME cells / BBN, and distinctive meshwork/stellate fragments

— Fibroadenoma

— —Plentiful BBN / ME cells and stromal fragments

— Low-Grade Invasive Ductal Carcinoma

— —Can be indistinguishable from DCIS; increased single cells may favor invasion

— Atypical Ductal Hyperplasia

— —A specific diagnosis not made on FNAB

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Predominantly Small Discohesive Epithelial Tissue Fragments With Plentiful Dispersed Cells (Breast Pattern 5)

Cytology

— High cellularity

— Dominantly small, discohesive, irregular epithelial fragments

— Plentiful dispersed single malignant cells

— Absence of ME cells and BBN

— Nuclear atypia varies according to grade (low to high)

— Intracytoplasmic lumina may be present

— Infiltrated stromal fragments

DDx

— Invasive Ductal Carcinoma (most common)

— Tubular Carcinoma

— —Angulated, rigid tubules with low-grade nuclei

— Carcinoma with Medullary Features

— —Syncytial sheets with pleomorphic nuclei and prominent lymphocytes

— Invasive Micropapillary Carcinoma

— —"Jigsaw" fragments, often with peripheral mucin

— Lobular Carcinoma

— —Small uniform cells, intracytoplasmic lumina, discohesion "from within"

— Metaplastic and Metastatic Carcinomas

— Benign lesion that is heavily smeared (e.g., Fibroadenoma)

— —ME cells / BBN and characteristic stromal fragments

— High-Grade DCIS

— —Prominent necrosis

— Intraductal Papilloma (Pattern 3)

— —ME cells / BBN and true papillary architecture

Notes

— Beware of smearing artifact causing pseudo-discohesion

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Dispersed Cells (Breast Pattern 6)

Cytology

— Highly dispersed population of single epithelial cells

— Scattered minute, discohesive fragments and short single files with nuclear molding

— Cells are small- to intermediate-sized, often with eccentric (plasmacytoid) cytoplasm

— Intracytoplasmic lumina ("targetoid bodies") and signet ring cells are common

— Nuclei uniform, round/angulated with mild pleomorphism

— Absent / scarce BBN and ME cells

— Infiltrated stromal fragments are diagnostic of invasion

DDx

— Lobular Carcinoma (classic presentation)

— High-Grade Invasive Ductal Carcinoma (shows more nuclear atypia)

— Pleomorphic Lobular Carcinoma

— Apocrine Carcinoma

— Lymphoma

— —Complete dispersal, lymphoglandular bodies

— Metastatic Melanoma / Carcinoma

— Benign Dispersed Cells (e.g., from fibrocystic change or smeared fibroadenoma)

— —Distinguished by presence of other benign elements (BBN, apocrine sheets)

Note

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Prominent Necrosis (Breast Pattern 7)

Cytology

— Background of prominent, granular necrotic debris

— Irregular, discohesive epithelial fragments and dispersed single cells

— High-grade nuclear atypia: pleomorphism, hyperchromasia, coarse chromatin, prominent nucleoli

— Cells may have dense eosinophilic or apocrine-type cytoplasm

— Granular or psammomatous calcifications are common

DDx

— Fat Necrosis

— —Lacks atypical epithelium; shows histiocytes and necrotic fat

— Infarcted Papilloma

— —Can show necrosis but may have other features of a papilloma

Note

— Pattern often correlates with TNBC or HER2+ subtypes

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Mucinous Background (Breast Pattern 8)

Cytology

— Abundant, stringy, fibrillary mucin background

— Discohesive sheets, small fragments, and single cells floating in mucin

— Cells have mild - moderate nuclear atypia

— Absence of ME cells / BBN

— Intracytoplasmic lumina and signet ring cells may be present

— Branching capillaries can be seen within the mucin

DDx

— Mucinous Carcinoma (stereotypical lesion)

— Secretory Carcinoma (rare, prominent vacuoles)

— Myxoid Fibroadenoma

— —Distinguished by presence of BBN and ME cells; background is more granular

— Mucocele-like Lesions / Fibrocystic Change

— —Low cellularity and lacks significant atypia

— Metastatic Mucinous Carcinoma (e.g., Colorectal)

— —Consider with relevant history; may show necrosis

— Ultrasound Gel Artifact

— —Can mimic mucin; appears as dense granular blue material on Giemsa

Special Notes

— Mucinous carcinoma is typically ER/PR positive, HER2 negative

— Secretory carcinoma is ER/PR/HER2 negative and has a characteristic ETV6-NTRK3 fusion

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Normal (Breast)

Cells

─ Ductal epithelial cells arranged in 2Dmonolayer sheets or 3D aggregates

─ Myoepithelial cells seen associated with ductal sheets or as stripped nuclei in background

─ Apocrine metaplastic cells, foam cells (histiocytes), and stromal cells may be present

Cytoplasm

─ Ductal cells: Indistinct cell borders, scant cytoplasm

─ Apocrine cells: Abundant, granular cytoplasm with distinct polygonal borders

─ Myoepithelial cells: Inapparent cytoplasm

─ Foam cells: Abundant, vacuolated cytoplasm

Nuclei

─ Ductal cells: Smooth nuclear membranes, finely granular chromatin; 1.5-2 x RBC size

─ Myoepithelial cells: Ovoid nuclei, smaller and darker than ductal nuclei; seen as bare, bipolar nuclei in the background

─ Apocrine cells: Round, centrally or eccentrically placed nuclei with single visible nucleoli

Background

─ Generally clean; may contain mature adipose tissue

─ Myoepithelial cells present as stripped, bare bipolar nuclei

Absent

─ Significant atypia, cellular dyshesion, or 3D crowding

─ Necrosis or significant inflammation

Note

─ The presence of myoepithelial cells, both within epithelial clusters and as bare bipolar nuclei in the background, is the hallmark of a benign process

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Fibroadenoma

Benign, common fibroepithelial tumor characterized by a combination of branching epithelial clusters, fibromyxoid stroma, and abundant bare bipolar nuclei

Clinical

─ Younger women, 20s and 30s

─ Presents as a firm, freely mobile, well-circumscribed, round nodule

Cytology

Cells

─ Hypercellular smears (typically)

─ Large, cohesive, branching 3D clusters ("staghorn" or "antler-horn" shaped)

Cytoplasm

─ Ductal cells have scant to moderate cytoplasm

Nuclei

─ Abundant stripped, bare, bipolar myoepithelial cell nuclei in the background

─ Ductal cell nuclei generally bland, can show mild atypia

Background

─ Fragments of fibromyxoid stroma characteristic

─ Stroma can be myxoid (fuchsia on Romanowsky, translucent on Papanicolaou) or hyalinized and dense

Absent

─ True papillary structures with fibrovascular cores

─ Significant cellular dyshesion, high-grade nuclear atypia, or necrosis

DDx

─ Phyllodes Tumor: increased number of dispersed spindle stromal cells, not just oval bare nuclei; more stromal cellularity/atypia

─ Well-Differentiated Carcinoma: lacks abundant bare nuclei, more cellular dyshesion and crowding; Tubular carcinoma has rigid, angulated tubules, not staghorn sheets

─ Papillary Neoplasm: True papillary fronds with fibrovascular cores, columnar cells, and often a cystic background with histiocytes/siderophages

Note

─ A common cause of false-positive diagnoses due to hypercellularity and focal atypia

─ Combo of 3 classic features (epithelium, stroma, and bare nuclei) essential for diagnosis

─ On liquid-based preps, branching clusters are smaller, stroma less apparent and translucent, and stripped nuclei are reduced

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Fibrocystic Changes

A broad category encompassing a spectrum of non-proliferative (simple cysts, apocrine metaplasia) and proliferative lesions with or without atypia (sclerosing adenosis, epithelial hyperplasia)

Clinical

─ Exceedingly common, especially in premenopausal women

─ Often presents as ill-defined, lumpy, or tender areas in the breast that may fluctuate with the menstrual cycle

Cytology

Cells

─ Cellularity is highly variable depending on the specific components present (eg, paucicellular in cysts, hypercellular in hyperplasia)

─ A mixture of benign cell types is the hallmark: ductal cells in flat sheets, apocrine metaplastic cells, and foam cells (histiocytes)

Cytoplasm

─ Varies by cell type: ductal (scant), apocrine (abundant, granular), foam cells (vacuolated)

Nuclei

─ Ductal cells are bland with smooth nuclear membranes and associated myoepithelial cells

─ Apocrine cells have round nuclei with a single prominent, central nucleolus but maintain a low N/C ratio

Background

─ Often contains proteinaceous fluid ("cyst contents"), foam cells, and sometimes siderophages or multinucleated histiocytes

─ Stripped myoepithelial nuclei are usually present

Absent

─ True fibromyxoid stromal fragments characteristic of a fibroadenoma

─ Unequivocal malignant features

Ancillary studies

─ Not applicable

DDx

─ Well-Differentiated Adenocarcinoma: A key challenge is detecting a focal carcinoma within FCC Look for clusters that lack myoepithelial cells and show subtle atypia (crowding, nuclear irregularities, dyshesion) The single cells of lobular carcinoma can mimic histiocytes but have higher N/C ratios

─ Papillary Neoplasm: A key differential for cystic lesions Distinguished by the presence of tightly cohesive, rounded papillary clusters, numerous hemosiderin-laden macrophages, and large degenerative cytoplasmic vacuoles

─ Fibroadenoma: Can be difficult to distinguish from nodular or proliferative FCC The presence of prominent fibromyxoid stroma favors fibroadenoma; foam cells favor FCC The distinction is not critical as both are benign

Note

─ This is a heterogeneous category; reports should specify the components seen (eg, cyst, apocrine metaplasia, epithelial hyperplasia) to best correlate with clinical and imaging findings

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Simple Cyst (Breast)

A common non-proliferative lesion consisting of a fluid-filled sac lined by epithelium

Clinical

─ Rounded mass that typically disappears completely after fluid aspiration

─ Fluid can range from clear yellow to turbid or bloody

Cytology

Cells

─ Paucicellular

─ Contains foam cells (histiocytes), siderophages, and sometimes scant apocrine or ductal cells

─ Reactive cyst lining cells appear spindled with low N:C, can have atypical-appearing nuclei

Cytoplasm

─ Foam cells have abundant, vacuolated cytoplasm

─ Apocrine cells, if present, have abundant, granular cytoplasm

Nuclei

─ Nuclei of foam cells and benign epithelial cells are bland with smooth membranes

─ Reactive lining cells can show nuclear enlargement and hyperchromasia but retain a low N:C

Background

─ Proteinaceous fluid ("cyst contents"), may contain cholesterol crystals or calcific debris

Absent

─ High cellularity of cohesive epithelial groups

DDx

─ Cystic Carcinoma: Atypical epithelial cells, high N:C, significant nuclear irregularity, dyshesion

─ Papillary Neoplasm: 3D papillary clusters, numerous histiocytes/siderophages (often large, degenerative cytoplasmic vacuoles)

Note

─ A diagnosis of "cyst contents" is made when only proteinaceous fluid and histiocytes are present and the lesion resolves on imaging after aspiration

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Duct Ectasia

Dilated major ducts, typically retroareolar, associated with periductal inflammation and fibrosis

Clinical

─ Perimenopausal, multiparous women

─ Mimics malignancy (palpable mass, nipple inversion, or skin retraction)

Cytology

Cells

─ Low cellularity

─ Chronic inflammatory infiltrate (lymphocytes, plasma cells, multinucleated giant cells) characteristic

Background

─ Amorphous, granular debris from inspissated secretions characteristic, can mimic necrosis

─ Cholesterol crystals often present

Absent

─ True necrosis (karyorrhectic nuclear debris)

─ Significant population of atypical epithelial cells

DDx

─ Necrotic Carcinoma: True necrosis (with karyorrhexis) and high-grade cytology

─ Granulomatous Mastitis: Granulomatous inflammatory component, though there is overlap

Note

─ Key to avoid misdiagnosis of malignancy is recognizing granular background (inspissated secretions) rather than true tumor necrosis

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Sclerosing Adenosis

A benign proliferative lesion involving an increase in the number of acini (adenosis) and stromal fibrosis (sclerosis), which can form a palpable mass

Clinical

─ May present as a mammographic mass, calcifications, or distortion, mimicking carcinoma

Cytology

Cells

─ Markedly cellular

─ Epithelial cells in flat sheets, branching clusters, or small acinar structures

─ Mild cytologic atypia and single intact cells are common

Background

─ Fragments of dense, hyalinized stroma associated with the epithelial groups

─ Generally clean apart from the stripped nuclei

DDx

─ Tubular Carcinoma: Lacks abundant myoepithelial cells and has more rigid, angulated tubules

─ Fibroadenoma: Prominent myxoid stroma; staghorn-like epithelial clusters

Note

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Columnar Cell Lesion

A proliferative lesion of TDLUs lined by columnar cells; exists on spectrum from simple change to hyperplasia with or without atypia (i.e., flat epithelial atypia)

Clinical

─ Often incidental, frequently associated with microcalcifications

Cytology

Cells

─ Moderately to highly cellular with cohesive, flat, two-dimensional sheets

─ May show large, "ballooned" or rounded tissue fragments (represents dilated ductules)

Cytoplasm

─ Moderate amount sometimes with apical snouts or blebs

─ Resembles apocrine cytoplasm but less abundant and less coarsely granular

Nuclei

─ Nuclei round to oval

─ Atypia from minimal to severe

─ Myoepithelial cells are often scant or absent from the sheets

Background

─ Often proteinaceous

─ Microcalcifications are common

─ Bare bipolar nuclei may be sparse

Absent

─ Significant 3D crowding or cellular dyshesion

─ Prominent fibromyxoid stroma of a fibroadenoma

DDx

─ Well-Differentiated Carcinoma (DCIS): More architectural complexity (cribriform, micropapillae) and crowding

─ Apocrine Metaplasia: More abundant, coarsely granular cytoplasm and associated with other features of fibrocystic change

─ Fibroadenoma: Prominent branching clusters, fibromyxoid stroma, bare bipolar nuclei

Note

─ Columnar cell lesion with atypia = "Atypical", prompting surgical biopsy

─ Lack of significant crowding and dyshesion avoids overdiagnosis of malignancy

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Lactational Change

Benign physiologic changes in the breast during pregnancy and lactation, which can form a solid mass (lactational adenoma) or a milk-filled cyst (galactocele)

Clinical

─ Occurs in pregnant or lactating women, or as a result of medications

─ Presents as well-defined, mobile mass or cyst

Cytology

Cells

─ Hypercellular

─ Intact, expanded lobular units

─ Cells are fragile with easily disrupted cytoplasm

Cytoplasm

─ Abundant, delicate cytoplasm that is foamy, wispy, or vacuolated

─ Sharply demarcated clear vacuoles (lipid/milk product)

Nuclei

─ Nuclei enlarged ("activated") with prominent nucleoli and coarse chromatin; round, smooth nuclear membranes

─ Numerous bare, round ductal cell nuclei in background due to cytoplasmic fragility (not to be confused with myoepithelial cells)

Background

─“”Milky" proteinaceous fluid containing lipid droplets, best seen on air-dried smears

─ Galactoceles are paucicellular with a predominance of vacuolated, lipid-laden macrophages

Absent

─ True nuclear pleomorphism

─ Fibromyxoid stromal fragments

DDx

─ Adenocarcinoma: true nuclear pleomorphism, membrane irregularity, lacks intact lobular units

─ Secretory Carcinoma: Rare, More signet-ring cells and a lack of intact lobular units

─ Papillary Neoplasm: Lack milky quality and lipid droplets, have true papillary clusters and large degenerative vacuoles, unlike the foamy/small vacuoles of lactation

Note

─ Infarction can introduce necrosis into the background

─ "Atypical" or "suspicious" diagnosis if any doubt exists, prompting biopsy

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Papillary Neoplasm

A growth characterized by fibrovascular cores lined by epithelium, encompassing a spectrum from benign intraductal papilloma to papillary carcinoma

Clinical

─ May present as a subareolar mass or with a unilateral bloody or serous nipple discharge

Cytology

Cells

─ Moderately to highly cellular

─ 3D papillary clusters, may have fibrovascular cores, columnar cells often present

─ Specific benign patterns include "meshwork" and "stellate papillary" fragments with fibroelastotic cores

Cytoplasm

─ Large, degenerative cytoplasmic vacuoles that displace the nucleus are highly specific

─ Apocrine metaplasia is common

Nuclei

─ Nuclei range from bland to markedly atypical; degenerative changes can mimic malignancy

─ Myoepithelial cells variably present, often decreased or absent

Background

─ Cystic background of foam cells and hemosiderin-laden macrophages (siderophages) is key

─ A proteinaceous or hemorrhagic background is common

– Necrosis may be present due to infarction, even in benign papillomas

Absent

─ Large, staghorn-shaped clusters with fibromyxoid stroma (as in fibroadenoma)

─ Milky background with lipid droplets (as in lactational change)

DDx

─ Fibroadenoma: branching epithelial clusters, lacks cystic background, shows prominent fibromyxoid stroma, abundant bare bipolar nuclei (absent in papillary neoplasms)

─ Fibrocystic Change: Cystic background with histiocytes, but lacks 3D papillary structures and degenerative vacuoles

─ Papillary Carcinoma: Cannot be reliably distinguished based on cytology, requiring excision for histologic diagnosis

Note

─ Combination of papillary architecture, cystic background with macrophages, and degenerative vacuoles is key

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Adenocarcinoma (Breast)

A malignant proliferation of epithelial cells, encompassing ductal and lobular types, both in situ and invasive

Clinical

─ The most common cancer in women, typically seen in women in their 40s and older

─ Can present as a palpable mass, mammographic density, or as microcalcifications

Cytology

Cells

─ Cellularity ranges from paucicellular (eg, lobular carcinoma) to markedly hypercellular

─ Cellular dyshesion is a key feature, manifesting as loosely cohesive clusters and single intact malignant cells

Cytoplasm

─ Scant to moderate amount, often dense

─ Intracytoplasmic lumens (sharply delineated vacuoles with a central mucin dot) are a helpful feature when present

Nuclei

─ Exhibit features of malignancy: irregular nuclear contours, enlargement (often >2x RBC size), pleomorphism, and prominent or irregular nucleoli

─ Cellular crowding and 3D aggregates without myoepithelial cells are common

Background

─ Can be clean, necrotic (especially in high-grade tumors), or mucinous

─ Stripped malignant nuclei may be seen

Absent

─ A significant population of myoepithelial cells, either overlying clusters or as bare bipolar nuclei in the background

─ Benign architectural patterns like true fibromyxoid stroma

Ancillary studies

─ IHC (+): Hormone receptors (ER, PR) and HER2 status are assessed, typically on cell block or subsequent tissue biopsy

─ IHC (+): E-cadherin is positive in ductal carcinoma and negative in lobular carcinoma

DDx

─ Fibroadenoma: Distinguished by the presence of abundant bare bipolar nuclei and fibromyxoid stroma, despite potential hypercellularity and focal atypia

─ Proliferative Fibrocystic Change (eg, Sclerosing Adenosis): Distinguished by the presence of myoepithelial cells or a lack of significant cellular dyshesion and crowding

─ Papillary Neoplasm: Distinguished by a cystic background with numerous histiocytes, true papillary fronds, and/or large degenerative cytoplasmic vacuoles

Note

─ A reliable distinction between in situ and invasive carcinoma cannot be made on cytology alone

─ The report should include a comment on nuclear grade (low vs high)

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Post-therapeutic Changes (Breast)

A spectrum of reactive and reparative changes seen after surgery, radiation, or trauma, including fat necrosis and radiation atypia

Clinical

─ Occurs in patients with a history of breast-conserving therapy or trauma

─ Can clinically and radiographically mimic recurrent carcinoma, presenting as a firm, irregular mass with skin retraction or dystrophic calcifications

Cytology

Cells

─ Smears are often paucicellular

─ Fat Necrosis: Shows lipid-laden histiocytes (lipophages), multinucleated giant cells, and reactive fibroblasts, which can show marked pleomorphism

─ Radiation Atypia: Both epithelial and mesenchymal cells can be markedly enlarged with bizarre, pleomorphic, hyperchromatic nuclei

Cytoplasm

─ Lipophages have abundant, foamy cytoplasm with lipid vacuoles

─ Irradiated cells often have abundant, vacuolated cytoplasm, helping to maintain a low N:C ratio

Nuclei

─ Reactive fibroblasts/histiocytes can have large, pleomorphic nuclei and prominent nucleoli, mimicking malignancy

─ Irradiated cells have large, hyperchromatic, irregular nuclei, but the chromatin is often pale, smudgy, or indistinct due to degeneration

Background

─ Fat necrosis shows a "dirty" background with acellular lipid globules and inflammatory cells

─ Scarring and dense fibrosis from surgery/radiation may yield scant material

Absent

─ A hypercellular aspirate with numerous dyshesive malignant cells

─ True tumor necrosis and numerous single intact malignant cells are infrequent with radiation change alone and raise suspicion for recurrence

Ancillary studies

─ Not applicable

DDx

─ Recurrent Adenocarcinoma: This is the most important differential Recurrence is favored by hypercellularity, numerous single malignant cells with high N:C ratios, and true tumor necrosis, features which are generally absent in pure post-therapeutic change

Note

─ These changes are a major diagnostic pitfall for a false-positive diagnosis of malignancy

─ Clinical history of prior therapy is essential for correct interpretation

─ Radiation changes can persist for many years after treatment

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Granular Cell Tumor

A tumor of Schwann cell origin that can clinically and radiographically mimic carcinoma

Clinical

─ Presents as a firm, spiculated mass, sometimes fixed to skin or chest wall

Cytology

Cells

─ Moderate to high cellularity with a pattern of small discohesive tissue fragments and plentiful dispersed cells

─ Cells are polygonal and arranged in sheets and singly, resembling histiocytes or apocrine cells

Cytoplasm

─ Abundant, distinctly granular cytoplasm with ill-defined borders

─ A faint granular quality may be seen in the background

Nuclei

─ Small, round, centrally located regular nuclei with bland chromatin

─ Nucleoli and mitoses are typically absent

Background

─ Generally clean, but may have a faint granular appearance from disrupted cytoplasm

─ Occasional spindle stromal fragments may be present

Absent

─ True necrosis (its presence suggests a malignant variant)

─ Myoepithelial cells and bare bipolar nuclei

Ancillary studies

─ IHC (+): S100

─ IHC (-): Cytokeratin

DDx

─ Apocrine Carcinoma: Apocrine carcinoma shows more significant nuclear atypia, pleomorphism, and prominent nucleoli

─ Fibrocystic Change with Apocrine Metaplasia: Benign apocrine cells occur in flatter sheets and are often seen with other elements of FCC like foam cells and a proteinaceous background

Note

─ The combination of granular cytoplasm with bland, central nuclei is the key to diagnosis

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Epithelial Hyperplasia (Breast)

A benign proliferation of ductal epithelial and myoepithelial cells within breast ducts and lobules

Clinical

─ A common finding, often seen in the context of fibrocystic change

─ May be associated with palpable lumps, mammographic asymmetry, or calcifications

Cytology

Cells

─ Moderate to high cellularity

─ Large, cohesive, 3D tissue fragments with a chaotic, haphazard arrangement of cells

─ Smaller cohesive ductal epithelial tissue fragments are also present, with few dispersed single cells

Cytoplasm

─ Scant, ill-defined cytoplasm corresponding to ductal-type cells

Nuclei

─ Myoepithelial cells are numerous, seen both overlying the epithelial fragments and as bare bipolar nuclei in the background

─ Ductal cell nuclei are small, mildly pleomorphic, and stream around irregular, slit-like secondary lumina

Background

─ Generally clean, apart from numerous bare bipolar nuclei

─ Collagenous spherulosis (small, rounded magenta/pale green globules) may be present within epithelial fragments

Absent

─ True stromal fragments (as seen in fibroadenoma)

─ Rigid architectural patterns (eg, cribriform, micropapillary) or significant dispersal of atypical cells

Ancillary studies

─ Not applicable on cytology

DDx

─ Low-Grade Ductal Carcinoma In Situ: DCIS lacks the prominent myoepithelial component and shows more rigid architecture (true cribriform holes, micropapillae) and greater nuclear atypia

─ Fibroadenoma: Distinguished by the presence of true fibromyxoid stromal fragments and characteristic "staghorn" epithelial clusters

─ Papilloma: Distinguished by the presence of specific meshwork or stellate papillary tissue fragments with fibroelastotic cores, often in a proteinaceous background with histiocytes

Note

─ This is the stereotypical benign proliferative pattern; identifying the bimodal population of cells (ductal and myoepithelial) and streaming nuclei is key

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Radial Scar / Complex Sclerosing Lesion

A benign proliferative lesion with central sclerosis and entrapped, distorted tubules that can mimic invasive carcinoma on imaging

Clinical

─ Usually a non-palpable, mammographically detected stellate lesion

─ Histologically associated with a range of proliferative changes, including epithelial hyperplasia, adenosis, and sometimes atypia or low-grade carcinoma

Cytology

Cells

─ Moderate to high cellularity, resembling florid fibrocystic change with epithelial hyperplasia

─ Plentiful large, 3D hyperplastic ductal epithelial tissue fragments and monolayered sheets of apocrine cells

─ Smaller epithelial fragments, some tubular, are also present with a minor component of dispersed cells

Cytoplasm

─ Ductal and apocrine types are present

Nuclei

─ Abundant myoepithelial cells are present on tissue fragments

─ Bare bipolar nuclei are present in small numbers in the background

─ Mild nuclear atypia can be seen

Background

─ Foamy macrophages and a proteinaceous background are usually present

─ Small, sclerotic stromal tufts may be seen

Absent

─ The angulated, rigid tubules of tubular carcinoma

─ Lack of a significant myoepithelial component

Ancillary studies

─ Not applicable on cytology

DDx

─ Tubular Carcinoma: A major radiologic and cytologic differential Tubular carcinoma is distinguished by its rigid, angulated tubules, lack of myoepithelial cells, and more frequent dispersed atypical cells

─ Invasive Ductal Carcinoma: Carcinoma lacks the prominent myoepithelial component and shows more significant nuclear atypia and dispersal

─ Epithelial Hyperplasia / FCC: Overlap is significant; radial scars tend to be more cellular with more ragged epithelial fragments and occasional sclerotic stromal tufts

Note

─ It is essential to recognize the benign cytologic features of this entity to avoid a false-positive diagnosis, as it is often presented with a malignant diagnosis on imaging

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Phyllodes Tumors

Biphasic fibroepithelial tumors with a prominent, cellular stromal component, forming a spectrum from benign to borderline to malignant

Clinical

─ Uncommon lesions presenting similarly to fibroadenomas but often with a history of more rapid growth

─ Borderline and malignant variants can recur and metastasize (stromal component)

Cytology

Cells

─ Moderate to high cellularity with a biphasic pattern of epithelial and stromal components

─ Epithelial component shows large, hyperplastic ductal cell fragments, similar to fibroadenoma

─ Stromal component is hypercellular, with plump spindle cells arranged in large fragments

Cytoplasm

─ Stromal cells are spindle-shaped with elongated cytoplasm

Nuclei

─ Stromal fragments show increased cellularity and mild to marked nuclear atypia, depending on grade

─ A key feature is an increased number of single, dispersed spindle stromal cells in the background

─ Bare bipolar nuclei are present

Background

─ Characterized by large, hypercellular stromal fragments

Absent

─ In high-grade (malignant) phyllodes, the epithelial component may be scant or absent, leaving a picture resembling a sarcoma

Ancillary studies

─ Not applicable on cytology; diagnosis is based on morphology

DDx

─ Fibroadenoma: The primary differential, and distinction can be impossible for benign/borderline tumors Features favoring phyllodes are prominent stromal hypercellularity, stromal nuclear atypia, and an increased number of single spindle cells

─ Metaplastic Carcinoma (Sarcomatoid): High-grade phyllodes can mimic sarcomatoid carcinoma Metaplastic carcinoma will have a component that is positive for keratin markers, while the stroma of phyllodes is negative

─ Primary Sarcoma: Very rare High-grade phyllodes without an epithelial component is cytologically indistinguishable from a primary sarcoma

Note

─ A definitive distinction from fibroadenoma is often not possible on FNA; if features are suggestive of phyllodes, surgical excision is recommended

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Low- and Intermediate-Grade Intraductal Carcinoma / DCIS

A non-invasive carcinoma characterized by malignant cells proliferating within ducts, with low to intermediate nuclear grade and characteristic architectural patterns

Clinical

─ Often presents as mammographic calcifications or an indeterminate mass

─ Includes several architectural subtypes (eg, cribriform, micropapillary, solid)

Cytology

Cells

─ Moderate to high cellularity

─ Pattern of large, complex 3D epithelial tissue fragments, smaller discohesive fragments, and a variable number of dispersed single cells

─ Architecture is key: look for rigid arrays of cells, true cribriform patterns (punched-out holes), or micropapillary fragments (bulbous tips, narrow necks)

Cytoplasm

─ Scant to moderate, dense cytoplasm

Nuclei

─ Mild to moderate nuclear atypia, enlargement, and pleomorphism

─ Nuclei in cribriform patterns are often rigidly arranged and oriented toward the lumina

─ Apoptotic debris can be seen within fragments

Background

─ Can be clean or proteinaceous

─ Psammomatous or irregular calcifications may be present

Absent

─ A significant population of myoepithelial cells or bare bipolar nuclei

─ Necrosis (which is a feature of high-grade DCIS)

Ancillary studies

─ IHC (+): ER is uniformly positive (in contrast to patchy staining in hyperplasia)

─ IHC (-): High molecular weight keratins (CK5/6, CK14)

DDx

─ Epithelial Hyperplasia: Distinguished by the presence of myoepithelial cells and a haphazard, streaming arrangement of nuclei around irregular, slit-like spaces, rather than the rigid, punched-out holes of cribriform DCIS

─ Intraductal Papilloma: Distinguished by the presence of specific meshwork or stellate papillary fragments with fibroelastotic cores, and a prominent myoepithelial component

─ Invasive Carcinoma: The distinction may not be possible on cytology alone Invasion is suggested by a greater degree of dispersal, higher nuclear grade, and definitive stromal infiltration

Note

─ The diagnosis relies heavily on recognizing abnormal architectural patterns in the absence of a prominent myoepithelial cell population

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Encysted Papillary Carcinoma

A variant of intraductal carcinoma that grows as papillary fronds within a large, dilated cystic space, often surrounded by a thick fibrous capsule

Clinical

─ Tends to occur in older women

─ Presents as a cystic or complex solid and cystic mass on imaging

Cytology

Cells

─ High cellularity

─ Arborizing, true papillary fragments with thin fibrovascular cores covered in crowded, multilayered epithelium

─ A variable number of dispersed single cells, which may be columnar

Cytoplasm

─ Scant to moderate cytoplasm

Nuclei

─ Mild to moderately atypical, enlarged nuclei

Background

─ A cystic background with numerous macrophages and siderophages is common

Absent

─ Myoepithelial cells on the papillary fronds

─ Bare bipolar nuclei in the background

Ancillary studies

─ Not applicable on cytology

DDx

─ Intraductal Papilloma: This is the main differential Papillomas have a prominent myoepithelial layer on the fronds (though may be hard to see) and often show apocrine metaplasia and other benign changes Papillary carcinoma lacks the myoepithelial layer and shows more cytologic atypia and discohesion

─ Invasive Papillary Carcinoma: Very rare It is generally not possible to distinguish invasive from encysted (in situ) papillary carcinoma on cytology alone

Note

─ Even with features of a papillary neoplasm, a Code 5 "Malignant" diagnosis should be avoided unless unequivocal features of high-grade carcinoma or invasion are present

─ A diagnosis of "Suspicious, consistent with papillary neoplasm" is often appropriate, requiring excision

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High-Grade Intraductal Carcinoma / DCIS

A non-invasive carcinoma with high-grade nuclear features, often associated with central "comedo-type" necrosis and casting calcifications

Clinical

─ Frequently presents as linear, branching, "casting" microcalcifications on mammography

─ May present as a palpable mass, which often indicates an associated invasive component

Cytology

Cells

─ Cellularity is variable but can be high

─ Small to large, irregular, crowded, and discohesive epithelial tissue fragments

─ A variable number of single, pleomorphic malignant cells are present

Cytoplasm

─ Often dense and eosinophilic, sometimes with an apocrine appearance

Nuclei

─ Marked nuclear pleomorphism, enlargement, hyperchromasia, coarse chromatin, and large, irregular nucleoli

─ Mitotic figures may be seen

Background

─ Abundant granular, necrotic debris (comedonecrosis) is the hallmark feature

─ Irregular, granular microcalcifications are often seen within the necrotic background

Absent

─ Myoepithelial cells and bare bipolar nuclei

Ancillary studies

─ Not applicable on cytology for diagnosis

DDx

─ High-Grade Invasive Carcinoma: Often cytologically indistinguishable An invasive component is more likely with higher cellularity and features of stromal invasion A Code 4 "Suspicious" or Code 5 "Malignant" diagnosis is made, with a note about features of high-grade DCIS

─ Fat Necrosis: Can also have a necrotic background, but lacks the high-grade malignant epithelial cells Fat necrosis shows lipophages, multinucleated giant cells, and ghost outlines of adipocytes

─ Infarcted Papilloma: Can have necrosis but the epithelial cells, if preserved, show features of a papillary neoplasm rather than high-grade ductal carcinoma

Note

─ The combination of high-grade malignant cells with extensive comedonecrosis is highly suggestive of high-grade DCIS

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Infiltrating Ductal Carcinoma

The most common type of invasive breast cancer, characterized by malignant ductal cells infiltrating the stroma

Clinical

─ Constitutes about 75% of breast carcinomas

─ Presents usually as a palpable mass or a solid or stellate lesion on imaging

Cytology

Cells

─ High cellularity in most cases

─ A pattern of small discohesive epithelial tissue fragments and plentiful dispersed single cells

─ Tubular tissue fragments may be seen in grade 1 and 2 tumors

Cytoplasm

─ Often dense-staining with a variable number of intracytoplasmic lumina

Nuclei

─ Show a range of atypia from low-grade (mild enlargement, regular contours) to high-grade (marked pleomorphism, coarse chromatin, prominent nucleoli)

─ Cellular crowding and overlapping are prominent within clusters

Background

─ Fragments of sclerotic or myxoid stroma infiltrated by carcinoma cells are diagnostic of invasion when present

─ Tufted fragments of fibroblastic or sclerotic stroma may be seen

Absent

─ Benign components such as bare bipolar nuclei and myoepithelial cells

Ancillary studies

─ IHC (+): E-cadherin

─ Molecular: Hormone receptor (ER, PR) and HER2 status are determined on cell block or tissue biopsy to guide therapy

DDx

─ High-Grade DCIS: Can be cytologically indistinguishable DCIS is favored by prominent comedonecrosis and calcifications in the absence of definite stromal invasion

─ Lobular Carcinoma: Classic lobular carcinoma has a more highly dispersed pattern of smaller, more uniform cells, is E-cadherin negative, and frequently has intracytoplasmic lumina

─ Fibroadenoma with Atypia: A common pitfall Distinguished by the definitive presence of bare bipolar nuclei and fibromyxoid stromal fragments

Note

─ "Microbiopsies" of stromal fragments infiltrated by carcinoma cells are a specific sign of invasion

─ Cytologic grading (low vs high) based on nuclear features correlates well with histologic grade

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Invasive Micropapillary Carcinoma

An aggressive variant of invasive carcinoma with a distinctive histologic pattern and a high propensity for lymphatic invasion

Clinical

─ Uncommon as a pure tumor but seen as a component in up to 7% of breast cancers

─ Associated with a high rate of lymph node metastases and a worse prognosis

Cytology

Cells

─ Moderate to high cellularity

─ A pattern of small, discohesive tissue fragments and plentiful dispersed cells

─ Characterized by rounded, angulated, or micropapillary small, crowded tissue fragments with well-defined edges, sometimes in a loose "jigsaw" pattern

Cytoplasm

─ Moderate amount, can be columnar or apocrine-like

Nuclei

─ Moderate to high-grade nuclear atypia with large, hyperchromatic nuclei and large nucleoli

Background

─ Mucin may be seen rimming the tissue fragments or focally in the background

─ Psammomatous calcifications can be present

Absent

─ A myoepithelial layer or fibrovascular cores within the micropapillary clusters

Ancillary studies

─ IHC: Epithelial membrane antigen (EMA) shows a characteristic "inside-out" staining pattern on the outer surface of cell clusters on cell block

DDx

─ Low-Grade Micropapillary DCIS: Invasive micropapillary carcinoma is distinguished by higher nuclear grade and a greater degree of cellular dispersal

─ Intraductal Papillary Carcinoma: Has true fibrovascular cores and generally a lower nuclear grade

Note

─ The combination of a "jigsaw" pattern of small, rounded, or angulated tissue fragments with high-grade nuclei is highly suggestive

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Carcinoma With Medullary Features

A high-grade carcinoma characterized by syncytial sheets of pleomorphic cells with a prominent lymphoplasmacytic infiltrate

Clinical

─ Classically forms a quick-growing, rounded mass that can mimic a fibroadenoma or cyst on imaging

─ Associated with BRCA1 germline mutations and has a better prognosis than typical high-grade ductal carcinomas

Cytology

Cells

─ High cellularity

─ Small, syncytial sheets of cells and a variable number of large, dispersed single malignant cells

─ A prominent infiltrate of lymphocytes is seen, both in the background and within the epithelial clusters

Cytoplasm

─ Moderate amount of pale, granular cytoplasm with a high N:C ratio

Nuclei

─ Large, pleomorphic, vesicular nuclei with coarse chromatin and prominent macronucleoli

─ Mitoses can be numerous Plentiful stripped, bizarre nuclei are common

Background

─ Dominated by lymphocytes, occasional plasma cells, and lymphoid cell cytoplasmic fragments (lymphoglandular bodies)

Absent

─ Gland formation or stromal infiltration

Ancillary studies

─ IHC (-): Typically "triple-negative" (ER, PR, and HER2 negative)

─ IHC (+): Often shows a "basal-like" phenotype (positive for CK5/6 or CK14)

DDx

─ High-Grade Lymphoma: Can also show a dispersed pattern of large atypical cells, but lymphoma lacks true epithelial syncytial sheets and will be positive for lymphoid markers (eg, CD45) and negative for keratins

─ Metastatic Carcinoma in a Lymph Node: Can be indistinguishable, but medullary features in a breast primary should be considered if no other primary is known

─ Metastatic Melanoma: Can also have large pleomorphic cells and prominent nucleoli, but melanoma cells are often less cohesive and will be S100 positive

Note

─ The triad of syncytial growth, high-grade nuclei, and a prominent lymphoplasmacytic infiltrate is characteristic

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Metaplastic Carcinoma

A rare, heterogeneous group of tumors containing a mixture of adenocarcinoma with squamous and/or mesenchymal (sarcomatous) elements

Clinical

─ Can present as a rapidly growing mass, sometimes with cystic change

─ Prognosis is generally worse than for typical ductal carcinoma; most are "triple-negative"

Cytology

Cells

─ Moderate to high cellularity with a pattern of small discohesive tissue fragments and dispersed cells

─ Shows variable patterns depending on the components present:

─ 1) Poorly differentiated carcinoma with marked dispersal and high nuclear grade

─ 2) Squamous cell carcinoma with keratinization

─ 3) Sarcomatous, plump spindle cells seen singly or in fragments

Cytoplasm

─ Can be glandular, dense and keratinizing (squamous), or spindled

Nuclei

─ Typically high-grade, pleomorphic nuclei are seen in all components

Background

─ Necrosis is present in about 50% of cases

─ Chondroid or myxoid stromal fragments may be seen if there is chondrosarcomatous differentiation

Absent

─ Benign components like bare bipolar nuclei or myoepithelial cells

Ancillary studies

─ IHC (+): The carcinomatous component (including spindle cell carcinoma) is positive for pankeratin and/or p63 is positive in the sarcomatous component

DDx

─ Malignant Phyllodes Tumor: The main differential for biphasic lesions Malignant phyllodes lacks a keratin-positive carcinomatous component and typically has a benign epithelial element (though it can be scant)

─ Primary Sarcoma: Very rare If no keratin-positive component is identified, it cannot be distinguished from a primary sarcoma on cytology alone

─ Squamous Metaplasia (Benign): Benign squamous cells lack the high-grade nuclear atypia of squamous cell carcinoma

Note

─ The key to the diagnosis is identifying a biphasic population of malignant epithelial (carcinoma) and mesenchymal (sarcoma) cells

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Invasive Lobular Carcinoma

An invasive carcinoma characterized by a diffuse, single-file infiltrative growth pattern, which often results in low cellularity on aspiration

Clinical

─ Constitutes around 15% of breast carcinomas

─ Often presents as a non-specific palpable thickening or architectural distortion on imaging, rather than a discrete mass

Cytology

Cells

─ Cellularity is often low to moderate

─ A highly dispersed pattern of single cells is classic, with scattered minute, loosely cohesive tissue fragments and short, single-file "Indian files"

Cytoplasm

─ Scant to moderate amount, often eccentric (plasmacytoid)

─ Intracytoplasmic lumina (vacuoles with a central mucin dot, sometimes indenting the nucleus to form "signet ring" cells) are a very common and helpful feature

Nuclei

─ Typically small to intermediate in size, with mild to moderate pleomorphism

─ Nuclei are often round or slightly angulated with relatively bland chromatin and inconspicuous nucleoli

Background

─ Can be clean or contain fragments of sclerotic stroma infiltrated by single malignant cells

─ Smearing artifact with stripped nuclei is common

Absent

─ Large, cohesive epithelial sheets

─ A significant population of myoepithelial cells or bare bipolar nuclei

Ancillary studies

─ IHC (-): E-cadherin is characteristically negative, which helps distinguish it from ductal carcinoma

─ Molecular: Typically positive for hormone receptors (ER, PR) and negative for HER2

DDx

─ Low-Grade Ductal Carcinoma: Can have overlapping features, but ductal carcinoma is E-cadherin positive and typically forms more cohesive clusters

─ Benign Intramammary Lymph Node/Lymphoma: Both can show a dispersed cell pattern Lymphoma cells have lymphoid features (eg, lymphoglandular bodies), and benign nodes show a mixed lymphoid population

─ Undersampled Fibroadenoma: Smearing can create a dispersed pattern, but careful search will reveal bare bipolar nuclei and stromal fragments

Note

─ The diffuse infiltration can lead to false-negative FNAs due to low cellularity

─ Pleomorphic lobular carcinoma is a variant with high-grade nuclear features, mimicking high-grade ductal carcinoma, but is still E-cadherin negative

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Mucinous Carcinoma (Breast)

A carcinoma characterized by clusters of relatively bland tumor cells floating in abundant extracellular mucin

Clinical

─ Constitutes about 2% of breast carcinomas, typically in older women

─ Tends to have a favorable prognosis

─ Presents as a rounded, well-defined mass on imaging, mimicking a fibroadenoma or cyst

Cytology

Cells

─ Moderate cellularity

─ Discohesive sheets, small rounded tissue fragments, single files, and dispersed epithelial cells are seen

Cytoplasm

─ Scant to moderate, sometimes with intracytoplasmic vacuoles or signet-ring cell features

Nuclei

─ Typically show low to moderate nuclear grade, with mild enlargement and atypia

Background

─ Dominated by abundant, thick, fibrillary mucin (magenta on Giemsa, stringy green/orange on Pap)

─ Branching, anastomosing capillaries may be seen within the mucin

Absent

─ Myoepithelial cells and bare bipolar nuclei

─ High-grade nuclear features (in pure mucinous carcinoma)

Ancillary studies

─ Molecular: Typically strongly positive for ER and PR, and negative for HER2

DDx

─ Myxoid Fibroadenoma: Can have a background that mimics mucin, but is distinguished by the presence of benign branching epithelial clusters, myoepithelial cells, and abundant bare bipolar nuclei

─ Mucocele-like Lesion: Represents extravasated mucin from ruptured ducts and is typically paucicellular with only tiny clusters of bland ductal cells and numerous histiocytes

Note

─ The combination of abundant extracellular mucin with at least some architecturally and cytologically atypical epithelial clusters is diagnostic

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Secretory Carcinoma (Breast)

A rare, low-grade carcinoma with a favorable prognosis, characterized by prominent intra- and extracellular secretions

Clinical

─ Occurs mainly in women younger than 30, but also in older women and men

─ Presents as a well-circumscribed, subareolar mass

Cytology

Cells

─ Moderate cellularity with large, relatively cohesive tissue fragments, smaller discohesive groups, and dispersed cells

Cytoplasm

─ Abundant, granular, or pale and bubbly/vacuolated cytoplasm with a moderate to low N:C ratio

─ Large intracytoplasmic vacuoles containing mucin globules are characteristic and may form signet ring cells

Nuclei

─ Mildly pleomorphic, often round nuclei with fine chromatin and single prominent nucleoli

Background

─ A thin mucinous background is present

Absent

─ High-grade nuclear features

Ancillary studies

─ Molecular: Associated with a characteristic ETV6-NTRK3 gene fusion

─ IHC (-): Typically triple-negative (ER, PR, HER2 negative)

─ IHC (+): S100

DDx

─ Lactational Change: Distinguished by the presence of intact lobular units and a milky background with lipid droplets, rather than true mucin

─ Mucinous Carcinoma: Has abundant extracellular mucin but typically lacks the prominent intracytoplasmic vacuoles of secretory carcinoma

Note

─ The bubbly cytoplasm with prominent intracytoplasmic vacuoles and signet ring cells is a key feature

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Adenoid Cystic Carcinoma (Breast)

A rare carcinoma identical to its salivary gland counterpart, characterized by a dual population of cells and extracellular matrix material

Clinical

─ Uncommon, typically occurring in elderly women

─ Good prognosis with a low incidence of axillary metastases

Cytology

Cells

─ Moderate cellularity with a mixed pattern of large and small tissue fragments

─ Composed of small, basaloid-type cells with scant cytoplasm

Cytoplasm

─ Poorly defined, scant cytoplasm

Nuclei

─ Mildly enlarged and pleomorphic nuclei with bland chromatin

Background

─ Characterized by hyaline globules (magenta on Giemsa, pale green on Pap) surrounded by tumor cells

─ Larger cribriform tissue fragments with spaces filled with hyaline material may be seen

─ Stripped, round to oval nuclei in the background can mimic bare bipolar nuclei

Absent

─ High-grade nuclear features

Ancillary studies

─ IHC: Shows a dual population; ductal cells are CK5/6 positive, while basal/myoepithelial cells are p63 and S100 positive

─ IHC (-): Typically triple-negative (ER, PR, HER2 negative)

DDx

─ Collagenous Spherulosis: The main differential Spherulosis is distinguished by being a component within otherwise benign hyperplastic epithelial fragments that are associated with myoepithelial cells and bare bipolar nuclei

─ Pleomorphic Adenoma: Very rare in the breast; distinguished by its classic myxofibrillary stroma

Note

─ The presence of numerous, often large, hyaline globules surrounded by basaloid cells is the key diagnostic feature

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Neuroendocrine Carcinoma (Breast)

A rare primary breast carcinoma showing morphologic features of neuroendocrine differentiation

Clinical

─ Can be well-differentiated (carcinoid-like) or poorly differentiated (small cell carcinoma)

─ A component of ductal, lobular, or papillary carcinoma is frequently present

Cytology

Cells

─ Dispersed cell pattern with some minute tissue fragments

─ Cells are plasmacytoid or spindled with moderate cytoplasm

Cytoplasm

─ Moderate amount, granular

Nuclei

─ "Salt and pepper" chromatin (finely and coarsely granular)

─ Nuclear molding may be seen in tissue fragments

Background

─ Apoptotic debris and smearing of chromatin are common

Absent

─ Glandular or squamous features (in pure forms)

Ancillary studies

─ IHC (+): Synaptophysin, Chromogranin

─ Molecular: Often positive for ER

DDx

─ Invasive Lobular Carcinoma: Can also have a dispersed, plasmacytoid pattern, but typically lacks the classic "salt and pepper" chromatin

─ Malignant Lymphoma: Also a dispersed cell tumor, but lymphoma cells will have lymphoid features and be positive for lymphoid markers and negative for keratin and neuroendocrine markers

─ Metastatic Neuroendocrine Carcinoma: A primary breast neuroendocrine carcinoma is a diagnosis of exclusion after ruling out a primary elsewhere (eg, lung, GI tract)

Note

─ Up to 30% of breast carcinomas can show focal neuroendocrine marker positivity, so the diagnosis requires both characteristic morphology and IHC confirmation

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Non-Hodgkin Lymphoma (Breast)

A malignant proliferation of lymphoid cells, which can occur as a primary breast tumor or as secondary involvement from systemic disease

Clinical

─ Rare as a primary breast malignancy

─ Often mimics carcinoma clinically and on imaging

Cytology

Cells

─ An almost completely dispersed pattern of atypical lymphoid cells

─ The specific cell morphology depends on the lymphoma type (eg, large cells resembling centroblasts in DLBCL, a mixed population in MALT lymphoma)

Cytoplasm

─ Typically scant and basophilic, with a high N:C ratio

Nuclei

─ Atypical lymphoid nuclei with irregular contours, coarse or vesicular chromatin, and sometimes prominent nucleoli

Background

─ Lymphoid cell cytoplasmic fragments (lymphoglandular bodies) are a characteristic feature

Absent

─ True epithelial cohesion (syncytial sheets or glands)

Ancillary studies

─ Ancillary Studies: Flow cytometry on a fresh sample is essential for diagnosis and classification

─ IHC (+): Lymphoid markers (eg, CD45, CD20 for B-cell, CD3 for T-cell)

─ IHC (-): Keratins

DDx

─ Carcinoma with Medullary Features: Can have a prominent lymphoid infiltrate, but is distinguished by the presence of true syncytial sheets of large, pleomorphic epithelial cells that are keratin-positive

─ High-Grade Ductal Carcinoma: Can be highly discohesive but lacks lymphoglandular bodies and will be keratin-positive

─ Benign Intramammary Lymph Node: Shows a heterogeneous lymphoid population of small lymphocytes, tingible body macrophages, and germinal center fragments, rather than a monotonous atypical population

Note

─ Immediate on-site evaluation is crucial to recognize a lymphoid process so that a fresh sample can be collected for flow cytometry

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Angiosarcoma (Breast)

A rare malignant tumor of endothelial origin, which can be a primary breast sarcoma or arise as a complication of radiation therapy

Clinical

─ Primary angiosarcoma tends to occur in younger women

─ Secondary angiosarcoma occurs in older women, a median of 6 years post-radiation

─ Can present as a mass or a bluish skin discoloration

Cytology

Cells

─ Cellularity is variable, from low to high

─ Shows small, loosely cohesive acinar, pseudorosette, or spindle cell tissue fragments and single malignant cells

Cytoplasm

─ Can be spindled or epithelioid with intracytoplasmic vacuoles or hemosiderin

Nuclei

─ High-grade nuclear atypia with hyperchromasia, nuclear indentations, and one to two nucleoli

Background

─ Typically hemorrhagic

Absent

─ An epithelial component or myoepithelial cells

Ancillary studies

─ IHC (+): Endothelial markers (CD31, CD34, ERG)

─ IHC (-): Keratins, S100

DDx

─ High-Grade Phyllodes Tumor / Sarcoma: Can also present as a spindle cell malignancy, but will be negative for endothelial markers

─ Spindle Cell Metaplastic Carcinoma: Distinguished by positivity for keratin markers

─ Granulation Tissue: Can have reactive, atypical endothelial cells but is set in an inflammatory background and lacks sheets of frankly malignant cells

Note

─ Diagnosis on FNA is difficult and should be confirmed with core biopsy

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Metastases to the Breast

Malignant tumors from other primary sites that have spread to the breast

Clinical

─ Uncommon, accounting for less than 5% of malignant breast FNAs

─ Most common sources are contralateral breast, melanoma, lymphoma, and lung carcinoma

─ Often presents as multiple, rounded, well-circumscribed masses on imaging

Cytology

Cells

─ Pattern is based on the primary tumor (eg, dispersed large pleomorphic cells for melanoma, molding and "salt and pepper" chromatin for small cell lung cancer)

─ The key is a morphology that is unusual for a primary breast carcinoma

Cytoplasm

─ Varies with primary tumor (eg, melanin pigment may be seen in melanoma)

Nuclei

─ Varies with primary tumor

Background

─ Varies with primary tumor

Absent

─ Features of a typical primary breast carcinoma or a benign proliferative lesion

─ An in situ component

Ancillary studies

─ IHC: A panel is crucial for diagnosis (eg, S100/SOX10 for melanoma; TTF-1 for lung; CDX2 for colorectal; PAX8 for gynecologic/renal)

DDx

─ High-Grade Primary Breast Carcinoma: Can have unusual features, but the clinical history and a targeted IHC panel can usually resolve the differential

─ Malignant Lymphoma: Differentiated by lymphoid markers

Note

─ A metastasis should always be considered when the cytologic features do not fit a known primary breast entity, especially if there is a history of a non-breast malignancy

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♀️Cervix

Non-Diagnostic, Unsatisfactory

This section discusses adequacy criteria.

The assessment of specimen adequacy is a critical component of the cervical cytology report, ensuring that the sample is suitable for evaluation of epithelial abnormalities

Clinical

─ Unsatisfactory specimens generally require a repeat Pap test in 2-4 months; hrHPV triage is not recommended for unsatisfactory cytology

─ Specimens negative for intraepithelial lesion or malignancy (NILM) but lacking an endocervical/transformation zone (EC/TZ) component have specific follow-up guidelines based on age and HPV status

Cell patterns

─ Satisfactory: Estimated minimum of 8,000-12,000 well-visualized squamous cells (conventional smears) or 5,000 (liquid-based preparations, LBP); presence or absence of EC/TZ component (at least 10 well-preserved endocervical or squamous metaplastic cells) should be reported

Background

─ Unsatisfactory if >75% of epithelial cells obscured by blood, inflammation, debris, air-drying, or other artifacts; lubricants with carbomers/Carbopol polymers can adversely affect LBP adequacy

Absent

─ Unsatisfactory if insufficient squamous epithelial cells below the minimum estimated numbers (unless atypia present or other specific exceptions for low cellularity are met)

Note

─ Any specimen with ASC-US or a more significant epithelial abnormality is, by definition, satisfactory for evaluation

─ Laboratories should not rigidly apply the 5,000 cell threshold for LBP in vaginal and post-therapy specimens

─ Reporting of EC/TZ component is a quality indicator, though its absence in a negative Pap test does not necessarily mandate early repeat screening

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NILM

(Negative for Intraepithelial Lesion or Malignancy, i.e., Benign)

This category is used for specimens that show no evidence of intraepithelial neoplasia or malignancy, but may include non-neoplastic findings such as normal cellular elements, reactive changes, or organisms

Clinical

─ Management is typically routine age-appropriate screening, unless specific non-neoplastic findings (e,g,, certain organisms, endometrial cells in older women) or clinical history warrant other follow-up

Cell patterns

─ Predominantly mature superficial and intermediate squamous cells; endocervical cells and/or squamous metaplastic cells (EC/TZ component) may be present; endometrial cells may be seen (reported if woman ≥45 years)

Background

─ Generally clean or may show findings consistent with specific non-neoplastic conditions (e,g,, inflammation, cytolysis, atrophy)

Absent

─ Evidence of SIL, AGC, or carcinoma

Note

─ The Bethesda System provides detailed criteria for various normal cellular elements, non-neoplastic cellular variations, reactive changes, and organisms that fall under the NILM category

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Superficial cells (Cervix)

The most mature squamous cells, typically seen in the proliferative phase of the menstrual cycle or with estrogenic stimulation

Cell patterns

─ Large polygonal cells, often isolated or in loose sheets

Cytoplasm

─ Abundant, thin, eosinophilic (pink) or cyanophilic (blue-green); may contain keratohyaline granules

Nuclei

─ Small (~5-6 μm diameter), pyknotic (dense, condensed chromatin), centrally located

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Intermediate cells (IMCs) (Cervix)

Squamous cells from the mid-zone of the epithelium, predominant during the secretory phase, pregnancy, or with progestational agents

Cell patterns

─ Large polygonal cells, often with folded cytoplasm ("boat cells" esp in pregnancy); may show cytolysis (bare nuclei) in the presence of Döderlein bacilli (Lactobacillus)

Cytoplasm

─ Abundant, thin, typically cyanophilic (blue-green); often rich in glycogen (appearing clear or vacuolated)

Nuclei

─ Larger than superficial cell nuclei (~8-10 μm diameter), vesicular (open chromatin), finely granular chromatin, often with a longitudinal groove

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Parabasal cells (Cervix)

Immature squamous cells typically seen in atrophic smears (postmenopausal, postpartum) or from deeper layers if sampled vigorously

Cell patterns

─ Smaller, round to oval cells with a higher N:C ratio than mature squamous cells; often in sheets or isolated

Cytoplasm

─ Denser, thicker, often cyanophilic

Nuclei

─ Larger than intermediate cell nuclei (~10-12 μm diameter), round to oval, finely granular chromatin, smooth nuclear membranes; nucleoli generally inconspicuous

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Glandular cells

Normal glandular epithelial cells found in cervical cytology specimens, originating from the endocervix or endometrium

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Endocervical glandular cells

Cells lining the endocervical canal, characterized by their mucin-producing nature

Cell patterns

─ Arranged in sheets with a "honeycomb" appearance (en face view) or in strips with a "picket fence" arrangement (side view); single cells may also be present; cells larger than intermediate squamous cells, polarized

Cytoplasm

─ Abundant, finely granular or vacuolated (mucin-rich), basophilic or amphophilic; cilia may be present (tubal metaplasia often involves ciliated endocervical-type cells)

Nuclei

─ Round to oval, often basally located in columnar cells, uniform size (similar to or slightly larger than an intermediate cell nucleus); finely granular, evenly distributed chromatin; nucleoli usually small and inconspicuous but can be prominent if reactive

Absent

─ Significant nuclear atypia, hyperchromasia, or architectural disarray beyond reactive changes

Note

─ Reactive endocervical cells can show nuclear enlargement, prominent nucleoli, and some crowding but maintain overall cohesion and polarity

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Endometrial glandular cells (exfoliated)

Cells shed from the endometrium, typically seen during menses (days 1-5) and the proliferative phase (up to day 12); their presence in women ≥45 years old is reported

Clinical

─ Presence in women ≥45 years old requires clinical correlation to exclude endometrial pathology, though most are benign/physiologic

Cell patterns

─ Small, tightly cohesive, three-dimensional clusters ("exodus balls" often seen days 6-10, with central stromal cells rimmed by glandular cells); isolated cells less common and harder to identify; cells smaller than endocervical cells

Cytoplasm

─ Scant, often dense, basophilic, may be vacuolated; cell borders indistinct within clusters

Nuclei

─ Small (similar to or smaller than an intermediate cell nucleus), round to oval, often hyperchromatic and degenerated with smudgy chromatin; nucleoli usually inconspicuous but may be visible in LBP; apoptotic bodies (karyorrhexis) common within clusters

Background

─ Often bloody with inflammatory cells during menses; cleaner background in LBP

Absent

─ Significant nuclear atypia beyond degenerative changes

Note

─ Distinguishing exfoliated endometrial cells from small HSIL cells or AIS can be challenging; endometrial cells are generally smaller, more tightly clustered, and show degenerative nuclear changes rather than true dysplastic features

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Directly sampled endometrial cells (stromal & glandular)

Endometrial tissue fragments obtained by vigorous sampling, esp with endocervical brush or after cervical procedures (LEEP, cone); not considered clinically significant like exfoliated endometrial cells in older women

Cell patterns

─ Larger, more cellular, and often more organized fragments than exfoliated cells; may show glandular-stromal complexes with branching glands and dense stromal components; capillaries may be visible

Cytoplasm

─ Glandular cells: Columnar, scant to moderate; Stromal cells: Spindled, scant

Nuclei

─ Glandular cells: Round to oval, may be crowded and overlapping, variably hyperchromatic, smooth contours, inconspicuous nucleoli; mitoses may be seen in proliferative phase

─ Stromal cells: Oval to spindled, finely granular chromatin, inconspicuous nucleoli

Absent

─ Significant atypia beyond proliferative changes

Note

─ Can mimic atypical glandular cells or even HSIL due to hyperchromatic crowded groups (HCGs); recognition of biphasic (glandular and stromal) pattern and bland cytology helps in correct interpretation

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Benign Reactions

Non-neoplastic cellular responses to various stimuli such as inflammation, trauma, or hormonal changes

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Repair (Typical Repair) (Cervix)

Reactive cellular changes in squamous or glandular epithelium due to tissue injury and subsequent healing processes

Clinical

─ Often associated with inflammation, infection, trauma (e,g,, biopsy, IUD), or radiation

Cell patterns

─ Cohesive, flat sheets of cells, often with a streaming or "school of fish" appearance; cell borders usually well-defined; minimal nuclear overlap in a single plane

Cytoplasm

─ Abundant, often delicate or attenuated; may be eosinophilic or basophilic (polychromatic); vacuolization or perinuclear halos can occur; intracytoplasmic neutrophils common

Nuclei

─ Enlarged (often 1,5-2x normal intermediate or endocervical nucleus), round to oval, smooth nuclear contours; finely granular, evenly distributed chromatin, sometimes vesicular or hypochromatic; prominent, often multiple, smooth, round nucleoli are characteristic; mitoses may be present but are typical

Background

─ Often inflammatory; may contain fibrin or blood

Absent

─ Significant hyperchromasia, coarse or irregular chromatin, marked nuclear membrane irregularities, or significant loss of cohesion (features of "atypical repair" which would be classified as ASC or AGC)

Note

─ Key features are cellular cohesion, smooth nuclear outlines, fine chromatin, and prominent regular nucleoli

─ "Atypical repair" showing more significant atypia should be classified as ASC or AGC

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Metaplastic Squamous cells (Cervix)

Immature squamous cells replacing glandular epithelium, a common physiologic response in the transformation zone

Cell patterns

─ Cohesive sheets or isolated cells; cells vary from small, round/oval (immature) to larger, more polygonal (mature metaplasia); "spider cells" (cells with cytoplasmic projections) more common in conventional smears

Cytoplasm

─ Dense, often cyanophilic in immature cells; becomes more abundant and thinner with maturation

Nuclei

─ Round to oval, often slightly larger than an intermediate cell nucleus (mean area ~50 μm²); finely granular, evenly distributed chromatin; smooth nuclear membranes; nucleoli usually inconspicuous but can be prominent if reactive

Absent

─ Significant nuclear atypia (hyperchromasia, irregular contours, coarse chromatin) beyond mild reactive changes

Note

─ Immature squamous metaplasia with high N:C ratios can be a mimic of HSIL; however, metaplastic cells typically have smoother nuclear contours and finer chromatin

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Tubal metaplasia (Cervix)

Replacement of endocervical epithelium by ciliated and non-ciliated (peg) cells resembling fallopian tube epithelium; a benign finding

Cell patterns

─ Strips or small clusters of columnar cells, often with pseudostratification; cilia and/or terminal bars are diagnostic

Cytoplasm

─ Eosinophilic to amphophilic; apical cilia on ciliated cells; peg cells have scant cytoplasm

Nuclei

─ Round to oval, may be enlarged and mildly hyperchromatic; chromatin finely granular and evenly distributed; nucleoli usually inconspicuous; nuclear crowding and overlap can be prominent

Absent

─ Significant pleomorphism, coarse chromatin, or mitotic activity beyond that seen in reactive endocervical cells

Note

─ Can mimic Atypical Glandular Cells (AGC) or Adenocarcinoma in situ (AIS) due to nuclear crowding, enlargement, and hyperchromasia; identification of cilia/terminal bars is key to benign diagnosis

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Atrophy (Cervix)

Epithelial thinning due to decreased estrogen stimulation, typically seen in postmenopausal women or other low-estrogen states

Clinical

─ Smears may be sparsely cellular; inflammation (atrophic vaginitis) common

Cell patterns

─ Predominantly parabasal cells, often in flat monolayer sheets with preserved polarity or as dispersed single cells; intermediate cells may be present; superficial cells usually absent

Cytoplasm

─ Parabasal cells: Denser, cyanophilic

Nuclei

─ Parabasal cells: Round to oval, slightly larger than intermediate cell nuclei, finely granular chromatin, smooth nuclear membranes; mild hyperchromasia and nuclear enlargement may be seen; autolytic changes (stripped nuclei) can occur

Background

─ May be clean or show granular debris ("blue blobs" - inspissated mucus or degenerated cells), inflammation (atrophic vaginitis); pseudoparakeratosis (degenerated orangeophilic parabasal cells)

Absent

─ True dysplastic changes (though atrophic atypia can mimic SIL)

Note

─ Atrophic changes with atypia (ASC-US or ASC-H) should be reported if nuclear abnormalities exceed those of simple atrophy

─ Estrogen cream application can mature the epithelium and resolve atrophic atypia

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Pregnancy related changes

Navicular cells

Glycogen-rich intermediate squamous cells with a "boat-shaped" appearance, characteristic of pregnancy or progestational effect

Cell patterns

─ Intermediate squamous cells, often with folded cytoplasm imparting a boat shape; may form dense clusters

Cytoplasm

─ Abundant, basophilic to clear (due to glycogen)

Nuclei

─ Vesicular, finely granular chromatin, often eccentric

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Decidua

Hormonally stimulated endocervical or endometrial stromal cells seen during pregnancy or postpartum

Cell patterns

─ Single cells or small loose clusters; large cells

Cytoplasm

─ Abundant, granular or finely vacuolated, may have cytoplasmic processes

Nuclei

─ Large (35–50 μm² area), may be lobulated or multinucleated; finely granular, evenly distributed chromatin, normochromatic to hyperchromatic; smooth nuclear membranes; nucleoli usually prominent and basophilic

Note

─ Can be misinterpreted as LSIL or HSIL if not aware of pregnancy status; smooth nuclear contours and fine chromatin favor decidual cells

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Cytotrophoblast

Placental cells rarely seen in late pregnancy or postpartum

Cell patterns

─ Typically single cells, occasionally small clusters; small cells

Cytoplasm

─ Scant, may have prominent vacuoles

Nuclei

─ Enlarged, high N:C ratio, hyperchromasia; evenly distributed chromatin

Background

─ Often highly inflamed and sometimes bloody

Note

─ Can resemble reactive squamous cells or HSIL/ASC-H; clinical history is key

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Syncytiotrophoblast

Multinucleated placental cells rarely seen in late pregnancy or postpartum

Cell patterns

─ Large, multinucleated cells (up to 50+ nuclei)

Cytoplasm

─ Granular, often tapering at one end

Nuclei

─ Normochromatic with even chromatin distribution, often with irregular nuclear contours

Note

─ Differentiate from herpes (lacks ground-glass inclusions) and other multinucleated cells by history and nuclear features

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Arias Stella reaction

Benign glandular cell changes (endocervical or endometrial) associated with pregnancy or hormonal stimulation

Cell patterns

─ Glandular cells, singly or in clusters

Cytoplasm

─ Variable quantity, may be vacuolated

Nuclei

─ Large, hyperchromatic with contour irregularities (grooves, pseudoinclusions); granular to smudgy chromatin; multiple prominent nucleoli; N:C ratio variable, often high

Background

─ Usually inflammatory, often with leukophagocytosis

Note

─ Can mimic AGC or adenocarcinoma; history of pregnancy or hormonal stimulation is critical

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Intrauterine device (IUD) effect

Reactive glandular cell changes (endocervical or endometrial) associated with IUD use

Cell patterns

─ Glandular cells singly or in small clusters (usually 5–15 cells); signet-ring appearance due to large cytoplasmic vacuoles displacing nucleus; occasional single cells with high N:C

Cytoplasm

─ Variable amount, frequently large vacuoles

Nuclei

─ May be enlarged; degenerative changes ("wrinkled" chromatin, nuclear "cracking") may be present; nucleoli may be prominent

Background

─ Often clean; Actinomyces-like organisms may be present (up to 25% of cases)

Absent

─ True features of malignancy (though can mimic adenocarcinoma or HSIL)

Note

─ Changes may persist for months after IUD removal; if atypia is concerning, recommend repeat Pap after IUD removal or further investigation

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Parakeratosis (Cervix)

Miniature superficial squamous cells with dense orangeophilic/eosinophilic cytoplasm and small pyknotic nuclei; a reactive change

Cell patterns

─ Miniature superficial squamous cells, isolated, in sheets, or whorls; round, oval, polygonal, or spindle-shaped

Cytoplasm

─ Dense, orangeophilic or eosinophilic

Nuclei

─ Small (~10 μm² area), dense (pyknotic)

Absent

─ Significant nuclear atypia (if present, consider ASC or SIL)

Note

─ "Atypical parakeratosis" (with nuclear atypia) is classified as ASC or SIL

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Hyperkeratosis (Cervix)

Anucleate mature polygonal squamous cells, often associated with keratohyaline granules; a reactive change

Cell patterns

─ Anucleate mature polygonal squamous cells, isolated or in plaques

Cytoplasm

─ Mature, polygonal; may show keratohyaline granules

Nuclei

─ Absent; "ghost nuclei" (empty spaces) may be noted

Absent

─ Nuclear atypia in accompanying nucleated cells (if atypia present, consider ASC or SIL)

Note

─ Extensive hyperkeratosis may obscure underlying lesions; vulvar contamination can also introduce anucleate squames

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Lymphocytic (Follicular) Cervicitis

Chronic cervicitis with formation of lymphoid follicles in the subepithelium

Cell patterns

─ Polymorphous population of lymphocytes (small lymphocytes, centrocytes, centroblasts, immunoblasts, plasma cells); tingible body macrophages often present; germinal center fragments may be seen

Background

─ Lymphoglandular bodies

Note

─ In LBP, lymphocytes may be more dispersed or in loose aggregates; in CP, often in clusters or mucus strands

─ DDx includes HSIL (small cell type) and lymphoma; polymorphous population and presence of tingible body macrophages favor benign

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Radiation (Cervix)

Cellular changes due to ionizing radiation, which can persist long-term

Cell patterns

─ Marked cytomegaly with proportional karyomegaly (N:C ratio often preserved); bizarre cell shapes; multinucleation common

Cytoplasm

─ Often abundant, vacuolated, or polychromatic (two-toned); intracytoplasmic neutrophils

Nuclei

─ Variably sized, some very large; mild hyperchromasia; degenerative changes (pallor, wrinkling, smudging of chromatin, vacuolization); nucleoli may be prominent (esp with repair)

Absent

─ True malignant features (though can mimic SIL or carcinoma)

Note

─ Acute changes resolve within ~6 months; chronic changes can persist indefinitely

─ Distinguish from recurrent malignancy (more hyperchromasia, irregular chromatin, higher N:C in malignancy)

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Glandular cells status post hysterectomy

Benign endocervical-like glandular cells in vaginal smears after hysterectomy

Cell patterns

─ Benign-appearing endocervical-type glandular cells; goblet cell or mucinous metaplasia may be seen

Note

─ Origin may be vaginal adenosis, metaplasia, or prolapsed fallopian tube (if supracervical hysterectomy, from cervical stump)

─ If not atypical, no clinical significance; reporting is optional

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Contaminants and miscellaneous (Cervix)

Extraneous elements or non-cervical/vaginal cells sometimes encountered in cervical cytology specimens

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Spermatozoa

Male germ cells, may be seen in cervical cytology specimens

Cell patterns

─ Characteristic oval head with a dense, dark nucleus and a pale anterior acrosomal cap; long, delicate flagellum (tail) often visible

Note

─ Presence is usually of no clinical significance in routine screening; may be noted if relevant to clinical history (e,g,, postcoital sample, fertility assessment, forensic cases)

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Pollen grains (Cervix)

Airborne plant microspores, common environmental contaminants

Cell patterns

─ Variably sized and shaped (round, oval, triangular), often with a thick, refractile, and sometimes sculptured cell wall; may appear yellow, brown, or refractile; internal contents may or may not be visible

Note

─ Can be mistaken for fungal spores or parasite ova if morphology is not carefully assessed; usually larger and more complex than true pathogens

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Lubricant (Cervix)

Material used during speculum insertion, which can contaminate the cytologic sample

Cell patterns

─ Appears as amorphous, stringy, granular, or gel-like material, often basophilic or purple; may obscure epithelial cells or cause cellular distortion

Background

─ Can cause a "streaky" or "clumpy" appearance, esp in LBP

Note

─ Certain lubricants (esp those containing carbomers or Carbopol polymers) can significantly impair LBP adequacy, leading to unsatisfactory specimens due to scant cellularity or obscuration

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Other contaminants (Cervix)

Includes various fibers (e,g,, cotton, synthetic), talc (from gloves, though less common now), starch granules, and other debris

Cell patterns

─ Fibers are elongated, refractile structures; talc appears as small, birefringent crystals under polarized light; starch granules are round to oval with a central hilum, often showing a "Maltese cross" pattern under polarized light

Note

─ Usually easily recognizable and of no clinical significance, but extensive contamination can obscure cellular detail

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Trichomonas vaginalis (Cervix)

A flagellated protozoan parasite, a common cause of vaginitis

Clinical

─ May cause itching, burning, and a malodorous, frothy, yellow-green vaginal discharge; many infections are asymptomatic

─ Sexually transmitted infection

Cell patterns

─ Pear-shaped or oval organisms, typically 15-30 μm long (variable size); pale, eccentrically placed nucleus; reddish cytoplasmic granules (often inconspicuous); flagella usually not visible on Pap stain; often associated with a polymorphous inflammatory infiltrate and "cannonball" clusters of neutrophils on squamous cells ("Trich parties")

Background

─ Often inflammatory, with neutrophils; "leptothrix" (long, filamentous bacteria) frequently coexists; perinuclear halos in squamous cells ("pseudokoilocytosis") may be seen but lack the nuclear atypia of true koilocytes

Absent

─ True hyphae or budding yeast (to distinguish from Candida)

Note

─ Reporting is recommended by Bethesda; treatment of patient and partners is indicated

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Candida (Cervix)

Yeast and pseudohyphae, common cause of vulvovaginal candidiasis ("yeast infection")

Clinical

─ May cause itching, burning, and a thick, white, "cottage cheese-like" vaginal discharge; many colonizations are asymptomatic

Cell patterns

─ Budding yeast forms (3-7 μm diameter) and/or pseudohyphae (chains of elongated budding yeast cells); true hyphae may also be present; typically stain pink/eosinophilic or basophilic; "shish kebab" arrangement (squamous cells skewered by pseudohyphae) may be seen

Background

─ Variable inflammation; squamous cells may show reactive changes

Absent

─ True septate hyphae with acute angle branching (seen in Aspergillus, a rare contaminant/pathogen)

Note

─ Reporting is recommended by Bethesda; treatment usually for symptomatic women

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Bacterial vaginosis (BV) / Gardnerella vaginalis

A polymicrobial clinical syndrome resulting from replacement of normal Lactobacillus-predominant vaginal flora with high concentrations of anaerobic bacteria (e,g,, Gardnerella vaginalis, Prevotella spp, Atopobium vaginae, Mobiluncus spp)

Clinical

─ May cause a thin, homogeneous, malodorous (fishy) vaginal discharge and elevated vaginal pH (>4,5); many cases are asymptomatic

─ Associated with adverse obstetric outcomes (e,g,, preterm labor) and increased risk of acquiring STIs

Cell patterns

─ "Clue cells" (squamous cells coated by a lawn of coccobacilli, obscuring cell borders); marked decrease or absence of normal Lactobacilli; predominance of small, pleomorphic coccobacillary forms

Background

─ Often "filmy" or granular due to numerous bacteria; neutrophils usually sparse or absent (unless co-infection)

Absent

─ Predominance of Lactobacilli; significant numbers of Trichomonas or Candida (though co-infections can occur)

Note

─ Reporting is recommended by Bethesda; diagnosis of BV is clinical (Amsel criteria or Nugent score on Gram stain), but cytology can suggest the diagnosis

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Actinomyces (Cervix)

Anaerobic or microaerophilic Gram-positive filamentous bacteria

Clinical

─ Strongly associated with intrauterine device (IUD) use, esp long-term; most women are asymptomatic carriers

─ Rarely, can cause pelvic actinomycosis (an invasive infection)

Cell patterns

─ Dense, tangled clumps of filamentous bacteria ("cotton balls" or "dust bunnies"), often with a radiating periphery; individual filaments are thin and branching; may be associated with neutrophils

Background

─ Often clean, but can be inflammatory if associated with IUD effect or infection

Absent

─ True fungal hyphae or yeast forms

Note

─ Reporting is recommended by Bethesda; clinical significance in asymptomatic IUD users is controversial, treatment usually not indicated unless symptomatic or pelvic infection suspected

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Herpes Simplex Virus (HSV) (Cervix)

Viral cytopathic effect due to HSV-1 or HSV-2 infection

Clinical

─ Primary infection may cause painful genital vesicles, ulcers, fever, and lymphadenopathy; recurrent episodes are usually milder

─ Viral shedding can occur in the absence of visible lesions

Cell patterns

─ The "3 Ms": Multinucleation, Nuclear molding (nuclei indenting each other), and Margination of chromatin (condensed along nuclear membrane); "ground glass" appearance of nuclei (homogeneous, pale, opaque chromatin); +/- distinct eosinophilic intranuclear inclusions (Cowdry type A)

Background

─ May be inflammatory

Absent

─ Cilia (to distinguish from multinucleated endocervical cells); prominent nucleoli (unless reactive changes superimposed)

Note

─ Reporting is recommended by Bethesda; antiviral treatment can manage outbreaks but does not eradicate latent virus

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Cytomegalovirus (CMV) (Cervix)

Viral cytopathic effect, rare in cervical cytology, usually seen in immunocompromised individuals

Clinical

─ Most infections are asymptomatic in immunocompetent hosts; can cause significant disease in immunocompromised patients or congenital infection

Cell patterns

─ Marked cytomegaly and karyomegaly of single cells (often glandular or stromal); characteristic large, basophilic, intranuclear "owl's eye" inclusion surrounded by a clear halo; smaller granular basophilic cytoplasmic inclusions may also be present

Background

─ Variable

Absent

─ Multinucleation and nuclear molding typical of HSV

Note

─ Reporting is recommended by Bethesda; clinical significance depends on host immune status

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Atypical Squamous Cells of Undetermined Significance (ASC-US)

Cytologic changes suggestive of a Squamous Intraepithelial Lesion (SIL) that are qualitatively or quantitatively insufficient for a definitive interpretation; encompasses atypia that is more marked than reactive changes but falls short of LSIL

Clinical

─ Most common epithelial abnormality reported

─ Risk of underlying HSIL (CIN 2/3) on biopsy is ~10-20%; risk of invasive cancer is low (~0,1-0,2%)

─ Management typically involves HPV testing (reflex or co-testing); if HPV positive, colposcopy is indicated; if HPV negative, co-testing in 3 years is recommended for women ≥25 years

Cell patterns

─ Usually mature superficial or intermediate-type squamous cells, singly or in sheets; atypical parakeratosis or cells with incomplete koilocytic features may be present

Cytoplasm

─ Generally abundant, similar to normal mature squamous cells; may show perinuclear halos or vacuolization suggestive but not diagnostic of koilocytosis; dense orangeophilic cytoplasm in atypical parakeratotic cells

Nuclei

─ Enlarged, approximately 2,5 to 3 times the area of a normal intermediate cell nucleus (or twice the size of a normal squamous metaplastic cell nucleus)

─ N:C ratio slightly increased but generally <50%

─ Mild hyperchromasia; chromatin evenly distributed or slightly granular; nuclear contours may be minimally irregular

─ Binucleation or multinucleation may be present

Background

─ Variable; may be clean or inflammatory

Absent

─ Definitive features of LSIL (esp unequivocal koilocytes with diagnostic nuclear atypia) or HSIL

Note

─ ASC-US is an interpretation of the entire specimen, not just individual cells

─ Criteria for ASC-US may differ subtly among labs due to variations in stains and preparation techniques

─ Common patterns include: Atypical parakeratosis (APK), atypical repair, and atypia in postmenopausal women/atrophy

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Atypical Squamous Cells, cannot exclude HSIL (ASC-H)

Cytologic changes suggestive of HSIL that are qualitatively or quantitatively insufficient for a definitive interpretation; reserved for a minority of ASC cases (<10% of all ASC)

Clinical

─ Higher risk of underlying HSIL (CIN 2/3) on biopsy than ASC-US (~25-50%, can be higher); risk of invasive cancer also higher than ASC-US but still low

─ Management is colposcopy, regardless of HPV status (reflex HPV testing not recommended for ASC-H)

Cell patterns

─ Usually immature squamous metaplastic-type cells, often in small groups (<10-15 cells) or as single cells; may present as "crowded sheet pattern" or atypical repair concerning for HSIL/cancer; cells often smaller than typical ASC-US cells

Cytoplasm

─ Often scant and dense (metaplastic type); N:C ratio is significantly increased, often approximating that of HSIL

Nuclei

─ Enlarged (may be only 1,5-2,5 times larger than normal metaplastic nucleus but N:C ratio is high)

─ Hyperchromasia, often with irregular chromatin distribution or coarse granularity

─ Nuclear contours frequently irregular, with notching or indentations

─ Nucleoli generally absent

Background

─ Variable; may be clean or inflammatory

Absent

─ Unequivocal features of HSIL (esp in terms of quantity of abnormal cells or classic HSIL morphology)

DDx

─ HSIL (esp small cell HSIL or poorly preserved HSIL)

─ Immature squamous metaplasia with reactive changes (can have high N:C ratio but nuclei usually smoother and chromatin finer)

─ Atrophy with degeneration (can show hyperchromasia and some nuclear irregularity, but N:C ratio usually not as high as HSIL)

─ Reactive endocervical cells or tubal metaplasia (beware of "endocervical cells seen on end" mimicking small atypical squamous cells)

─ AIS (if glandular features are subtle and cells appear in crowded groups)

Note

─ ASC-H is intended for cases where HSIL is a significant concern, but the changes are not definitive

─ Common patterns include "atypical immature metaplasia" (small cells with high N:C ratios) and "crowded sheet pattern"

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Low-Grade Squamous Intraepithelial Lesion (LSIL)

Encompasses human papillomavirus (HPV) cytopathic effect (koilocytosis) and what was formerly termed mild dysplasia or Cervical Intraepithelial Neoplasia grade 1 (CIN 1)

Clinical

─ Caused by HPV infection (both low-risk and high-risk types)

─ Most LSILs represent transient HPV infections and regress spontaneously, esp in young women (<25 years)

─ Risk of underlying HSIL (CIN 2/3) on biopsy is ~15-30%

─ Management for women ≥25 years is colposcopy; for women 21-24 years, repeat cytology at 12 months is preferred; HPV co-testing with LSIL cytology is generally not recommended for triage due to high rates of HPV positivity

Cell patterns

─ Cells usually mature superficial or intermediate type, occurring singly, in sheets, or loose clusters; koilocytes (cells with perinuclear cavitation and nuclear atypia) are pathognomonic but not required for diagnosis

Cytoplasm

─ Abundant, mature (superficial or intermediate type); koilocytotic change includes a sharply defined, broad perinuclear clear zone (halo) with a peripheral rim of condensed, often densely stained cytoplasm

Nuclei

─ Enlarged (at least 3 times the area of a normal intermediate nucleus, or ~100-175 μm² area); N:C ratio is low but slightly increased

─ Hyperchromasia is common, chromatin may be smudgy, coarsely granular, or opaque

─ Nuclear contours often irregular (wrinkled, "raisinoid") but can be smooth

─ Binucleation or multinucleation common

─ Nucleoli generally absent or inconspicuous

Background

─ Variable; may be clean or inflammatory

Absent

─ Features of HSIL (esp significantly increased N:C ratio in immature-appearing cells, marked hyperchromasia with very coarse chromatin)

DDx

─ Reactive changes with "pseudokoilocytosis" (e,g,, Trichomonas infection, glycogen effect): Perinuclear halos are usually smaller, less well-defined, and lack significant nuclear atypia (esp hyperchromasia and irregular contours)

─ ASC-US: Nuclear atypia or koilocytic features are suggestive but quantitatively or qualitatively insufficient for LSIL

─ HSIL: Cells usually smaller with higher N:C ratio and more severe nuclear atypia

Note

─ Koilocytosis is the hallmark of HPV infection; to be diagnostic, koilocytes must exhibit both the characteristic cytoplasmic halo and nuclear atypia (enlargement, hyperchromasia, irregular contours)

─ Non-koilocytic LSIL is diagnosed based on nuclear atypia in mature squamous cells that exceeds ASC-US criteria but falls short of HSIL

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High-Grade Squamous Intraepithelial Lesion (HSIL)

Encompasses what was formerly termed moderate and severe dysplasia, carcinoma in situ (CIS), CIN 2, and CIN 3; represents a true precancerous lesion

Clinical

─ Caused by persistent infection with high-risk HPV types (esp HPV 16 and 18)

─ Higher risk of progression to invasive squamous cell carcinoma if untreated compared to LSIL

─ Risk of underlying invasive cancer on biopsy is ~1-2% for cytologic HSIL

─ Management is colposcopy for all non-pregnant women; see-and-treat (excisional procedure) is an acceptable option for women ≥25 years if HSIL is present and colposcopy adequate

Cell patterns

─ Cells usually smaller than LSIL cells, often immature (metaplastic or parabasal-like); occur singly, in sheets, or syncytial-like aggregates (hyperchromatic crowded groups, HCGs)

Cytoplasm

─ Scant and often dense (immature/metaplastic type), but can be delicate or occasionally keratinized; N:C ratio is markedly increased (generally >50-60%)

Nuclei

─ Enlarged (may be similar in size to LSIL nuclei, but N:C ratio is much higher; or nuclei may be smaller than LSIL but still disproportionately large for cell size)

─ Hyperchromasia is usually marked; chromatin often coarsely granular and irregularly distributed, but can be finely granular or even hypochromatic

─ Nuclear contours are very irregular, with notching, indentations, and angulation

─ Nucleoli generally absent or inconspicuous

─ Mitotic figures may be seen, esp in tissue fragments

Background

─ Variable; may be clean, inflammatory, or show tumor diathesis if associated with invasive cancer or extensive necrosis

Absent

─ Features of LSIL (esp koilocytosis with only mild nuclear atypia and low N:C ratio)

─ Unequivocal features of invasive squamous cell carcinoma (e,g,, macronucleoli, definite tumor diathesis, bizarre cell shapes in keratinizing SCC)

DDx

─ LSIL: Larger cells, lower N:C ratio, less severe nuclear atypia

─ ASC-H: Atypical features suggestive of HSIL but quantitatively or qualitatively insufficient

─ Atrophy with reactive atypia or degeneration: Can mimic HSIL due to high N:C ratio and hyperchromasia; atrophic cells typically have smoother nuclear contours, finer chromatin (unless degenerated), and lack the marked irregularity of HSIL

─ Immature squamous metaplasia (reactive): Can have high N:C ratio, but nuclei are usually round/oval with smooth contours and fine, evenly distributed chromatin

─ Endometrial cells or directly sampled lower uterine segment: Can form HCGs; endometrial cells are smaller, often degenerated, and may have associated stroma; directly sampled LUS has biphasic pattern

─ AIS/AGC: Glandular features (columnar shape, feathering, rosettes, true glandular lumina) distinguish from HSIL, though HSIL involving glands can be a pitfall

Note

─ HSIL is a spectrum; "small cell HSIL" (CIN3-like) has very high N:C ratios and scant cytoplasm; "large cell HSIL" (CIN2-like) has slightly more cytoplasm but still high N:C and significant nuclear atypia

─ Keratinizing HSIL shows dense, orangeophilic cytoplasm with marked nuclear atypia; may mimic invasive keratinizing SCC

─ p16 immunohistochemistry is often diffusely positive (block positivity) in HSIL and can be helpful in biopsy correlation but is not typically used on cytology specimens for primary diagnosis

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Atypical Glandular Cells (AGC)

Glandular cells (endocervical, endometrial, or not otherwise specified) that display nuclear atypia exceeding obvious reactive or reparative changes but lacking unequivocal features of endocervical adenocarcinoma in situ (AIS), invasive adenocarcinoma, or endometrial carcinoma

Clinical

─ AGC is an uncommon interpretation (0,1-0,5% of Pap tests)

─ Associated with a higher risk of significant underlying pathology (SIL, esp HSIL; AIS; adenocarcinoma; endometrial carcinoma) compared to ASC-US

─ Risk of CIN 2/3+ is ~10-40%; risk of AIS or invasive adenocarcinoma is ~3-10%; risk of endometrial cancer (esp with atypical endometrial cells) varies by age and symptoms

─ Management for all AGC categories (except atypical endometrial cells) is colposcopy with endocervical sampling; endometrial sampling is also indicated for women ≥35 years or those <35 with risk factors for endometrial cancer (e,g,, abnormal bleeding, obesity, anovulation)

─ For atypical endometrial cells, endometrial and endocervical sampling is indicated; colposcopy may be deferred if endometrial pathology is identified

─ HPV testing may be useful in risk stratification for some AGC categories

Note

─ The Bethesda System recommends qualifying AGC as to endocervical or endometrial origin if possible; if not, "AGC, Not Otherwise Specified (NOS)" is used

─ "Atypical Endocervical Cells, NOS" and "Atypical Glandular Cells, NOS" may be further qualified as "favor neoplastic" if features are more worrisome

─ "Atypical Endometrial Cells" are not further qualified as "favor neoplastic"

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Atypical Endocervical Cells, Not Otherwise Specified

Endocervical-type cells displaying nuclear atypia that exceeds obvious reactive or reparative changes but lacks unequivocal features of endocervical adenocarcinoma in situ (AIS) or invasive adenocarcinoma

Cell patterns

─ Sheets or strips of endocervical-type cells with some cell crowding, nuclear overlap, and/or pseudostratification; cells usually maintain some polarity

Cytoplasm

─ May be fairly abundant, but N:C ratio is increased compared to normal endocervical cells; cell borders often discernible

Nuclei

─ Enlarged (up to 3-5 times normal endocervical nucleus area); some variation in nuclear size and shape; mild hyperchromasia; mild chromatin irregularity; occasional small nucleoli; mitotic figures rare

Background

─ Variable, may be clean or inflammatory

Absent

─ Unequivocal features of AIS or invasive adenocarcinoma (e,g,, numerous complex groups with feathering/rosettes, marked hyperchromasia, coarse chromatin, prominent irregular nucleoli, frequent mitoses/apoptosis)

DDx

─ Reactive endocervical cells (less crowding, smoother nuclei, finer chromatin, prominent but regular nucleoli)

─ Tubal metaplasia (cilia or terminal bars, often more nuclear elongation and finer chromatin)

─ Directly sampled lower uterine segment (LUS) or endometrium (often larger fragments, biphasic pattern with stroma, less atypia)

─ AIS or adenocarcinoma (more severe atypia, more complex architecture, more discohesion)

─ HSIL involving glands (squamous features in some cells, more irregular chromatin, lack of true glandular architecture)

Note

─ This is a heterogeneous category; includes changes that may be reactive mimics or true glandular neoplasia

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Atypical Endocervical Cells, Favor Neoplastic

Endocervical-type cells with cytologic and architectural features quantitatively or qualitatively borderline for, but highly suspicious of, endocervical adenocarcinoma in situ (AIS) or invasive adenocarcinoma

Cell patterns

─ Sheets, strips, or three-dimensional clusters with nuclear crowding, overlap, and pseudostratification; rare cell groups with rosettes or feathering may be present

Cytoplasm

─ Scant to moderate; N:C ratio increased

Nuclei

─ Enlarged, often elongated or irregular; hyperchromasia common; chromatin may be coarse and irregularly distributed; nucleoli may be prominent; occasional mitoses or apoptotic bodies

Background

─ Variable, may be clean or contain some debris

Absent

─ Unequivocal features of AIS or invasive adenocarcinoma (often a quantitative issue – too few abnormal groups)

DDx

─ AIS or invasive adenocarcinoma (distinction may be based on quantity of abnormal cells or subtlety of features)

─ Reactive endocervical changes or tubal metaplasia (less atypia, cilia in tubal metaplasia)

─ HSIL involving glands (squamous features, different chromatin pattern)

Note

─ This category carries a higher risk of significant glandular neoplasia than AGC-EC, NOS

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Atypical Endometrial Cells

Cells interpreted as endometrial in origin that display nuclear atypia beyond that of benign exfoliated or directly sampled endometrial cells, but lacking unequivocal features of endometrial adenocarcinoma

Clinical

─ Esp concerning in postmenopausal women or those with abnormal bleeding

─ Management involves endometrial and endocervical sampling

Cell patterns

─ Small groups (usually 5-10 cells) or isolated cells; cells often small and degenerated

Cytoplasm

─ Scant, often basophilic, may be vacuolated; cell borders poorly defined

Nuclei

─ Slightly enlarged compared to normal endometrial cells (may be only 1,5-2x intermediate nucleus); mild to moderate hyperchromasia; chromatin heterogeneity; nucleoli may be small but visible (esp in LBP)

Background

─ Variable; may be bloody or contain inflammatory cells or diathesis (esp if adenocarcinoma present)

Absent

─ Unequivocal features of endometrial adenocarcinoma (e,g,, numerous atypical cells, prominent nucleoli, definite tumor diathesis)

DDx

─ Benign exfoliated endometrial cells (smaller nuclei, more degenerative changes, less atypia)

─ Directly sampled LUS/endometrium (larger fragments, biphasic pattern, less atypia)

─ Endometrial adenocarcinoma (more severe atypia, often more cellular, tumor diathesis)

─ HSIL (can mimic small endometrial cells but usually has coarser chromatin, more irregular nuclear contours, and lacks glandular features)

─ IUD effect (vacuolated cytoplasm, but nuclear changes usually degenerative or reactive)

Note

─ This category is not further qualified as "favor neoplastic" due to difficulty in reliable subclassification

─ Watery diathesis (granular proteinaceous background) is suggestive of endometrial adenocarcinoma

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Squamous cell carcinoma (SCC) (Cervix)

An invasive malignancy composed of squamous cells, which may be keratinizing or non-keratinizing; most arise from pre-existing HSIL

Clinical

─ Symptoms may include abnormal vaginal bleeding (esp postcoital), vaginal discharge, or pain; many early SCCs are asymptomatic and detected by screening

─ Most SCCs are associated with high-risk HPV infection (esp HPV 16 and 18)

─ Management depends on stage and includes surgery, radiation, and/or chemotherapy

Cell patterns

─ Variable, depending on differentiation; may present as single cells, cohesive sheets, or syncytial-like aggregates; bizarre cell shapes (tadpole, spindle cells) common in keratinizing type

Cytoplasm

─ Keratinizing SCC: Often dense, orangeophilic or eosinophilic ("hard" cytoplasm); bizarre shapes

─ Non-keratinizing SCC: Usually less abundant, cyanophilic or amphophilic, more delicate; cell borders less distinct

Nuclei

─ Markedly atypical: Enlarged, pleomorphic, hyperchromatic (often with irregular, coarsely clumped chromatin); irregular nuclear contours are prominent; macronucleoli common in non-keratinizing SCC, often pyknotic/obscured in keratinizing SCC

Background

─ Often contains tumor diathesis (granular proteinaceous debris, old blood, necrotic tumor cells); acute inflammation common

Absent

─ Features of a benign process or lower-grade SIL (unless co-existing)

Ancillary studies

─ p16 IHC is usually diffusely positive (block-like staining) but is not specific for invasion

─ HPV testing is usually positive for high-risk types

DDx

─ HSIL (esp keratinizing HSIL): Lacks definite tumor diathesis and often has less pleomorphism and less prominent macronucleoli than invasive SCC

─ Repair/Reactive changes: Can show prominent nucleoli and some atypia but lack the marked hyperchromasia, coarse chromatin, and significant pleomorphism of SCC; diathesis absent

─ Adenocarcinoma: Glandular features (acini, columnar shape, mucin) distinguish from SCC, though poorly differentiated tumors can overlap

─ Metastatic SCC from other sites: Clinical history is key

Note

─ Cytologic grading (well, moderately, poorly differentiated) is not typically reported in Pap tests as it has limited clinical utility and reproducibility

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Non-keratinizing SCC (including basaloid) (Cervix)

A subtype of squamous cell carcinoma characterized by malignant cells lacking significant keratinization

Cell patterns

─ Syncytial aggregates and single cells; cells often smaller than keratinizing SCC, may have a basaloid appearance with scant cytoplasm

Cytoplasm

─ Scant to moderate, typically cyanophilic or amphophilic, indistinct cell borders

Nuclei

─ Hyperchromatic, with coarsely clumped, irregularly distributed chromatin; parachromatin clearing often evident; nuclear contours irregular; prominent nucleoli and/or macronucleoli are characteristic

Background

─ Tumor diathesis (necrotic debris, old blood) often prominent

Absent

─ Significant cytoplasmic keratinization (orangeophilia, dense "hard" cytoplasm, bizarre cell shapes like tadpoles or fiber cells)

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Keratinizing SCC (Cervix)

A subtype of squamous cell carcinoma characterized by malignant cells showing obvious keratinization

Cell patterns

─ Predominantly isolated single cells, less commonly in aggregates; marked variation in cell size and shape, with caudate (tadpole) and spindle cells often present

Cytoplasm

─ Dense, "hard", orangeophilic or eosinophilic; keratin pearls may be seen (rarely in smears)

Nuclei

─ Often pyknotic and hyperchromatic, obscuring chromatin detail; when discernible, chromatin is coarse and irregularly distributed; nuclear contours markedly irregular; macronucleoli less common or obscured by pyknosis compared to non-keratinizing SCC

Background

─ Tumor diathesis may be present but can be less prominent or different in quality (more keratin debris) than in non-keratinizing SCC

Absent

─ Predominance of non-keratinized malignant cells

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Adenocarcinoma (Cervix)

Malignant glandular neoplasms of the female genital tract that can be detected by cervical cytology include endocervical adenocarcinoma, endometrial adenocarcinoma, and, rarely, extrauterine adenocarcinomas (e,g,, ovarian, fallopian tube, metastatic from other sites)

Clinical

─ Endocervical adenocarcinoma is increasing in incidence, esp in younger women; most are HPV-related (esp HPV 18 and 16)

─ Endometrial adenocarcinoma is primarily a disease of postmenopausal women; symptoms include abnormal bleeding

─ Cytologic detection of adenocarcinoma can be challenging due to overlapping features with benign reactive changes, AGC, and AIS

Cell patterns

─ Variable, depending on origin and differentiation; generally show crowded groups, sheets, strips, rosettes, or papillae; single malignant cells often present

Cytoplasm

─ Variable, from scant to abundant; may be mucinous, clear, or eosinophilic; N:C ratio usually high

Nuclei

─ Enlarged, pleomorphic, often with irregular contours; hyperchromasia with coarse, irregularly distributed chromatin; macronucleoli common

Background

─ May be clean or show tumor diathesis (granular debris, old blood, necrosis), esp with invasive lesions

Absent

─ Definitive squamous differentiation (unless adenosquamous carcinoma)

Ancillary studies

─ IHC for p16 (diffuse block-like staining often seen in HPV-related endocervical adenocarcinomas/AIS), CEA, ER/PR, vimentin, and HPV DNA testing can aid in distinguishing endocervical from endometrial origin and from benign mimics

DDx

─ Reactive endocervical/endometrial cells; tubal metaplasia; Arias-Stella reaction; IUD effect; AIS; HSIL involving glands; metastatic adenocarcinoma

Note

─ The Bethesda System specifies reporting adenocarcinoma by probable site of origin if possible (endocervical, endometrial, extrauterine) or as Adenocarcinoma, Not Otherwise Specified (NOS)

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Endocervical Adenocarcinoma in situ (AIS)

A precursor to invasive endocervical adenocarcinoma, characterized by replacement of normal endocervical epithelium by cytologically malignant glandular cells confined to the native glandular structures

Clinical

─ Often associated with concurrent HSIL or invasive SCC; most are HPV-related (esp HPV 18)

─ Management typically involves excisional procedure (cone biopsy) to exclude invasion and assess margins

Cell patterns

─ Crowded sheets, strips, rosettes, or "feathered" groups of columnar cells; loss of normal honeycomb architecture; pseudostratification common; single atypical cells rare

Cytoplasm

─ Scant to moderate, often basophilic or amphophilic; mucin depletion common in usual type; N:C ratio increased

Nuclei

─ Enlarged (2-3x normal endocervical nucleus), oval to elongated, often cigar-shaped; hyperchromatic with coarsely granular, evenly distributed chromatin; nuclear membrane irregularities usually subtle; nucleoli generally inconspicuous or small; mitotic figures and apoptotic bodies common

Background

─ Usually clean; tumor diathesis absent (by definition, as it's an in situ lesion)

Absent

─ Stromal invasion; features of squamous differentiation (unless co-existing SIL)

Ancillary studies

─ IHC: (+) p16 (strong, diffuse block-like staining), CEA (cytoplasmic); (-) ER, PR, vimentin (usually)

─ HPV DNA testing usually positive for high-risk types (esp HPV 18)

DDx

─ Reactive endocervical cells/repair (less crowding, smoother nuclei, prominent but regular nucleoli, no feathering/rosettes usually)

─ Tubal metaplasia (cilia, less nuclear atypia, more nuclear elongation)

─ Directly sampled LUS/endometrium (biphasic pattern, less atypia)

─ Invasive endocervical adenocarcinoma (may show macronucleoli, tumor diathesis, more discohesion)

─ HSIL involving glands (squamous features, more irregular chromatin, p16+ but different cell morphology)

Note

─ Cytologic features can overlap with invasive endocervical adenocarcinoma; biopsy is required for definitive diagnosis and to rule out invasion

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Endocervical Adenocarcinoma

An invasive malignancy arising from the endocervical glands

Clinical

─ May present with abnormal bleeding, discharge, or be detected by screening

─ Most are HPV-related (esp HPV 18 and 16); non-HPV related types (e,g,, gastric-type, clear cell) exist and have different morphology/prognosis

Cell patterns

─ Highly cellular; crowded sheets, strips, clusters, papillae, or acinar structures; single malignant cells common; loss of polarity and architectural disarray

Cytoplasm

─ Variable: mucinous (usual type, intestinal, signet-ring), clear (clear cell type), eosinophilic (serous type); N:C ratio usually markedly increased

Nuclei

─ Enlarged, pleomorphic, irregular contours; hyperchromatic with coarse, irregularly distributed chromatin; parachromatin clearing often seen; macronucleoli common and often irregular; mitotic figures, including atypical forms, may be frequent

Background

─ Tumor diathesis (necrotic debris, old blood) often present, esp in LBP as "clinging diathesis"

Absent

─ Ovarian-type stroma; definitive squamous differentiation (unless adenosquamous)

Ancillary studies

─ IHC: (+) p16 (diffuse, HPV-related), CEA, CK7; (-) ER, PR, vimentin (usual endocervical type); specific markers for variants (e,g,, HNF1B for clear cell; Napsin A, MUC6 for gastric type)

─ HPV DNA testing usually positive for high-risk types (usual type)

DDx

─ AIS (lacks diathesis, often less pleomorphism and fewer macronucleoli)

─ Endometrial adenocarcinoma (often ER/PR/vimentin (+), p16 patchy, CEA (-); different morphology)

─ Metastatic adenocarcinoma (clinical history, IHC panel)

─ HSIL involving glands (squamous features, different chromatin)

─ Reactive changes/repair (less atypia, no diathesis)

Note

─ Subtyping (e,g,, usual endocervical, mucinous gastric-type, endometrioid, clear cell, serous, mesonephric) is important for prognosis and management but often requires histology

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Endometrial Adenocarcinoma

An invasive malignancy arising from the endometrial glands, occasionally detected in cervical cytology

Clinical

─ Most common gynecologic malignancy in developed countries; typically affects postmenopausal women; presents with abnormal uterine bleeding

─ Risk factors include unopposed estrogen, obesity, nulliparity, tamoxifen use, Lynch syndrome

Cell patterns

─ Often scant cellularity unless high-grade or advanced stage; small, tight clusters (esp low-grade endometrioid) or more dispersed, pleomorphic cells (high-grade, serous); single cells may be present

Cytoplasm

─ Scant to moderate, often basophilic or vacuolated; intracytoplasmic neutrophils ("bag of polys") can be seen, esp in endometrioid type

Nuclei

─ Enlarged (may be only slightly in low-grade), round to irregular; hyperchromasia variable; chromatin fine to coarse; nucleoli often prominent, esp in serous and clear cell types; macronucleoli in high-grade tumors

Background

─ Often bloody, esp if symptomatic bleeding; tumor diathesis (watery, granular debris) may be present, esp with higher-grade/stage tumors

Absent

─ Definitive endocervical features (e,g,, tall columnar cells in picket-fence or honeycomb, abundant apical mucin unless mucinous endometrial variant)

Ancillary studies

─ IHC: (+) ER, PR, vimentin (esp endometrioid type); (-) CEA, p16 (or patchy); specific markers for subtypes (e,g,, p53 aberrant in serous, Napsin A in clear cell)

DDx

─ Benign endometrial cells (smaller, more degenerated, less atypia)

─ Atypical endometrial cells (lesser degree of atypia)

─ Endocervical adenocarcinoma (often ER/PR/vimentin (-), p16 diffuse block (+), CEA (+))

─ Metastatic adenocarcinoma (clinical history, IHC)

─ HSIL (can mimic small cell endometrial carcinoma; look for squamous features)

Note

─ Cytologic detection of endometrial cancer is insensitive, esp for low-grade tumors; Pap test is not a screening tool for endometrial cancer

─ "Atypical endometrial cells" should be reported if criteria for adenocarcinoma are not met

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Other Malignant Neoplasms

This category includes rare malignant tumors of the cervix and uterus, such as small cell neuroendocrine carcinoma and certain uncommon adenocarcinoma variants

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Small cell carcinoma (Cervix)

A high-grade neuroendocrine carcinoma, often associated with HPV 16/18, characterized by small, relatively uniform cells with scant cytoplasm and neuroendocrine features

Clinical

─ Rare, aggressive tumor, often presenting at an advanced stage with early metastases

─ May be associated with paraneoplastic syndromes (e,g,, Cushing syndrome due to ACTH production)

─ Prognosis is generally poor

Cell patterns

─ Small, relatively uniform cells, often in loosely cohesive clusters, sheets, or singly dispersed; nuclear molding and crush artifact common

Cytoplasm

─ Very scant, often imperceptible, cyanophilic

Nuclei

─ Round to oval or angulated, hyperchromatic; chromatin finely granular or stippled ("salt-and-pepper"), sometimes smudged; nucleoli inconspicuous or absent

Background

─ Often shows extensive necrosis, apoptotic bodies, and mitotic figures; crush artifact prominent

Absent

─ Features of squamous or typical glandular differentiation (unless a mixed tumor)

Ancillary studies

─ IHC: (+) Neuroendocrine markers (Synaptophysin, Chromogranin A, CD56, INSM1); (+) Cytokeratins (often dot-like perinuclear)

─ IHC: (+) p16 (usually diffuse block-like if HPV-related)

─ HPV DNA testing often positive for high-risk types

DDx

─ HSIL (small cell type): HSIL cells usually larger, more pleomorphic, coarser chromatin, no prominent molding or neuroendocrine marker positivity

─ Endometrial cells (exfoliated or stromal): Smaller, more degenerated, lack prominent molding and neuroendocrine markers

─ Lymphoma: Dispersed pattern, lymphoglandular bodies, (+) lymphoid markers, (-) cytokeratin

─ Embryonal rhabdomyosarcoma: Rare in adults, strap cells, (+) desmin/myogenin

Note

─ Cytologic features are identical to small cell carcinoma of other sites (e,g,, lung)

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Mucinous Carcinoma, Gastric Type (includes Minimal Deviation Adenocarcinoma/Adenoma Malignum)

A rare subtype of endocervical adenocarcinoma characterized by gastric-type mucinous differentiation, often with bland cytologic features in its well-differentiated form (Minimal Deviation Adenocarcinoma/Adenoma Malignum); typically not HPV-related

Clinical

─ May present with profuse watery or mucoid vaginal discharge

─ Minimal Deviation Adenocarcinoma (MDA) is an extremely well-differentiated variant that can be very difficult to diagnose due to its bland cytology, often requiring deep cone biopsy

─ Associated with Peutz-Jeghers syndrome in some cases

─ Prognosis variable; MDA can be aggressive despite bland morphology

Cell patterns

─ Abundant glandular cells, often in large sheets, clusters, or isolated; cells columnar with copious apical mucin or goblet cell morphology

Cytoplasm

─ Abundant, pale, foamy, or clear (gastric-type mucin); may have a yellowish tinge; goblet cells common

Nuclei

─ Minimal Deviation Adenocarcinoma: Often bland, round to oval, basally located, with smooth contours and inconspicuous nucleoli, mimicking benign endocervical cells; subtle atypia (enlargement, mild hyperchromasia, slight irregularity) may be the only clue

─ Higher-grade gastric-type mucinous carcinoma: More overt nuclear atypia, pleomorphism, hyperchromasia, and prominent nucleoli

Background

─ Abundant extracellular mucin, often thick and viscous

Absent

─ Features of usual HPV-related endocervical adenocarcinoma (e,g,, feathering, rosettes, prominent apoptosis, p16 block positivity)

─ Definitive squamous differentiation

Ancillary studies

─ IHC: (+) CK7, CEA, MUC6, HIK1083 (gastric mucin markers)

─ IHC: (-) p16 (or only patchy/focal), ER, PR, vimentin

─ HPV DNA testing usually negative

DDx

─ Benign endocervical cells/reactive changes (esp in MDA: look for subtle atypia, architectural disarray, abnormal configuration of cell groups, clinical context)

─ Usual-type endocervical adenocarcinoma/AIS (HPV-related, p16 block (+), different mucin profile)

─ Metastatic mucinous adenocarcinoma (esp from GI tract or pancreas: clinical history, IHC for site-specific markers like CDX2, CK20)

Note

─ Diagnosis of MDA on cytology is extremely challenging and often missed; high index of suspicion needed in cases with abundant bland mucinous epithelium, esp with watery discharge

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🫘Kidney

Mixed Small Tissue Fragments in Clean Background With or Without Glomeruli (Kidney Pattern 1)

Cystic Proteinaceous Background With Variable Number of Macrophages (Kidney Pattern 2)

Predominantly Dispersed Inflammatory Cells (Kidney Pattern 3)

Loosely Cohesive Tissue Fragments of Polygonal Cells With Thin Fibrovascular Strands and Dispersed Cells With Eosinophilic or Clear Cytoplasm With or Without a Hemorrhagic and/or Necrotic Background (Kidney Pattern 4)

Loosely Cohesive Papillary Tissue Fragments and Dispersed Cells With or Without a Hemorrhagic and/or Necrotic Background (Kidney Pattern 5)

Loosely Cohesive Tissue Fragments With Dispersed Atypical Cells, With or Without Necrosis and Hemorrhage (Kidney Pattern 6)

Dispersed Atypical Small Round Cells With Variable Mix of Discohesive Tissue Fragments of Epithelial or Spindle Cells With Hemorrhage and Necrosis (Kidney Pattern 7)

Mixed Cohesive Tissue Fragments of Spindle Cells and Vessels, With Fatty Globules and Spindle Cells in Bloody Background (Kidney Pattern 8)

💊Liver

Background Predominant (Liver Pattern 1)

Mildly Cellular With Small Tissue Fragments (Liver Pattern 2)

Moderately to Markedly Cellular With Tissue Fragments Ranging From Small to Large Without Dispersal (Liver Pattern 3)

Moderately to Markedly Cellular With Tissue Fragments Ranging From Small to Large and Dispersed Cells (Liver Pattern 4)

Moderately to Markedly Cellular With Dispersed Cells (Liver Pattern 5)

🛡️Lymph Node

Dispersed Hypercellular (Lymph Node Pattern 1)

Cytology

─ High cellularity

─ Predominantly dispersed, single cells with minimal cohesion

─ Clear or granular background with lymphoglandular bodies

─ Diffusely basophilic smear at low power

DDx

─ Reactive / Inflammatory

─ ─ Reactive Lymphoid Hyperplasia

─ ─ ─ Polymorphous population, tingible-body macrophages, germinal center fragments

─ ─ Infectious Mononucleosis

─ ─ ─ Polymorphous population with numerous immunoblasts and plasmacytoid cells

─ ─ Toxoplasmic Lymphadenitis

─ ─ ─ Polymorphous population with syncytial microgranulomas

─ ─ Langerhans Cell Histiocytosis

─ ─ ─ Mixed with eosinophils and characteristic Langerhans cells (nuclear grooves)

─ ─ Rosai-Dorfman Disease

─ ─ ─ Numerous large histiocytes with emperipolesis

─ Low-Grade B-Cell Lymphoma

─ ─ Small Lymphocytic Lymphoma (SLL/CLL)

─ ─ ─ Monotonous small, round lymphocytes with "block-like" chromatin; smudge cells

─ ─ Mantle Cell Lymphoma

─ ─ ─ Monotonous small, irregular/indented lymphocytes

─ ─ Follicular Lymphoma

─ ─ ─ Mix of centrocytes (cleaved) and centroblasts (large, non-cleaved)

─ High-Grade B-Cell Lymphoma

─ ─ Diffuse Large B-Cell Lymphoma (DLBCL)

─ ─ ─ Monomorphous large lymphoid cells with prominent nucleoli

─ ─ Burkitt Lymphoma

─ ─ ─ Intermediate cells with deep blue cytoplasm, lipid vacuoles, "starry sky" pattern

─ T-Cell Lymphoma

─ ─ Peripheral T-Cell Lymphoma, NOS

─ ─ ─ Heterogeneous population with highly irregular/convoluted nuclei

─ ─ Anaplastic Large Cell Lymphoma

─ ─ ─ Pleomorphic large cells with "hallmark" (reniform) nuclei

─ Precursor Lymphoid Neoplasm

─ ─ Lymphoblastic Lymphoma

─ ─ ─ Monomorphous lymphoblasts with fine chromatin, scant cytoplasm, high mitotic rate

─ Non-Lymphoid Malignancies

─ ─ Metastatic Melanoma

─ ─ ─ Pleomorphic cells, macronucleoli, intranuclear pseudoinclusions, +/- pigment

─ ─ Metastatic Seminoma

─ ─ ─ Large uniform cells, prominent nucleoli, "tigroid" background, stripped nuclei

─ ─ Metastatic Signet Ring Cell Carcinoma

─ ─ ─ Dispersed monomorphic cells with large, eccentric mucin vacuoles

Note

─ The presence of lymphoglandular bodies confirms a lymphoid aspirate but does not distinguish benign from malignant

─ The key distinction is between a polymorphous (reactive) and monomorphous (neoplastic) population

─ Flow cytometry and IHC are essential for definitive diagnosis and classification of lymphomas

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Dispersed Hypocellular (Lymph Node Pattern 2)

Cytology

─ Low cellularity

─ Predominantly dispersed, single cells

─ Background may show prominent necrosis or granular debris

DDx

─ Hodgkin Lymphoma (esp. Nodular Sclerosis)

─ ─ Look for scattered diagnostic Reed-Sternberg cells in a mixed inflammatory background

─ Granulomatous Lymphadenitis (paucicellular)

─ ─ Scattered epithelioid granulomas, +/- necrosis (e.g., caseous in TB)

─ Extensive Necrosis / Infarction

─ ─ Abundant necrotic debris with ghost cells; requires careful search for viable tumor or organisms

─ Treatment Effect / Lymphocyte Depletion

─ ─ Paucity of lymphoid cells; clinical history is essential

─ Undersampled Lesion

─ ─ Any hypercellular lesion can appear hypocellular due to sampling error

Note

─ This is a paucicellular pattern that requires a careful search for diagnostic elements

─ Extensive necrosis can be the cause of hypocellularity; the underlying etiology (infection, malignancy) must be sought

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Hypercellular Mixed Dispersed and Tissue Fragment (Lymph Node Pattern 3)

Cytology

─ High cellularity

─ Mix of dispersed single cells and cohesive tissue fragments

─ Dispersed component is typically lymphoid; cohesive component is variable (epithelial, germinal centers, granulomas)

DDx

─ Metastatic Carcinoma

─ ─ Stereotypical lesion for this pattern (partial replacement of the node)

─ Reactive Follicular Hyperplasia

─ ─ Cohesive fragments are reactive germinal centers in a polymorphous lymphoid background

─ Granulomatous Lymphadenitis

─ ─ Cohesive fragments are epithelioid granulomas

─ Hodgkin Lymphoma (Syncytial Variant)

─ ─ Cohesive fragments are syncytial aggregates of Reed-Sternberg cells

─ Metastatic Melanoma / Seminoma

─ ─ Cohesive fragments of non-epithelial malignant cells

─ Benign Nodal Inclusions

─ ─ Cohesive fragments of benign glandular or nevus cells

Note

─ This pattern is highly suspicious for metastatic carcinoma partially replacing a lymph node

─ The key to diagnosis is identifying the nature of the cohesive fragments (malignant vs. reactive)

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Hypocellular Mixed Dispersed and Tissue Fragment Pattern (Lymph Node Pattern 4)

Cytology

─ Low cellularity

─ Mix of dispersed single cells and cohesive tissue fragments

─ Background may show prominent necrosis or sclerosis

DDx

─ Metastatic Carcinoma with Sclerosis/Necrosis

─ ─ Can be treatment-related or a feature of the tumor (e.g., colorectal, squamous)

─ Necrotizing Granulomatous Lymphadenitis

─ ─ Paucicellular smear with scattered granulomas and extensive necrosis (e.g., TB)

─ Cat Scratch Disease

─ ─ Suppurative granulomas with necrotic background; can be paucicellular

Note

─ This pattern often reflects an underlying process causing cell death or fibrosis (e.g., treatment, necrosis, sclerosis)

─ A careful search for viable tumor cells or organisms in the necrotic debris is critical

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Tissue Fragment (Lymph Node Pattern 5)

Cytology

─ Smear is dominated by cohesive tissue fragments

─ Paucity of dispersed single cells

─ Background lymphoid tissue may be scant or absent

DDx

─ Metastatic Carcinoma

─ ─ Stereotypical lesion for this pattern (near-total replacement of the node)

─ Malignant Mesothelioma

─ ─ Cohesive fragments of malignant mesothelial cells, often with necrosis

─ Benign Nodal Inclusions

─ ─ Cohesive fragments of benign glandular or nevus cells without a significant lymphoid background

Note

─ This pattern strongly suggests near-complete replacement of the lymph node by a metastatic process

─ Distinguishing metastatic carcinoma from benign inclusions is the key diagnostic challenge

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Spindle Cell (Lymph Node Pattern 6)

Cytology

─ Variable cellularity

─ Predominantly composed of spindle-shaped cells

─ Cells can be single or in syncytial aggregates

DDx

─ Malignant

─ ─ Metastatic Sarcoma (e.g., Angiosarcoma, Synovial Sarcoma)

─ ─ ─ Malignant spindle cells with features of the primary sarcoma

─ ─ Follicular Dendritic Cell Sarcoma

─ ─ ─ Plump spindle cells in syncytial aggregates

─ ─ Metastatic Spindle Cell Melanoma / Carcinoma

─ ─ ─ Look for specific features (pigment, keratinization) and confirm with IHC

─ ─ Kaposi Sarcoma

─ ─ ─ Spindle cells in a lymphoid background

─ Benign / Reactive

─ ─ Sclerosing Granulomatous Disease (e.g., TB, Sarcoid)

─ ─ ─ Bland spindle cells (fibroblasts) admixed with epithelioid histiocytes

─ ─ Other Benign Spindle Cell Lesions

─ ─ ─ Includes myofibroblastoma, inflammatory pseudotumor, etc.

Note

─ This pattern has a broad differential, including reactive, benign, and malignant entities

─ IHC is essential to differentiate between mesenchymal, melanocytic, and epithelial origins

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Insufficient/Inadequate/Non-diagnostic (Lymph Node, Spleen, and Thymus WHO)

This category is for a specimen that, for qualitative or quantitative reasons, lacks sufficient material for a reliable diagnosis.

Criteria

─ The specimen is quantitatively insufficient due to low cellularity, containing only blood, or being acellular.

─ The specimen is qualitatively insufficient because cellular material is obscured by excessive blood or preparation artifacts (e.g., air-drying, poor fixation, contamination with ultrasound gel).

─ A specific number of lymphoid cells is not required for adequacy; any sample that demonstrates a pathological process consistent with the clinical and imaging findings is considered adequate.

─ If a sample from a clinically or radiologically suspicious lesion contains only benign lymphoid material, it may be categorized as non-diagnostic because it may not be representative. Alternatively, it can be called "Benign" with a clear statement that the findings may not correlate with the suspicious lesion. Institutions should be consistent in their approach.

Clinical

─ The risk of malignancy (ROM) for this category is highly variable, with studies reporting a wide range from 17% to 67% (pooled ROM ~34%). The high ROM is often because features leading to an inadequate sample (e.g., necrosis, hemorrhage) can be associated with malignancy.

─ By definition, if a specimen is truly unsuitable for interpretation, the ROM is undefined. These cases should never be reported as "Negative for malignancy".

─ Management requires correlation with clinical and imaging findings. If there is a high suspicion of malignancy, repeat sampling (e.g., FNAB with ROSE, core needle biopsy, or excisional biopsy) is recommended. If suspicion is low, clinical follow-up may be appropriate.

Note

─ Before a final "Non-diagnostic" categorization, all prepared material, including cell blocks or residual fluid, should be examined.

─ The presence of any atypical, suspicious, or malignant cells, regardless of how scant, precludes a non-diagnostic categorization.

─ The presence of non-lymphoid material like mucin or specific organisms in a necrotic background implies a pathological process and should be categorized accordingly, not as non-diagnostic.

─ The reason for the inadequacy should be documented in the report to guide future procedures. For example, a report of "Necrotic material only" is more informative than simply "Insufficient," as it raises suspicion for a neoplastic process.

─ Laboratories should audit their inadequacy rates as part of a quality management program.

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Benign (Lymph Node, Spleen, and Thymus WHO)

This category is for a specimen that demonstrates unequivocal benign cytopathological features. The findings may be diagnostic of a specific benign process (e.g., reactive hyperplasia, infection) or benign neoplasm.

Criteria

─ The sample contains features diagnostic of a specific benign entity or consists of a polymorphous lymphoid population consistent with a reactive process.

─ In reactive lymphoid hyperplasia, there is a mixed population of lymphocytes at various stages of maturation, including small lymphocytes, centrocytes, centroblasts, and immunoblasts. Tingible-body macrophages within germinal center fragments are often present.

─ Specific infectious or inflammatory patterns may be identified, such as:

─ Suppurative inflammation: A background of numerous neutrophils and necrotic debris, suggestive of an abscess.

─ Granulomatous inflammation: The presence of well-formed or poorly formed granulomas (collections of epithelioid histiocytes), with or without necrosis or giant cells.

─ Dermatopathic lymphadenopathy: A mixed lymphoid population with numerous melanin-laden histiocytes.

─ Viral-associated changes (e.g., infectious mononucleosis): A florid, mixed population of lymphoid cells including numerous, singly dispersed immunoblasts.

─ The absence of features suggestive of a lymphoproliferative disorder or metastatic malignancy.

Clinical

─ The risk of malignancy (ROM) for this category is low, generally reported between 2% and 16% (pooled ROM ~5%). False negatives are typically due to sampling error.

─ Management is generally conservative. If the benign diagnosis aligns with the clinical context, clinical follow-up is appropriate.

─ If the benign cytological findings conflict with suspicious clinical or imaging findings (e.g., a rapidly enlarging hard mass, B symptoms), further investigation such as repeat FNAB with flow cytometry, core needle biopsy, or excisional biopsy is recommended.

Note

─ The report should provide a specific diagnosis whenever possible (e.g., "Granulomatous inflammation consistent with sarcoid," "Reactive lymphoid hyperplasia").

─ A systematic, pattern-based approach is crucial for diagnosis, evaluating the background, predominant cell type, and overall heterogeneity of the population.

─ Ancillary tests are used selectively. Flow cytometry is valuable to exclude a low-grade lymphoma when a monotonous population of small lymphocytes is present. Special stains (e.g., Ziehl-Neelsen) and microbiological cultures are essential when an infectious etiology is suspected.

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Atypical (Lymph Node, Spleen, and Thymus WHO)

This category is for a specimen that demonstrates features predominantly seen in benign lesions but also has minimal features that raise the possibility of a malignant lesion, where the evidence is insufficient, either in quantity or quality, to make a definitive diagnosis.

Criteria

─ The category is used for cases with diagnostic uncertainty, most commonly when cytological features overlap between a florid reactive process and a low-grade lymphoproliferative disorder.

─ A common scenario is a highly cellular smear with a monotonous population of small lymphocytes or a follicular pattern with a relative lack of tingible-body macrophages, raising the differential of reactive hyperplasia versus follicular lymphoma or small lymphocytic lymphoma.

─ It can also be used for cases with a mixed population of lymphoid cells that includes scattered large, atypical cells, where a high-grade process like Hodgkin lymphoma cannot be excluded but definitive diagnostic cells are not identified.

─ The specimen may be technically limited (e.g., scant cellularity, poor preservation), but the presence of any atypical cells, no matter how few, moves the case from the "Insufficient" to the "Atypical" category.

─ The presence of unexpected cell types, such as scant keratinizing squamous cells where the differential is between a benign process (e.g., branchial cleft cyst) and a metastatic carcinoma.

Clinical

─ The risk of malignancy (ROM) is intermediate but significant, with studies reporting a wide range of 29% to 77% and a pooled ROM of approximately 65%.

─ Management requires close correlation with clinical and imaging findings. The first step is often a multidisciplinary discussion.

─ Further investigation is almost always required. This may include repeat FNAB (ideally with ROSE and triage for ancillary studies), core needle biopsy, or excisional biopsy, depending on the level of clinical suspicion and the differential diagnosis.

Note

─ This category should be used sparingly, and its use should be audited by the laboratory.

─ The report should clearly describe the atypical features and state the differential diagnosis.

─ Ancillary studies, particularly flow cytometry for lymphoid populations, are crucial. If ancillary tests resolve the diagnosis, the case should be re-categorized as "Benign" or "Malignant". The "Atypical" category is often a provisional diagnosis pending these results or is used when ancillary testing is not possible or inconclusive.

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Suspicious for Malignancy (Lymph Node, Spleen, and Thymus WHO)

This category is for a specimen that demonstrates cytopathological features suggestive of malignancy but with features insufficient, either in number or in quality, to make an unequivocal diagnosis. It is used when the cytopathologist is close to a definitive malignant diagnosis but is hesitant due to some degree of uncertainty.

Criteria

─ The cytomorphological features are highly suggestive but not diagnostic of malignancy. This can apply to both haematolymphoid and metastatic neoplasms.

─ The uncertainty is often due to a paucity of diagnostic cells (quantitative insufficiency) or suboptimal preservation.

─ Common scenarios include:

─ A monomorphic population of small or intermediate-sized lymphoid cells suspicious for a low-grade lymphoma, but definitive cytological features are subtle and flow cytometry is unavailable or inconclusive.

─ Occasional large, atypical cells in a mixed inflammatory background, raising the possibility of Hodgkin lymphoma, but definitive Reed-Sternberg cells are not identified or immunophenotyping is equivocal.

─ Scant atypical non-lymphoid cells suspicious for metastasis, but insufficient material for confirmatory ancillary studies like immunocytochemistry.

─ The clinical context is crucial; the same cytomorphology might be categorized as "Atypical" in a low-suspicion setting but "Suspicious" when clinical and imaging findings are highly concerning for malignancy.

Clinical

─ This category carries a very high risk of malignancy (ROM), with studies reporting a range of 88% to 100% and a pooled ROM of approximately 93%. The ROM is at the higher end of this range when ancillary tests like flow cytometry are utilized.

─ A "Suspicious" report necessitates further action to obtain a definitive diagnosis. Management options include repeat FNAB with triage for ancillary studies, core needle biopsy, or excisional biopsy, depending on the clinical scenario and suspected diagnosis.

Note

─ This category should be used sparingly to maintain the high positive predictive value of the "Malignant" category.

─ The report should always describe the features that are suspicious and, whenever possible, state the type of malignancy suspected or provide a differential diagnosis (e.g., "Suspicious for metastatic carcinoma," "Suspicious for lymphoma").

─ If ancillary testing clarifies the diagnosis, the case should be re-categorized into "Benign" or "Malignant" in an integrated final report.

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Malignant (Lymph Node, Spleen, and Thymus WHO)

This category is for a specimen that demonstrates unequivocal cytopathological features of malignancy.

Criteria

─ The cytomorphological features are diagnostic of a malignant neoplasm, which can be either a haematolymphoid malignancy or a metastatic disease.

─ For haematolymphoid neoplasms, features may include a monotonous population of lymphoid cells (small, intermediate, or large), often with nuclear atypia, and architectural disruption (e.g., loss of a polymorphous background). Diagnosis of aggressive lymphomas is often possible on morphology, while indolent lymphomas may have deceptively bland cells.

─ For metastatic disease, there is a population of non-lymphoid cells with malignant features, which may form cohesive clusters, glands, or be present as single cells.

─ The background may show features suggestive of malignancy, such as necrosis or apoptotic debris ("lymphoglandular bodies" in high-grade lymphomas).

Clinical

─ The risk of malignancy (ROM) for this category is extremely high, with studies reporting a range of 98% to 100% and a pooled ROM of 100%.

─ A definitive "Malignant" diagnosis is sufficient for clinical management, including staging and therapy.

─ While FNAB with ancillary studies is sufficient for diagnosing many lymphomas and most metastases, excisional biopsy may still be recommended for the initial classification of certain lymphomas (e.g., Hodgkin lymphoma, T-cell lymphomas) or for grading follicular lymphomas.

Note

─ A comprehensive report should describe the cytomorphological features, provide a specific diagnosis whenever possible (e.g., "Diffuse large B-cell lymphoma," "Metastatic adenocarcinoma"), and integrate all ancillary test results.

─ Ancillary studies are crucial. Flow cytometry is essential for definitively diagnosing and subtyping most B-cell lymphomas. Immunocytochemistry on cell blocks is vital for diagnosing Hodgkin lymphoma and for identifying the origin of metastatic tumors. Molecular studies (e.g., FISH, NGS) can provide further diagnostic and prognostic information.

─ Clinical correlation is fundamental. In some cases, such as a recurrent indolent lymphoma in a patient with a known history, a malignant diagnosis can be made on morphology alone. For a de novo diagnosis of lymphoma, ancillary confirmation is the standard of care.

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🧠Neuro

Perivascular Gradient Pattern (Neuro Pattern 1a)

Angiocentric and Diffuse Pattern (Neuro Pattern 1b)

Randomized Tissue Fragment With or Without Vascular Affinity Pattern (Neuro Pattern 1c)

Thin-Walled Blood Vessels Without Endothelial Cell Proliferation (Nonproliferative) (Neuro Pattern 2a)

Blood Vessels With Endothelial Cell Proliferation (Proliferative) (Neuro Pattern 2b)

Billiard Table/Feltlike or Granular Background (Neuro Pattern 3a)

Fibrillary or Threadlike Background (Neuro Pattern 3b)

Vascular Coronal Pattern (Neuro Pattern 4)

Randomized Loose Tissue Fragment and Dispersed Single Cell Pattern (Neuro Pattern 5)

Randomized Loose Tissue Fragment and Dispersed Small Cell Pattern (Neuro Pattern 6)

Syncytial Tissue Fragments With or Without Whorls (Neuro Pattern 7)

Anastomosing Blood Vessels Associated With Epithelioid Cells With Indistinct or Foamy Cytoplasm (Neuro Pattern 8)

"Old Fishnet/Twisted Rope" Pattern (Neuro Pattern 9)

🍤Pancreas

Inflammatory Cells Predominating With or Without Epithelial Tissue Fragments (Pancreas Pattern 1)

Cytology

—  Mixed inflammatory infiltrate (neutrophils, lymphocytes, histiocytes, plasma cells)

—  May be admixed with granulation tissue or fibrous stromal fragments

—  Pancreatic epithelial cells (ductal, acinar) may be present or absent

DDx

—  Acute Pancreatitis

—   -Neutrophils and histiocytes with extensive fat necrosis and coagulative necrosis

—  Chronic Pancreatitis

—   -Paucicellular with lymphocytes/histiocytes, fibrous stromal fragments, and calcifications

—  Autoimmune Pancreatitis

—   -Cellular stromal fragments with a lymphoplasmacytic infiltrate and eosinophils

—  Abscess

—   -Predominantly neutrophils with degeneration

—  Ectopic Spleen

—   -Mixed lymphoplasmacytic infiltrate with sinusoidal vessels and capillaries of red/white pulp

—  Lymphoma

—   -Monomorphous population of atypical lymphoid cells

—  Malignancy with Inflammation

—   -Underlying carcinoma (e.g., Ductal, Medullary) can be obscured by inflammation

Note

—  Inflammation can be secondary to an underlying neoplasm or cyst

—  A thorough search for atypical epithelial cells is mandatory in a dense inflammatory background

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Mucinous Background (Pancreas Pattern 2)

Cytology

— Mucinous background

— Cellularity is variable (can be paucicellular to hypercellular)

— Mucin quality is variable: thin and watery to thick and viscous ("ferning")

— Background may contain histiocytes and degenerated "oncotic" cells

DDx

— Benign / Contaminant

— —GI Tract Contamination

— — -Thin, watery mucin with well-formed honeycomb sheets (gastric) or villiform fragments with goblet cells (duodenal)

— —Ciliated Foregut Cyst

— — -Viscous mucin with ciliated columnar cells and needle-like crystals

— —Squamoid Cyst of Pancreatic Ducts

— — -Thick mucin with both benign squamous and benign mucinous columnar cells

— Neoplastic / Malignant

— —IPMN / MCN

— — -Thick, viscous mucin ("ferning") with mucinous columnar cells showing variable dysplasia

— —Colloid (Mucinous Noncystic) Carcinoma

— — -Malignant ductal cells floating in abundant, thick background mucin

— —Signet Ring Cell Carcinoma

— — -Predominantly single, dispersed signet ring cells

Note

— Distinguishing GI contaminant from a true mucinous neoplasm is a key challenge

— Viscous fluid and high CEA levels are characteristic of mucinous neoplasms (MCN/IPMN)

— GNAS mutations are specific for IPMN (not seen in MCN)

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Dirty or Necrotic Background Predominating (Pancreas Pattern 3)

Cytology

— Predominantly dirty, granular, and/or necrotic background

— Fat necrosis may be present

— Often contains a mixed inflammatory infiltrate (neutrophils, histiocytes)

— Epithelial component, if present, may be scant and obscured by necrosis

DDx

— Benign

— —Acute Pancreatitis

— — -Mixed inflammation, fat necrosis, and degenerate cellular debris

— —Pseudocyst

— — -Hemosiderin-laden macrophages, bile pigment, and debris

— —Abscess

— — -Almost exclusively neutrophils with degeneration

— Malignant

— —High-Grade Ductal Adenocarcinoma

— — -Disorganized ductal groups with marked nuclear atypia; may be scant

— —Undifferentiated (Anaplastic) Carcinoma

— — -Bizarre, pleomorphic, and giant tumor cells; may show cytophagocytosis

— —Undifferentiated Carcinoma with Osteoclast-like Giant Cells

— — -Dual population of malignant mononuclear cells and benign osteoclast-like giant cells

— —Adenosquamous Carcinoma

— — -Shows both malignant glandular and squamous components; keratinous debris

— —Metastatic Carcinoma (e.g., Colorectal)

— — -"Dirty necrosis" with features of the primary tumor (e.g., columnar cells for colorectal)

Note

— Abundant inflammation or necrosis can obscure an underlying malignancy

— A thorough search for atypical epithelial cells is mandatory in a necrotic/inflammatory background

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Predominantly Cohesive Epithelial or Ductal-Type Tissue Fragments (Pancreas Pattern 4)

Cytology

— Predominantly cohesive, tight epithelial/ductal fragments

— Large, flat sheets with honeycomb or "picket fence" architecture

— Few dispersed single cells

— Background is typically clean

DDx

— Benign

— —Benign Ductal Cells (including Reactive Atypia)

— — -Flat honeycomb sheets with minimal atypia and low N:C ratio; may have infiltrating neutrophils

— —GI Contamination (Gastric/Duodenal)

— — -Look for specific cell types (foveolar, goblet) and architecture (villi)

— —Normal Pancreas

— — -Mix of both ductal sheets and "grapelike" acinar clusters

— Neoplastic (Benign/Precursor)

— —Pancreatic Intraepithelial Neoplasia (PanIN)

— — -Tightly cohesive groups with nuclear crowding, grooves, and pale chromatin (thyroid-like nuclei)

— —Serous Cystadenoma

— — -Scant, flat sheets of cuboidal cells with clear cytoplasm and uniform, round nuclei

— Malignant

— —Well-Differentiated Ductal Adenocarcinoma

— — -Stereotypical lesion for this pattern; disorganized "drunken honeycomb," nuclear irregularities, and anisonucleosis (>4:1)

— —Medullary Carcinoma

— — -Syncytial groups of cells with eosinophilic cytoplasm and prominent nucleoli; prominent lymphoid infiltrate

— —Pancreatoblastoma

— — -Primitive small blue cells with acinar, endocrine, and/or squamoid differentiation

— —Metastatic Adenocarcinoma

— — -Morphology "foreign" to pancreas; requires clinical history and IHC

Note

— The key diagnostic challenge is distinguishing reactive atypia from well-differentiated adenocarcinoma

— Architectural disorganization ("drunken honeycomb") and significant nuclear atypia favor adenocarcinoma

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Loosely Cohesive Tissue Fragments With Predominantly Dispersed Single Cells (Pancreas Pattern 5)

Cytology

— Predominantly dispersed single cells with some loosely cohesive groups

— Typically high cellularity

— Background is variable (clean, necrotic, or mucinous)

— Cell morphology is highly variable depending on the underlying entity

DDx

— Neuroendocrine Neoplasms

— —Pancreatic Neuroendocrine Tumor (PanNET)

— — -Monomorphic plasmacytoid cells, "salt-and-pepper" chromatin, +/- rosettes

— —Poorly Differentiated Neuroendocrine Carcinoma

— — -Small or large cell types with high N:C ratio, necrosis, crush, and high mitotic rate

— Acinar Neoplasms

— —Acinar Cell Carcinoma

— — -Organoid/acinar groups, granular cytoplasm, prominent single nucleoli

— Ductal and Related Neoplasms

— —Pancreatic Ductal Adenocarcinoma (High-Grade)

— — -Marked pleomorphism, irregular nuclei, "drunken honeycomb," necrotic background

— —Undifferentiated (Anaplastic) Carcinoma

— — -Bizarre, pleomorphic, and giant tumor cells; marked necrosis and inflammation

— —Signet Ring Cell Carcinoma

— — -Predominantly single signet ring cells

— —Oncocytic Carcinoma

— — -Cohesive groups and single cells with dense, granular oncocytic cytoplasm; prominent nucleoli

— Other Primaries

— —Pancreatoblastoma

— — -Primitive small blue cells with acinar, endocrine, and/or squamoid differentiation

— Metastatic Neoplasms

— —Metastatic Melanoma

— — -Pleomorphic cells, prominent macronucleoli, intranuclear pseudoinclusions, +/- pigment

— —Metastatic Renal Cell Carcinoma

— — -Clear cells on fibrovascular strands, prominent nucleoli

— —Other Metastases (e.g., Breast)

— — -Requires clinical history; morphology mimics primary site

— Benign / Contaminant

— —Benign Hepatocytes

— — -Polygonal cells with granular cytoplasm and prominent central nucleoli

Note

— Pattern has a very broad DDx, from benign contaminants to high-grade malignancies

— IHC is essential to differentiate between the many possibilities in this pattern

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Epithelial Proliferations With Fibrovascular Stroma or Cores Within Epithelial Tissue Fragments (Pancreas Pattern 6)

Cytology

— Epithelial groups arranged on fibrovascular cores

— Fibrovascular stroma is variable in quantity and size

— Epithelial component is variable (monomorphic, clear cell, granular, etc.)

DDx

— Solid Pseudopapillary Neoplasm (SPN)

— —Monomorphic cells with nuclear grooves on branching papillae with myxoid stroma

— —Pathognomonic myxoid globules

— Pancreatic Neuroendocrine Tumor (PanNET)

— —Monomorphic plasmacytoid cells loosely attached to capillaries; "salt-and-pepper" chromatin

— Acinar Cell Carcinoma

— —Acinar cells with granular cytoplasm and prominent nucleoli arranged on vessels

— Intraductal Papillary Mucinous Neoplasm (IPMN)

— —Mucinous columnar epithelium forming papillae

— Metastatic Renal Cell Carcinoma (RCC)

— —Clear cells with prominent nucleoli arranged on prominent vasculature

— Metastatic Hepatocellular Carcinoma (HCC)

— —Polygonal cells with granular eosinophilic cytoplasm on trabecular vessels

— Benign Hepatocytes (Contaminant)

— —Can be seen in reactive fragments with fibrovascular cores

Note

— This pattern has a broad DDx, often requiring IHC for definitive diagnosis

— Nuclear beta-catenin is diagnostic for SPN

— Key IHC: Neuroendocrine markers (PanNET), Trypsin/Bcl-10 (ACC), PAX8/CD10 (RCC), HepPar1 (HCC)

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Squamous Cells Predominating (Pancreas Pattern 7)

Cytology

— Predominantly squamous cells

— Can show a spectrum from benign anucleated squames to malignant keratinizing cells

— Background is variable: can be clean, inflammatory, keratinous, or mucinous

DDx

— Benign

— —Lymphoepithelial Cyst (LECP)

— — -Abundant anucleated squames, keratinous debris, lymphocytes, and cholesterol crystals

— —Squamoid Cyst of Pancreatic Ducts (SCOPD)

— — -Biphasic population of benign squamous and mucinous columnar cells

— —Dermoid Cyst

— — -Similar to LECP; may have adnexal structures (if sampled)

— Malignant

— —Adenosquamous Carcinoma

— — -Dual population of malignant glandular and malignant squamous cells

— —Metastatic Squamous Cell Carcinoma

— — -Malignant squamous cells only; requires clinical history to exclude primary

— —Pancreatoblastoma

— — -Primitive small blue cells with characteristic squamoid corpuscles

Note

— Benign squamous cysts (LECP, SCOPD) can have high CEA levels, mimicking a mucinous neoplasm

— The key to diagnosis is assessing the nuclear features of the squamous cells (benign vs. malignant)

— IHC (p40, CK5/6) can confirm a squamous component

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Stromal Fragments With or Without Epithelial Tissue Fragments (Pancreas Pattern 8)

Cytology

— Stromal fragments with or without an epithelial component

— Cellularity is variable

— Stroma can be fibrous or myxoid; epithelial component is variable (ductal, acinar, squamoid)

DDx

— Benign

— —Chronic Pancreatitis

— — -Paucicellular with fibrous (not cellular) stromal fragments and mixed inflammation

— —Acute Pancreatitis

— — -Dirty, necrotic background with fat necrosis and acute inflammation

— Malignant

— —Pancreatoblastoma

— — -Cellular smears with epithelial and mesenchymal components; squamoid corpuscles are characteristic

— —Mesenchymal Neoplasm (e.g., GIST)

— — -Spindle cell proliferation; diagnosis confirmed with IHC

Note

— Chronic pancreatitis typically has fibrous, acellular stroma

— Squamoid corpuscles are a key feature differentiating pancreatoblastoma from other entities

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Non-Diagnostic (Pancreas WHO)

This category is used for specimens that are unsatisfactory for evaluation. This may be due to an insufficient quantity of well-preserved epithelial cells, the presence of obscuring elements, or other qualitative limitations.

Criteria

─ Insufficient number of interpretable pancreaticobiliary epithelial cells. For solid lesions, some guidelines suggest at least a few clusters of well-visualized epithelial cells are needed.

─ Acellular specimen, or a sample containing only blood, acellular mucin, or clear cyst fluid without an epithelial component.

─ Presence of only gastrointestinal contaminants (e.g., gastric or duodenal mucosa) without accompanying pancreatic elements.

─ Specimen is markedly obscured by excessive blood, thick mucus, extensive inflammation, or widespread necrosis, preventing adequate evaluation of epithelial cells.

─ Significant preparation artifacts (e.g., extensive air-drying, crush artifact, poor fixation or staining) that preclude interpretation.

─ For a targeted solid mass, the presence of only normal pancreatic elements (acinar and ductal cells) is considered non-diagnostic as it likely represents a sampling miss.

Clinical

─ This category carries a risk of malignancy (ROM) that can range from approximately 5% to over 25%. A non-diagnostic result does not exclude malignancy.

─ Management typically involves repeat sampling, preferably with EUS-FNA and the use of rapid on-site evaluation (ROSE) to ensure adequacy.

Note

─ The presence of any atypical cells, regardless of how few, generally precludes a non-diagnostic interpretation; such cases are classified as "Atypical" or higher.

─ The reason for the non-diagnostic interpretation (e.g., scant cellularity, obscuring blood) should be stated in the report to guide subsequent procedures.

─ Correlation with clinical and imaging findings is essential. For example, a specimen with only inflammatory cells and debris might be considered diagnostic of an abscess if that is the clinical and radiological impression, but non-diagnostic if a solid mass was targeted.

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Benign / Negative (for Malignancy) (Pancreas WHO)

This category is for specimens with adequate cellularity and unequivocally benign cytological features. The findings may be diagnostic of a specific benign entity or may represent normal tissue.

Criteria

─ Presence of well-preserved, benign pancreaticobiliary elements, including ductal cells, acinar cells, and potentially islet cells.

─ Ductal cells typically form cohesive, flat, honeycomb-like sheets with round to oval, uniformly spaced nuclei, fine chromatin, and inconspicuous nucleoli.

─ Acinar cells are often in grape-like clusters, with abundant granular cytoplasm and round, eccentric nuclei.

─ For cystic lesions, specific benign findings may be present, such as the glycogen-rich cuboidal cells of a serous cystadenoma, or histiocytes and inflammatory debris consistent with a pseudocyst in the proper clinical context.

─ The background may be clean or contain evidence of inflammation (neutrophils, lymphocytes, histiocytes), fat necrosis, or calcific debris, as seen in chronic pancreatitis.

Clinical

─ The risk of malignancy (ROM) in this category is low, generally reported as 0-10%, with false negatives usually attributed to sampling error.

─ Management typically involves clinical and radiological follow-up. However, if the benign finding does not explain a suspicious mass lesion on imaging, repeat sampling should be considered.

Note

─ A specific benign diagnosis should be provided whenever possible (e.g., chronic pancreatitis, lymphoepithelial cyst, serous cystadenoma).

─ The presence of normal pancreatic elements alone in a sample from a targeted solid mass may be considered non-diagnostic, as it could represent a sampling miss. The report should clarify this discrepancy.

─ Significant cytologic atypia, features suspicious for malignancy, or evidence of a high-grade neoplasm are absent.

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Atypical (Pancreas WHO)

This category is for specimens with cytologic atypia that exceeds definite reactive changes but falls short of being suspicious for malignancy. The findings are quantitatively or qualitatively insufficient for a more definitive diagnosis.

Criteria

─ Presence of epithelial cells (usually ductal) with features that are concerning but not diagnostic of a neoplasm.

─ Architectural atypia may be present, such as minor crowding, some loss of the classic honeycomb sheet arrangement, and slight nuclear overlapping.

─ Nuclear atypia is mild to moderate and may include nuclear enlargement (e.g., 2–3 times the size of a red blood cell), some variation in nuclear size and shape (anisonucleosis), and minor nuclear membrane irregularities.

─ Chromatin may be finely granular but is not coarsely clumped or cleared. Nucleoli, if present, are generally small and not prominent.

─ This category is often used when there is an overlap between significant reactive/reparative changes (e.g., due to pancreatitis or an indwelling stent) and a low-grade neoplasm (like PanIN or well-differentiated adenocarcinoma).

Clinical

─ The risk of malignancy (ROM) for this category is intermediate, often reported in the range of 35–60%. It signifies a substantial risk that requires further action.

─ Management typically involves close clinical and radiological correlation. Repeat FNA, often with core biopsy, or close imaging surveillance is usually recommended.

Note

─ The "Atypical" category should be used sparingly to maintain its clinical utility.

─ The report should describe the atypical features and, if possible, suggest a differential diagnosis (e.g., "atypia favored to be reactive" vs. "atypia cannot rule out a low-grade neoplasm").

─ This category acts as a crucial intermediate step between "Benign" and "Neoplastic/Suspicious," acknowledging diagnostic uncertainty while highlighting the need for further investigation.

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Suspicious for Malignancy (Pancreas WHO)

A specimen that contains cells with cytological features highly worrisome for, but not diagnostic of, malignancy. This category is used when the evidence is qualitatively or quantitatively insufficient for an unequivocal diagnosis.

Criteria

─ The specimen contains a limited number of cells exhibiting high-grade cytological features, or the features are partially obscured.

─ Architectural features may include disorganized three-dimensional clusters, loss of polarity, and single atypical cells.

─ Nuclear features are highly abnormal and may include significant nuclear enlargement (often >4 times the size of a red blood cell), marked pleomorphism, irregular nuclear contours, and coarsely clumped or cleared chromatin.

─ Nucleoli are often prominent and irregular.

─ These features are strongly suggestive of malignancy but fall short of a definitive diagnosis due to low cellularity or other technical limitations.

Clinical

─ This interpretation carries a very high risk of malignancy (ROM), often reported as >80-90%, most commonly for pancreatic ductal adenocarcinoma (PDAC).

─ Clinical and imaging correlation is crucial. Further investigation, such as repeat FNA with core biopsy, or surgical exploration based on multidisciplinary discussion, is nearly always warranted.

Note

─ This category should be used sparingly to maintain a high positive predictive value for a "Malignant" diagnosis.

─ A common reason for this interpretation is scant sampling of a malignancy, especially a well-differentiated one.

─ While severe reactive changes (e.g., from stents or pancreatitis) can mimic malignancy, the "Suspicious" category is reserved for cases where the features strongly favor a neoplastic process over a reactive one, even if definitive criteria are not met.

─ The report should ideally state what malignancy is suspected (e.g., "Suspicious for adenocarcinoma").

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Malignant (Pancreas WHO)

This category is for specimens with unequivocal cytological features of malignancy. A specific tumor type should be provided whenever possible.

Criteria (General, for Pancreatic Ductal Adenocarcinoma) ─

─ Architectural disarray, including loss of the normal honeycomb structure, disorganized three-dimensional clusters, and single malignant cells.

─ Marked nuclear abnormalities, including a high nuclear-to-cytoplasmic (N:C) ratio, significant variation in nuclear size and shape (pleomorphism), and irregular nuclear contours with notches and indentations.

─ Coarsely clumped or cleared ("powdery") chromatin.

─ Prominent, irregular nucleoli or macronucleoli.

─ A necrotic or inflammatory background (tumor diathesis) is often present.

─ Mitotic figures, including atypical forms, may be seen.

Clinical

─ This diagnosis carries a very high risk of malignancy (ROM), approaching 100%.

─ A definitive "Malignant" diagnosis, especially when correlated with clinical and imaging findings, is sufficient for planning definitive management, such as surgery or neoadjuvant therapy.

Note

─ This category is used only when there is sufficient qualitative and quantitative evidence for a definitive diagnosis.

─ An effort should always be made to classify the malignancy (e.g., ductal adenocarcinoma, acinar cell carcinoma, neuroendocrine carcinoma, lymphoma, metastasis).

─ Ancillary studies, such as immunohistochemistry on a cell block, are often crucial for accurate classification and to guide therapy. Material should be preserved for potential molecular testing.

─ The report should clearly state the diagnosis of malignancy and the specific tumor type.

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Normal Pancreatic Acinar Cells

Cells derived from the exocrine acini of the pancreas.

Cells

 ─ Cellularity often high, few single cells

 ─ Cohesive, grape-like (acinar) clusters, often attached to fibrovascular stroma

Cytoplasm

 ─ Abundant, granular (zymogen granules), often bichromatic (basophilic at base, eosinophilic at apex)

 ─ Cell borders indistinct within clusters

Nuclei

 ─ Round to oval, typically eccentric

 ─ Finely granular, evenly distributed chromatin

 ─ Single, small, but often distinct/prominent nucleolus (can be larger if reactive)

 ─ Some naked nuclei may be present

Absent

 ─ Significant pleomorphism, hyperchromasia, or nuclear membrane irregularity

 ─ Mucinous features

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Normal Pancreatic Ductal Cells

Cells lining the pancreatic ductal system.

Cells

 ─ Cohesive flat sheets, often in a honeycomb arrangement

 ─ May form small tubules or clusters

Cytoplasm

 ─ Scant to moderate, pale, non-mucinous, or finely vacuolated

 ─ Well-defined cell borders

Nuclei

 ─ Round to oval, relatively uniform in size and shape, evenly spaced

 ─ Finely granular, evenly distributed chromatin

 ─ Inconspicuous nucleoli

 ─ Smooth nuclear membranes

Absent

 ─ Significant crowding, stratification, or loss of polarity (unless reactive)

 ─ Prominent atypia

Note

 ─ Unlike larger mesothelial cells, typically lack prominent intercellular "windows"

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Duodenal Epithelium (Contaminant)

Epithelial cells from the duodenum, a common contaminant in EUS-FNA of the pancreatic head.

Cells

 ─ Cohesive flat sheets (honeycomb) or papillary-like groups (representing villi)

 ─ Biphasic population: enterocytes and goblet cells

Cytoplasm

 ─ Enterocytes: columnar, non-mucinous, with an apical brush border (cilia-like, but shorter, denser)

 ─ Goblet cells: distended with mucin, "fried egg" appearance in sheets, nucleus pushed to base

Nuclei

 ─ Enterocytes: oval, basally located, uniform

 ─ Goblet cells: small, compressed, basal

 ─ Intraepithelial lymphocytes ("sesame seeds") often scattered within the epithelium

Background

 ─ May see detached brush borders, mucin

Absent

 ─ True pancreatic acinar or islet cells (unless mixed sample)

Note

 ─ Presence of brush border and goblet cells are key diagnostic features

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Gastric Epithelium (Contaminant)

Epithelial cells from the stomach, a common contaminant in EUS-FNA.

Cells

 ─ Small sheets, strips, or isolated cells; may see intact gastric pits/crypts

 ─ Predominantly foveolar (surface mucous) cells; chief and parietal cells less common on FNA

Cytoplasm

 ─ Foveolar cells: columnar, with distinct apical mucin caps (neutral mucin)

 ─ Chief cells (if present): granular, basophilic

 ─ Parietal cells (if present): larger, eosinophilic, often fried-egg appearance

Nuclei

 ─ Foveolar cells: small, round to oval, basal, often bland; may see nuclear grooves in naked foveolar nuclei

 ─ Chief/Parietal cells: round, central

Absent

 ─ Brush border, goblet cells (helps distinguish from duodenal)

 ─ True pancreatic acinar or islet cells (unless mixed sample)

Note

 ─ Apical mucin caps are characteristic of foveolar cells

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Mesothelium (Contaminant/Rare Primary)

Cells lining serosal surfaces, may be sampled if the lesion abuts the peritoneum or during transephrenic approaches.

Cells

 ─ Flat sheets, clusters, or single cells

 ─ Characteristic intercellular "windows" or clefts between cells in sheets

Cytoplasm

 ─ Moderate amount, dense or somewhat pale, may be "two-toned"

 ─ Well-defined cell borders

Nuclei

 ─ Round to oval, often centrally located

 ─ Smooth nuclear contours

 ─ Finely granular chromatin

 ─ Nucleoli can be small to prominent, especially if reactive

 ─ Binucleation or multinucleation can be seen, especially in reactive states

Absent

 ─ True glandular formation, mucin production (vacuoles can be present)

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Hepatocytes (Contaminant)

Liver cells, may be sampled if the lesion is near or involves the liver, or during transhepatic FNA.

Cells

 ─ Large, polygonal cells; may be in small groups, trabeculae, or single

Cytoplasm

 ─ Abundant, granular, eosinophilic

 ─ May contain lipofuscin (brown pigment) or bile pigment

Nuclei

 ─ Round to oval, often centrally located

 ─ Prominent, single, centrally located nucleolus is characteristic

 ─ Binucleation common

 ─ Chromatin can be vesicular

Absent

 ─ Ductal structures with honeycomb pattern (unless bile ductules are sampled)

 ─ Acinar formations

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Acute Pancreatitis

Acute inflammatory condition, often associated with gallstones or alcohol abuse.

Cells

 ─ Mostly neutrophils

 ─ Scant reactive/reparative ductal cells may be present

 ─ Foamy histiocytes

 ─ Fat necrosis (ghost-like outlines of adipocytes, saponification)

Cytoplasm

 ─ Ductal cells (if present): May show reactive changes, vacuolization

Nuclei

 ─ Ductal cell nuclei (if present): May be enlarged, have irregular nuclear membranes, and conspicuous nucleoli (reactive atypia)

Background

 ─ "Dirty" background with abundant inflammatory debris, necrotic material

 ─ Fibrin strands

 ─ Hemorrhage

 ─ Calcifications may be present, especially in necrotizing pancreatitis

Absent

 ─ Significant number of lymphocytes or plasma cells (unless evolving to chronic)

 ─ Granulomas (unless specific etiology like TB)

 ─ Malignant cells

Note

 ─ Cytologic findings reflect the acute inflammatory process and tissue damage

 ─ Reactive atypia in ductal cells should not be overinterpreted as malignancy in this context

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Chronic Pancreatitis

Progressive inflammatory condition leading to irreversible pancreatic damage, fibrosis, and loss of exocrine/endocrine function.

Cells

 ─ Often a hypocellular smear

 ─ Atrophic acinar cells (may be sparse or absent)

 ─ Ductal epithelial cells, often showing reactive atypia

 ─ Fibroblasts and myofibroblasts (spindle cells), may be in cellular stromal fragments

 ─ Chronic inflammatory cells: Lymphocytes, plasma cells, histiocytes

 ─ +/- Islet cells (may appear relatively prominent due to acinar atrophy)

Cytoplasm

 ─ Ductal cells: May show reactive changes, vacuolization, squamous metaplasia

 ─ Acinar cells (if present): Often atrophic, cytoplasm may be pale or vacuolated

Nuclei

 ─ Ductal cells: May be enlarged, show variable size, irregular contours, and prominent nucleoli (reactive atypia)

 ─ Acinar cells (if present): May be small and pyknotic, or show reactive enlargement

 ─ Fibroblasts/Myofibroblasts: Elongated, bland nuclei

Background

 ─ Fibrous stromal fragments, sometimes cellular

 ─ Calcifications (may be grossly gritty during FNA)

 ─ Fat necrosis

 ─ Inspissated proteinaceous material (protein plugs in ducts)

Absent

 ─ Unequivocal features of malignancy (though reactive atypia can be a significant pitfall)

 ─ Abundant neutrophils (unless there is an acute exacerbation)

Note

 ─ Reactive atypia in ductal cells can be marked and mimic adenocarcinoma

 ─ Cellular stromal fragments with spindle cells may mimic a mesenchymal neoplasm but typically lack significant atypia or mitoses

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Autoimmune and IgG4-related Pancreatitis

An inflammatory condition of the pancreas, often part of systemic IgG4-related disease, characterized by a dense lymphoplasmacytic infiltrate and often storiform fibrosis.

Clinical

 ─ May present as a discrete pancreatic mass (mimicking carcinoma) or diffuse pancreatic enlargement

 ─ Can cause obstructive jaundice

 ─ Often associated with elevated serum IgG4 levels

 ─ May involve other organs (e.g., bile ducts, salivary glands, kidneys, retroperitoneum)

 ─ Typically responds well to steroid therapy

Cells

 ─ Often hypocellular on FNA

 ─ Lymphocytes and plasma cells, sometimes numerous and forming aggregates

 ─ +/- Eosinophils

 ─ Ductal cells, may show reactive atypia

 ─ Acinar cells, often atrophic or absent

 ─ Spindle cells (fibroblasts from stroma)

Cytoplasm

 ─ Ductal cells: May show reactive changes

 ─ Plasma cells: Typically show eccentric nuclei, basophilic cytoplasm, and a perinuclear hof

Nuclei

 ─ Ductal cells: May show reactive atypia (enlargement, prominent nucleoli)

 ─ Lymphocytes: Mostly small, round, with dark, condensed chromatin

 ─ Plasma cells: Eccentric, with characteristic clock-face chromatin

 ─ Fibroblasts: Bland, elongated

Background

 ─ Cellular stromal fragments composed of fibroblasts, lymphocytes, and plasma cells

 ─ Storiform fibrosis (a swirling, "cartwheel" pattern of fibrosis) is a key histologic feature but often not apparent on FNA

 ─ +/- Obliterative phlebitis (inflammation and fibrosis of veins) is another histologic feature rarely seen on FNA

Absent

 ─ Unequivocal features of malignancy

 ─ Granulomas

 ─ Abundant neutrophils (unless there is a secondary acute pancreatitis component)

Ancillary studies

 ─ Serum IgG4 levels are often elevated (but can be normal)

 ─ IgG4 immunostaining (on cell block or biopsy, if sufficient material) can show an increased number of IgG4-positive plasma cells (e.g., >10/HPF or IgG4/IgG ratio >40% are common thresholds, but vary); sensitivity on FNA material is limited

DDx

 ─ Pancreatic ductal adenocarcinoma (especially when reactive ductal atypia is prominent)

 ─ Other forms of chronic pancreatitis (the lymphoplasmacytic infiltrate can be nonspecific)

 ─ Lymphoma (especially if the lymphoid infiltrate is very dense and appears monotonous)

Note

 ─ FNA findings are often nonspecific, resembling chronic pancreatitis with a prominent lymphoplasmacytic component

 ─ Diagnosis usually relies on a combination of clinical presentation, serologic findings (IgG4 levels), imaging characteristics, cytologic/histologic features, and response to steroid therapy

 ─ Key histologic features like storiform fibrosis and obliterative phlebitis are difficult to assess reliably on FNA alone

 ─ Reactive ductal atypia can be a significant diagnostic pitfall for adenocarcinoma

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Lymphoepithelial Cyst (Pancreas)

Benign cyst, unilocular or multilocular; squamous lining plus lymphoid tissue in the cyst wall.

Clinical

 ─ Can occur in peripancreatic lymph nodes or intrapancreatic

 ─ May be associated with HIV infection or other causes of lymphoid proliferation

Cells

 ─ Mature squamous cells, often anucleated (squames) or with small pyknotic nuclei

 ─ Lymphocytes (small, mature, in aggregates or germinal centers)

 ─ Histiocytes, including multinucleated forms

Background

 ─ Proteinaceous fluid, often thick

 ─ Abundant keratinous debris

 ─ +/- Cholesterol crystals

Absent

 ─ Significant atypia

 ─ Mucin-producing cells

 ─ Features of malignancy

Ancillary studies

 ─ Cyst fluid CEA very low (unlike mucinous cysts)

Note

 ─ Cytologic diagnosis is usually straightforward with the characteristic triad of squamous cells, lymphocytes, and keratin debris

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Pseudocyst (Pancreas)

A localized collection of fluid, rich in pancreatic enzymes, lacks true epithelial lining; arises after acute pancreatitis, trauma, or in setting of chronic pancreatitis.

Clinical

 ─ Most common cystic lesion of pancreas

Cells

 ─ Predominantly inflammatory cells: Neutrophils (especially if acute/infected), lymphocytes, histiocytes (often numerous and foamy)

 ─ Epithelial cells absent

Background

 ─ "Dirty" proteinaceous debris; necrotic material

Absent

 ─ True epithelial lining (by definition); malignant cells

 ─ Thick, viscous mucin (characteristic of mucinous neoplasm)

Ancillary studies

 ─ Cyst fluid amylase high ( >1000 U/L) and CEA low (<192 ng/mL, often <5 ng/mL)

DDx

 ─ Mucinous cyst (mucin in the background)

 ─ Serous cystadenoma (clear fluid and bland cuboidal cells)

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Splenule (Accessory Spleen)

Ectopic splenic tissue; an incidental finding; mimics pancreatic neoplasm on imaging.

Cells

 ─ Polymorphous lymphoid cells, endothelial cells (lining sinusoids), histiocytes/macrophages

Background

 ─ Bloody with lymphoglandular bodies (cytoplasmic fragments of lymphocytes)

Ancillary studies

 ─ IHC: CD8 highlights sinusoidal lining cells; CD20/CD3 for B/T lymphocytes; CD68 for histiocytes

Note

 ─ Key is recognizing the mixed lymphoid population and characteristic vascular structures (sinusoids) if visible

 ─ Can be confused with intrapancreatic lymph node or lymphoma

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Serous Cystadenoma (Pancreas)

Benign cystic neoplasm of small, uniform, glycogen-rich cuboidal cells forming microcysts.

Clinical

 ─ More common in women, body or tail of pancreas

 ─ Microcystic variant has "spongy" appearance on imaging; central stellate scar is classic

Cells

 ─ Often hypocellular or acellular (cyst fluid aspirate)

 ─ If cellular: Bland, cuboidal epithelial cells arranged in flat sheets or loose clusters

Cytoplasm

 ─ Scant to moderate, clear, pale, or finely vacuolated/granular (due to glycogen)

Nuclei

 ─ Small, round to oval, centrally or eccentrically located, monomorphic

 ─ Smooth nuclear contours, even chromatin, nucleoli inconspicuous, minimal to no atypia

Background

 ─ Colloid-like material (proteinaceous) may be present, not prominent or thick like mucin

 ─ Hemosiderin-laden macrophages

Absent

 ─ Significant atypia, pleomorphism, or mitotic activity

 ─ Thick, viscous mucin (distinguishes from mucinous cysts)

 ─ Lymphoid component (distinguishes from lymphoepithelial cyst)

 ─ Squamous cells or keratin debris

Ancillary studies

 ─ Cyst fluid: Low CEA (<5 ng/mL) & low amylase (variable)

 ─ PAS-D will show cytoplasmic glycogen (PAS positive, diastase sensitive)

 ─ IHC: (+) inhibin & GLUT-1 (membranous); (-) CEA, MUC1, MUC5AC

 ─ Molecular: VHL mutations

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Lymphangioma (Pancreas)

A benign congenital malformation of lymphatic channels, rare in the pancreas.

Clinical

 ─ More common in females, wide age range; often distal pancreas

 ─ Imaging: Well-circumscribed, thin-walled, uni- or multilocular cystic lesion

Cells

 ─ Often hypocellular

 ─ Predominantly small, mature lymphocytes

 ─ +/- Endothelial cells (flat, bland, lining lymphatic spaces – often difficult to identify)

 ─ +/- Histiocytes

Cytoplasm

 ─ Lymphocytes: Scant

 ─ Endothelial cells: Attenuated, difficult to see

Nuclei

 ─ Lymphocytes: Small, round, dark, mature-appearing

 ─ Endothelial cells: Flat, elongated, bland

Background

 ─ Clear, watery, chylous (milky), or serosanguinous fluid (proteinaceous)

 ─ +/- Fat globules

 ─ +/- Cholesterol crystals

Absent

 ─ Significant epithelial component (unless contaminant)

 ─ Atypia in lymphoid or endothelial cells

 ─ Mucin

 ─ Features of malignancy

Ancillary studies

 ─ Cyst fluid: Typically low CEA and low amylase; triglycerides may be elevated if chylous

 ─ IHC: Endothelial cells (+) D2-40, CD31, CD34

Note

 ─ MRI can be useful to exclude ductal communication (seen in some other cystic lesions)

 ─ Cytologic diagnosis can be challenging due to paucicellularity; main finding is often proteinaceous fluid with lymphocytes

 ─ DDx includes other paucicellular cysts like simple cysts, pseudocysts (if inflammation is scant), or cystic degeneration in other neoplasms. Lymphoid component can mimic lymphoepithelial cyst, but lymphangiomas lack squamous cells and keratin.

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Pancreaticobiliary Neoplasm (Low-Grade and High-Grade)

Per Papanicolaou Society encompasses neoplasms with features of ductal or biliary differentiation that are cytologically low-grade or high-grade but lack definitive features of invasion on FNA; includes precursor lesions (PanIN & BilIN) as well as some intraductal and cystic neoplasms

Note

 ─ This is a broad cytologic category, specific entities within it (like IPMN, MCN) have distinct clinicopathologic features and are detailed below; The distinction between low-grade and high-grade is based on the degree of cytologic and architectural atypia

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Pancreatic Intraepithelial Neoplasia (PanIN)

A microscopic, flat or micropapillary, non-invasive epithelial proliferation confined to pancreatic ducts; Graded low-grade (PanIN-1A, -1B, -2) to high-grade (PanIN-3)

Clinical

 ─ Incidental finding in resected specimens

Cells

 ─ Rarely specifically identified on FNA unless high-grade and exfoliating

 ─ Low-Grade PanIN: Small, crowded groups of ductal cells; columnar or cuboidal; minimal atypia

 ─ High-Grade PanIN: Crowded, disorganized groups; increased nuclear atypia, pleomorphism, hyperchromasia, prominent nucleoli; loss of polarity; may show micropapillary tufts

Cytoplasm

 ─ Low-Grade PanIN: May be mucinous or non-mucinous

 ─ High-Grade PanIN: Often scant, N:C ratio increased

Nuclei

 ─ Low-Grade PanIN: Round to oval, uniform or mildly enlarged, smooth contours, inconspicuous nucleoli

 ─ High-Grade PanIN: Enlarged, pleomorphic, irregular contours, hyperchromatic, coarse chromatin, prominent nucleoli; mitoses may be seen

Background

 ─ Clean (unless associated with pancreatitis or obstruction)

Absent

 ─ Stromal invasion

 ─ Features of other specific neoplasms (e.g., abundant extracellular mucin of IPMN, ovarian stroma of MCN)

Ancillary studies

 ─ Not typically performed on FNA for PanIN specifically due to diagnostic difficulty

 ─ Molecular: KRAS mutations common and early; TP53, CDKN2A/p16, SMAD4 mutations accumulate with progression to high-grade PanIN and invasive cancer

DDx

 ─ Reactive ductal atypia

 ─ IPMN (especially main duct or branch duct with minimal cystic change)

 ─ Invasive ductal adenocarcinoma (high-grade PanIN can be difficult to distinguish from well-differentiated adenocarcinoma on cytology alone if invasion isn't seen)

Note

 ─ Cytologic diagnosis of PanIN, especially low-grade, is very challenging and often not possible on FNA

 ─ High-grade PanIN cells may be indistinguishable from invasive adenocarcinoma cells

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Biliary Intraepithelial Neoplasia (BilIN)

A preinvasive neoplastic lesion of the biliary tract epithelium, analogous to PanIN in the pancreas, considered a precursor to cholangiocarcinoma; Graded from low-grade (BilIN-1, -2) to high-grade (BilIN-3)

Clinical

 ─ Incidental microscopic finding

Cells

 ─ Rarely specifically identified on FNA unless high-grade and exfoliating

 ─ Cells would likely be categorized as "Atypical" or "Pancreaticobiliary Neoplasm"

 ─ Low-Grade BilIN: Crowded groups of biliary-type cells; columnar; minimal atypia

 ─ High-Grade BilIN: More disorganized, increased nuclear atypia, pleomorphism, hyperchromasia; loss of polarity

Cytoplasm

 ─ Low-Grade BilIN: May be scant or slightly mucinous

 ─ High-Grade BilIN: Scant, increased N:C ratio

Nuclei

 ─ Low-Grade BilIN: Mildly enlarged, slightly irregular, inconspicuous nucleoli

 ─ High-Grade BilIN: Enlarged, pleomorphic, hyperchromatic, prominent nucleoli

Absent

 ─ Stromal invasion

Note

 ─ Cytologic diagnosis is very challenging on FNA

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Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN)

Intraductal, grossly visible ( >1 cm) mucin-producing epithelial neoplasm arising in the main pancreatic duct or its branches, characterized by papillary proliferation of mucinous cells

Clinical

 ─ Symptoms depend on location and duct involvement

 ─ Main duct IPMN (MD-IPMN) and mixed-type have higher risk of malignancy than branch duct IPMN (BD-IPMN)

 ─ Sendai and Fukuoka guidelines are used for risk stratification and management

Cells

 ─ Variable cellularity

 ─ Cohesive groups, sheets, clusters, and true papillary fronds with fibrovascular cores

 ─ Columnar mucinous cells characteristic

 ─ Single cells may be present, esp in higher-grade lesions

Cytoplasm

 ─ Abundant, clear to pale, foamy or finely vacuolated (mucin-rich)

 ─ Apical mucin caps may be seen

 ─ Oncocytic, intestinal, or pancreatobiliary epithelial types can occur, influencing cytoplasmic appearance

Nuclei

 ─ Low-Grade (esp gastric-type): Round, basally located, uniform, smooth contours, inconspicuous nucleoli

 ─ High-Grade (intestinal, pancreatobiliary, or oncocytic): Enlarged, pleomorphic, irregular contours, hyperchromatic, coarse chromatin, prominent/irregular nucleoli, loss of polarity, stratification, mitoses

Background

 ─ Abundant, thick, viscous, colloid-like extracellular mucin is a hallmark feature ("string sign" on aspiration)

 ─ Inflammatory cells, histiocytes

Absent

 ─ Ovarian-type stroma (unlike MCN)

 ─ Stromal invasion (if present, categorized as IPMN with an associated invasive carcinoma)

Ancillary studies

 ─ Cyst fluid: CEA elevated (>192 ng/mL, often >800 ng/mL); Amylase variable (high if duct communication, low if obstructed)

 ─ Molecular: KRAS and GNAS mutations common; RNF43, TP53, SMAD4 mutations with progression

DDx

 ─ Mucinous Cystic Neoplasm (MCN): Lacks ductal communication, has ovarian-type stroma (not seen on FNA), almost exclusively in women

 ─ Pancreatic Ductal Adenocarcinoma (PDAC): More discohesion, single malignant cells, and infiltrative pattern

 ─ Chronic pancreatitis with mucinous metaplasia/hyperplasia: Less architectural complexity, less atypia, background of chronic pancreatitis

 ─ Simple mucinous cyst/retention cyst: Thin mucin, bland flat lining, low CEA

Note

 ─ Grading (low vs high) is crucial for management

 ─ Type of epithelium (gastric, intestinal, pancreatobiliary, oncocytic) influences morphology and risk

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Intraductal Papillary Neoplasm of the Bile Duct (IPNB)

Intraductal growth of biliary epithelium with papillary or villous architecture; a rare papillary neoplasm arising in the intrahepatic or extrahepatic bile ducts, considered a precursor to invasive cholangiocarcinoma

Clinical

 ─ Can cause biliary obstruction, cholangitis, or be an incidental finding

Cells

 ─ Similar to pancreatic IPMN but arising in bile ducts

 ─ Papillary clusters, sheets of columnar cells

 ─ Four epithelial subtypes described: Pancreatobiliary, intestinal, gastric, oncocytic

Cytoplasm

 ─ Variable depending on subtype; may be mucinous or eosinophilic (oncocytic)

Nuclei

 ─ Range from low-grade to high-grade atypia, similar to IPMN

Background

 ─ May see mucin (less consistently thick or abundant as in IPMN)

 ─ Inflammatory cells

Absent

 ─ Features of invasion into stroma (on cytology sample)

Note

 ─ Analogous to pancreatic IPMN

 ─ Cytologic features depend on the grade and histologic subtype

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Mucinous Cystic Neoplasm (MCN) (Pancreas)

Mucin-producing cystic epithelial neoplasm of the pancreas that does not connect with the pancreatic duct system and is characterized by an ovarian-type stroma beneath the epithelium

Clinical

 ─ Almost exclusively occurs in women in the body or tail; large, unilocular or multilocular cysts

Cells

 ─ Variable cellularity; paucicellular if only cyst fluid aspirated

 ─ Columnar mucinous epithelial cells in flat sheets, strips, clusters, or papillae

 ─ Ovarian-type stromal cells (spindle cells) are diagnostic but rarely sampled by FNA

Cytoplasm

 ─ Epithelial cells: Abundant, clear to pale, foamy or vacuolated (mucin-rich)

Nuclei

 ─ Epithelial cells: Range from bland (low-grade) to markedly atypical (high-grade)

 ─ Low-Grade: Small, round to oval, basally located, uniform, smooth contours

 ─ High-Grade: Enlarged, pleomorphic, irregular contours, hyperchromatic, prominent nucleoli, mitoses

Background

 ─ Thick, viscous, extracellular mucin

 ─ Inflammatory cells, histiocytes, debris

Absent

 ─ Communication with the pancreatic duct system

 ─ Stromal invasion (if present, categorized as MCN with an associated invasive carcinoma)

Ancillary studies

 ─ Cyst fluid analysis: CEA elevated (>192 ng/mL); Amylase low

 ─ Molecular: KRAS mutations; RNF43 mutations also seen; TP53 mutations with progression

DDx

 ─ Intraductal Papillary Mucinous Neoplasm (IPMN): Connects with duct system, lacks ovarian stroma

 ─ Pseudocyst: Inflammatory background, high amylase, low CEA, no true epithelial lining

 ─ Serous Cystadenoma: Clear fluid, glycogen-rich cells, low CEA, low amylase

 ─ Simple cyst/retention cyst: Thin mucin, bland flat lining, low CEA

Note

 ─ Presence of ovarian-type stroma is pathognomonic but rarely seen on FNA; Diagnosis often presumptive based on clinical (female, body/tail cyst), imaging, and cyst fluid (high CEA, low amylase) with mucinous epithelium

 ─ All MCNs are considered to have malignant potential and are usually recommended for resection

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Intraductal Oncocytic Papillary Neoplasm (IOPN)

Intraductal papillary neoplasm with complex arborizing papillae lined by oncocytic cells with eosinophilic cytoplasm and prominent nucleoli, involves main pancreatic duct or major branch ducts

Cells

 ─ Hypercellular smears

 ─ Large, complex papillary fronds, often with delicate fibrovascular cores

 ─ Sheets and clusters of oncocytic cells

 ─ Cells are typically large, polygonal to columnar

Cytoplasm

 ─ Abundant, dense, granular, eosinophilic (oncocytic)

 ─ Intracytoplasmic lumina or vacuoles may be present

Nuclei

 ─ Round to oval, eccentrically placed, enlarged, with vesicular or finely granular chromatin

 ─ Prominent, centrally located, eosinophilic macronucleoli are characteristic

 ─ Mild to moderate anisonucleosis; high-grade atypia can be seen

Absent

 ─ Significant extracellular mucin

 ─ Ovarian-type stroma

Ancillary studies

 ─ Molecular: Rearrangement of PRKACA or PRKACB; KRAS & GNAS mutations absent

DDx

 ─ IPMN subtypes (gastric, intestinal, pancreatobiliary): Lack diffuse oncocytic change and prominent macronucleoli; often have more extracellular mucin

 ─ Solid-pseudopapillary neoplasm: Lacks true oncocytic features; characteristic nuclear grooves, fine chromatin, and β-catenin nuclear positivity

 ─ Acinar cell carcinoma: More discohesive, prominent acinar formations, different nuclear features (zymogen granules)

 ─ Pancreatic neuroendocrine tumor: Different chromatin (salt-and-pepper), less prominent nucleoli, positive neuroendocrine markers

 ─ Serous cystadenoma: If oncocytic change is focal in an SCA, but SCA lacks true papillae and has clear, glycogen-rich cells predominantly

Note

 ─ Cytologically appears high-grade, but behavior can be relatively indolent if non-invasive

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Intraductal Tubulopapillary Neoplasm (ITPN)

Intraductal neoplasm with tubular and tubulopapillary growth, cuboidal to columnar cells with minimal or no overt mucin production

Clinical

 ─ Rare, distinct from IPMN and MCN, can occur in main or branch ducts

 ─ May cause duct obstruction, pancreatitis, or be an incidental finding

Cells

 ─ Cellular smears

 ─ Cohesive, complex, 3D groups, back-to-back tubular structures or short/stubby papillae

 ─ Cells cuboidal to low columnar

Cytoplasm

 ─ Scant to moderate, eosinophilic or amphophilic, non-mucinous (or only focal apical mucin)

Nuclei

 ─ Round to oval, uniform, with smooth contours; chromatin granular to moderately coarse

 ─ Nucleoli usually conspicuous, no macronucleoli

 ─ High-grade atypia common

Background

 ─ Clean; some necrotic debris in higher-grade lesions

Absent

 ─ Abundant extracellular mucin (unlike IPMN)

 ─ Ovarian-type stroma (unlike MCN)

 ─ Prominent oncocytic features (unlike IOPN)

Ancillary studies

 ─ Molecular: KRAS, GNAS, and RNF43 mutations are absent

DDx

 ─ Pancreatic ductal adenocarcinoma (PDAC): ITPN is intraductal; PDAC is invasive with desmoplasia; ITPN cells often more uniform with less pleomorphism than typical PDAC, though high-grade ITPN can mimic PDAC

 ─ IPMN, particularly pancreatobiliary subtype: IPMN usually has more overt mucin production and often cystic change; ITPN is more solid/tubular

 ─ PanIN: PanIN is a microscopic flat lesion, ITPN is grossly visible and forms complex structures

Note

 ─ High-risk precursor lesion, frequently associated with high-grade dysplasia and invasive carcinoma

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Cholangiocarcinoma (Intrahepatic, Hilar, Extrahepatic)

Adenocarcinoma arising from biliary epithelium lining the intra or extrahepatic bile ducts

Clinical

 ─ Risk factors include primary sclerosing cholangitis, choledochal cysts, liver flukes (Clonorchis, Opisthorchis), hepatolithiasis, and chronic biliary inflammation

 ─ Intrahepatic cholangiocarcinoma may present as liver mass

 ─ Hilar (Klatskin tumor) and extrahepatic cholangiocarcinoma presents with obstructive jaundice

 ─ Serum CA 19-9 and CEA elevated

Cell patterns

 ─ Malignant glandular cells in sheets, clusters, acini, or papillae, often single cells; cuboidal to columnar, pleomorphic; moderate to high cellularity

Cytoplasm

 ─ Scant to moderate, basophilic, pale, or vacuolated (mucin-containing)

 ─ Signet-ring cells may be present

Nuclei

 ─ Enlarged, irregular contours, notching, and grooves

 ─ Hyperchromatic, coarse or clumped chromatin; parachromatin clearing may be seen

 ─ Nucleoli prominent and irregular; macronucleoli can be seen

 ─ Anisonucleosis and pleomorphism apparent

 ─ Mitotic figures may be present

Background

 ─ "Dirty" with necrotic debris and inflammation; bile pigment if obstructed; desmoplastic stromal fragments

Absent

 ─ Features specific to HCC (endothelial wrapping, tumor cell bile production, HepPar-1); features specific to other pancreatic neoplasms

Ancillary studies

 ─ IHC: (+) CK7, CK19, CEA, MUC1, MUC5AC; CK20 variable

 ─ IHC: (-) Hepatocellular markers (HepPar-1, Arginase-1, Glypican-3), neuroendocrine markers (synaptophysin, chromogranin), often TTF-1 (hilar cholangiocarcinomas can be (+) TTF-1)

 ─ SMAD4/DPC4 loss common, similar to PDAC

 ─ FISH for polysomy of chromosomes 3, 7, 17 and 9p21 (CDKN2A/p16) deletion can be helpful in biliary brushings, esp in PSC patients

DDx

 ─ Pancreatic ductal adenocarcinoma: Similar or identical; distinction based on location

 ─ Metastatic adenocarcinoma

 ─ Reactive biliary atypia: Can be very difficult, esp in the setting of stents or PSC; reactive cells usually show less architectural disarray, smoother nuclear contours, finer chromatin, and lack numerous atypical single cells

 ─ Hepatocellular carcinoma: esp poorly differentiated variants; HCC typically shows trabecular patterns, sinusoidal capillarization, and positive hepatocellular markers

Note

 ─ Cytologic diagnosis challenging, particularly in well-differentiated tumors or with reactive changes

 ─ Bile duct brushings high specificity but variable sensitivity; FNA higher sensitivity for mass lesions

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Solid Pseudopapillary Neoplasm (SPN)

A low-grade malignant epithelial neoplasm with solid and pseudopapillary architecture, composed of relatively uniform cells with round to oval nuclei, often with nuclear grooves, and eosinophilic or clear cytoplasm

Clinical

 ─ young women (mean age 20s-30s)

 ─ large, well-circumscribed, encapsulated mass, frequently in the tail

 ─ many are incidental findings

 ─ Excellent prognosis after complete surgical resection, even with invasion or metastases (primarily to liver or peritoneum)

Cell patterns

 ─ Highly cellular; monomorphic cells in branching papillary-like fronds with fibrovascular cores, solid sheets, loose clusters, or single; round to polygonal/plasmacytoid

Cytoplasm

 ─ Moderate, finely granular, eosinophilic, or clear/vacuolated

 ─ Cytoplasmic hyaline globules (PAS-D positive) may be present

 ─ Indistinct cell borders

Nuclei

 ─ Round to oval, eccentrically placed; Finely granular, "powdery" or "salt-and-pepper"

 ─ Longitudinal nuclear grooves characteristic

 ─ Nucleoli inconspicuous or small

 ─ Mitotic figures sparse

Background

 ─ Often hemorrhagic; myxoid or hyalinized material (stroma of fibrovascular stalks); cholesterol crystals, foamy macrophages, necrotic debris (esp if cystic degeneration)

Absent

 ─ Significant pleomorphism; overt glandular or acinar differentiation; abundant extracellular mucin

Ancillary studies

 ─ IHC: (+) β-catenin (nuclear and cytoplasmic), CD10 (membranous), CD56, vimentin, α1-antitrypsin, progesterone receptor

 ─ IHC: (-) Chromogranin (or only focal), trypsin, CK7 (usually)

 ─ Molecular: CTNNB1 (gene encoding β-catenin) mutations

DDx

 ─ Pancreatic neuroendocrine tumor (PanNET): Can have plasmacytoid cells and granular cytoplasm; PanNETs more salt-and-pepper chromatin, lack nuclear grooves, and (+) chromogranin/synaptophysin, (-) nuclear β-catenin

 ─ Acinar cell carcinoma: granular cytoplasm (zymogen granules), prominent nucleoli, (+) trypsin/BCL10

 ─ Pancreatoblastoma: Occurs in children, squamous morules, may show acinar or neuroendocrine differentiation

 ─ Serous cystadenoma: If SPN is predominantly cystic; serous cystadenoma has clear, glycogen-rich cells and lacks the nuclear features or IHC profile of SPN

Note

 ─ combination of delicate papillary fronds, monomorphic cells with nuclear grooves, and characteristic IHC (nuclear β-catenin) is diagnostic

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Pancreatoblastoma

rare malignant epithelial neoplasm of childhood, acinar differentiation and squamous morules

Clinical

 ─ Most common pancreatic neoplasm in children ( <10 years old); very rare in adults

 ─ associated with Beckwith-Wiedemann syndrome or familial adenomatous polyposis (FAP)

 ─ presents as a large abdominal mass; serum AFP may be elevated

Cell patterns

 ─ Highly cellular; dual population (primitive cells in clusters/sheets/rosettes; larger cells with acinar differentiation); characteristic squamous morules

Cytoplasm

 ─ Primitive cells: Scant, basophilic

 ─ Acinar cells: Moderate, granular (zymogen granules), eosinophilic or basophilic

 ─ Squamous cells: Dense, eosinophilic/orangeophilic

Nuclei

 ─ Primitive cells: Round to oval, hyperchromatic, coarse chromatin, inconspicuous nucleoli

 ─ Acinar cells: Round, eccentric, vesicular chromatin, prominent nucleolus

 ─ Squamous cells: Bland, often pyknotic

Background

 ─ May be clean or contain blood, necrotic debris

Absent

 ─ Significant extracellular mucin; ovarian-type stroma; prominent neuroendocrine features (focal neuroendocrine differentiation can occur)

Ancillary studies

 ─ IHC: (+) Trypsin, chymotrypsin, BCL10 (acinar component); Keratins (squamoid corpuscles); β-catenin (nuclear, often)

 ─ IHC: (+) Synaptophysin, chromogranin (focally in some cases)

 ─ AFP can be positive

DDx

 ─ Pancreatic neuroendocrine tumor (PanNET): Lacks squamoid corpuscles and true acinar differentiation; diffusely (+) neuroendocrine markers

 ─ Acinar cell carcinoma: Predominantly acinar differentiation, lacks squamoid corpuscles and primitive component ( some overlap exists, esp in adults)

 ─ Solid pseudopapillary neoplasm (SPN): Lacks squamoid corpuscles and acinar differentiation; characteristic nuclear grooves and nuclear β-catenin

 ─ Hepatoblastoma (metastatic): Can have squamoid morules and AFP production; clinical context and liver imaging important

Note

 ─ Squamoid corpuscles are the most distinctive cytologic feature

 ─ Prognosis better in children than in rare adult cases

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Pancreatic Ductal Adenocarcinoma (PDAC)

An invasive malignant epithelial neoplasm showing glandular (ductal) differentiation, accounts for majority of pancreatic cancers

Clinical

 ─ older adults ( 60s-70s), presents late with painless jaundice (head lesions), abdominal/back pain, weight loss, anorexia

 ─ Most common in head of pancreas

 ─ Serum CA 19-9 often elevated but not specific

 ─ Poor prognosis, high rate of local invasion and distant metastases

Cell patterns

 ─ Variable cellularity; malignant ductal cells in disorganized crowded 3D clusters, poorly formed glands, sheets, chains, or single; cell-in-cell arrangements; marked anisonucleosis

Cytoplasm

 ─ Variable, scant to moderate, pale, basophilic, or vacuolated (mucin)

 ─ N:C is high

Nuclei

 ─ Enlarged, pleomorphic (variable size and shape), with irregular nuclear contours (notching, angulation, membrane thickening)

 ─ Hyperchromasia, coarsely granular, clumped, or irregularly distributed chromatin

 ─ Parachromatin clearing prominent

 ─ Nucleoli enlarged, irregular, and multiple; macronucleoli can be present

 ─ Mitotic figures, including atypical forms, may be seen but are not always numerous

Background

 ─ Often "dirty"; fragments of desmoplastic stroma; extracellular mucin may be seen

Absent

 ─ Features of specific differentiation (e.g., neuroendocrine, acinar, squamous, unless a variant); ovarian-type stroma

Ancillary studies

 ─ IHC: (+) CK7, CK19, CEA (often strong cytoplasmic/luminal), CA19-9, MUC1, MUC5AC; p53 (aberrant expression - strong diffuse positivity or complete absence often)

 ─ IHC: (-) SMAD4/DPC4 (loss in ~55% of cases, highly specific)

 ─ Molecular: KRAS mutations in >90%; TP53, CDKN2A/p16, SMAD4 mutations also common

DDx

 ─ Reactive ductal atypia (pancreatitis, stents): Can be very challenging; reactive changes usually show less architectural disarray, smoother nuclear contours, finer chromatin, less prominent nucleoli, and lack numerous single atypical cells

 ─ Cholangiocarcinoma: Morphologically and immunophenotypically very similar/identical; distinction based on primary site

 ─ High-grade PanIN or dysplasia in IPMN/MCN: Lack stromal invasion (though this is hard to assess on FNA alone)

 ─ Other adenocarcinomas (metastatic or other primary pancreatic types): Clinical history and IHC panel crucial

Note

 ─ Diagnosis relies on a combination of architectural disarray and high-grade nuclear atypia

 ─ Well-differentiated PDAC can be particularly difficult to distinguish from reactive changes

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Pancreatic Neuroendocrine Tumor (PanNET)

Neoplasm showing neuroendocrine differentiation, arising from islet cells or ductal pluripotent stem cells; graded by WHO as G1, G2, or G3 based on mitotic rate and Ki-67 index

Clinical

 ─ functional (hormone-secreting) or non-functional (most common)

 ─ Non-functional tumors often present due to mass effect or incidentally

 ─ May be part of MEN1 syndrome

 ─ Prognosis varies widely depending on grade, stage, and functionality

Cell patterns

 ─ Highly cellular; dispersed single cells, loose clusters, trabeculae, rosettes, or acinar-like arrangements; monomorphic round, oval, or plasmacytoid cells

Cytoplasm

 ─ Moderate amount, finely granular ("salt-and-pepper" on Romanowsky stains, eosinophilic to amphophilic on Pap), or clear

Nuclei

 ─ Round to oval, often eccentric (plasmacytoid appearance)

 ─ Finely stippled, "salt-and-pepper" or "powdery" chromatin characteristic

 ─ Nucleoli inconspicuous or small; can be more prominent in higher-grade lesions

 ─ Nuclear molding may be seen in cohesive groups

 ─ Minimal anisonucleosis in low-grade tumors; more pleomorphism in higher grades

 ─ Mitoses rare in G1, frequent in G2/G3

Background

 ─ Often bloody (high vascularity); lymphoglandular bodies (stripped cytoplasm); amyloid (in some types e.g., insulinoma)

Absent

 ─ Significant extracellular mucin; true glandular lumina or well-formed acini (unless mixed tumor); squamoid corpuscles

Ancillary studies

 ─ IHC: (+) Synaptophysin, Chromogranin A (Chromogranin may be focal or negative in poorly differentiated NETs/NECs), CD56, INSM1; Specific hormones (insulin, glucagon, gastrin, etc, if functional)

 ─ Ki-67 index: G1: <3%; G2: 3-20%; G3 PanNET: >20%

DDx

 ─ Acinar cell carcinoma: More cohesive, true acinar structures, coarser chromatin, prominent nucleoli, (+) trypsin/BCL10

 ─ Solid pseudopapillary neoplasm (SPN): Papillary structures, nuclear grooves, (+) nuclear β-catenin, CD10

 ─ Pancreatoblastoma: Squamoid corpuscles, acinar differentiation, typically in children

 ─ Well-differentiated PDAC: Glandular structures, mucin, different IHC

 ─ Lymphoma: Usually more pleomorphic lymphoid cells, (+) lymphoid markers

Note

 ─ "Salt-and-pepper" chromatin is a key feature

 ─ Grading (G1, G2, G3 PanNET) is essential for prognosis and management and relies on mitotic count and Ki-67 index, ideally assessed on histologic material or cell block

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Pancreatic Neuroendocrine Carcinoma (PanNEC)

high-grade, poorly differentiated neuroendocrine neoplasm, morphologically similar to small cell carcinoma or large cell neuroendocrine carcinoma of the lung

Clinical

 ─ Rare, aggressive tumors with poor prognosis; large at presentation, early metastases

 ─ May or may not be associated with a well-differentiated PanNET component

Cell patterns

 ─ Highly cellular; Small cell type (sheets/clusters/dispersed small cells, scant cytoplasm, molding, crush, mitoses/apoptosis) or Large cell type (sheets/clusters larger cells, more cytoplasm, vesicular nuclei, prominent nucleoli, mitoses/necrosis)

Cytoplasm

 ─ Small cell type: Very scant, often indistinct

 ─ Large cell type: Moderate, eosinophilic or amphophilic

Nuclei

 ─ Small cell type: Round to oval or spindled, hyperchromatic, finely granular to smudged chromatin, inconspicuous nucleoli, marked nuclear molding

 ─ Large cell type: Large, round to oval, vesicular or coarse chromatin, prominent nucleoli

 ─ High mitotic rate and extensive necrosis/apoptosis are characteristic of both

Background

 ─ Often necrotic, bloody, extensive crush artifact (esp small cell type)

Absent

 ─ Features of well-differentiated PanNET (e.g., plasmacytoid cells, salt-and-pepper chromatin throughout); glandular or acinar differentiation (unless combined tumor)

Ancillary studies

 ─ IHC: (+) Synaptophysin (often strong), CD56, INSM1, Cytokeratins (dot-like pattern can be seen); Chromogranin A (may be focal or negative)

 ─ Ki-67 index is very high (typically >50-60%, WHO defines NEC as >20% but most are much higher)

 ─ TP53 and RB alterations are common

DDx

 ─ Poorly differentiated pancreatic ductal adenocarcinoma: May show some neuroendocrine marker expression but usually has glandular features and different cytomorphology

 ─ Metastatic small cell or large cell neuroendocrine carcinoma (esp from lung): Clinically indistinguishable; IHC (TTF-1 may be positive in lung origin) and clinical history essential

 ─ Lymphoma/Leukemia: Dispersed atypical cells; (+) lymphoid markers

 ─ Acinar cell carcinoma: Can be poorly differentiated but usually shows some acinar features/markers

Note

 ─ Diagnosis requires neuroendocrine marker expression and high-grade morphology (high mitotic rate, necrosis)

 ─ Distinction from G3 PanNET can be challenging; PanNECs are generally more poorly differentiated with small cell or large cell neuroendocrine morphology, while G3 PanNETs still resemble their lower-grade counterparts but have higher proliferation

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Acinar Cell Carcinoma (Pancreas)

A malignant epithelial neoplasm showing predominantly acinar differentiation

Clinical

 ─ Rare, accounting for ~1-2% of exocrine pancreatic neoplasms

 ─ Can occur at any age, slight male predominance

 ─ May present with nonspecific abdominal symptoms, mass effect, or paraneoplastic syndromes (e.g., panniculitis due to lipase hypersecretion - Schmid's triad: subcutaneous fat necrosis, polyarthritis, eosinophilia)

 ─ Serum lipase may be elevated

 ─ Generally aggressive with poor prognosis, though better than PDAC for localized disease

Cell patterns

 ─ Highly cellular; cohesive clusters, acinar structures, sheets, or dispersed single cells; medium to large polygonal cells

Cytoplasm

 ─ Abundant, finely granular to coarsely granular (zymogen granules), eosinophilic or basophilic

 ─ Apical cytoplasmic granularity may be prominent in well-formed acini

 ─ Cell borders often distinct

Nuclei

 ─ Round to oval, often eccentric

 ─ Vesicular or coarsely granular chromatin

 ─ Single, prominent, centrally located nucleolus is characteristic

 ─ Anisonucleosis and pleomorphism can be variable; some tumors are quite monomorphic, others more pleomorphic

 ─ Mitotic figures may be present

Background

 ─ May be clean, hemorrhagic, or show necrosis; stripped nuclei with intact cytoplasm (acinar "ghosts") can be seen

Absent

 ─ Significant extracellular mucin; neuroendocrine features (unless mixed acinar-neuroendocrine carcinoma); ovarian-type stroma or squamoid corpuscles

Ancillary studies

 ─ IHC: (+) Trypsin, Chymotrypsin, BCL10 (nuclear and cytoplasmic), Pancreatic lipase, Cytokeratins (CK8/18, CAM5,2)

 ─ IHC: (-) Chromogranin, Synaptophysin (unless mixed tumor), nuclear β-catenin

DDx

 ─ Pancreatic neuroendocrine tumor (PanNET): Plasmacytoid cells, salt-and-pepper chromatin, (+) neuroendocrine markers

 ─ Solid pseudopapillary neoplasm (SPN): Papillary structures, nuclear grooves, (+) nuclear β-catenin

 ─ Pancreatoblastoma: Squamoid corpuscles, primitive component, typically in children

 ─ Well-differentiated PDAC with oncocytic or clear cell features: Lacks true acinar differentiation and zymogen granules; different IHC

 ─ Islet cell hyperplasia or normal acinar tissue: Less cellularity, no atypia, no discohesion

Note

 ─ Prominent nucleoli and granular cytoplasm are key features

 ─ Cytologic features can overlap with PanNET, requiring IHC for definitive classification

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🫁Respiratory

Inflammatory Cells Predominate (Lung Pattern 1)

Cytology

— Suppurative (Pneumonia): Numerous neutrophils, fibrinous/proteinaceous background, +/- organisms

— Histiocytic (Organizing Pneumonia): Predominantly histiocytes, thickened septal fragments, +/- pigment

— Granulomatous (Infection/Sarcoid): Epithelioid granulomas, +/- necrosis, +/- giant cells

DDx

— Squamous Cell Carcinoma

— —Can cavitate and be associated with suppuration or a granulomatous reaction to keratin

— Reactive Pneumocytes

— —Can show significant atypia and mimic adenocarcinoma

— Squamous Metaplasia

— —Can show significant atypia, mimicking squamous cell carcinoma

— Lymphoma / Seminoma

— —Can be associated with a granulomatous reaction

Note

— Cultures and special stains (GMS, ZN) are mandatory for suspected infection

— Non-infectious granulomatous disease (Sarcoid, Wegener) must be excluded

— The specific diagnosis depends on identifying the predominant inflammatory cell type and excluding malignancy

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Dispersed Lymphoid Cells (Lung Pattern 2)

Cytology

— Predominantly dispersed lymphoid cells

— High cellularity

— Population can be polymorphous (reactive) or monomorphous (neoplastic)

— Lymphoglandular bodies (cytoplasmic fragments) in background

DDx

— Reactive Lymphoid Hyperplasia

— —Polymorphous population with tangible body macrophages and germinal center fragments

— Non-Hodgkin Lymphoma (e.g., DLBCL, MALT)

— —Monomorphous population of atypical lymphoid cells

— Hodgkin Lymphoma

— —Diagnostic Reed-Sternberg cells in a mixed inflammatory background

— Thymoma

— —Bland epithelial cells (spindle or polygonal) admixed with mature lymphocytes

— Small Cell Carcinoma

— —Shows nuclear molding, crush artifact, and "salt-and-pepper" chromatin; lacks lymphoglandular bodies

Note

— Flow cytometry is essential to assess for clonality in non-Hodgkin lymphomas

— IHC is crucial for subtyping (e.g., CD30 for Hodgkin, CD20 for B-cell, TdT for lymphoblastic)

— Secondary involvement of the lung/mediastinum by lymphoma is more common than primary disease

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Epithelial Tissue Fragments With or Without Glandular Differentiation and With a Variable Number of Dispersed Cells, and With or Without Necrosis or Mucinous Background (Lung Pattern 3)

Cytology

— High cellularity

— Cohesive sheets, 3D groups with glandular, acinar, or papillary architecture

— Round/oval nuclei with fine chromatin and prominent, single central nucleoli

— Eccentric, pale, vacuolated cytoplasm

— Variable dispersed cells; may resemble histiocytes in mucinous type

— Necrosis or a mucinous background may be present

DDx

— Adenocarcinoma (Primary Lung)

— —Stereotypical lesion for this pattern; TTF1 and Napsin A positive

— Squamous Cell Carcinoma (Poorly Differentiated)

— —Differentiated by IHC (P40, CK5/6 positive)

— Metastatic Adenocarcinoma

— —Requires clinical history and IHC panel (e.g., CDX2 for colon, GATA3/ER for breast)

— Malignant Mesothelioma

— —Dense cytoplasm, intercellular "windows"; positive for calretinin, WT1

— Reactive Pneumocytes / Bronchial Cells

— —Less cellular, less architectural complexity, ciliation may be present

Note

— IHC is mandatory to differentiate adenocarcinoma from squamous cell carcinoma

— ROSE is crucial to ensure adequate material is triaged for molecular studies

— All adenocarcinomas require molecular testing (EGFR, ALK, etc.) for targeted therapy

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Epithelial Tissue Fragments and Plentiful Dispersed Cells Showing Varying Degrees of Squamous Differentiation With or Without Keratinous Debris and Necrosis (Lung Pattern 4)

Cytology

— Variable to high cellularity

— Cohesive sheets and dispersed single cells

— Squamous differentiation (keratinization, dense cytoplasm, tadpole/spindle cells)

— Hyperchromatic, irregular nuclei; pyknotic in well-differentiated forms

— Necrotic and/or keratinous background

DDx

— Squamous Cell Carcinoma (Primary vs. Metastatic)

— —Stereotypical lesion for this pattern

— —Cannot distinguish primary from metastatic on cytology alone

— Adenocarcinoma (Poorly Differentiated)

— —Lacks true keratinization; typically has eccentric nuclei, prominent nucleoli, and mucin

— Basaloid Carcinoma

— —Smaller basaloid cells, peripheral palisading, scant cytoplasm, high N:C ratio

— Squamous Metaplasia (Reactive)

— —Less cellular and less atypical than carcinoma; often in an inflammatory background

— Thymoma

— —Admixed with a significant benign lymphoid population

Note

— IHC is essential for confirmation (P40 and CK5/6 positive)

— p16 / HPV ISH can help identify metastatic origin from GYN or head and neck sites

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Predominantly Dispersed Cells With Discohesive Epithelial Tissue Fragments With or Without Chromatin Smearing and Karyorrhectic Debris (Lung Pattern 5)

Cytology

— High cellularity

— Dispersed cells and small, discohesive groups

— Scant cytoplasm, high N:C ratio

— "Salt-and-pepper" chromatin, inconspicuous nucleoli

— Prominent nuclear molding

— Crush artifact (chromatin smearing) and karyorrhectic debris

DDx

— Small Cell Carcinoma

— —Stereotypical lesion for this pattern

— Lymphoma

— —Lacks molding and crush; has lymphoglandular bodies in background

— Carcinoid Tumor

— —More cohesive, organoid pattern; more cytoplasm, lacks significant crush/necrosis

— Large Cell Neuroendocrine Carcinoma (LCNEC)

— —Larger cells with prominent nucleoli and more cytoplasm

— Basaloid Squamous Carcinoma

— —More cohesive, peripheral palisading, may have focal keratinization

— Poorly Differentiated Non-Small Cell Carcinoma

— —May show evidence of glandular (mucin) or squamous (dense cytoplasm) differentiation

Note

— IHC is essential for diagnosis (Synaptophysin, Chromogranin, CD56, TTF1 positive)

— Ki67 proliferation index is very high (>75%)

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Small Loosely Cohesive Epithelial Tissue Fragments and Dispersed Cells and Scattered Thin Capillary Meshworks (Lung Pattern 6)

Cytology

— High cellularity

— Loosely cohesive groups, dispersed cells, and thin capillary meshworks

— Monotonous round/oval cells with granular, plasmacytoid cytoplasm

— "Salt-and-pepper" chromatin, inconspicuous nucleoli

— Organoid architecture (rosettes, ribbons, trabeculae)

DDx

— Typical Carcinoid

— —Stereotypical lesion for this pattern

— Atypical Carcinoid

— —Features of typical carcinoid plus necrosis and/or increased mitoses

— Small Cell Carcinoma

— —Lacks significant molding, crush, and necrosis; has more cytoplasm

— Well-Differentiated Adenocarcinoma

— —Lacks true glandular formation; nuclei are stippled without prominent macronucleoli

— Metastatic Neuroendocrine Tumor

— —Cannot be distinguished from primary carcinoid on morphology alone; requires clinical history

Note

— IHC is essential for diagnosis (Synaptophysin, Chromogranin, CD56 positive)

— Ki67 proliferation index is low (<10%)

— A definitive diagnosis of 'atypical carcinoid' is difficult on FNA alone

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Stromal and Epithelial Components (Lung Pattern 7)

Cytology

— Variable cellularity

— Biphasic population of stromal and epithelial cells

— Key feature is the mix of mesenchymal elements: fibromyxoid stroma, cartilage, and fat

— Benign bronchial epithelium, sometimes with mild reactive atypia

DDx

— Pulmonary Hamartoma

— —Stereotypical lesion for this pattern

— Carcinosarcoma / Pleomorphic Carcinoma

— —Both epithelial and stromal components are frankly malignant

— Pulmonary Blastoma

— —Primitive epithelial (fetal adenocarcinoma) and mesenchymal (sarcomatous) components

— Sclerosing Pneumocytoma

— —Dual population of surface cuboidal cells and round stromal cells; prominent vascular meshwork

— Salivary Gland-Type Tumors (e.g., Adenoid Cystic)

— —Shows characteristic features of salivary gland tumors (e.g., "gum balls" in AdCC)

— Organizing Pneumonia

— —Fragments of thickened alveolar septa with histiocytes (lacks true cartilage/fat)

Note

— The diagnosis of hamartoma relies on identifying the classic triad of cartilage, fibromyxoid stroma, and benign epithelium

— Myxoid stroma is metachromatic (magenta) on Giemsa but can be missed on Pap stain

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Stromal Components Without Epithelium (Lung Pattern 8)

Cytology

— High cellularity

— Plump spindle cells, singly and in groups

— Atypical features: bizarre cells, large/hyperchromatic nuclei, prominent nucleoli

— Lacks a definitive epithelial component

DDx

— Metastatic Sarcoma

— —Most common entity in this pattern; requires clinical history

— Primary Sarcoma (e.g., Synovial Sarcoma)

— —Diagnosis often relies on IHC and molecular (e.g., t(X;18) for synovial)

— Sarcomatoid Mesothelioma

— —Spindle cell proliferation; confirmed by positive mesothelial IHC markers (Calretinin, WT1, etc.)

— Solitary Fibrous Tumor

— —Spindle cells with fibrovascular material; confirmed by IHC (CD34, STAT6 positive)

— Inflammatory Myofibroblastic Tumor

— —Mildly pleomorphic spindle cells with a prominent inflammatory background

Note

— IHC is essential to differentiate sarcoma from sarcomatoid carcinoma

— A broad IHC panel (pankeratin, vimentin, S100, actin, desmin) is recommended for initial workup

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Insufficient, Inadequate, or Non-diagnostic (Lung WHO)

This category indicates that the specimen is unsatisfactory for a diagnostic interpretation because it lacks sufficient material in quantity or quality for a reliable diagnosis, or that the findings do not explain the targeted lesion or clinical symptoms.

Criteria

─ Paucity of cellular material, extensive necrosis, or poor preparation (e.g., extensive air-drying, crush, poor staining) that precludes evaluation

─ Excessive blood, inflammatory cells, or mucus that obscures cellular material

─ Sputum samples that lack a sufficient number of alveolar macrophages, suggesting the sample is from the upper airway rather than a deep-cough specimen

─ Targeted FNAB of a discrete mass/lesion that yields only normal cellular elements (e.g., bronchial cells) that do not explain the lesion

─ EBUS-TBNA of a lymph node target that lacks adequate lymphoid material (e.g., <40 lymphocytes per high-power field) and contains only benign bronchial cells or blood

─ Bronchial brushing (BB) specimens that lack abundant bronchial epithelial cells

Clinical

─ Provides no useful diagnostic information about the targeted lesion. The overall risk of malignancy (ROM) for this category is approximately 40–60%, varying by the sampling method: ~40% for EBUS-TBFNAB, up to 60% for transthoracic FNAB, and >60% for exfoliative samples. Management requires a review of clinical and imaging findings, often in a multidisciplinary setting, to decide whether to repeat the procedure or use a more invasive test. The reason for the inadequacy should be stated in the report to help guide subsequent procedures.

Note

─ Any degree of cellular atypia, however scant, generally precludes this category; such cases are categorized as "Atypical".

─ The entire specimen should be processed and examined before designating it as nondiagnostic.

─ Correlation with clinical and imaging findings is essential. If a specimen contains adequate, benign cellular material that does not explain a suspicious mass lesion, it is recommended to report it as "Benign" with a comment that the material may not be representative and that further sampling is recommended, rather than classifying it as "Non-diagnostic".

Benign or Negative for Malignancy (Lung WHO)

This category is used for specimens that demonstrate unequivocal benign cytopathological features, which may or may not be diagnostic of a specific benign process or neoplasm.

Criteria

─ The sample contains unequivocally benign features, which may be diagnostic of a specific inflammatory process (e.g., granulomas) or a benign neoplasm (e.g., hamartoma), or may consist of normal lung components (bronchial cells, alveolar macrophages, alveolar septa).

─ The cytopathological findings must be correlated with clinical and imaging findings to ensure they adequately explain the targeted lesion.

─ Cells exhibit features of benignity, such as cilia on columnar cells, orderly cell groups, low nuclear-to-cytoplasmic ratios, smooth nuclear contours, and fine chromatin.

─ For exfoliative specimens like sputum or BAL, the presence of adequate alveolar macrophages is a key feature of sample adequacy.

Note

─ The risk of malignancy (ROM) for this category is highly variable, generally reported to be between 24% and 42%, due to the possibility of sampling error.

─ Correlation with imaging is critical. If an FNA of a nodule suspicious for malignancy yields only benign components, the case can be categorized as "Benign," but the report must include a caveat stating that "the material may not represent the lesion seen on imaging" and that further evaluation may be required.

─ Management depends on the clinical context. If the benign diagnosis correlates with imaging, routine follow-up is typically recommended. If there is a discrepancy, further investigation (e.g., repeat sampling, core biopsy) is necessary.

Inflammatory

─ Acute inflammation (e.g., bacterial pneumonia, abscess); characterized by a predominance of neutrophils.

─ Granulomatous inflammation (e.g., sarcoidosis, mycobacterial or fungal infection); features epithelioid histiocytes, giant cells, and lymphocytes. Necrosis may be present. Samples should be triaged for special stains and microbiological cultures.

─ Other inflammatory patterns include histiocytic, lymphocytic, or eosinophilic inflammation. Specific diagnoses like lipid pneumonia or foreign body aspiration should be made when possible.

Neoplasm

─ Pulmonary hamartoma (a mix of cartilage, fibromyxoid stroma, benign epithelium, and fat).

─ Sclerosing pneumocytoma (shows a dual population of surface cuboidal cells and stromal round cells).

─ Other benign neoplasms include granular cell tumor, bronchial papillomas, and schwannoma.

─ Treatment for benign neoplasms depends on symptoms. Symptomatic or endobronchial lesions are often treated with limited surgical resection, while asymptomatic tumors may be clinically followed.

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Atypical (Lung WHO)

This category is for specimens that show features predominantly seen in benign lesions but also have minimal features that raise the possibility of malignancy, with insufficient evidence in quantity or quality to make a definitive benign or malignant diagnosis.

Criteria

─ Cytomorphologic features (architectural or nuclear) exceed those of benign reactive conditions but fall short of a "Suspicious for Malignancy" or "Malignant" diagnosis. The atypia may be qualitative or quantitative.

─ Extreme reactive and reparative cellular changes that mimic malignancy, often occurring in the context of inflammation, infection, radiation, or chemotherapy.

─ Squamous or other metaplastic changes (e.g., goblet cell hyperplasia) that cannot be definitively distinguished from a neoplastic process.

─ Scant cellularity, with only a few cells showing cytomorphological features suggestive of malignancy.

─ Background elements are suggestive of a neoplasm (e.g., necrotic or keratinous debris, thick mucin), but definitive malignant cells are absent or poorly preserved.

─ Bland-appearing spindle cell lesions where ancillary testing is needed for a specific diagnosis.

Note

─ This category helps maintain a high negative predictive value for the "Benign" category and a high positive predictive value for the "Malignant" category. It should be used sparingly.

─ Clinical and radiologic correlation is critical. A key feature favoring neoplasia is a distinct population of atypical cells, whereas a continuum from normal to atypical cells suggests a reactive process.

─ The term "inflammatory atypia" should be avoided. If changes are confidently reactive, the "Benign" category is preferred.

─ If additional laboratory studies resolve the diagnostic dilemma, the case may be upgraded to "Suspicious" or "Malignant" or downgraded to "Benign."

Risk of Malignancy (ROM)

─ The reported ROM for the "Atypical" category varies widely, from 22% to 62%.

─ More recent studies distinguish it from the "Suspicious" category and report a ROM of 50–60%.

Management

─ The initial step is correlation with clinical and imaging findings.

─ If imaging is atypical or concerning for malignancy, further investigation is required, such as a repeat cytologic study or a more invasive procedure (e.g., core needle biopsy).

─ If clinical and imaging features are benign, a period of clinical observation may be appropriate.

─ Ancillary tests on specimens with scant atypical cells are generally not recommended, but for adequately cellular samples (e.g., atypical lymphoid cells), further studies like flow cytometry can be useful.

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Suspicious for Malignancy (SM) (Lung WHO)

This category is for specimens that demonstrate some cytopathological features suggestive of malignancy but have insufficient features, either in number or quality, to make an unequivocal diagnosis of malignancy. It is used for cases the cytopathologist assesses as most likely malignant but where there is a degree of uncertainty.

Criteria

─ The category is applied in cases with significant cytopathological atypia, including nuclear enlargement, anisonucleosis, irregular nuclear membranes, coarse or hyperchromatic chromatin, and prominent or irregular nucleoli.

─ Architectural features are concerning, such as loss of polarity, nuclear crowding, and molding.

─ The uncertainty is due to either a small number of cells showing these features (quantitative) or because the qualitative features are not definitive for malignancy.

─ This category may be used in specific scenarios:

─ Necrotic tumors yielding limited intact cells.

─ Dense, obscuring inflammatory or granulomatous backgrounds.

─ Tumors with a prominent fibrotic component.

─ Well-differentiated adenocarcinoma where subtle atypia overlaps with inflamed reactive epithelium.

─ Significant atypia in a low-cellularity sample following radiation or chemotherapy.

Note

─ This category is applicable to any suspected malignant tumor type (e.g., non-small cell carcinoma, neuroendocrine tumors, lymphoma, metastasis), and the suspected tumor type or differential diagnosis should be stated in the report.

─ The use of this category has a high rate of interobserver variability; consultation with experienced colleagues is recommended.

─ Ancillary techniques like immunohistochemistry can assist but may be limited by the quantity or quality of the suspicious cells. Markers like TTF1 and p40 do not definitively separate benign from malignant cells.

─ This diagnosis should not be used as the sole basis for definitive therapy but is meant to convey a high degree of concern to the clinical team.

Risk of Malignancy (ROM)

─ The risk of malignancy is high, estimated to be 75–100% for exfoliative samples and 75–88% for FNAB. The overall ROM is approximately 82%.

Management

─ It is mandatory to review the clinical presentation and imaging findings, ideally in a multidisciplinary setting.

─ Further diagnostic steps are typically required to establish a definitive diagnosis.

─ This may include repeating the cytologic procedure (preferably with rapid onsite evaluation), obtaining a core needle biopsy, or proceeding to a surgical biopsy.

─ While not a final diagnosis of malignancy, in cases with correlating suspicious clinical and imaging findings, a multidisciplinary team may decide to proceed to specific treatment.

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Malignant (Lung WHO)

This category is used when the specimen demonstrates unequivocal cytopathological features of malignancy. A diagnosis should be rendered only in specimens with adequate cellularity demonstrating definitive key diagnostic criteria.

General Criteria for Malignancy (Non-Small Cell Carcinoma)

─ Cytomorphology showing features of either adenocarcinoma (distinct glandular morphology with or without mucin production) or squamous cell carcinoma (keratinization).

─ Increased cellularity with dyscohesion or abnormal architectural arrangements.

─ High nuclear-to-cytoplasmic (N:C) ratio.

─ Nuclear pleomorphism (variation in size and shape).

─ Irregular nuclear membranes.

─ Hyperchromasia and irregular chromatin clumping.

─ Macronucleoli or irregular nucleoli.

─ Necrotic background (tumor diathesis) may be present.

Note

─ Subtyping and Ancillary Studies: Precise characterization is essential for targeted therapy.

─ Good accuracy (>70%) can be achieved in differentiating non-small cell carcinoma from small cell neuroendocrine carcinoma based on morphology alone.

─ However, the current standard of care requires specific classification of non-small cell carcinoma as adenocarcinoma or squamous cell carcinoma, which can be achieved with a limited immunohistochemistry (ICC) panel (e.g., TTF1, p40, napsin A).

─ The designation "Non-small cell carcinoma, NOS" is appropriate for poorly differentiated carcinomas lacking clear differentiation by both morphology and ICC.

─ It is critical to conserve tissue for molecular biomarker testing (e.g., EGFR, ALK, ROS1), which can be successfully performed on cytology samples.

─ Reporting: The report should include the "Malignant" category, a specific diagnosis according to the WHO classification if possible, and a brief differential diagnosis if not. Any ancillary test results (ICC, molecular) should be incorporated into a final, integrated report.

─ Other Malignancies: This category also includes salivary gland–type carcinomas, neuroendocrine tumors (NETs), lymphoproliferative malignancies, mesenchymal tumors, mesothelioma, and metastatic malignancies. The cytopathologist should provide as specific a diagnosis as possible.

Risk of Malignancy (ROM)

─ The risk of malignancy for this category is very high.

─ Sputum: 100%

─ Exfoliative (Bronchial Wash/Brush): 94–100%

─ FNAB: 87–100%

Management

─ Management is determined after correlation with clinical and imaging findings, ideally in a multidisciplinary setting.

─ A diagnosis of malignancy on a cytology specimen, when correlated with clinical and imaging findings, is often sufficient to proceed to definitive treatment.

─ Sputum: If a sputum sample is malignant, the next step is typically bronchoscopy and/or imaging to localize the lesion for biopsy and staging.

─ Bronchial Wash/Brush: For a peripheral non-small cell lung cancer without metastasis, management depends on imaging. Small tumors may proceed directly to surgical resection. Larger tumors or those with suspicious lymph nodes on imaging require mediastinal staging, usually via endobronchial ultrasound–guided FNAB.

─ FNAB: If the FNAB is malignant and correlates with findings, treatment decisions can be made. If there is insufficient material for necessary ancillary testing, a repeat FNAB with or without a core needle biopsy should be considered.

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Granular cell tumor (Lung)

An uncommon benign neoplasm, thought to be of Schwann cell origin, that can occur in the tracheobronchial tree and is composed of cells with abundant eosinophilic granular cytoplasm

Clinical

─ Typically occurs in middle-aged adults (4th-6th decades), but wide age range

─ Slight female predominance noted in some series, others report male predominance or no sex predilection for pulmonary lesions

─ Most are endobronchial, arising in larger airways; less commonly parenchymal

─ Patients may be asymptomatic (incidental finding on bronchoscopy or imaging) or present with cough, wheezing, dyspnea, or hemoptysis if the tumor causes obstruction

─ Often solitary, but multiple tumors can occur, especially in the tracheobronchial tree

Cytology

─ Cells are polygonal to round, arranged in cohesive clusters, syncytial groups, or as isolated cells; cellularity can be variable

─ Cytoplasm is abundant, dense, and strikingly granular (eosinophilic with Pap stain, can be basophilic with Giemsa); granules are fine and uniform; cell borders are often distinct but can be ill-defined in groups

─ Nuclei show small, round to oval features, often eccentrically placed; chromatin is finely granular and evenly distributed; nucleoli are typically inconspicuous or absent

─ Background shows may contain numerous stripped, bare nuclei and granular cytoplasmic debris due to cell fragility; generally clean otherwise, without significant inflammation or necrosis unless ulcerated

─ Absence of significant nuclear pleomorphism, hyperchromasia, mitotic activity, or true necrosis (in benign cases); absence of keratinization or glandular features

Ancillary studies

─ IHC (+): S100 protein (strong and diffuse); SOX10; CD68 (lysosomal marker, highlights granules); PAS-D (Periodic Acid-Schiff with diastase, highlights granules); Inhibin-alpha; TFE3

─ IHC (-): Cytokeratins (AE1/AE3, CAM5.2); Neuroendocrine markers (Chromogranin, Synaptophysin); TTF-1; Desmin; Myogenin

DDx

─ Macrophages/Histiocytes (less cohesive, more variable nuclei, cytoplasm often foamy or vacuolated rather than densely granular, CD68 positive but S100/SOX10 negative)

─ Oncocytic cells / Oncocytoma (more prominent nucleoli, mitochondria-rich cytoplasm but not as distinctly granular, S100 negative or focal)

─ Carcinoid tumor (neuroendocrine nuclear features – salt-and-pepper chromatin, more cohesive, synaptophysin/chromogranin positive)

─ Squamous metaplasia (more cohesive sheets, denser cytoplasm, intercellular bridges if visible, keratin positive)

─ Alveolar soft part sarcoma (rare in lung, different clinical context, prominent nucleoli, characteristic crystals, TFE3 positive but S100 negative)

─ Rhabdomyoma (extremely rare in lung, may show cross-striations, desmin/myogenin positive)

─ Melanoma (can have granular cells, but usually more pleomorphism, prominent nucleoli, other melanoma markers like Melan-A/HMB45 positive)

Prognosis

─ Almost always benign; malignant granular cell tumors are exceedingly rare, especially in the lung

─ Local recurrence is possible if incompletely excised

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Pulmonary Hamartomas (Lung)

A benign mesenchymal neoplasm of the lung, the most common benign lung tumor, typically discovered incidentally as a solitary, well-circumscribed peripheral "coin lesion"

Clinical

─ Most common benign lung tumor

─ Usually discovered incidentally in adults (peak 50-70 years) on imaging

─ Slight male predominance

─ Typically a solitary, peripheral, well-circumscribed, slow-growing "coin lesion" <4 cm

─ Less commonly central/endobronchial, which may cause obstructive symptoms

─ Multiple hamartomas are rare, may be associated with Carney triad (pulmonary hamartoma, GIST, paraganglioma) or Cowden syndrome

─ Radiologic "popcorn" calcification is characteristic but not always present

Cytology

─ Cells are a biphasic admixture of mesenchymal and epithelial elements; aspirates may be variably cellular depending on the components sampled

─ Cytoplasm is variable: epithelial cells (bronchial type) have scant to moderate, often pale or clear cytoplasm, may be ciliated; spindle cells (fibromyxoid stroma) have scant, wispy cytoplasm; chondrocytes have clear cytoplasm within lacunae; adipocytes have abundant clear cytoplasm

─ Nuclei show benign features: epithelial cells have round to oval, normochromatic nuclei with smooth contours and fine chromatin; spindle cells have bland, elongated nuclei; chondrocytes have small, dark, round nuclei; adipocyte nuclei are small and peripheral

─ Background shows often a key diagnostic feature: fragments of mature hyaline cartilage (chondroid material – dense, glassy, metachromatic with Giemsa, pale blue/green with Pap); fibromyxoid stroma (loose, fibrillary, metachromatic with Giemsa); mature adipose tissue fragments; benign respiratory epithelial cells in flat sheets or small clusters

─ Absence of significant atypia, mitoses, or necrosis; absence of a predominant atypical epithelial population (unlike adenocarcinoma); absence of atypical chondrocytes (unlike chondrosarcoma)

Ancillary studies

─ IHC (+): Mesenchymal spindle cells and chondrocytes are S100 positive; Epithelial cells are cytokeratin positive (e g , CK7, CAM5.2) and TTF-1 positive

─ Molecular ─ Clonal chromosomal abnormalities involving HMGA2 (12q14-15) or HMGA1 (6p21) genes are common, confirming neoplastic nature

DDx

─ Adenocarcinoma, well-differentiated (especially lepidic or acinar; shows more atypia, complex glandular architecture, lacks mesenchymal components)

─ Carcinoid tumor (neuroendocrine features, lacks mesenchymal components)

─ Metastatic chondrosarcoma (rare, more cellular and atypical cartilage, clinical history)

─ Reactive bronchial cells (may show some atypia but usually ciliated, no mesenchymal elements)

─ Sclerosing pneumocytoma (dual population of cuboidal surface cells and stromal round cells, lacks cartilage and fat)

─ Organizing pneumonia (fibroblastic proliferation, inflammatory cells, no true cartilage)

Prognosis

─ Benign with excellent prognosis; malignant transformation is exceptionally rare

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Schwannoma (Lung)

A benign, encapsulated neoplasm arising from Schwann cells of nerve sheaths; primary pulmonary schwannomas are rare

Clinical

─ Primary pulmonary schwannomas are very rare (0.2% of all lung neoplasms)

─ Can occur at any age, no strong sex predilection for pulmonary lesions

─ Often asymptomatic and discovered incidentally as a solitary, well-circumscribed peripheral nodule or an endobronchial mass

─ Endobronchial lesions may cause cough, dyspnea, or obstruction

─ Multiple lesions may occur in the context of neurofibromatosis type 2 (NF2) or schwannomatosis

Cytology

─ Cells are predominantly spindle-shaped, arranged in cohesive fascicles, Verocay bodies (palisading nuclei around acellular eosinophilic zones – Antoni A areas), or loosely textured myxoid areas (Antoni B areas); cellularity varies with Antoni A areas being more cellular

─ Cytoplasm is typically scant to moderate, pale, fibrillary, with indistinct cell borders; may appear wavy or "shredded"

─ Nuclei show elongated, slender, wavy, buckled, or comma-shaped features with pointed ends; chromatin is finely granular and evenly distributed; nucleoli are usually inconspicuous; "ancient change" may show focal pleomorphism and hyperchromasia but lacks mitoses

─ Background shows often contains fragments of collagenous or myxoid stroma; generally clean unless cystic degeneration (common in larger lesions) or hemorrhage has occurred; hemosiderin-laden macrophages may be seen with cystic change

─ Absence of significant mitotic activity (usually rare or absent), necrosis (unless ancient/cystic change), or epithelial features (glands, keratinization)

Ancillary studies

─ IHC (+): S100 protein (strong and diffuse, nuclear and cytoplasmic); SOX10; Vimentin; CD57 (Leu-7); GFAP (variable, often focal)

─ IHC (-): Cytokeratins (AE1/AE3, CAM5.2); EMA; Desmin; SMA; CD34; TTF-1

DDx

─ Neurofibroma (less cellular, more haphazard arrangement, wavy cells in a collagenous stroma, admixed mast cells, S100 often less diffuse and includes staining of admixed axons)

─ Leiomyoma (blunt-ended "cigar-shaped" nuclei, more abundant eosinophilic cytoplasm, desmin/SMA positive)

─ Solitary fibrous tumor (patternless architecture, "hemangiopericytoma-like" vessels, CD34/STAT6 positive)

─ Spindle cell (sarcomatoid) carcinoma (more atypia, pleomorphism, mitoses, cytokeratin positive)

─ Malignant peripheral nerve sheath tumor (MPNST) (more cellularity, atypia, mitoses, necrosis, often associated with NF1, S100 often lost or focal)

─ Fibroblastic/myofibroblastic lesions (variable S100, other markers depending on entity)

Prognosis

─ Benign; recurrence after complete excision is rare; malignant transformation is exceptionally rare (usually in NF1 setting or large, deep-seated tumors)

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PEComa (Perivascular epithelioid cell tumor) (Lung)

A rare mesenchymal neoplasm family characterized by distinctive perivascular epithelioid cells, co-expressing melanocytic and smooth muscle markers; pulmonary PEComas include the benign clear cell "sugar" tumor and lymphangioleiomyomatosis (LAM)

Clinical

─ Primary pulmonary PEComas (including "sugar tumor") are very rare

─ "Sugar tumors" typically occur in middle-aged adults (median 50s), slight female predilection; usually asymptomatic, incidental peripheral solitary nodules

─ LAM almost exclusively affects women of reproductive age, often associated with tuberous sclerosis complex (TSC); presents with cystic lung disease, dyspnea, pneumothorax

─ Other PEComas can occur at various sites and may rarely metastasize to the lung

Cytology

(Features primarily describe benign clear cell "sugar" tumor, as LAM is usually diagnosed on biopsy/imaging) ─ Cells are polygonal to epithelioid, sometimes spindle-shaped, arranged in loose clusters, sheets, or as single cells; often intimately associated with thin-walled blood vessels; aspirates can be variably cellular, sometimes paucicellular

─ Cytoplasm is typically abundant, clear to pale eosinophilic, and finely granular or vacuolated due to glycogen (PAS positive, diastase sensitive); cell borders are usually distinct

─ Nuclei show round to oval features with smooth contours; finely granular, evenly distributed chromatin; nucleoli are generally small and inconspicuous in benign lesions; minimal pleomorphism

─ Background shows usually clean; may have delicate capillary network; necrosis is absent in benign lesions

─ Absence of significant nuclear atypia, hyperchromasia, high mitotic activity, or necrosis (in benign "sugar tumor"); absence of overt keratinization or glandular formation

Ancillary studies

─ IHC (+): HMB-45 (often strong and diffuse); Melan-A (MART-1); Smooth muscle actin (SMA); Desmin (variable); Calponin; MiTF (microphthalmia-associated transcription factor)

─ IHC (-): Cytokeratins (AE1/AE3, CAM5.2 usually); S100 protein (usually); TTF-1; Neuroendocrine markers (Chromogranin, Synaptophysin); CD34

─ Molecular ─ Mutations in TSC1 or TSC2 genes are characteristic of LAM and a subset of other PEComas, leading to mTOR pathway activation; TFE3 gene fusions (e g , with SFPQ) reported in a distinct subset of PEComas not associated with TSC

DDx

─ Metastatic clear cell renal cell carcinoma (RCCAM positive, PAX8 positive, CD10 positive, cytokeratin positive)

─ Metastatic adrenal cortical carcinoma (inhibin, calretinin, Melan-A positive, but different morphology and clinical context, SF-1 positive)

─ Metastatic melanoma (S100, SOX10 positive, HMB-45/Melan-A also positive but usually more pleomorphism and prominent nucleoli if not amelanotic)

─ Granular cell tumor (S100 positive, more distinctly granular cytoplasm, HMB-45/Melan-A negative)

─ Clear cell variant of adenocarcinoma (TTF-1, Napsin A, cytokeratin positive)

─ Oncocytoma/oncocytic carcinoid (oncocytic features, neuroendocrine markers for carcinoid, HMB-45/Melan-A negative)

─ Alveolar soft part sarcoma (ASPSCR1-TFE3 fusion, different morphology, characteristic crystals, HMB-45/Melan-A negative)

─ Paraganglioma (neuroendocrine markers positive, S100 positive sustentacular cells, HMB-45/Melan-A negative)

Prognosis

─ Benign clear cell "sugar" tumors of the lung are indolent with excellent prognosis after resection

─ LAM is a progressive disease, though mTOR inhibitors (e g , sirolimus) can stabilize lung function

─ Other PEComas have a variable prognosis; malignant PEComas are defined by features like large size, infiltrative growth, high nuclear grade, necrosis, and mitotic activity, and can metastasize

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Meningioma (Lung)

Benign neoplasms arising from arachnoidal (meningothelial) cells; primary intrapulmonary or mediastinal meningiomas are exceedingly rare, but can occur, and are more common in middle-aged women

Clinical

─ Primary pulmonary or mediastinal meningiomas are rare; usually asymptomatic and found incidentally as solitary, well-circumscribed peripheral nodules

─ More common in middle-aged to elderly women (F>M)

─ Metastatic meningioma to the lung is more common than primary pulmonary meningioma, though CSF spread of CNS meningiomas is itself uncommon

─ May be associated with a history of meningioma elsewhere if metastatic

Cytology

─ Cells are spindle to epithelioid, arranged in cohesive, syncytial-type clusters, sheets, nests, and characteristic whorls; cellularity can be moderate

─ Cytoplasm is usually pale, eosinophilic, and ill-defined with wispy cell borders; amount is moderate

─ Nuclei show bland, oval to elongated features with smooth contours and finely granular chromatin; small, indistinct nucleoli; intranuclear cytoplasmic pseudoinclusions are characteristic and can be numerous; nuclear grooves may be seen

─ Background shows psammoma bodies (laminated calcifications) may be present, especially in the psammomatous variant; generally clean unless hemorrhage or cystic change has occurred

─ Absence of significant atypia, frequent mitoses (in benign WHO Grade I cases); absence of prominent macronucleoli (unlike some carcinomas); absence of diffuse S100 positivity (unlike schwannoma); absence of TTF-1 (unlike lung adenocarcinoma)

Ancillary studies

─ IHC (+): EMA (epithelial membrane antigen, often strong), Vimentin, Progesterone receptor (PR, often strong in female patients), Somatostatin receptor 2A (SSTR2A)

─ IHC (-): Cytokeratins (AE1/AE3, CAM5.2 usually, though focal positivity can occur), S100 protein (usually negative or only focal/weak, helps distinguish from schwannoma), TTF-1, Napsin A, Chromogranin, Synaptophysin

─ Molecular ─ NF2 gene mutations are common in CNS meningiomas (especially fibrous, transitional, psammomatous types); data for primary pulmonary meningiomas is limited but similar alterations can be seen

DDx

─ Solitary fibrous tumor (STAT6 positive, CD34 positive, EMA negative)

─ Schwannoma (S100 and SOX10 strong/diffuse positive, EMA negative, lacks whorls and pseudoinclusions)

─ Carcinoid tumor (neuroendocrine markers positive, EMA negative or focal)

─ Low-grade adenocarcinoma of lung (TTF-1, Napsin A positive, more glandular features)

─ Metastatic carcinoma (e g , breast, renal; depends on primary, specific markers like GATA3, PAX8 helpful)

─ Reactive fibroblasts or mesothelial cells (especially if few cells and prominent spindle morphology or if pleural-based)

─ Well-differentiated papillary mesothelioma (if pleural based, calretinin, WT-1, D2-40 positive)

Prognosis

─ Primary pulmonary/mediastinal WHO Grade I meningiomas are typically benign and have an excellent prognosis after complete resection

─ WHO Grade II (atypical) and Grade III (anaplastic/malignant) meningiomas are much rarer in extraneuraxial sites but behave more aggressively

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Sclerosing Pneumocytoma (Lung)

A rare, benign neoplasm of the lung, previously termed sclerosing hemangioma, thought to derive from primitive respiratory precursor cells related to type II pneumocytes; typically presents in middle-aged women as an incidental peripheral, well-circumscribed nodule

Clinical

─ More common in middle-aged women (4th-6th decades), particularly in Asian populations

─ Usually an asymptomatic, incidental finding as a solitary, peripheral, well-circumscribed nodule on imaging (often <3 cm)

─ Rarely, patients may present with cough or hemoptysis

─ Multiple lesions are very rare

─ Low 18F-fluorodeoxyglucose (FDG) avidity on PET scan is typical

Cytology

─ Cells are typically a dual population: (1) cuboidal to polygonal surface cells lining papillae or small spaces, and (2) round to oval, sometimes spindled, stromal-like cells forming solid sheets or clusters, often predominating; poorly formed papillary structures and hemorrhagic background are common

─ Cytoplasm is scant to moderate and pale or eosinophilic in stromal-like cells; surface cuboidal cells have features similar to type II pneumocytes with clear, vacuolated, or granular eosinophilic cytoplasm

─ Nuclei show monomorphic, round to ovoid features with smooth nuclear contours, finely granular chromatin, and inconspicuous or small nucleoli in both cell types; intranuclear pseudoinclusions may be seen in surface cells

─ Background shows often hemorrhagic; hemosiderin-laden macrophages may be present; sclerosis (fibrous stroma) is a key histologic feature but may be difficult to appreciate as distinct stromal fragments cytologically, though some hyalinized stromal fragments can be seen

─ Absence of significant atypia, high mitotic activity, or necrosis; the dual population with bland cytology is characteristic

Ancillary studies

─ IHC (+): Both surface cuboidal cells and stromal-like cells are positive for TTF-1 and EMA (EMA often dot-like or membranous in stromal cells); Surface cells are also positive for cytokeratins (e g , CK7, CAM5.2) and surfactant proteins (e g , Napsin A)

─ IHC (-): Both cell types are negative for neuroendocrine markers (Chromogranin, Synaptophysin, CD56) and S100 protein

DDx

─ Adenocarcinoma, well-differentiated (especially lepidic or papillary predominant; typically shows more nuclear atypia, architectural complexity, prominent nucleoli, and lacks the distinct bland round stromal cell component; stromal cells of pneumocytoma are CK negative or only focally positive unlike adenocarcinoma)

─ Carcinoid tumor (neuroendocrine features, "salt-and-pepper" chromatin, synaptophysin/chromogranin positive, lacks dual population)

─ Pulmonary hamartoma (contains cartilage and often fibromyxoid stroma, lacks the characteristic dual cell population of pneumocytoma)

─ Metastatic papillary thyroid carcinoma (papillary structures, psammoma bodies may be present, characteristic nuclear features of PTC, thyroglobulin and PAX8 positive)

─ Reactive pneumocyte hyperplasia (often in a background of inflammation or injury, lacks the distinct stromal cell component and organized papillary/solid architecture)

─ Meningioma (if prominent stromal cells; meningioma has whorls, pseudoinclusions, EMA/PR positive, TTF-1 negative)

Prognosis

─ Benign, with excellent prognosis after complete resection; recurrence or metastasis is exceptionally rare

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Solitary tracheobronchial papilloma

A rare, benign exophytic tumor of the larger airways (trachea and bronchi), characterized by fibrovascular cores lined by squamous, glandular (respiratory or mucinous), or mixed epithelium

Clinical

─ Rare, accounting for <1% of all lung tumors

─ Can occur at any age, but often in adults; squamous type more common in adults, glandular in children

─ Patients may be asymptomatic or present with cough, hemoptysis, wheezing, or postobstructive pneumonia due to airway obstruction

─ Usually solitary, but multiple squamous papillomas (papillomatosis) can occur, especially in children and young adults, strongly associated with HPV types 6 and 11 (often acquired from maternal genital infection)

─ Glandular papillomas are not typically HPV-related

Cytology

(Obtained via bronchial brushing, washing, or FNA of an endobronchial lesion) ─ Cells are dependent on the papilloma subtype:

─ Squamous papillomas: Show clusters and sheets of mature squamous cells, which may be keratinizing or non-keratinizing; koilocytic atypia (perinuclear halo, nuclear atypia) may be seen if HPV-related; anucleated squames and parakeratotic cells can be present

─ Glandular papillomas: Show clusters of benign-appearing columnar cells, which may be ciliated (respiratory type) or mucin-producing (goblet cell type); cells are often arranged in papillary fronds or tight clusters

─ Mixed papillomas: Show features of both squamous and glandular types

─ Cytoplasm is typically abundant and corresponds to cell type (e g , dense/keratinized in squamous, vacuolated/mucinous in glandular, ciliated in respiratory)

─ Nuclei show generally bland features consistent with benign squamous or glandular epithelium; mild reactive atypia (nuclear enlargement, slight hyperchromasia) may be present, especially if inflamed or previously manipulated; mitoses are usually few or absent

─ Background shows may be clean or contain inflammatory cells (neutrophils, lymphocytes) if secondarily infected or irritated; mucin may be present with glandular or mixed types; fragments of fibrovascular cores are rarely seen but are diagnostic if present

─ Absence of high-grade malignant features (significant pleomorphism, coarse chromatin, macronucleoli, atypical mitoses); absence of true stromal invasion if tissue fragments are evaluable

Ancillary studies

─ IHC (+): Squamous cells are pankeratin positive, p40/p63 positive; Glandular cells are pankeratin positive (e g , CK7); HPV (by ISH or PCR, especially for HPV 6/11 in squamous papillomas/papillomatosis)

─ Molecular ─ BRAF V600E mutations have been reported in some peripheral glandular papillomas/adenomas; EGFR and KRAS mutations also described in some benign papillary lesions of distal airways; significance in tracheobronchial papillomas less clear

DDx

─ Squamous cell carcinoma (if squamous papilloma with atypia; carcinoma shows more significant atypia, pleomorphism, irregular chromatin, often necrosis, and invasive pattern if tissue fragments present)

─ Adenocarcinoma (if glandular papilloma with atypia; carcinoma shows more complex glands, infiltrative features if evaluable, and greater atypia)

─ Adenosquamous carcinoma (if mixed papilloma with atypia; shows features of both SCC and adenocarcinoma)

─ Reactive epithelial changes/metaplasia (may show atypia but usually lack the distinct exophytic papillary architecture if sampled adequately; clinical context of irritation important)

─ Papillary carcinoma metastatic to lung (e g , thyroid, renal, breast; clinical history and site-specific IHC markers are key)

─ Mucoepidermoid carcinoma (if glandular/mucinous features; typically shows intermediate cells and often MAML2 rearrangement)

Prognosis

─ Benign; however, malignant transformation has been reported rarely, most commonly in squamous papillomas (especially in adults with long-standing papillomatosis) to squamous cell carcinoma

─ Recurrence can occur if incompletely excised, particularly for HPV-related multiple papillomas

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Adenocarcinoma (Lung)

A malignant epithelial tumor with glandular differentiation (e g , acini, papillae) or mucin production by tumor cells, representing the most common histologic subtype of lung cancer in many populations

Clinical

─ Most common type of lung cancer, particularly in never-smokers, women, and younger patients

─ Often arises peripherally, but can be central; may present as solitary nodule, multiple nodules, or consolidation

─ Symptoms are variable: cough, dyspnea, hemoptysis, chest pain, or incidental finding; may present with paraneoplastic syndromes or symptoms of metastatic disease

─ Precursor lesions include Atypical Adenomatous Hyperplasia (AAH) and Adenocarcinoma in Situ (AIS); Minimally Invasive Adenocarcinoma (MIA) is an early invasive form

─ Invasive adenocarcinomas are subtyped by predominant histologic pattern (lepidic, acinar, papillary, micropapillary, solid) and include variants like invasive mucinous adenocarcinoma

Cytology

─ Cells are arranged in flat sheets, three-dimensional clusters, acini, papillae with or without fibrovascular cores, or micropapillary tufts; single malignant cells are also common; cellularity is often moderate to high

─ Cytoplasm is usually moderate to abundant, delicate, translucent, finely vacuolated (foamy), or granular; distinct mucin vacuoles (intracytoplasmic or pushing nucleus aside like signet-ring cells) may be present; cell borders can be distinct or ill-defined

─ Nuclei show round to oval or irregular contours; typically enlarged with an increased N:C ratio; chromatin is often finely to moderately granular, sometimes vesicular with parachromatin clearing; nucleoli are usually prominent, often single and central, but can be multiple or irregular; intranuclear pseudoinclusions and nuclear grooves may be seen

─ Background shows may be clean, contain mucin (especially in mucinous subtypes), or show necrosis/inflammatory cells in higher-grade or cavitating tumors; psammoma bodies can be seen with papillary patterns

─ Absence of extensive keratinization (unlike squamous cell carcinoma); absence of prominent nuclear molding and finely stippled "salt & pepper" chromatin with scant cytoplasm (unlike small cell carcinoma); absence of a definite biphasic population with chondromyxoid stroma (unlike hamartoma)

Ancillary studies

─ IHC (+): TTF-1 (most, ~75-85%, except some mucinous/enteric variants), Napsin A (most, similar sensitivity to TTF-1, but more specific for lung primary vs thyroid), CK7, CEA

─ IHC (-): p40, p63 (or only focal/weak), CK5/6 (usually), CK20 (except some mucinous/enteric variants, which can be CK20+ and TTF-1-), CDX2 (except enteric variant), Thyroglobulin, GATA3, Calretinin, WT1

─ Molecular ─ EGFR mutations (common in never-smokers, Asian ethnicity, women, lepidic/papillary patterns), ALK rearrangements (younger patients, never-smokers, solid/signet ring/mucinous patterns), ROS1 rearrangements, KRAS mutations (common in smokers, mucinous patterns), BRAF mutations, MET exon 14 skipping alterations, RET fusions, ERBB2 (HER2) mutations, NTRK fusions, PIK3CA mutations

DDx

─ Reactive bronchial epithelial cells/Creola bodies (cilia often present, less atypia, tight clustering, smooth nuclear contours)

─ Reactive type II pneumocytes (often in background of diffuse lung injury, less architectural complexity, uniform atypia, prominent nucleoli but smooth nuclear membranes)

─ Squamous cell carcinoma, poorly differentiated (p40/p63, CK5/6 positive; TTF-1/Napsin A negative)

─ Large cell neuroendocrine carcinoma (neuroendocrine markers positive, often high mitotic rate, coarser chromatin)

─ Carcinoid tumor (organoid pattern, salt-and-pepper chromatin, neuroendocrine markers positive)

─ Mesothelial cells/Malignant mesothelioma (especially peripheral lesions; mesothelioma is calretinin, WT-1, D2-40 positive, TTF-1/Napsin A negative, MOC31/BerEP4 negative)

─ Metastatic adenocarcinoma (clinical history and site-specific IHC markers: e g , CDX2 for colorectal, PAX8 for gynecologic/renal, GATA3/ER for breast, PSA for prostate)

─ Sclerosing pneumocytoma (dual population of surface cuboidal and stromal round cells, lacks significant atypia)

Prognosis

─ Variable; depends on stage, histologic subtype/grade (e g , micropapillary and solid patterns generally have poorer prognosis), and molecular profile (presence of targetable mutations offers specific therapeutic options)

─ AIS and MIA have excellent prognosis with complete resection

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Squamous Cell Carcinoma (Lung)

Clinical

-Strongly associated with smoking history; more common in men.

-Typically arises centrally in major bronchi, causing cough, hemoptysis, or post-obstructive pneumonia.

-Can also occur peripherally and may cavitate.

-Precursor lesions include squamous dysplasia and carcinoma in situ.

Cytology

-Cells appear as single cells or in irregular, syncytial-like sheets and clusters.

-Well-differentiated tumors show obvious keratinization with dense, refractile, eosinophilic or orangeophilic cytoplasm and bizarre shapes (tadpole, spindle, fiber cells); keratin pearls may be seen.

-Poorly-differentiated tumors show limited or no keratinization, with scant, dense, basophilic or amphophilic cytoplasm and less distinct cell borders.

-Nuclei show marked pleomorphism, hyperchromasia, and irregular, angulated contours; chromatin is coarsely granular or opaque.

-Prominent nucleoli can be seen, especially in poorly-differentiated forms.

-Background often contains a necrotic tumor diathesis, keratinous debris (anucleate squames), and acute inflammation.

Ancillary

-IHC (+): p40 (highly specific), p63, CK5/6, High Molecular Weight Cytokeratins (e.g., 34βE12).

-IHC (-): TTF-1, Napsin A, CK7 (usually), Neuroendocrine markers (Chromogranin, Synaptophysin).

DDx

-Reactive squamous metaplasia/atypia (less pleomorphism, smoother nuclear contours, lacks tumor diathesis).

-Poorly differentiated non-small cell carcinoma (requires IHC for definitive classification).

-Adenocarcinoma (TTF-1/Napsin A positive; may have squamous metaplasia).

-Large cell neuroendocrine carcinoma (positive neuroendocrine markers, prominent nucleoli).

-Small cell carcinoma (finer chromatin, nuclear molding, scant cytoplasm, positive neuroendocrine markers).

-Metastatic squamous cell carcinoma (clinical history is crucial; p16 may be helpful).

-Large cell lymphoma (dispersed single cells, lymphoid markers positive).

-Melanoma (S100/SOX10/Melan-A positive, prominent nucleoli).

Prognosis

-Primarily dependent on stage.

-Poorly differentiated tumors generally have a worse prognosis than well-differentiated tumors of the same stage.

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Neuroendocrine tumor / Carcinoid (Lung)

A relatively low-grade malignant epithelial neoplasm with neuroendocrine differentiation, subdivided histologically into typical carcinoid (low-grade) and atypical carcinoid (intermediate-grade) based on mitotic activity and presence of necrosis

Clinical

─ Epid: Typically adults, mean age 50s, but can occur in adolescence; atypical carcinoids tend to occur in slightly older patients

─ Etio: Typical carcinoids are generally not related to smoking; atypical carcinoids have a stronger association with smoking

─ Site: Central (endobronchial or peribronchial, ~75-80%) > peripheral (intraparenchymal, ~20-25%); atypical carcinoids are more often peripheral

─ Clin: Often asymptomatic (incidental finding); symptomatic cases (especially central) may present with cough, hemoptysis, wheezing, post-obstructive pneumonia; hormonal or paraneoplastic syndromes (e g , carcinoid syndrome, Cushing syndrome) are uncommon with pulmonary carcinoids (<5%)

─ Imaging: Central lesions are often well-defined, round to oval endobronchial nodules or peribronchial masses; Peripheral lesions are typically sharply circumscribed solitary nodules

Cytology

─ Cells are relatively uniform, small to medium-sized, round, oval, or occasionally spindled (especially peripheral tumors); arranged in loose clusters, sheets, trabeculae, acinar structures, pseudorosettes, or as dispersed single cells; cellularity is often high

─ Cytoplasm is scant to moderate, finely granular (eosinophilic with H&E/Pap, grey-blue with Pap, magenta with Giemsa), often with eccentrically placed nuclei giving a plasmacytoid appearance; cell borders are usually indistinct

─ Nuclei show monotonous, round to oval features with smooth contours; chromatin is characteristically finely granular, stippled ("salt and pepper" appearance); nucleoli are typically small and inconspicuous (may be more prominent in atypical carcinoid)

─ Background shows often clean or may contain stripped bare nuclei; branching, thin fibrovascular strands with attached tumor cells may be seen; significant necrosis is absent in typical carcinoid but may be present (usually focal) in atypical carcinoid

─ Absence of extensive nuclear molding, significant crush artifact, or widespread necrosis (unlike small cell carcinoma or LCNEC); absence of high-grade pleomorphism

Ancillary studies

─ IHC (+): Synaptophysin (diffuse), Chromogranin A (often patchy), CD56 (NCAM), Cytokeratins (AE1/AE3, CAM5.2, often dot-like), TTF-1 (positive in ~50-70%, more often in peripheral tumors and atypical carcinoids)

─ IHC (-): p40, p63, Napsin A

─ Note: Ki-67 proliferation index is low in typical carcinoid (<2-5%), higher in atypical carcinoid (up to 20%, but generally <10% by cytology criteria if assessable); mitotic counts are difficult and often not validated for cytologic assessment (<2 mitoses/2mm² and no necrosis for typical; 2-10 mitoses/2mm² OR necrosis for atypical, histologically)

─ Mol: No specific molecular alterations are routinely tested for therapeutic targets in typical/atypical carcinoids

DDx

─ Small cell lung carcinoma (more atypia, nuclear molding, crush artifact, high Ki-67, often scantier cytoplasm, different IHC profile for TTF-1 which is usually strong, and p53 aberrant expression)

─ Large cell neuroendocrine carcinoma (larger cells, more pleomorphism, prominent nucleoli, higher mitotic rate, more necrosis)

─ Adenocarcinoma (glandular structures, mucin, TTF-1/Napsin A positive, neuroendocrine markers negative)

─ Lymphoma/Lymphoid hyperplasia (dispersed lymphoid cells, lymphoglandular bodies, CD45 positive, keratin/neuroendocrine markers negative)

─ Basal cell hyperplasia/Reserve cell hyperplasia (tight clusters, scant cytoplasm, but more regular nuclei and associated with bronchial epithelium, p40 positive)

─ Metastatic neuroendocrine tumor (clinical history, IHC profile may vary e g , CDX2 for GI, PAX8/Islet-1 for pancreatic)

Prognosis

─ Typical carcinoid: Excellent prognosis, >90% 5-year survival; metastases are rare (<15%, usually to regional lymph nodes)

─ Atypical carcinoid: Intermediate prognosis, ~40-70% 5-year survival; higher risk of lymph node and distant metastases (~20-50%)

─ Mitotic counts and necrosis are key prognostic factors but are best assessed on histology

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Small cell neuroendocrine carcinoma (Lung)

A high-grade neuroendocrine carcinoma composed of small cells with scant cytoplasm, finely granular chromatin, absent or inconspicuous nucleoli, and frequent mitoses and necrosis; strongly associated with smoking

Aka ─ Oat cell carcinoma

Clinical

─ Etio: Strongly associated with cigarette smoking (>95% of cases); rarely, may arise as a transformation mechanism of TKI resistance in EGFR-mutated NSCLC

─ Epid: Represents ~13-15% of all lung cancers; incidence has been declining in some regions with decreased smoking rates

─ Site: Typically central, arising from major bronchi, but can be peripheral

─ Clin: Aggressive clinical course, often presents with advanced (metastatic) disease at diagnosis; common sites of metastases include brain, liver, bone, adrenals, contralateral lung; frequently associated with paraneoplastic syndromes (e g , SIADH, Cushing syndrome due to ectopic ACTH, Lambert-Eaton myasthenic syndrome)

─ Imaging: Often large central mass with extensive mediastinal/hilar lymphadenopathy; peripheral nodules less common

Cytology

─ Cells are small (typically 2-3 times the size of a mature lymphocyte), round, oval, or spindled, often arranged in loose clusters, sheets, linear arrays (Indian filing), or as dispersed single cells; nuclear molding is a characteristic feature in cell groups; crush artifact is common

─ Cytoplasm is very scant, often appearing as a thin rim or inapparent, leading to high N:C ratios and "naked nuclei" appearance

─ Nuclei show round to oval or angulated/irregular contours; chromatin is finely granular ("salt and pepper") to coarsely granular or smudged/pyknotic, especially in degenerated cells or due to crush artifact; nucleoli are usually absent or inconspicuous, if present they are small

─ Background shows often necrotic (tumor diathesis), with granular debris and apoptotic bodies; Azzopardi phenomenon (basophilic staining of vascular walls by DNA from necrotic tumor cells) may be seen

─ Absence of prominent nucleoli, abundant cytoplasm, or distinct glandular/squamous differentiation (though combined SCLC with NSCLC components can occur)

Ancillary studies

─ IHC (+): Synaptophysin, Chromogranin A (often focal), CD56 (NCAM), TTF-1 (most cases, ~85-90%), Cytokeratins (AE1/AE3, CAM5.2, often with a perinuclear dot-like pattern); Ki-67 proliferation index is very high (typically >70-80%, often approaching 100%); aberrant p53 expression (overexpression or null pattern) is common

─ IHC (-): p40, p63 (or only rare scattered positive cells), Napsin A, CD45 (LCA), S100 protein

─ Mol: RB1 inactivation (mutation or deletion) and TP53 mutations are nearly ubiquitous; other alterations (e g , MYC family amplification, CREBBP/EP300 mutations) are common but not currently used for routine targeted therapy decisions

DDx

─ Carcinoid tumor (more cytoplasm, more organoid patterns, less atypia, no/rare molding, lower Ki-67)

─ Large cell neuroendocrine carcinoma (larger cells, more cytoplasm, often prominent nucleoli)

─ Basaloid squamous cell carcinoma (more cohesive, peripheral palisading, p40/p63 positive, neuroendocrine markers negative)

─ Lymphoma (dispersed cells, lymphoglandular bodies, CD45 positive, keratin/neuroendocrine markers negative)

─ Reserve cell hyperplasia (tight cohesive clusters, associated with bronchial cells, lacks necrosis and high Ki-67)

─ Crushed benign bronchial cells or lymphocytes (can mimic SCLC, but benign cells lack true atypia and high Ki-67; lymphocytes CD45+)

─ Metastatic small cell carcinoma (from other sites like prostate, bladder, cervix; clinical history and IHC for site-specific markers if applicable, e g , PSA for prostate)