Main Document

Endocrine Pathology

Table of Contents

Table of Contents

Pituitary Gland

Normal Pituitary Histology

Pituitary Adenoma (Pituitary Neuroendocrine Tumor - PitNET)

Lactotroph Adenoma (Prolactinoma)

Somatotroph Adenoma (GH Adenoma)

Corticotroph Adenoma

Thyrotroph Adenoma

Gonadotroph Adenoma

Null Cell Adenoma

Plurihormonal Pituitary Adenoma

Pituitary Carcinoma

Adamantinomatous Craniopharyngioma

Papillary Craniopharyngioma

Pituicytoma

Granular Cell Tumor of the Sellar Region

Spindle Cell Oncocytoma (of the Adenohypophysis)

Pituitary Gangliocytoma (including mixed Gangliocytoma-PitNET)

Sellar Neurocytoma and Neuroblastoma

Inflammatory Lesions of the Pituitary (Hypophysitis)

Rathke's Cleft Cyst

Empty Sella Syndrome

Metastases to Pituitary

Pineal Gland

Normal Pineal Gland Histology

Pineal Cysts

Pineocytoma

Pineoblastoma

Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID)

Papillary Tumor of the Pineal Region (PTPR)

Germ Cell Tumors of Pineal Region

Germinoma (of Pineal Region)

Embryonal Carcinoma (of Pineal Region)

Yolk Sac Tumor (Endodermal Sinus Tumor, of Pineal Region)

Choriocarcinoma (of Pineal Region)

Teratoma (of Pineal Region)

Normal Thyroid Histology & Developmental Anomalies

Solid Cell Nests (SCN)

Ectopic Thyroid (including Lingual Thyroid)

Thyroglossal Duct Cyst

Branchial Cleft Cyst

Bronchogenic Cyst

Follicular Nodular Disease (Multinodular Goiter, Adenomatoid Nodule)

Acute Thyroiditis (Suppurative Thyroiditis, Infectious Thyroiditis)

Granulomatous (De Quervain) Thyroiditis (Subacute Thyroiditis)

Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis, Autoimmune Thyroiditis)

Riedel Thyroiditis (Invasive Fibrous Thyroiditis, Struma Fibrosa)

Focal Lymphocytic Thyroiditis

Postpartum Thyroiditis

Silent Thyroiditis (Painless Thyroiditis, Lymphocytic Thyroiditis with Spontaneously Resolving Hyperthyroidism)

Palpation Thyroiditis (Multifocal Granulomatous Folliculitis)

Graves' Disease (Diffuse Toxic Goiter)

Pituitary Gland

Normal Pituitary Histology

The pituitary gland, or hypophysis, is a neuroendocrine organ located at the base of the brain, composed of the anterior adenohypophysis and the posterior neurohypophysis, responsible for regulating multiple endocrine functions
Clinical ─ Essential for homeostasis, regulating stress, growth, reproduction, and lactation; dysfunction leads to a wide range of endocrine disorders
Macro ─ Small, bean-shaped gland, ~1 cm in diameter, weighing ~0.5-1.0 g; sits in the sella turcica of the sphenoid bone; connected to the hypothalamus by the pituitary stalk
Micro ─

Adenohypophysis (Anterior Lobe):
─ Composed of nests and acini of epithelial cells interspersed with a rich sinusoidal capillary network
─ Cells are traditionally classified based on tinctorial properties (acidophils, basophils, chromophobes) and more accurately by immunohistochemistry for specific hormones
─ Acidophils:
─ Somatotrophs: Secrete growth hormone (GH), typically ~50% of cells, often in lateral wings
─ Lactotrophs (Mammotrophs): Secrete prolactin (PRL), ~15-20% of cells, increase in pregnancy
─ Basophils:
─ Corticotrophs: Secrete adrenocorticotropic hormone (ACTH), proopiomelanocortin (POMC), melanocyte-stimulating hormone (MSH), endorphins; ~15-20% of cells, often in mucoid wedge (pars intermedia remnants may show basophilic invasion)
─ Thyrotrophs: Secrete thyroid-stimulating hormone (TSH), ~5% of cells, often anteromedial
─ Gonadotrophs: Secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), ~10% of cells, scattered
─ Chromophobes: Cells with pale cytoplasm, may represent degranulated cells, stem cells, or follicular cells
─ Folliculostellate cells: Sustentacular, non-hormone producing, S100 positive, form small follicles

Pars Intermedia:
─ Rudimentary in humans, located between anterior and posterior lobes
─ Contains colloid-filled cysts (Rathke's cysts remnants) and basophilic cells (corticotrophs) that may infiltrate the neurohypophysis (basophil invasion)

Neurohypophysis (Posterior Lobe, Pars Nervosa):
─ Composed of unmyelinated axons of neurosecretory cells whose cell bodies are in the supraoptic and paraventricular nuclei of the hypothalamus
─ Pituicytes: Modified glial cells (astrocytes), supportive function, GFAP positive
─ Herring bodies: Eosinophilic, granular axonal swellings containing stored vasopressin (ADH) and oxytocin
─ Does not synthesize hormones but stores and releases them

Infundibulum (Pituitary Stalk):
─ Connects pituitary to hypothalamus; contains axons from hypothalamus to posterior pituitary and portal vessels for anterior pituitary regulation

Ancillary studies ─

─ IHC (+)
─ Adenohypophysis: Synaptophysin, chromogranin (variable), specific hormones (GH, PRL, ACTH, TSH, LH, FSH), transcription factors (Pit-1 for GH, PRL, TSH; SF-1 for gonadotrophs; TPIT for corticotrophs)
─ Folliculostellate cells: S100, cytokeratin
─ Neurohypophysis: GFAP (pituicytes), neurofilament (axons), synaptophysin (neurosecretory granules)
─ IHC (-)
─ Hormone-producing cells are generally negative for high molecular weight cytokeratins (distinction from some carcinomas)
─ Molecular ─ Not typically used for normal histology assessment, but critical for tumor classification

DDx ─

─ Pituitary adenoma (distinguished by monoclonal expansion of one cell type, loss of reticulin network architecture)
─ Craniopharyngioma (epithelial tumor with distinct features like wet keratin, palisading, calcification)
─ Pituicytoma (tumor of pituicytes in neurohypophysis)

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Pituitary Adenoma (Pituitary Neuroendocrine Tumor - PitNET)

Benign glandular neoplasms of the adenohypophysis, representing the most common cause of pituitary hyperfunction or hypofunction in adults
Clinical ─ Symptoms vary based on hormone produced (hyperpituitarism) or mass effect (hypopituitarism, visual disturbances, headaches); can be functional or non-functional; incidental findings in ~10-20% of autopsies/radiologic studies; associations include MEN1, Carney complex, familial isolated pituitary adenoma (FIPA)
Macro ─ Typically well-circumscribed, soft, tan-gray tumors; <1 cm (microadenoma) or ≥1 cm (macroadenoma); large tumors can compress optic chiasm or invade surrounding structures (cavernous sinus, sphenoid sinus)
Micro ─

General Features:
─ Monomorphic proliferation of polygonal cells arranged in sheets, nests, cords, papillae, or diffuse patterns
─ Uniform, round to oval nuclei with stippled (salt-and-pepper) chromatin; cytoplasm can be acidophilic, basophilic, or chromophobic depending on cell type and granulation
─ Loss of the normal acinar architecture and reticulin network (reticulin stain shows disruption/loss of normal acinar pattern, with elongated or collapsed fibers around tumor cell groups rather than individual acini)
─ Stroma is typically scant with a rich capillary network
─ Cellular pleomorphism, nuclear atypia, and mitoses can be seen but do not reliably predict aggressive behavior or malignancy
─ Densely granulated adenomas: Abundant eosinophilic or basophilic cytoplasm
─ Sparsely granulated adenomas: Pale or chromophobic cytoplasm
─ Fibrosis can be prominent, especially after treatment or hemorrhage (pituitary apoplexy)
─ Calcification is uncommon but can occur (e.g., in prolactinomas, especially after treatment)
─ Amyloid deposition can be seen, particularly in prolactinomas

Ancillary studies ─

─ IHC (+)
─ General neuroendocrine markers: Synaptophysin, Chromogranin A (often weaker in sparsely granulated adenomas), Neuron-specific enolase (NSE)
─ Pituitary hormones: GH, PRL, ACTH, TSH, FSH, LH (alpha-subunit often positive in gonadotroph and null cell adenomas)
─ Transcription factors for cell lineage:
─ Pit-1 (POU1F1): For somatotroph, lactotroph, thyrotroph, and plurihormonal Pit-1 lineage adenomas
─ SF-1 (Steroidogenic Factor 1): For gonadotroph adenomas
─ TPIT (T-box pituitary transcription factor): For corticotroph adenomas
─ Cytokeratins: CAM5.2 or other low molecular weight cytokeratins usually positive
─ Ki-67 (MIB-1): Proliferation index, typically low (<3%); higher in atypical adenomas or pituitary carcinomas
─ IHC (-)
─ GFAP (negative, helps distinguish from pituicytoma or glioma)
─ S100 (usually negative in adenoma cells, but positive in entrapped folliculostellate cells)
─ High molecular weight cytokeratins (usually negative)
─ TTF-1 (negative, distinguishes from pituicytoma in some contexts)
─ Molecular ─
GNAS activating mutations: Common in densely granulated somatotroph adenomas (McCune-Albright syndrome)
MEN1 gene mutations: Associated with MEN1 syndrome
AIP gene mutations: Associated with FIPA, often somatotroph or lactotroph adenomas in younger patients
─ Other genes implicated in some adenomas:
USP8 (corticotroph adenomas), PRKAR1A (Carney complex)

DDx ─

─ Normal pituitary gland (polymorphous cell population, intact reticulin network)
─ Pituitary hyperplasia (polyclonal proliferation, preserved acinar architecture)
─ Pituitary carcinoma (metastases required for diagnosis; higher Ki-67, more atypia, p53 often positive)
─ Pituicytoma (GFAP positive, derived from pituicytes of neurohypophysis)
─ Granular cell tumor of sellar region (S100 positive, PAS-diastase resistant granules)
─ Craniopharyngioma (biphasic pattern, wet keratin, calcification, β-catenin nuclear positivity in adamantinomatous type; BRAF V600E in papillary type)
─ Meningioma (EMA positive, SSTR2A positive, characteristic whorls, psammoma bodies)
─ Lymphoma (CD45 positive, specific lymphoid markers)
─ Metastasis (history of primary malignancy, often atypical cytology, CK7/CK20 profile can help)

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Lactotroph Adenoma (Prolactinoma)

A benign neuroendocrine tumor of the anterior pituitary composed of lactotroph cells, characterized by prolactin (PRL) production, and is the most common type of functional pituitary adenoma
Clinical ─ Females: amenorrhea, galactorrhea, infertility; Males: decreased libido, erectile dysfunction, visual disturbances, headaches (often macroadenomas); Hyperprolactinemia; most are microadenomas in females, macroadenomas in males; responds well to dopamine agonists (e.g., bromocriptine, cabergoline)
Macro ─ Microadenomas (<1 cm) are typically laterally located; macroadenomas (≥1 cm) can be large and locally invasive; may be soft and tan to red-brown; cystic changes or calcification (psammoma bodies, "pituitary stone") can occur, especially after treatment
Micro ─

Two main histological patterns:
─ Sparsely granulated lactotroph adenoma:
─ Most common type
─ Sheets or trabeculae of chromophobic cells with round, vesicular nuclei and inconspicuous nucleoli
─ Cytoplasm is pale, weakly acidophilic or chromophobic
─ Paranuclear Golgi prominence (juxtanuclear TSH immunoreactivity due to mis-shapen PRL) may be seen
─ Amyloid deposition is relatively common
─ Psammoma bodies may be present, especially in treated cases
─ Densely granulated lactotroph adenoma:
─ Less common
─ Cells are more acidophilic with granular cytoplasm
─ Diffuse cytoplasmic PRL staining
─ Resembles densely granulated somatotroph adenoma but distinguished by IHC for PRL

Other features:
─ Fibrosis can be prominent, particularly in treated tumors
─ Rarely, "acidophil stem cell adenoma" is a distinct bimorphous variant with features of both lactotroph and somatotroph differentiation, often aggressive

Ancillary studies ─

─ IHC (+)
─ Prolactin (PRL): Diffuse in densely granulated type; focal, often with paranuclear "Golgi pattern" in sparsely granulated type
─ Pit-1 (transcription factor): Nuclear positivity
─ CAM5.2 (low molecular weight cytokeratin)
─ Synaptophysin (may be weak or focal)
─ Chromogranin A (often weak or negative in sparsely granulated type, more positive in densely granulated type)
─ IHC (-)
─ Other pituitary hormones (GH, ACTH, TSH, LH, FSH) are typically negative, except in plurihormonal adenomas or acidophil stem cell adenoma (which shows GH co-expression)
─ SF-1, TPIT
─ Molecular ─
─ No specific recurrent mutations are diagnostic for typical lactotroph adenomas
MEN1 gene mutations in MEN1 syndrome context
AIP gene mutations in some familial cases (FIPA)

DDx ─

─ Other pituitary adenoma types (especially sparsely granulated somatotroph or null cell adenoma; distinguished by IHC)
─ Lactotroph hyperplasia (e.g., during pregnancy, estrogen therapy, hypothyroidism; polyclonal, preserved reticulin network)
─ Normal anterior pituitary (polymorphous population, intact reticulin)
─ Lymphocytic hypophysitis (inflammatory infiltrate, may cause hyperprolactinemia via stalk effect)

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Somatotroph Adenoma (GH Adenoma)

A benign neuroendocrine tumor of the anterior pituitary composed of somatotroph cells, characterized by autonomous growth hormone (GH) secretion, leading to acromegaly in adults or gigantism in children
Clinical ─ Acromegaly: coarse facial features, enlarged hands and feet, prognathism, arthralgias, carpal tunnel syndrome, diabetes mellitus, hypertension, cardiomegaly; Gigantism: excessive growth if occurs before epiphyseal closure; Elevated serum GH and IGF-1 levels; often macroadenomas
Macro ─ Typically macroadenomas (≥1 cm), may be invasive; cut surface is often pink-tan and fleshy; can be firm or soft
Micro ─

Two main histological patterns:
─ Densely granulated somatotroph adenoma:
─ Cells are usually acidophilic with abundant granular cytoplasm, arranged in diffuse or sinusoidal patterns
─ Nuclei are round, centrally located, with prominent nucleoli
─ Strong and diffuse GH immunoreactivity
─ Often associated with
GNAS mutations
─ Sparsely granulated somatotroph adenoma:
─ Cells are chromophobic or weakly acidophilic with less granular cytoplasm
─ Nuclei may be more pleomorphic, and nucleoli can be prominent
─ Often show a characteristic "fibrous body" – a paranuclear aggregate of cytokeratin filaments (Type I and II CAM5.2 positive), which is a hallmark
─ GH immunoreactivity may be focal or diffuse, but often less intense than densely granulated type
─ Generally more aggressive behavior than densely granulated type and less likely to have
GNAS mutations

Other features:
─ Mixed somatotroph-lactotroph adenomas: Co-express GH and PRL, often with features of both cell types
─ Mammosomatotroph adenoma: A monomorphous adenoma with cells co-expressing GH and PRL, typically densely granulated
─ Acidophil stem cell adenoma: Rare, aggressive, bi-hormonal (PRL and GH) sparsely granulated tumor with oncocytic features and giant mitochondria, often invasive

Ancillary studies ─

─ IHC (+)
─ Growth Hormone (GH): Diffuse in densely granulated, may be focal in sparsely granulated
─ Pit-1 (transcription factor): Nuclear positivity
─ CAM5.2 (low molecular weight cytokeratin): Cytoplasmic staining; highlights fibrous bodies in sparsely granulated type
─ Prolactin (PRL): May be co-expressed in mixed adenomas or mammosomatotroph adenomas
─ Alpha-subunit: Can be positive
─ Synaptophysin, Chromogranin A (often stronger in densely granulated type)
─ IHC (-)
─ ACTH, TSH, LH, FSH (except in plurihormonal adenomas)
─ SF-1, TPIT
─ Molecular ─
GNAS activating mutations (Arg201 or Gln227): Common in densely granulated somatotroph adenomas (~40%), less common in sparsely granulated type
AIP gene mutations: Associated with FIPA, often younger patients with somatotroph adenomas (pituitary gigantism)
MEN1 gene mutations in MEN1 syndrome context

DDx ─

─ Other pituitary adenoma types (especially lactotroph or null cell adenoma; distinguished by IHC for hormones and transcription factors)
─ Somatotroph hyperplasia (rare, may be associated with GHRH-producing tumors; polyclonal, preserved reticulin)
─ Normal anterior pituitary

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Corticotroph Adenoma

A benign neuroendocrine tumor of the anterior pituitary composed of corticotroph cells, characterized by ACTH production, leading to Cushing's disease (if pituitary source) or Nelson syndrome (if develops after bilateral adrenalectomy)
Clinical ─ Cushing's disease: central obesity, moon facies, buffalo hump, skin striae, hypertension, hyperglycemia, osteoporosis, psychiatric changes; Nelson syndrome: hyperpigmentation, visual field defects, headaches due to large tumor mass; Elevated serum ACTH and cortisol (in Cushing's), or very high ACTH (in Nelson's); most are microadenomas in Cushing's disease, macroadenomas in Nelson syndrome
Macro ─ Microadenomas (<1 cm) are common for Cushing's disease, often basophilic and centrally located; Macroadenomas (≥1 cm) are typical for Nelson syndrome, may be invasive and hemorrhagic
Micro ─

Three main histological patterns:
─ Densely granulated corticotroph adenoma:
─ Most common type
─ Cells are typically basophilic (due to POMC glycoprotein), with granular cytoplasm, arranged in sheets, nests, or sinusoidal patterns
─ Nuclei are round to oval, often with prominent nucleoli
─ PAS positivity (cytoplasmic granules) is characteristic
─ Strong and diffuse ACTH immunoreactivity
─ Sparsely granulated corticotroph adenoma:
─ Cells are chromophobic or pale basophilic with less granular cytoplasm
─ May be associated with more aggressive behavior
─ ACTH immunoreactivity can be focal
─ Crooke's cell adenoma:
─ Rare variant, composed predominantly of Crooke's cells (corticotrophs with peripheral hyaline cytoplasmic ring due to accumulation of cytokeratin filaments, a change induced by high glucocorticoid levels)
─ Ironically, these adenomas themselves may be functional or silent; the Crooke's hyaline change indicates exposure to high cortisol, either endogenous from the tumor or exogenous
─ Often clinically silent or less aggressive despite the hyalinization if the tumor cells themselves show this change

Silent Corticotroph Adenomas:
─ Immunoreactive for ACTH but without clinical Cushing's disease; can be densely or sparsely granulated; may present with mass effects or be incidental findings

Other features:
─ Basophilic invasion of the posterior lobe is common
─ Nelson syndrome tumors are often large, pleomorphic, and may have higher mitotic activity

Ancillary studies ─

─ IHC (+)
─ ACTH (Adrenocorticotropic hormone): Usually strong and diffuse in densely granulated type
─ POMC (Pro-opiomelanocortin), MSH (Melanocyte-stimulating hormone), Endorphins
─ TPIT (T-box pituitary transcription factor): Nuclear positivity, specific for corticotroph lineage
─ CAM5.2 (low molecular weight cytokeratin): Highlights Crooke's hyaline change (ring-like perinuclear staining)
─ PAS (Periodic Acid-Schiff): Cytoplasmic positivity in densely granulated cells
─ Synaptophysin, Chromogranin A
─ IHC (-)
─ GH, PRL, TSH, LH, FSH (except in rare plurihormonal adenomas)
─ Pit-1, SF-1
─ Molecular ─
USP8 mutations: Found in a subset of corticotroph adenomas causing Cushing's disease (somatic, activating)
─ Somatic mutations in
USP48 and BRAF have also been reported in a smaller fraction
MEN1 gene mutations (rarely cause corticotroph adenomas)

DDx ─

─ Other pituitary adenoma types (distinguished by IHC for hormones and transcription factors)
─ Corticotroph hyperplasia (rare, can be diffuse or nodular; polyclonal, preserved reticulin)
─ Crooke's hyaline change in non-neoplastic corticotrophs adjacent to any cortisol-producing adrenal tumor or due to exogenous steroids (cells are not neoplastic)
─ Lymphocytic hypophysitis (inflammatory infiltrate, may rarely involve ACTH cells)

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Thyrotroph Adenoma

A rare benign neuroendocrine tumor of the anterior pituitary composed of thyrotroph cells, characterized by TSH (Thyroid Stimulating Hormone) production, which can lead to hyperthyroidism
Clinical ─ Symptoms of hyperthyroidism (goiter, tachycardia, weight loss, tremor, heat intolerance) with inappropriately normal or elevated TSH levels; may also present with mass effects (visual disturbances, headaches) if large; often macroadenomas and can be invasive; can be associated with longstanding primary hypothyroidism (as a secondary hyperplasia/adenoma)
Macro ─ Usually macroadenomas (≥1 cm) at diagnosis; may appear whitish or tan, often firm and fibrous; can invade surrounding structures like the cavernous sinus or sphenoid bone
Micro ─

─ Cells are typically chromophobic or pale basophilic, arranged in sheets, cords, or trabecular patterns
─ Nuclei are often angular or irregular, and cytoplasm is usually scant and pale
─ Prominent stromal fibrosis and perivascular fibrosis are characteristic features, contributing to their firm consistency
─ Cells may appear spindled in areas with significant fibrosis
─ Some degree of nuclear pleomorphism can be present
─ Ultrastructurally, neoplastic thyrotrophs have small, sparse secretory granules (average 100-150 nm)

Ancillary studies ─

─ IHC (+)
─ TSH-beta (Thyroid Stimulating Hormone beta subunit): Essential for diagnosis, often focally positive and may require careful searching; staining can be weak
─ Alpha-subunit (glycoprotein hormone alpha subunit): Often more strongly and diffusely positive than TSH-beta
─ Pit-1 (transcription factor): Nuclear positivity (shared with somatotrophs and lactotrophs)
─ Synaptophysin, Chromogranin A (may be focal)
─ CAM5.2 (low molecular weight cytokeratin)
─ IHC (-)
─ GH, PRL, ACTH, LH, FSH (except in rare plurihormonal adenomas)
─ SF-1, TPIT
─ Molecular ─
─ No specific recurrent mutations are consistently associated with sporadic thyrotroph adenomas
─ Mutations in the thyroid hormone receptor gene (TRβ) can cause resistance to thyroid hormone, leading to TSH elevation and potential thyrotroph hyperplasia/adenoma (rare cause)
MEN1 gene mutations in MEN1 syndrome context (thyrotroph adenomas are rare in MEN1)

DDx ─

─ Other pituitary adenoma types, especially null cell adenoma or gonadotroph adenoma (immunostains are crucial; TSH-beta is key)
─ Thyrotroph hyperplasia (secondary to primary hypothyroidism; diffuse enlargement, cells are polyclonal, reticulin network usually preserved, lacks prominent fibrosis of adenoma)
─ Lymphocytic hypophysitis (inflammatory infiltrate)
─ Pituitary involvement by Graves' disease (extremely rare, TSH receptor antibodies might theoretically stimulate thyrotrophs)

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Gonadotroph Adenoma

A common type of pituitary neuroendocrine tumor composed of gonadotroph cells, typically producing follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) and/or alpha-subunit (α-SU); often clinically non-functioning or silent
Clinical ─ Most are clinically non-functioning despite hormone production (hormones may be inefficiently secreted, biologically inactive, or secreted in insufficient amounts to cause a clinical syndrome); often present late as macroadenomas with mass effects (visual disturbances, headaches, hypopituitarism); Occasionally, may cause ovarian hyperstimulation in premenopausal women (rare) or testicular enlargement in men; men may experience decreased libido or impotence due to hypogonadism from pituitary compression rather than hormone excess
Macro ─ Usually macroadenomas (≥1 cm) at diagnosis; typically soft, tan-gray, and may show cystic change or hemorrhage
Micro ─

─ Cells are typically chromophobic, arranged in diffuse, trabecular, or papillary patterns; a pseudorosette pattern around blood vessels is common
─ Nuclei are usually round to oval, with finely stippled chromatin; nucleoli are generally inconspicuous
─ Cytoplasm is scant and pale; oncocytic change (abundant granular eosinophilic cytoplasm due to mitochondrial accumulation) is common, especially in older males
─ Some tumors may exhibit significant nuclear pleomorphism, but this does not necessarily correlate with aggressive behavior
─ Sparsely granulated appearance is typical

Ancillary studies ─

─ IHC (+)
─ FSH-beta (Follicle-Stimulating Hormone beta subunit): Positive in a majority, can be diffuse or focal
─ LH-beta (Luteinizing Hormone beta subunit): Positive in a subset, often less frequent or intense than FSH
─ Alpha-subunit (α-SU): Often strongly and diffusely positive, common to many gonadotroph adenomas
─ SF-1 (Steroidogenic Factor 1): Nuclear positivity, specific for gonadotroph lineage
─ Synaptophysin, Chromogranin A (often focal or weak, consistent with sparse granulation)
─ CAM5.2 (low molecular weight cytokeratin)
─ Estrogen Receptor (ER): Often positive, particularly in females
─ IHC (-)
─ GH, PRL, ACTH, TSH (except in plurihormonal adenomas)
─ Pit-1, TPIT
─ Molecular ─
─ No specific, consistent driver mutations are well-established for most sporadic gonadotroph adenomas
MEN1 gene mutations in MEN1 syndrome context

DDx ─

─ Null cell adenoma (immunohistochemically negative for all pituitary hormones including FSH/LH/alpha-subunit, but may be SF-1 positive if of gonadotroph lineage but not expressing hormones; distinction can be challenging)
─ Other pituitary adenoma types (especially sparsely granulated variants; distinguished by IHC for hormones and transcription factors)
─ Lymphocytic hypophysitis (inflammatory infiltrate, may mimic non-functioning adenoma clinically)
─ Pituicytoma (GFAP positive)

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Null Cell Adenoma

A pituitary neuroendocrine tumor that shows no immunohistochemical evidence of specific pituitary hormone production (GH, PRL, ACTH, TSH, FSH, LH, alpha-subunit) using standard antibodies, and lacks clinical symptoms of hormone hypersecretion
Clinical ─ Clinically non-functioning; typically present as macroadenomas with symptoms of mass effect (visual disturbances, headaches, hypopituitarism) or are found incidentally; represent a significant proportion of surgically resected pituitary adenomas
Macro ─ Usually macroadenomas (≥1 cm); appear tan-gray and can be soft or firm; cystic changes or hemorrhage may be present
Micro ─

─ Cells are typically chromophobic with scant cytoplasm, arranged in diffuse sheets, trabeculae, or nests
─ Nuclei are generally uniform, round to oval, with finely granular chromatin; nucleoli are usually not prominent
─ Oncocytic change (abundant granular eosinophilic cytoplasm due to mitochondria accumulation) is very common, leading to the term "pituitary oncocytoma" for null cell adenomas with extensive oncocytic features
─ Fibrosis can be variable
─ May show some nuclear pleomorphism, but usually low mitotic activity

Ancillary studies ─

─ IHC (+)
─ General neuroendocrine markers: Synaptophysin, Chromogranin A (often weak or focal)
─ CAM5.2 (low molecular weight cytokeratin)
─ Transcription factors:
─ Some null cell adenomas may express SF-1, suggesting a silent gonadotroph lineage that has lost hormone expression capability or produces hormones below detectable levels
─ Most are negative for Pit-1 and TPIT
─ IHC (-)
─ All specific pituitary hormones: GH, PRL, ACTH, TSH, FSH-beta, LH-beta, Alpha-subunit (by definition using a standard panel)
─ S100 (adenoma cells are negative; positive in entrapped folliculostellate cells)
─ GFAP
─ Molecular ─
─ No specific or consistent genetic signature is well-defined for null cell adenomas as a group
─ Some may share genetic alterations with gonadotroph adenomas if they represent a terminal differentiation of that lineage

DDx ─

─ Gonadotroph adenoma (especially sparsely granulated or silent variants; extensive IHC panel including SF-1 is needed; some SF-1 positive "null cell" adenomas are truly of gonadotroph lineage)
─ Other non-functioning or sparsely granulated pituitary adenoma types (careful IHC required)
─ Pituicytoma (GFAP positive, S100 positive)
─ Granular cell tumor of the sellar region (S100 positive, PAS-diastase resistant granules)
─ Metastatic carcinoma (history, atypia, CK7/CK20 profile)

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Plurihormonal Pituitary Adenoma

A pituitary neuroendocrine tumor characterized by the immunohistochemical expression of more than one pituitary hormone not typically found in a single cell lineage, or hormones from different transcription factor lineages
Clinical ─ Clinical presentation varies widely depending on the combination and amount of hormones produced and secreted; can be clinically functional (causing syndromes like acromegaly with hyperprolactinemia) or clinically silent despite hormone expression; often macroadenomas
Macro ─ Variable, often macroadenomas; appearance similar to other pituitary adenomas
Micro ─

─ Histology is highly variable, reflecting the diverse combinations of hormones
─ Can be monomorphous (one cell type appearing to produce multiple hormones) or plurimorphous (distinct cell populations each producing different hormones within the same tumor)
─ Cytoplasmic characteristics (acidophilic, basophilic, chromophobic) depend on the hormones being expressed and granulation state
─ Common combinations include GH and PRL (somatotroph-lactotroph lineage, often Pit-1 positive)
─ Unusual combinations involve hormones from different transcription factor lineages (e_g_, GH and ACTH)

Specific Subtypes/Examples:
─ Mixed Somatotroph-Lactotroph Adenoma: Composed of two distinct cell populations, one producing GH and one PRL
─ Mammosomatotroph Adenoma: Monomorphous tumor with cells co-expressing GH and PRL, usually densely granulated
─ Acidophil Stem Cell Adenoma:
─ A rare, aggressive sparsely granulated adenoma, considered a plurihormonal tumor of Pit-1 lineage, co-expressing PRL (predominantly) and GH (variably)
─ Characterized by oncocytic features, prominent 'giant mitochondria' (visible on EM or as cytoplasmic granularity), and often paranuclear fibrous bodies (keratin aggregates)
─ Clinically often causes hyperprolactinemia and may have rapid growth or invasion
─ Silent Subtype 3 Adenoma: A plurihormonal adenoma of Pit-1 lineage, usually a macroadenoma, co-expressing PRL, GH, TSH and alpha-subunit, but clinically silent; cells are often chromophobic
─ Other rare combinations (e_g_, ACTH with GH or PRL) exist

Ancillary studies ─

─ IHC (+)
─ Multiple pituitary hormones (e.g., GH + PRL; GH + PRL + TSH; ACTH + GH, etc) – specific combination defines the tumor
─ Corresponding transcription factors:
─ Pit-1: Positive in adenomas expressing GH, PRL, and/or TSH
─ SF-1: Positive if a gonadotroph component is present
─ TPIT: Positive if a corticotroph component is present
─ Synaptophysin, Chromogranin A, CAM5.2
─ IHC (-)
─ Hormones and transcription factors not part of the specific plurihormonal profile
─ Molecular ─
─ Genetic basis is diverse and depends on the specific type of plurihormonal adenoma
AIP mutations can be seen in some Pit-1 lineage plurihormonal adenomas, especially in younger patients
GNAS mutations may be present if there is a significant densely granulated somatotroph component

DDx ─

─ Monohormonal pituitary adenomas with focal entrapment of non-neoplastic cells of other types (careful assessment of morphology and staining patterns)
─ Collision tumors (two distinct adenomas occurring adjacent to each other; rare)
─ Pituitary hyperplasia (polyclonal, preserved architecture)
─ Misinterpretation of non-specific staining or cross-reactivity of antibodies (use of highly specific antibodies and appropriate controls is crucial)

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Pituitary Carcinoma

A malignant epithelial neoplasm of adenohypophyseal cells, defined by the presence of craniospinal dissemination or systemic metastases; it is exceptionally rare
Clinical ─ Patients usually have a history of a recurrent, invasive pituitary adenoma (often prolactin or ACTH-producing, but can be any type); symptoms relate to aggressive local growth, mass effects, and/or hormone hypersecretion; metastases can occur to lymph nodes, bone, liver, lung, or brain; prognosis is generally poor
Macro ─ Large, invasive tumors, often with extensive local destruction; appearance of metastases will vary by site
Micro ─

─ Histologically, pituitary carcinomas often resemble atypical pituitary adenomas, but cytologic features alone are insufficient for diagnosis of malignancy
─ Features that may be more pronounced than in typical adenomas (but not diagnostic of carcinoma without metastasis) include:
─ Increased nuclear pleomorphism and hyperchromasia
─ Increased mitotic activity (Ki-67 index often >10%)
─ Prominent nucleoli
─ Necrosis (comedo-like or diffuse)
─ Vascular invasion may be present
─ The diagnosis of carcinoma is definitively established
only by unequivocal evidence of tumor spread:
─ Cerebrospinal fluid (CSF) seeding / craniospinal dissemination
─ Metastases to distant sites (e.g., lymph nodes, bone, liver, brain parenchyma)
─ Most commonly arise from PRL-producing or ACTH-producing adenomas, but can arise from any adenoma type

Ancillary studies ─

─ IHC (+)
─ Hormones corresponding to the parent adenoma cell type (e.g., PRL, ACTH, GH)
─ General neuroendocrine markers (Synaptophysin, Chromogranin A - may be variable)
─ CAM5.2 (low molecular weight cytokeratin)
─ Ki-67 (MIB-1): Proliferation index typically significantly elevated (often >10%, but no absolute cutoff distinguishes from atypical adenoma without metastasis)
─ p53: Overexpression may be present in a subset, suggesting genetic instability
─ IHC (-)
─ Markers not relevant to pituitary epithelial cells (e.g., GFAP, S100 in tumor cells)
─ Molecular ─
─ No single consistent molecular marker defines pituitary carcinoma
─ Alterations seen in aggressive adenomas and carcinomas may include mutations in
TP53, dysregulation of cell cycle genes (e.g., RB1, CDKN2A), and pro-invasive signaling pathways
─ Whole-genome sequencing has revealed complex genomic alterations in some cases

DDx ─

─ Invasive pituitary adenoma (lacks metastases or craniospinal dissemination; distinction can be challenging on biopsy without clinical evidence of spread)
─ Atypical pituitary adenoma (shows worrisome features like elevated Ki-67 or p53, but still no metastases)
─ Metastatic carcinoma to the pituitary (from lung, breast, kidney, etc.; history of primary, different IHC profile e.g., CK7/CK20, specific tumor markers like TTF-1 for lung, GATA3 for breast)
─ Germ cell tumor (especially with CSF spread; PLAP, OCT3/4, SALL4 positive)
─ Lymphoma (CD45 positive, lymphoid markers)

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Adamantinomatous Craniopharyngioma

A benign (WHO Grade 1) but locally aggressive epithelial tumor of the sellar/suprasellar region, thought to arise from remnants of Rathke's pouch or oral ectoderm, characterized by cystic and solid components with calcification
Clinical ─ Bimodal age distribution (peaks at 5-15 years and 50-74 years); symptoms include headaches, visual disturbances (bitemporal hemianopsia), endocrine deficiencies (hypopituitarism, diabetes insipidus), and hypothalamic dysfunction (obesity, behavioral changes); high recurrence rate if incompletely excised
Macro ─ Typically lobulated, multicystic masses with solid areas; cysts often contain thick, dark brownish-yellow, cholesterol-rich fluid ("machine oil" or "crankcase oil" appearance); calcification is common and often visible on imaging; may adhere to or invade adjacent brain structures
Micro ─

─ Lobules of squamous epithelium forming a complex, often cystic, structure
─ Peripheral palisading of columnar or cuboidal epithelial cells with dark nuclei
─ Stellate reticulum: Loosely arranged, star-shaped epithelial cells internal to the palisading layer, resembling enamel organ of developing tooth
─ "Wet keratin": Compact, anucleated squamous cells forming lamellated nodules; often abundant and a hallmark feature
─ Cyst lining can be squamous or columnar, may show inflammation
─ Calcification: Common, can be dystrophic within wet keratin or psammomatous
─ Cholesterol clefts, hemosiderin-laden macrophages, and foreign body giant cell reaction are frequent in stroma and cyst contents
─ Gliotic brain tissue with Rosenthal fibers may be seen at the tumor-brain interface

Ancillary studies ─

─ IHC (+)
─ Epithelial cells: Pan-cytokeratin (AE1/AE3), CK5/6, CK7 (often in peripheral cells), EMA (membranous)
─ β-catenin: Nuclear accumulation in a significant proportion of tumor cells (especially in areas of wet keratin and palisading cells) is characteristic and reflects
CTNNB1 mutation
─ LEF1: Nuclear positivity, similar distribution to β-catenin
─ IHC (-)
─ GFAP (negative in tumor cells, positive in reactive glia)
─ Pituitary hormones
─ BRAF V600E (negative, distinguishes from papillary craniopharyngioma)
─ Molecular ─
CTNNB1 (beta-catenin gene) activating mutations in exon 3 are found in the vast majority of cases and are considered a pathognomonic molecular feature

DDx ─

─ Papillary craniopharyngioma (adults, lacks wet keratin, stellate reticulum, calcification, and CTNNB1 mutations; BRAF V600E positive)
─ Rathke's cleft cyst (simple cyst lined by cuboidal, columnar, or squamous epithelium, often ciliated and with goblet cells; lacks complex architecture, wet keratin, palisading, stellate reticulum, and
CTNNB1 mutations)
─ Epidermoid cyst (lined by keratinizing squamous epithelium with granular layer, contains lamellated keratin; lacks palisading, stellate reticulum, and "machine oil" cysts)
─ Dermoid cyst (contains skin adnexal structures like hair follicles and sebaceous glands)
─ Pituitary adenoma with squamous metaplasia (rare; background of adenoma, lacks true stellate reticulum and wet keratin)
─ Xanthogranuloma (inflammatory lesion with foamy macrophages, cholesterol clefts; lacks epithelial component of craniopharyngioma)

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Papillary Craniopharyngioma

A benign (WHO Grade 1) epithelial tumor of the sellar/suprasellar region, distinct from adamantinomatous craniopharyngioma, typically occurring in adults and characterized by a solid or mixed solid/cystic structure composed of well-differentiated, non-keratinizing squamous epithelium
Clinical ─ Almost exclusively occurs in adults (peak 40-60 years); symptoms similar to adamantinomatous type (headaches, visual disturbances, endocrine dysfunction) but often with a shorter clinical history; generally considered to have a better prognosis and lower recurrence rate than adamantinomatous type if completely resected
Macro ─ Often predominantly solid or mixed solid and cystic; cysts usually contain clear or serous fluid (not "machine oil"); calcification is rare; tends to be better circumscribed than adamantinomatous type
Micro ─

─ Composed of well-differentiated, non-keratinizing squamous epithelium forming anastomosing papillae with fibrovascular cores, or solid sheets
─ Epithelium is typically mature and lacks significant atypia; resembles squamous papilloma
─ No peripheral palisading of basal cells
─ No stellate reticulum
─ No "wet keratin" nodules
─ Calcification is typically absent or minimal
─ Cystic components, if present, are lined by the same squamous epithelium
─ Inflammatory infiltrate in the stroma can be variable

Ancillary studies ─

─ IHC (+)
─ Epithelial cells: Pan-cytokeratin (AE1/AE3), CK5/6
─ BRAF V600E specific antibody (VE1): Strong cytoplasmic and/or nuclear staining in tumor cells is characteristic
─ IHC (-)
─ β-catenin (nuclear staining absent or very focal, contrasts with adamantinomatous type)
─ LEF1 (negative)
─ Pituitary hormones
─ GFAP (negative in tumor cells)
─ Molecular ─
BRAF V600E mutation is present in the vast majority of cases and is a defining molecular feature
CTNNB1 mutations are absent (unlike adamantinomatous craniopharyngioma)

DDx ─

─ Adamantinomatous craniopharyngioma (children and older adults, has wet keratin, stellate reticulum, peripheral palisading, calcification, CTNNB1 mutations, BRAF V600E negative)
─ Rathke's cleft cyst (simple cyst lined by columnar, cuboidal, or squamous epithelium, may have goblet cells or cilia; lacks complex papillae and BRAF V600E mutation)
─ Squamous papilloma of sellar region (extremely rare, histologically identical but must exclude craniopharyngioma based on location/extent)
─ Pituitary adenoma with squamous metaplasia (background of adenoma, lacks true papillary architecture of this type, BRAF V600E negative)
─ Epidermoid cyst (keratinizing squamous epithelium with granular layer, lamellated keratin; lacks papillae)

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Pituicytoma

A rare, low-grade (WHO Grade 1) glial neoplasm of the sellar region, specifically arising from pituicytes of the neurohypophysis or infundibulum
Clinical ─ Primarily affects adults (mean age ~50 years); symptoms are often due to mass effect, including visual disturbances, hypopituitarism, diabetes insipidus, or headaches; generally slow-growing with a good prognosis after resection
Macro ─ Typically a well-circumscribed, solid, grayish, moderately vascular mass located in the posterior pituitary or pituitary stalk; may appear attached to or compress the anterior pituitary
Micro ─

─ Composed of relatively monomorphic, bipolar, spindle to epithelioid cells arranged in interlacing fascicles, sheets, or a storiform pattern
─ Cytoplasm is eosinophilic and finely granular or fibrillar; cell borders are indistinct
─ Nuclei are oval to elongated, with bland chromatin and inconspicuous nucleoli
─ Rosenthal fibers and granular bodies are characteristically absent (helps distinguish from pilocytic astrocytoma)
─ Mitotic activity is typically low; necrosis is rare
─ Perivascular hyalinization may be present
─ No significant pleomorphism or anaplasia

Ancillary studies ─

─ IHC (+)
─ S100 protein: Diffuse nuclear and cytoplasmic positivity
─ GFAP (Glial Fibrillary Acidic Protein): Variable positivity, can be focal or patchy; some cases may be weak or negative
─ Vimentin: Positive
─ TTF-1 (Thyroid Transcription Factor-1): Nuclear positivity is a characteristic finding in most pituicytomas (also seen in spindle cell oncocytoma and granular cell tumor of sellar region)
─ EMA (Epithelial Membrane Antigen): May show focal positivity in some cases
─ IHC (-)
─ Pituitary hormones (GH, PRL, ACTH, etc)
─ Neuroendocrine markers (Synaptophysin, Chromogranin)
─ Cytokeratins (CAM5.2, AE1/AE3 generally negative or only very focal)
─ Olig2
─ BRAF V600E
─ Molecular ─
─ Recent studies have identified recurrent alterations involving
MAPK pathway genes, notably ALK rearrangements (e.g., STRN::ALK fusion) in some cases, and also RAF1 fusions or mutations in others, but these are not universally present

DDx ─

─ Spindle cell oncocytoma (SCO) of the adenohypophysis (TTF-1 positive, S100 positive, but prominent oncocytic cytoplasm with abundant mitochondria, negative for GFAP, arises in anterior pituitary)
─ Granular cell tumor of the sellar region (TTF-1 positive, S100 positive, but cells have abundant coarse eosinophilic granules, PAS-D positive)
─ Pilocytic astrocytoma (more common in children/young adults, often cystic, GFAP strongly positive, Rosenthal fibers and eosinophilic granular bodies usually present, TTF-1 negative)
─ Meningioma (EMA positive, SSTR2A positive, characteristic whorls, psammoma bodies, TTF-1 negative)
─ Pituitary adenoma (especially null cell or sparsely granulated types; positive for neuroendocrine markers, negative for S100/GFAP in tumor cells, TTF-1 negative)
─ Schwannoma (S100 positive, SOX10 positive, Verocay bodies, Antoni A/B areas, GFAP negative, TTF-1 negative)

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Granular Cell Tumor of the Sellar Region

A rare, benign (WHO Grade 1) neoplasm of the neurohypophysis or pituitary stalk, composed of cells with abundant eosinophilic granular cytoplasm, similar to granular cell tumors elsewhere
Clinical ─ Typically occurs in adults (often middle-aged women); may be asymptomatic and found incidentally, or cause symptoms due to mass effect (visual disturbances, hypopituitarism, diabetes insipidus, headaches)
Macro ─ Usually well-circumscribed, solid, firm, yellowish-gray nodule in the posterior pituitary or stalk; can be small (incidental "granulomas") or larger masses
Micro ─

─ Composed of sheets, nests, or cords of large polygonal cells with abundant, coarse, eosinophilic, PAS-positive and diastase-resistant granules in the cytoplasm
─ Nuclei are small, round to oval, often eccentrically located, with bland chromatin and inconspicuous nucleoli
─ Cell borders are usually distinct
─ Mitotic activity is typically absent or very low; necrosis is rare
─ Stroma is delicate and vascular
─ No significant pleomorphism; however, nuclear atypia can rarely be seen (Atypical Granular Cell Tumor is recognized but rare in this location)

Ancillary studies ─

─ IHC (+)
─ S100 protein: Strong and diffuse nuclear and cytoplasmic positivity
─ PAS-diastase (Periodic Acid-Schiff with diastase digestion): Granules are strongly positive (indicating lysosomes)
─ CD68 (PGM1 or KP1): Strong positivity in granules (lysosomal marker)
─ Inhibin-alpha: Often positive
─ TFE3 (Transcription Factor E3): Nuclear positivity can be seen
─ TTF-1 (Thyroid Transcription Factor-1): Nuclear positivity is characteristic in sellar granular cell tumors (shared with pituicytoma and spindle cell oncocytoma)
─ Vimentin: Positive
─ IHC (-)
─ GFAP (Glial Fibrillary Acidic Protein): Usually negative or only focally weak (helps distinguish from some astrocytomas)
─ Pituitary hormones
─ Neuroendocrine markers (Synaptophysin, Chromogranin)
─ Cytokeratins (AE1/AE3, CAM5.2)
─ Molecular ─
─ Mutations in
ATP6AP1 or ATP6AP2 have been identified in many granular cell tumors from various sites, but studies specific to sellar location are limited

DDx ─

─ Pituicytoma (TTF-1 and S100 positive, but lacks coarse PAS-D positive granules, usually GFAP positive to some extent)
─ Spindle cell oncocytoma (TTF-1 and S100 positive, but has oncocytic cytoplasm due to mitochondria, not coarse granules, and is GFAP negative, arises in anterior pituitary)
─ Pituitary adenoma with oncocytic change (e.g., null cell adenoma/oncocytoma; distinguished by neuroendocrine markers, hormone IHC, transcription factors like SF-1 if gonadotroph lineage; S100 negative in tumor cells)
─ Corticotroph adenoma with Crooke's hyaline change (ACTH positive, TPIT positive; hyaline is perinuclear, not granular throughout cytoplasm)
─ Macrophage-rich lesions / Xanthogranuloma (CD68 positive, but foamy macrophages, cholesterol clefts, lacks diffuse S100 and TTF-1 positivity of tumor cells)
─ Metastatic carcinoma (e.g., renal cell carcinoma with granular cytoplasm; PAX8 positive, cytokeratin positive, S100 negative, TTF-1 negative)

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Spindle Cell Oncocytoma (of the Adenohypophysis)

A rare, benign (WHO Grade 1) non-endocrine neoplasm of the anterior pituitary, composed of spindle cells with prominent oncocytic cytoplasm rich in mitochondria
Clinical ─ Primarily affects adults (mean age ~50-60 years); presents with symptoms of mass effect due to its sellar location, such as visual disturbances, headaches, and hypopituitarism; not associated with hormone hypersecretion
Macro ─ Typically a well-circumscribed, solid, firm, reddish-brown or tan mass located within or replacing the anterior pituitary; usually macroadenoma-sized (≥1 cm)
Micro ─

─ Composed of relatively uniform, elongated spindle cells arranged in interlacing fascicles or a storiform pattern
─ Cytoplasm is abundant, eosinophilic, and finely granular (oncocytic) due to a high density of mitochondria (visible on EM)
─ Nuclei are oval to spindle-shaped, often with smooth contours, finely granular chromatin, and inconspicuous or small nucleoli; mild nuclear pleomorphism can be seen
─ Mitotic activity is typically low; necrosis is absent
─ Stroma contains a rich capillary network; perivascular hyalinization is not a prominent feature
─ No Rosenthal fibers or granular bodies

Ancillary studies ─

─ IHC (+)
─ S100 protein: Often positive, can be diffuse or patchy, nuclear and/or cytoplasmic
─ EMA (Epithelial Membrane Antigen): Usually positive, often with a membranous pattern
─ TTF-1 (Thyroid Transcription Factor-1): Nuclear positivity is characteristic (shared with pituicytoma and granular cell tumor of sellar region, though SCO arises in anterior pituitary)
─ Vimentin: Positive
─ Galectin-3: May be positive
─ IHC (-)
─ Pituitary hormones (GH, PRL, ACTH, TSH, FSH, LH, alpha-subunit) - defining feature
─ Neuroendocrine markers (Synaptophysin, Chromogranin A usually negative or very focal)
─ GFAP (Glial Fibrillary Acidic Protein): Negative (helps distinguish from pituicytoma)
─ Cytokeratins (AE1/AE3 often negative, CAM5.2 may be weak/focal in some but generally negative or less prominent than EMA)
─ Transcription factors specific to pituitary adenoma lineages (Pit-1, SF-1, TPIT)
─ Ultrastructure:
─ Abundant mitochondria filling the cytoplasm is the defining feature of oncocytic cells
─ Interdigitating cell processes and scattered desmosomes may be seen

DDx ─

─ Pituicytoma (TTF-1 and S100 positive, but arises in posterior pituitary/stalk, usually GFAP positive, lacks prominent oncocytic cytoplasm seen in SCO)
─ Granular cell tumor of the sellar region (TTF-1 and S100 positive, but has coarse PAS-D positive granules, CD68 positive, arises in posterior pituitary/stalk)
─ Pituitary adenoma, null cell type with oncocytic change (most important DDx; null cell adenomas are negative for hormones but typically show some synaptophysin/chromogranin, are EMA negative/weak, S100 negative, TTF-1 negative; SCO has characteristic spindle cell morphology)
─ Meningioma (EMA positive, SSTR2A positive, may have spindle cells, but usually distinct morphology, whorls, psammoma bodies; S100 can be positive in fibrous/transitional types, TTF-1 negative)
─ Schwannoma (S100 strongly positive, SOX10 positive, Verocay bodies, Antoni A/B areas; TTF-1 negative, EMA usually negative)
─ Solitary fibrous tumor (CD34 positive, STAT6 nuclear positive; rare in sellar region)

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Pituitary Gangliocytoma (including mixed Gangliocytoma-PitNET)

A rare, benign (WHO Grade 1) neuronal tumor of the sellar region, composed of mature ganglion cells, which may occur as a pure gangliocytoma or, more commonly, mixed with a pituitary adenoma (GH-producing adenoma being the most frequent partner)
Clinical ─ Pure gangliocytomas are very rare; mixed gangliocytoma-pituitary adenomas usually present with symptoms related to the hormone produced by the adenomatous component (e.g., acromegaly if GH-adenoma); mass effects can also occur; typically affects adults
Macro ─ Often well-circumscribed, solid or cystic masses; in mixed forms, the appearance is that of a pituitary adenoma; pure forms are typically grayish and firm
Micro ─

Pure Gangliocytoma:
─ Composed of large, mature neurons (ganglion cells) with vesicular nuclei, prominent nucleoli, and abundant Nissl substance in the cytoplasm
─ Ganglion cells are often haphazardly arranged in a fibrillary or loose neurophil-like stroma, which may contain Schwann cells or satellite cells
─ No significant atypia or mitotic activity in the ganglion cells

Mixed Gangliocytoma-Pituitary Adenoma (Gangliocytoma-PitNET):
─ Features an intimate admixture of neoplastic ganglion cells (as described above) and a conventional pituitary adenoma component
─ The adenoma component is most commonly a somatotroph adenoma, but lactotroph, corticotroph, or other adenoma types can occur
─ The two components are intermingled, not sharply demarcated collision tumors
─ The ganglion cells are thought to represent neoplastic transformation of intrapituitary neurons or neuronal metaplasia within the adenoma

Ancillary studies ─

─ IHC (+)
─ Ganglion cells:
─ Synaptophysin: Strong cytoplasmic positivity in ganglion cells and neuropil
─ Neurofilament protein (NFP): Highlights neuronal cell bodies and axons
─ Class III beta-tubulin (TUJ1): Marks neurons
─ Chromogranin A: Can be positive in ganglion cells
─ NeuN: Nuclear positivity in mature neurons
─ MAP2 (Microtubule Associated Protein 2): Positive in neuronal cytoplasm and dendrites
─ GHRH (Growth Hormone-Releasing Hormone): May be positive in some ganglion cells, particularly when mixed with GH adenoma, suggesting a pathogenic link
─ Adenoma component (in mixed tumors): Positive for pituitary hormones (e.g., GH, PRL) and relevant transcription factors (e.g., Pit-1) characteristic of the adenoma type
─ IHC (-)
─ Ganglion cells: Typically negative for GFAP (distinguishes from astrocytic tumors) and pituitary hormones (though adenoma component is positive)
─ S100 protein: May highlight associated Schwann cells or satellite cells, but ganglion cells themselves are typically negative or weakly positive

DDx ─

─ Pituitary adenoma (lacks mature ganglion cell component)
─ Pilocytic astrocytoma (GFAP positive, Rosenthal fibers, lacks mature neurons)
─ Schwannoma (S100 and SOX10 positive, Verocay bodies, lacks ganglion cells)
─ Metastatic neuroblastoma (immature neuroblasts, Homer Wright rosettes, more aggressive features)
─ Hypothalamic hamartoma (developmental lesion, often contains mature neurons but in a disorganized manner with glial elements, different clinical context and location usually)
─ Collision tumor (two separate neoplasms, e.g., adenoma and schwannoma, not intermingled)

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Sellar Neurocytoma and Neuroblastoma

Extremely rare neuroepithelial tumors in the sellar region; sellar neurocytoma resembles central neurocytoma, while sellar neuroblastoma is a primitive neuroectodermal tumor (PNET) occurring in this location
Clinical ─ Sellar Neurocytoma: Adults, non-specific symptoms of mass effect (visual loss, headache, hypopituitarism); generally indolent (WHO Grade 2 equivalent)
Clinical ─ Sellar Neuroblastoma: Very rare, typically in children or young adults; highly aggressive with poor prognosis; symptoms of mass effect, cranial nerve palsies, potential for CSF dissemination
Macro ─ Sellar Neurocytoma: Grayish, soft, sometimes calcified tumor
Macro ─ Sellar Neuroblastoma: Often large, infiltrative mass with necrosis and hemorrhage
Micro ─

Sellar Neurocytoma:
─ Monotonous, round cells with finely stippled (salt-and-pepper) chromatin, inconspicuous nucleoli, and scant cytoplasm
─ Cells often arranged in sheets or nests with delicate, branching "chicken-wire" vasculature
─ Areas of neuropil (fibrillary background) are characteristic
─ Calcification can be present
─ Mitotic activity is low; necrosis is rare

Sellar Neuroblastoma (PNET):
─ Highly cellular tumor composed of primitive, undifferentiated small round blue cells
─ High nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, frequent mitoses, and apoptosis
─ Homer Wright rosettes (neuroblasts surrounding fibrillary neuropil) may be present
─ Necrosis and vascular proliferation are common
─ Evidence of invasion

Ancillary studies ─

Sellar Neurocytoma:
─ IHC (+)
─ Synaptophysin: Strong and diffuse positivity in tumor cells and neuropil
─ NeuN: Often positive in tumor cell nuclei
─ Class III beta-tubulin (TUJ1): Positive
─ S100 protein: Can be focally positive in some cells or fibrillary areas
─ IHC (-)
─ GFAP (negative or only entrapped reactive astrocytes)
─ Pituitary hormones
─ Chromogranin A (often weak or negative compared to synaptophysin)
─ Olig2
─ Molecular:
IDH mutations are absent (unlike some gliomas)

Sellar Neuroblastoma (PNET):
─ IHC (+)
─ Synaptophysin: Can be positive
─ CD99 (MIC2): Membranous positivity can be seen (as in other PNETs/Ewing sarcomas)
─ FLI1: Nuclear positivity in a subset (shared with Ewing sarcoma)
─ Other neural markers (e.g., Class III beta-tubulin) may be positive
─ IHC (-)
─ Pituitary hormones, GFAP, muscle markers (desmin, myogenin), lymphoid markers (CD45)
─ Molecular: May show
EWSR1 gene rearrangements (similar to Ewing sarcoma/PNET family), but other genetic alterations specific to CNS PNETs can also occur

DDx ─

For Sellar Neurocytoma:
─ Pituitary adenoma (especially null cell or sparsely granulated types; positive for pituitary transcription factors like SF-1, or hormones; lacks extensive neuropil and "chicken-wire" vasculature in the same way)
─ Oligodendroglioma (GFAP and Olig2 positive, 1p/19q co-deletion common, different morphology)
─ Pineocytoma (if sellar extension; similar cytology but location and melatonin IHC if available)

For Sellar Neuroblastoma:
─ Other small round blue cell tumors: Lymphoma (CD45, lymphoid markers), Rhabdomyosarcoma (desmin, myogenin), Metastatic neuroblastoma from adrenal/sympathetic chain (clinical history, N-myc amplification), Ewing sarcoma metastasis
─ Pituitary carcinoma (evidence of pituitary hormone production, different IHC profile)
─ Undifferentiated olfactory neuroblastoma extending to sella

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Inflammatory Lesions of the Pituitary (Hypophysitis)

A group of inflammatory disorders affecting the pituitary gland, broadly classified into lymphocytic, granulomatous, xanthomatous, and other less common types; can mimic pituitary neoplasms clinically and radiologically
Clinical ─ Variable presentation depending on the extent and type of inflammation; symptoms can include headaches, visual disturbances, hypopituitarism (most commonly ACTH and TSH deficiency, leading to secondary adrenal insufficiency and hypothyroidism), diabetes insipidus (especially if posterior lobe/stalk involved); hyperprolactinemia can occur due to stalk compression; autoimmune associations are common, especially with lymphocytic hypophysitis

Lymphocytic Hypophysitis (Autoimmune Hypophysitis) ─ Most common form, often affects women during late pregnancy or postpartum; autoimmune etiology strongly suspected
─ Micro: Diffuse infiltration of the pituitary parenchyma (anterior lobe primarily, but can involve posterior lobe and stalk) by lymphocytes (mainly T-cells, some B-cells and plasma cells), often forming lymphoid follicles with germinal centers; associated with destruction of pituitary acini and fibrosis
─ IHC: Lymphoid markers (CD3, CD20, CD45), macrophages (CD68); remaining pituitary cells positive for respective hormones

Granulomatous Hypophysitis ─ Characterized by granulomatous inflammation; can be idiopathic or secondary to systemic diseases (e.g., tuberculosis, sarcoidosis, fungal infections, Crohn's disease, Wegener's granulomatosis/GPA) or rupture of Rathke's cleft cyst
─ Micro: Well-formed or poorly formed non-caseating or caseating granulomas (collections of epithelioid histiocytes, multinucleated giant cells) with surrounding lymphocytes and plasma cells; special stains for organisms (e.g., AFB for mycobacteria, GMS for fungi) should be performed
─ IHC: Macrophages (CD68), lymphoid markers

Xanthomatous Hypophysitis ─ Rare variant characterized by infiltration of foamy histiocytes (xanthoma cells), lymphocytes, and plasma cells; often cystic
─ Micro: Sheets of lipid-laden macrophages (foamy cells), admixed with lymphocytes and plasma cells; cholesterol clefts may be present; may be related to rupture of Rathke's cleft cyst or craniopharyngioma
─ IHC: Foamy histiocytes are CD68 positive

IgG4-Related Hypophysitis ─ A form of hypophysitis considered part of the spectrum of IgG4-related disease; characterized by lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis
─ Micro: Dense lymphoplasmacytic infiltrate, increased numbers of IgG4+ plasma cells (IgG4/IgG ratio >40% is supportive), storiform fibrosis, and eosinophils may be present
─ IHC: IgG4, IgG, CD138 (plasma cells)

Necrotizing Hypophysitis ─ Rare, characterized by extensive necrosis of the pituitary gland, often with associated inflammation; etiology can be autoimmune, ischemic, or infectious

Ancillary studies ─ (General for Hypophysitis)

─ IHC: Dependent on subtype; CD3, CD20, CD45 for lymphocytes; CD68 for histiocytes/macrophages; IgG4/IgG for IgG4-related disease; specific pituitary hormone stains will show destruction/loss of normal pituitary cells
─ Special stains: For microorganisms (AFB, GMS, PAS) if granulomatous or necrotizing type suspected

DDx ─ (General for Hypophysitis)

─ Pituitary adenoma (especially non-functioning; lacks prominent inflammatory infiltrate, neoplastic cells are monotonous, specific hormone/transcription factor profile)
─ Craniopharyngioma (epithelial tumor with characteristic features like wet keratin or papillary structures; inflammation can be secondary)
─ Germinoma (large atypical cells with prominent nucleoli, lymphoid infiltrate, PLAP/OCT3/4 positive)
─ Langerhans cell histiocytosis (S100, CD1a, Langerin positive Langerhans cells with characteristic grooved nuclei)
─ Metastasis (atypical cells, history of primary malignancy, specific IHC markers for primary)
─ Infection (specific organisms identified by culture or special stains)

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Rathke's Cleft Cyst

A benign, non-neoplastic cyst arising from remnants of Rathke's pouch, typically located in the sellar or suprasellar region, usually between the anterior and posterior pituitary lobes
Clinical ─ Often asymptomatic and discovered incidentally; symptomatic cysts can cause headaches, visual disturbances (due to optic chiasm compression), hypopituitarism (by compressing the normal pituitary), or diabetes insipidus; hyperprolactinemia can occur due to stalk effect; rarely, can cause pituitary apoplexy or aseptic meningitis if ruptured
Macro ─ Well-circumscribed, thin-walled cyst; size varies from millimeters to several centimeters; cyst fluid can be clear and serous, mucoid, gelatinous, or creamy white/yellow; hemorrhagic or cholesterol-rich fluid may be present
Micro ─

─ Cyst wall is typically lined by a single layer of cuboidal or columnar epithelium, which is often ciliated
─ Goblet cells (mucous-producing cells) are frequently interspersed within the epithelial lining and are a characteristic feature
─ Squamous metaplasia of the lining epithelium can occur
─ The cyst contents may be proteinaceous, mucoid (PAS-positive), or contain desquamated cells and inflammatory cells (if ruptured or inflamed)
─ The cyst wall is typically thin and composed of connective tissue; a surrounding compressed pituitary gland or reactive gliosis may be seen
─ Inflammatory infiltrates (lymphocytes, plasma cells, macrophages) can be present in the cyst wall, especially if there has been leakage or rupture
─ No complex papillary structures, stellate reticulum, wet keratin, or calcification (helps distinguish from craniopharyngioma)

Ancillary studies ─

─ IHC (+)
─ Epithelial lining: Pan-cytokeratin (AE1/AE3, CAM5.2), EMA
─ Goblet cells: PAS (for mucin), Alcian blue (for acidic mucin)
─ S100 protein: Can be positive in some lining cells or intermingled folliculostellate-like cells
─ IHC (-)
─ Pituitary hormones (in the cyst lining itself, though adjacent compressed pituitary is positive)
─ BRAF V600E (negative, distinguishes from papillary craniopharyngioma)
─ β-catenin (nuclear staining absent, distinguishes from adamantinomatous craniopharyngioma)

DDx ─

─ Adamantinomatous craniopharyngioma (complex epithelial proliferation, peripheral palisading, stellate reticulum, wet keratin, calcification, nuclear β-catenin positive)
─ Papillary craniopharyngioma (papillary non-keratinizing squamous epithelium, BRAF V600E positive)
─ Epidermoid cyst (lined by keratinizing squamous epithelium with granular layer, contains lamellated keratin)
─ Dermoid cyst (contains skin adnexal structures like hair follicles, sebaceous glands)
─ Arachnoid cyst (simple cyst lined by meningothelial cells, SSTR2A positive)
─ Cystic pituitary adenoma (neoplastic adenoma cells form part of the cyst wall, positive for neuroendocrine markers and specific hormones/transcription factors)
─ Abscess (neutrophilic infiltrate, necrosis, bacteria may be identified)
─ Xanthogranuloma / Xanthomatous hypophysitis (sheets of foamy macrophages, cholesterol clefts, often associated with ruptured Rathke's cleft cyst but a predominantly inflammatory lesion)

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Empty Sella Syndrome

A neuro-radiological and clinical condition where the sella turcica appears partially or completely empty on imaging, as it is filled with cerebrospinal fluid (CSF), causing flattening and compression of the pituitary gland against the sellar floor or walls
Clinical ─ Primary empty sella: Most common, often idiopathic, more frequent in obese, multiparous women with hypertension; usually asymptomatic, but can be associated with headaches, visual disturbances, or mild endocrine abnormalities (e.g., hyperprolactinemia, partial hypopituitarism). Secondary empty sella: Results from pituitary surgery, radiation, infarction (Sheehan's syndrome, apoplexy), or regression of a pituitary adenoma
Macro ─ Pathologically, the pituitary gland is present but significantly flattened and remodeled, often forming a thin rim of tissue at the base or periphery of an enlarged sella filled with CSF; the diaphragm sellae is often incompetent or deficient
Micro ─

─ The pituitary gland tissue, though compressed, typically shows preserved architecture of the anterior and posterior lobes, albeit attenuated
─ Acinar structures may be flattened, and cell density can appear reduced in some areas
─ No primary neoplastic or inflammatory process is inherent to primary empty sella, but features of prior pathology (e.g., fibrosis from infarction, postsurgical changes) may be seen in secondary empty sella
─ The overlying arachnoid mater may herniate into the sella

Ancillary studies ─

─ Not usually a surgical pathology diagnosis unless tissue is incidentally obtained or specifically biopsied (rare)
─ If pituitary tissue is examined, standard IHC for pituitary hormones would show the expected cell types in the compressed gland
─ Imaging (MRI) is key for diagnosis, showing CSF signal intensity within an enlarged sella and a flattened pituitary gland

DDx ─ (Primarily a radiological differential)

─ Cystic pituitary adenoma (tumor with cystic components, enhancing solid portions usually visible)
─ Rathke's cleft cyst (distinct cyst with characteristic lining, not just CSF)
─ Arachnoid cyst (true cyst lined by meningothelial cells within the sella)
─ Craniopharyngioma with large cystic component
─ Pituitary apoplexy (hemorrhage and necrosis within a pituitary adenoma, can lead to secondary empty sella)

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Metastases to Pituitary

Malignant neoplasms that spread to the pituitary gland from a primary cancer elsewhere in the body; relatively uncommon but can be clinically significant
Clinical ─ Often occur in older patients with known widespread malignancy; common primary sites include breast (most common in women), lung (most common in men), kidney, GI tract, prostate, and melanoma; symptoms include diabetes insipidus (most common presenting symptom, due to posterior lobe/stalk involvement), anterior pituitary dysfunction (hypopituitarism), headaches, and visual field defects; may be asymptomatic and found at autopsy
Macro ─ Metastases can be single or multiple nodules, or cause diffuse enlargement of the gland; often involve the posterior lobe more frequently than the anterior lobe due to its direct arterial blood supply, but both can be affected; tumors are often hemorrhagic or necrotic
Micro ─

─ Histological appearance reflects the primary malignancy (e.g., adenocarcinoma, squamous cell carcinoma, small cell carcinoma, melanoma)
─ Tumor cells are atypical, often with features not seen in primary pituitary tumors (e.g., glandular formation in adenocarcinoma, keratinization in squamous cell carcinoma, prominent nucleoli and melanin in melanoma)
─ Infiltration and destruction of normal pituitary parenchyma by malignant cells
─ May show desmoplastic stromal reaction or necrosis
─ Vascular invasion can be prominent
─ Careful comparison with the histology of any known primary tumor is crucial

Ancillary studies ─

─ IHC (+)
─ Markers specific to the suspected primary tumor:
─ Breast carcinoma: GATA3, ER, PR, mammaglobin, GCDFP-15
─ Lung adenocarcinoma: TTF-1, Napsin A, CK7
─ Lung squamous cell carcinoma: p63, p40, CK5/6
─ Lung small cell carcinoma: Synaptophysin, Chromogranin A, TTF-1, CD56 (but must distinguish from pituitary neuroendocrine cells)
─ Renal cell carcinoma: PAX8, CAIX, CD10
─ Colorectal adenocarcinoma: CK20, CDX2 (often CK7 negative)
─ Melanoma: S100, SOX10, HMB-45, Melan-A
─ Cytokeratins (e.g., CK7, CK20 patterns can help suggest origin)
─ IHC (-)
─ Pituitary hormones (negative in metastatic tumor cells, though entrapped pituitary cells will be positive)
─ Pituitary-specific transcription factors (Pit-1, SF-1, TPIT are negative in metastatic cells)

DDx ─

─ Pituitary adenoma (especially atypical or aggressive variants; positive for pituitary hormones/transcription factors, lacks features of specific metastatic carcinoma types)
─ Pituitary carcinoma (primary pituitary malignancy with metastases FROM pituitary; extremely rare; defined by CSF or systemic spread of a pituitary neuroendocrine neoplasm)
─ Germ cell tumor (PLAP, OCT3/4, SALL4 positive)
─ Lymphoma/Leukemia (CD45, specific lymphoid/hematopoietic markers)
─ Inflammatory lesions (hypophysitis; prominent inflammation, lacks overt malignant cells)
─ Sarcoma (rare in pituitary; specific mesenchymal markers)

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Pineal Gland

Normal Pineal Gland Histology

The pineal gland is a small neuroendocrine organ located in the posterior aspect of the third ventricle, near the center of the brain, primarily responsible for synthesizing and secreting melatonin
Clinical ─ Regulates circadian rhythms and sleep-wake cycles through melatonin production; melatonin secretion is stimulated by darkness and inhibited by light; may play roles in sexual development and immune function
Macro ─ Small, pine cone-shaped structure, typically ~5-8 mm in length and ~3-5 mm in width, weighing ~100-150 mg; grayish-pink color; often becomes calcified with age (corpora arenacea or "brain sand")
Micro ─

─ Composed primarily of pinealocytes (chief cells) and interstitial glial cells (astrocytes)
─ Pinealocytes:
─ Arranged in nests, cords, or indistinct lobules, often forming pineocytomatous rosettes (Homer Wright-like rosettes, but with more fibrillary processes in the center) in a loose, fibrillary background (neuropil)
─ Polygonal cells with round to slightly irregular, vesicular nuclei, prominent nucleoli, and amphophilic or pale eosinophilic cytoplasm
─ Cytoplasmic processes extend into the fibrillary stroma
─ Interstitial glial cells (Astrocytes):
─ Fewer in number than pinealocytes, scattered throughout the gland, particularly around blood vessels and at the periphery of lobules
─ Elongated or stellate cells with darker, more condensed nuclei and fibrillary processes
─ Corpora arenacea ("brain sand"):
─ Concentrically laminated calcifications, increase in number and size with age; composed of calcium phosphates and carbonates
─ Found in the stroma
─ Richly vascularized with fenestrated capillaries
─ Sympathetic nerve fibers (from superior cervical ganglion) innervate the gland but are not readily visible without special stains
─ No true blood-brain barrier
─ Cysts (pineal cysts) are common incidental findings

Ancillary studies ─

─ IHC (+)
─ Pinealocytes: Synaptophysin, Chromogranin A, Neuron-Specific Enolase (NSE), Class III beta-tubulin (TUJ1); may show focal S100 protein; some express neurofilament proteins (NFP); melatonin and serotonin (enzymes for synthesis like AANAT, HIOMT)
─ Interstitial glial cells (Astrocytes): GFAP, S100 protein
─ IHC (-)
─ Pinealocytes: Generally negative for GFAP (though processes can be intertwined with astrocytes)
─ Cytokeratins

DDx ─

─ Pineocytoma (hypercellular, more prominent rosettes, but distinction from normal can be subtle in small biopsies)
─ Pineal cyst (defined cystic structure with specific lining)
─ Germinoma (large atypical cells, lymphoid infiltrate, PLAP/OCT3/4 positive)
─ Astrocytoma/Gliosis (predominance of GFAP-positive cells, more atypia if neoplastic)

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Pineal Cysts

Common, benign, fluid-filled sacs within the pineal gland, usually discovered incidentally on neuroimaging
Clinical ─ Mostly asymptomatic and found in all age groups, with a slight female predominance; large cysts (>1.0-1.5 cm) can occasionally cause symptoms due to mass effect on adjacent structures (e.g., tectum of midbrain leading to Parinaud syndrome, aqueductal stenosis leading to hydrocephalus, headaches, visual disturbances); rarely, hemorrhage into a cyst can occur
Macro ─ Well-circumscribed, unilocular or multilocular cysts containing clear, yellowish, or hemorrhagic fluid; the cyst wall is typically thin; calcification may be present in the wall or adjacent pineal tissue
Micro ─

─ Cyst wall is typically composed of three layers:

  1. Inner lining (glial layer): Often discontinuous, composed of cuboidal to flattened ependymal-like cells, or more commonly, reactive fibrillary glial cells (astrocytes); true epithelial lining is uncommon.
  2. Middle layer (parenchymal layer): Composed of compressed, often gliotic, normal or atrophic pineal parenchymal tissue (pinealocytes and interstitial cells); corpora arenacea may be present.
  3. Outer layer (fibrous capsule): Thin layer of connective tissue.
    ─ Cyst contents are usually proteinaceous and acellular, or may contain hemosiderin-laden macrophages if there has been hemorrhage
    ─ No neoplastic cells, no complex epithelial structures like those in craniopharyngioma

Ancillary studies ─

─ IHC (+)
─ Glial lining cells: GFAP, S100 protein
─ Entrapped pinealocytes in the wall: Synaptophysin, Chromogranin A
─ IHC (-)
─ Cytokeratins (usually negative in the lining, unless rare squamous metaplasia)
─ Pituitary hormones, PLAP, OCT3/4 (to exclude germ cell tumor with cystic change)

DDx ─

─ Cystic pineal tumors (e.g., cystic pineocytoma, papillary tumor of the pineal region with cystic change; presence of neoplastic cells)
─ Epidermoid or Dermoid cyst (keratinizing squamous epithelium +/- adnexal structures; rare in pineal gland)
─ Arachnoid cyst (meningothelial cell lining, SSTR2A positive)
─ Craniopharyngioma (if suprasellar with extension; characteristic adamantinomatous or papillary features)
─ Cysticercosis (parasitic cyst; inflammatory reaction, presence of parasite)
─ Vascular malformation with cystic change

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Pineocytoma

A rare, well-differentiated (WHO Grade 1) neuroepithelial tumor of the pineal gland composed of mature-appearing pinealocytes, typically occurring in adults
Clinical ─ Slow-growing tumor, often presents with symptoms of increased intracranial pressure (hydrocephalus due to compression of the aqueduct of Sylvius), Parinaud syndrome (upward gaze palsy, pupillary abnormalities), or headaches; relatively good prognosis after surgical resection
Macro ─ Generally well-circumscribed, solid or partially cystic, grayish-tan mass; may show calcification; typically <3 cm in diameter
Micro ─

─ Composed of sheets of relatively uniform, small to medium-sized cells with round to oval, slightly irregular nuclei, finely stippled chromatin, and inconspicuous or small nucleoli
─ Cytoplasm is scant to moderate, pale eosinophilic or amphophilic
─ Characteristic feature: Large, well-formed pineocytomatous rosettes (homerogous rosettes or Homer Wright-like rosettes), which are large fibrillary zones surrounded by tumor cell nuclei; these are more prominent and larger than in normal pineal gland
─ Background often has a loose, fibrillary (neuropil-like) quality
─ Mitotic activity is typically very low (usually <1 mitosis per 10 high-power fields); necrosis is absent
─ Calcifications (corpora arenacea) may be present within the tumor
─ Glial component is usually minimal within the tumor bulk

Ancillary studies ─

─ IHC (+)
─ Synaptophysin: Strong and diffuse positivity in tumor cells and rosettes
─ Chromogranin A, Neuron-Specific Enolase (NSE), Class III beta-tubulin: Positive
─ S100 protein: Can be variably positive in tumor cells (often weaker than synaptophysin)
─ Neurofilament protein (NFP): Often highlights processes within rosettes and cytoplasm of some tumor cells
─ Melatonin, Serotonin (or enzymes for their synthesis): May be positive
─ IHC (-)
─ GFAP: Generally negative in tumor cells; positive in entrapped reactive astrocytes or if there is a glial differentiation component (rare)
─ Cytokeratins
─ Ki-67 proliferation index: Typically very low (<1-2%)

DDx ─

─ Normal pineal gland (distinction can be difficult in small biopsies; pineocytoma is more cellular, has larger and more numerous rosettes, and forms a discrete mass)
─ Pineal parenchymal tumor of intermediate differentiation (PPTID) (more cellularity, higher mitotic activity, more nuclear atypia, less well-formed rosettes than pineocytoma)
─ Pineoblastoma (highly malignant, small round blue cells, high N/C ratio, high mitotic rate, necrosis, Homer Wright rosettes are smaller and less fibrillary)
─ Central neurocytoma (intraventricular location more common, "chicken-wire" vasculature, clear cytoplasm; if in pineal region, IHC profile is similar)
─ Oligodendroglioma (GFAP and Olig2 positive, characteristic "fried egg" appearance, 1p/19q co-deletion)
─ Papillary tumor of the pineal region (PTTPR) (epithelial appearance, papillae, S100 positive, cytokeratin positive, Ependymin positive)
─ Germinoma (large cells with prominent nucleoli, lymphocytic infiltrate, PLAP/OCT3/4 positive)

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Pineoblastoma

A rare, highly malignant (WHO Grade 4) embryonal neuroepithelial tumor of the pineal gland, primarily occurring in children, considered a type of CNS primitive neuroectodermal tumor (CNS-PNET)
Clinical ─ Aggressive tumor with rapid growth; symptoms include increased intracranial pressure (hydrocephalus), Parinaud syndrome, and often signs of CSF dissemination (e.g., leptomeningeal spread, drop metastases); prognosis is generally poor despite multimodal therapy; may be associated with bilateral retinoblastoma (trilateral retinoblastoma syndrome, due to germline
RB1 mutations)
Macro ─ Large, poorly demarcated, infiltrative mass; often soft, friable, grayish-pink with areas of necrosis and hemorrhage; may invade adjacent brain structures and disseminate via CSF pathways
Micro ─

─ Highly cellular tumor composed of sheets of undifferentiated or poorly differentiated small round blue cells with scant cytoplasm and high nuclear-to-cytoplasmic ratios
─ Nuclei are hyperchromatic, often molded, and may show pleomorphism
─ Mitotic activity is brisk, and apoptotic bodies are numerous
─ Necrosis is common, often extensive
─ Homer Wright rosettes (small, poorly formed rosettes with central fibrillary material) may be present, but are not always seen
─ Vascular proliferation can be present
─ Evidence of invasion into surrounding tissues
─ Retinoblastomatous differentiation (fleurettes) can occur, particularly in trilateral retinoblastoma

Ancillary studies ─

─ IHC (+)
─ Synaptophysin: Often positive, can be diffuse or focal
─ Neuron-Specific Enolase (NSE), Class III beta-tubulin: May be positive
─ S100 protein: Usually negative or only focally positive in some cells
─ Chromogranin A: Often negative or weak
─ Some PNET markers like CD99 or FLI1 may be expressed but are not specific
─ Ki-67 proliferation index: Very high (often >30-40%)
─ IHC (-)
─ GFAP: Negative in tumor cells (positive in reactive astrocytes)
─ Cytokeratins
─ Pituitary hormones
─ PLAP, OCT3/4 (negative, helps distinguish from germinoma)
─ Molecular ─
RB1 gene mutations (germline in trilateral retinoblastoma, somatic in some sporadic cases)
DICER1 mutations have been identified in a subset of pediatric pineoblastomas, sometimes associated with DICER1 syndrome
─ Complex karyotypes are common; specific recurrent translocations are rare, unlike some other PNETs/Ewing sarcomas
─ Recent molecular classifications of embryonal tumors are refining subgroups of pineoblastoma

DDx ─

─ Other small round blue cell tumors:
─ Medulloblastoma (posterior fossa more common, but can occur supratentorially or spread; molecular subtyping is key)
─ Atypical Teratoid/Rhabdoid Tumor (AT/RT) (infants/young children, rhabdoid cells, loss of INI1/SMARCB1 expression)
─ Germinoma (large cells, distinct nucleoli, lymphoid infiltrate, PLAP/OCT3/4 positive)
─ Lymphoma (CD45 positive, specific lymphoid markers)
─ Metastatic neuroblastoma (from adrenal/sympathetic chain; clinical history, NMYC amplification)
─ Pineocytoma (well-differentiated, large rosettes, low Ki-67)
─ Pineal parenchymal tumor of intermediate differentiation (PPTID) (features intermediate between pineocytoma and pineoblastoma)

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Pineal Parenchymal Tumor of Intermediate Differentiation (PPTID)

A neuroepithelial tumor of the pineal gland with histological features intermediate between pineocytoma (WHO Grade 1) and pineoblastoma (WHO Grade 4); classified as WHO Grade 2 or 3 depending on mitotic activity and neuroblastic features
Clinical ─ Typically affects adults, though can occur at any age; presentation is similar to other pineal region masses (hydrocephalus, Parinaud syndrome, headaches); prognosis is intermediate, better than pineoblastoma but worse than pineocytoma; higher recurrence rate than pineocytoma
Macro ─ Usually relatively well-circumscribed but may show infiltration; grayish-tan, solid, and may have cystic areas or necrosis, especially in higher-grade lesions
Micro ─

─ More cellular than pineocytoma, with mild to moderate nuclear atypia and pleomorphism
─ Nuclei are more hyperchromatic than in pineocytoma, and nucleoli may be more apparent
─ Pineocytomatous rosettes are usually absent or poorly formed and less numerous than in pineocytoma
─ Fibrillary background is usually present
─ Mitotic activity is variable:
─ WHO Grade 2: <6 mitoses per 10 high-power fields (HPF), no or minimal evidence of neuroblastic (pineoblastomatous) differentiation
─ WHO Grade 3: ≥6 mitoses per 10 HPF, and/or presence of neuroblastic differentiation (areas resembling pineoblastoma)
─ Necrosis may be present, particularly in Grade 3 tumors
─ Diffuse growth pattern is more common than the lobulated pattern of pineocytoma

Ancillary studies ─

─ IHC (+)
─ Synaptophysin: Generally positive, may be less intense or uniform than in pineocytoma
─ Chromogranin A, Neuron-Specific Enolase (NSE), Class III beta-tubulin: Often positive
─ S100 protein: Variable positivity in tumor cells
─ Neurofilament protein (NFP): May be positive, often less organized than in pineocytoma rosettes
─ Ki-67 proliferation index: Elevated compared to pineocytoma (typically 5-20% or higher, variable by grade)
─ IHC (-)
─ GFAP: Generally negative in tumor cells (positive in reactive astrocytes)
─ Cytokeratins
─ Molecular ─
─ No specific molecular markers are consistently defined for PPTID distinct from other pineal parenchymal tumors, though research is ongoing
─ May share some alterations with pineocytomas or pineoblastomas depending on the spectrum

DDx ─

─ Pineocytoma (less cellularity, well-formed large rosettes, lower Ki-67, <1 mitosis/10 HPF)
─ Pineoblastoma (markedly increased cellularity, high N/C ratio, undifferentiated appearance, brisk mitotic activity, extensive necrosis, high Ki-67, Homer Wright rosettes)
─ Central neurocytoma (if in pineal region; "chicken-wire" vasculature, more uniform round cells, often perinuclear halos)
─ Oligodendroglioma (GFAP and Olig2 positive, "fried egg" cells, 1p/19q co-deletion)
─ Papillary tumor of the pineal region (PTPR) (epithelial papillary structures, CK, S100, Ependymin positive)
─ Germinoma (large cells, prominent nucleoli, lymphocytic infiltrate, PLAP/OCT3/4 positive)
─ Metastatic carcinoma (history of primary, specific IHC markers)

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Papillary Tumor of the Pineal Region (PTPR)

A rare neuroepithelial tumor of the pineal region, characterized by papillary architecture and epithelial-like differentiation, thought to arise from specialized ependymocytes of the subcommissural organ or related structures; classified as WHO Grade 2 or 3
Clinical ─ Occurs over a wide age range, most common in adults (mean age 30-40 years); symptoms are typically due to mass effect, including hydrocephalus, headaches, and visual disturbances; variable prognosis, with recurrence being common; higher grade (more mitoses, necrosis) correlates with worse outcome
Macro ─ Usually well-demarcated, solid or mixed solid and cystic mass in the pineal region; often large at presentation; may appear grayish or tan, sometimes with hemorrhage
Micro ─

─ Predominantly papillary architecture with fibrovascular cores, lined by columnar to cuboidal epithelial-like cells
─ Cells have eosinophilic cytoplasm, round to oval nuclei, often with stippled chromatin and inconspicuous nucleoli; nuclear grooves or pseudoinclusions may be seen
─ Ependymal-like features, such as perivascular pseudorosettes, may be present in more solid areas
─ Variable degrees of nuclear pleomorphism and mitotic activity
─ WHO Grade 2: Lower mitotic activity, less pleomorphism
─ WHO Grade 3: Higher mitotic activity (≥ 5 mitoses/10 HPF), increased pleomorphism, and/or necrosis
─ Vacuolated cytoplasm can be prominent in some cells
─ Hemosiderin deposition is common

Ancillary studies ─

─ IHC (+)
─ Cytokeratins (Pan-CK, CAM5.2, CK18): Strong and diffuse positivity in tumor cells (a key feature distinguishing from pineal parenchymal tumors)
─ S100 protein: Often positive, can be diffuse or patchy
─ Vimentin: Positive
─ Ependymin or transthyretin: May be positive (reflecting ependymal differentiation)
─ GFAP: Usually negative or only focally positive in tumor cells (can be positive in reactive astrocytes in stroma or at periphery)
─ EMA (Epithelial Membrane Antigen): Can be positive
─ Ki-67 proliferation index: Variable, correlates with grade (higher in Grade 3)
─ IHC (-)
─ Neuroendocrine markers (Synaptophysin, Chromogranin A): Typically negative or only very focally positive (key distinction from pineal parenchymal tumors)
─ Pituitary hormones
─ PLAP, OCT3/4 (negative, distinguishes from germ cell tumors)
─ Molecular ─
─ Recurrent chromosomal alterations like gains of chromosome 10 and losses of chromosome 22q have been reported
KCNK1 (potassium channel subfamily K member 1) gene alterations and SPDEF (SAM pointed domain containing ETS transcription factor) gene fusions have been described in some cases

DDx ─

─ Metastatic papillary carcinoma (e.g., from thyroid, lung, kidney; clinical history, different IHC profile e.g., TTF-1/PAX8 for thyroid/lung/kidney, thyroglobulin for thyroid)
─ Choroid plexus papilloma/carcinoma (more commonly intraventricular; strong S100, transthyretin, synaptophysin often negative or focal; cytokeratins positive)
─ Ependymoma (more common in other CNS locations, but can occur near pineal; GFAP strongly positive, characteristic perivascular pseudorosettes and true ependymal rosettes)
─ Pineal parenchymal tumors (PPTID, Pineocytoma; synaptophysin positive, cytokeratin negative)
─ Germ cell tumors (especially papillary yolk sac tumor or embryonal carcinoma with papillary areas; AFP/HCG, PLAP, OCT3/4, SALL4 positive)

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Germ Cell Tumors of Pineal Region

A heterogeneous group of neoplasms arising from primordial germ cells that have migrated ectopically to the pineal region; these are the most common tumors in the pineal gland, particularly in adolescents and young adults
Clinical ─ Predominantly affect males (especially germinomas and non-germinomatous GCTs); symptoms often include hydrocephalus (due to aqueductal compression), Parinaud syndrome (upward gaze palsy, convergence-retraction nystagmus, light-near dissociation of pupils), headaches, and endocrine dysfunction (e.g., diabetes insipidus, precocious puberty due to HCG production by some GCTs); serum and CSF tumor markers (AFP, HCG) can be elevated depending on the tumor type
Types ─ Include Germinoma (most common), Teratoma (mature, immature, with somatic-type malignancy), Embryonal Carcinoma, Yolk Sac Tumor, Choriocarcinoma, and Mixed Germ Cell Tumors (containing more than one GCT component)
Macro ─ Appearance varies with tumor type; Germinomas are often solid, grayish-white, and friable; Teratomas can be multicystic with heterogeneous areas (cartilage, hair, fat); Choriocarcinomas are often hemorrhagic and necrotic
Micro ─

(Detailed microscopic features will be described under specific GCT subtypes if requested, general features include:)
─ Germinoma: Large polygonal cells with clear cytoplasm, distinct cell membranes, prominent nucleoli, admixed with lymphocytes and often granulomatous inflammation
─ Teratoma: Derivatives of two or three germ cell layers (ectoderm, mesoderm, endoderm) such as skin, cartilage, glandular structures, neural tissue
─ Embryonal Carcinoma: Highly atypical, pleomorphic cells in sheets, cords, or papillary structures, high mitotic rate, necrosis
─ Yolk Sac Tumor: Characterized by Schiller-Duval bodies (glomerulus-like structures), microcystic pattern, hyaline globules (AFP positive)
─ Choriocarcinoma: Syncytiotrophoblastic cells (large, multinucleated, HCG positive) and cytotrophoblastic cells (smaller, mononucleated)

Ancillary studies ─ (General, specific markers depend on subtype)

─ IHC (+)
─ Germinoma: PLAP, OCT3/4 (OCT4), KIT (CD117), SALL4, D2-40 (podoplanin)
─ Embryonal Carcinoma: OCT3/4, SALL4, CD30, cytokeratins (AE1/AE3, CAM5.2)
─ Yolk Sac Tumor: AFP, Glypican-3, SALL4, cytokeratins
─ Choriocarcinoma: HCG (syncytiotrophoblasts), cytokeratins
─ Teratoma: Markers depend on the differentiated tissue types present
─ IHC (-)
─ Pineal parenchymal tumors: Germ cell markers are negative
─ Lymphoma: Germ cell markers are negative (CD45 positive)
─ Serum/CSF Markers:
─ AFP: Elevated in yolk sac tumors, some embryonal carcinomas, some mixed GCTs
─ HCG: Elevated in choriocarcinomas, some embryonal carcinomas, some germinomas with syncytiotrophoblastic giant cells, some mixed GCTs

DDx ─ (For pineal region masses in general, specific GCT DDx depends on subtype)

─ Pineal parenchymal tumors (Pineocytoma, PPTID, Pineoblastoma; synaptophysin positive, germ cell markers negative)
─ Gliomas (Astrocytoma, Oligodendroglioma; GFAP/Olig2 positive)
─ Lymphoma (CD45 positive, specific lymphoid markers)
─ Metastasis (history of primary, IHC profile of primary)
─ Inflammatory lesions/granulomas (if prominent in germinoma)

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Germinoma (of Pineal Region)

The most common type of intracranial germ cell tumor, including in the pineal region, composed of primitive germ cells identical to testicular seminoma and ovarian dysgerminoma
Clinical ─ Predominantly affects adolescent males (peak 10-20 years); symptoms include hydrocephalus, Parinaud syndrome, diabetes insipidus (if suprasellar involvement or extension); highly sensitive to radiation and chemotherapy, with a generally good prognosis; may secrete low levels of HCG due to scattered syncytiotrophoblastic giant cells (STGCs)
Macro ─ Typically solid, well-demarcated or infiltrative, soft, friable, grayish-white or tan mass; necrosis may be present but extensive hemorrhage is uncommon
Micro ─

─ "Two-cell pattern" is characteristic:
─ Large neoplastic germ cells: Polygonal cells with distinct cell membranes, abundant clear or pale eosinophilic glycogen-rich cytoplasm (PAS positive, diastase sensitive), large central vesicular nuclei with one or more prominent nucleoli
─ Stromal lymphocytes: Mature lymphocytes (mostly T-cells) and plasma cells forming a prominent inflammatory infiltrate between nests or sheets of tumor cells
─ Tumor cells are often arranged in sheets, nests, or cords separated by delicate fibrovascular septa containing the lymphoid infiltrate
─ Granulomatous inflammation (non-caseating epithelioid granulomas) is frequently present
─ Scattered syncytiotrophoblastic giant cells (STGCs) may be present, which can be HCG positive and responsible for mild HCG elevation
─ Mitotic figures can be variable

Ancillary studies ─

─ IHC (+)
─ Neoplastic germ cells: PLAP (Placental Alkaline Phosphatase), OCT3/4 (nuclear), SALL4 (nuclear), KIT (CD117, membranous/cytoplasmic), D2-40 (podoplanin, membranous)
─ Syncytiotrophoblastic giant cells (if present): HCG
─ Lymphoid infiltrate: CD3, CD20, CD45
─ IHC (-)
─ Neoplastic germ cells: AFP, Glypican-3 (distinguishes from yolk sac tumor), CD30 (distinguishes from embryonal carcinoma), EMA, cytokeratins (usually negative or only focally weak in perinuclear dots)
─ Pineal parenchymal markers (Synaptophysin)
─ Serum/CSF Markers: HCG may be mildly elevated if STGCs are present; AFP is typically normal (unless mixed with yolk sac tumor)

DDx ─

─ Other germ cell tumors (Embryonal carcinoma, Yolk Sac Tumor, Teratoma, Choriocarcinoma; distinguished by morphology and specific IHC markers like AFP, HCG, CD30, cytokeratins, and tissue differentiation)
─ Lymphoma (CD45 positive, specific lymphoid markers, lacks large OCT3/4 positive tumor cells)
─ Pineal parenchymal tumors (Synaptophysin positive, germ cell markers negative)
─ Inflammatory/granulomatous lesions (e.g., sarcoidosis, tuberculosis; presence of epithelioid granulomas but lacks neoplastic germ cells)
─ Metastatic carcinoma or melanoma (history, specific IHC markers for primary)

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Embryonal Carcinoma (of Pineal Region)

A highly malignant, primitive non-germinomatous germ cell tumor composed of undifferentiated epithelial-like cells resembling those of the embryonic disc, capable of differentiating towards somatic or extraembryonic lineages
Clinical ─ Rare in the pineal region, more common in gonads; typically affects adolescents and young adults; aggressive clinical course with early metastasis and poor prognosis; often presents with symptoms of increased intracranial pressure or focal neurological deficits; serum AFP and/or HCG may be elevated
Macro ─ Often poorly demarcated, infiltrative mass with areas of hemorrhage and necrosis; grayish-tan and friable
Micro ─

─ Highly pleomorphic, anaplastic epithelial-like cells arranged in solid sheets, cords, glands, or papillary structures
─ Cells have large, irregular, hyperchromatic nuclei with prominent nucleoli and frequent, often atypical, mitotic figures
─ Cytoplasm is usually scant to moderate, amphophilic or basophilic
─ Cell borders are often indistinct
─ Necrosis and hemorrhage are common features
─ Vascular invasion is often seen
─ May coexist with other germ cell tumor components (mixed GCT)

Ancillary studies ─

─ IHC (+)
─ OCT3/4 (nuclear): Strong and diffuse positivity
─ SALL4 (nuclear): Strong and diffuse positivity
─ CD30: Membranous positivity is characteristic
─ Cytokeratins (AE1/AE3, CAM5.2): Often strongly positive
─ PLAP: May be positive but often weaker or more focal than in germinoma
─ AFP: May be focally positive if yolk sac differentiation is present
─ HCG: May be positive if syncytiotrophoblastic cells are present
─ IHC (-)
─ KIT (CD117): Usually negative or weak (in contrast to germinoma)
─ Glypican-3 (unless yolk sac elements are present)
─ Serum/CSF Markers: AFP and/or HCG are often elevated

DDx ─

─ Germinoma (less pleomorphic, clear cytoplasm, lymphoid infiltrate, OCT3/4 and KIT positive, CD30 negative)
─ Yolk Sac Tumor (Schiller-Duval bodies, microcystic pattern, AFP and Glypican-3 positive, CD30 negative)
─ Choriocarcinoma (syncytiotrophoblastic and cytotrophoblastic cells, prominent HCG production)
─ Poorly differentiated carcinoma/metastasis (clinical history, different IHC profile e.g., site-specific markers, often OCT3/4 and SALL4 negative)
─ Pineoblastoma (primitive neuroectodermal tumor; synaptophysin may be positive, germ cell markers negative)

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Yolk Sac Tumor (Endodermal Sinus Tumor, of Pineal Region)

A malignant non-germinomatous germ cell tumor characterized by differentiation towards extraembryonic yolk sac structures; rare in the pineal region
Clinical ─ Typically occurs in children and young adults; aggressive tumor with a poor prognosis, though improved with modern chemotherapy; usually presents with symptoms of increased intracranial pressure or neurological deficits; markedly elevated serum and/or CSF AFP is characteristic
Macro ─ Heterogeneous mass, often large, poorly demarcated, with solid, cystic, gelatinous, and hemorrhagic areas; yellowish or tan cut surface
Micro ─

─ Variety of architectural patterns:
─ Microcystic/reticular pattern: Most common, anastomosing channels and cysts lined by flattened or cuboidal tumor cells
─ Schiller-Duval bodies: Pathognomonic (but not always present); glomerulus-like structures with a central capillary surrounded by tumor cells, within a cystic space lined by tumor cells
─ Festoon pattern: Papillary structures with edematous fibrovascular cores
─ Solid pattern: Sheets of pleomorphic cells
─ Glandular-alveolar, polyvesicular vitelline, hepatoid patterns may also occur
─ Tumor cells are cuboidal, columnar, or flattened, with variable atypia; cytoplasm can be clear, eosinophilic, or vacuolated
─ Hyaline globules: Eosinophilic, PAS-positive, diastase-resistant intracytoplasmic or extracellular globules, which are AFP positive, are a characteristic feature
─ Mitotic activity is usually high; necrosis is common

Ancillary studies ─

─ IHC (+)
─ AFP (Alpha-fetoprotein): Strong and diffuse positivity in tumor cells and hyaline globules (key marker)
─ Glypican-3: Strong and diffuse positivity (another key marker)
─ SALL4 (nuclear): Strong and diffuse positivity
─ Cytokeratins (AE1/AE3, CAM5.2): Positive
─ Lin28: May be positive
─ IHC (-)
─ OCT3/4: Usually negative (in contrast to germinoma and embryonal carcinoma) or only very focally positive
─ CD30: Negative (distinguishes from embryonal carcinoma)
─ PLAP: Usually negative or weak
─ HCG: Negative (unless mixed with choriocarcinoma or STGCs)
─ Serum/CSF Markers: AFP is markedly elevated

DDx ─

─ Other germ cell tumors:
─ Embryonal Carcinoma (CD30 positive, OCT3/4 positive, AFP may be focal but Glypican-3 less diffuse)
─ Germinoma (OCT3/4 and KIT positive, AFP and Glypican-3 negative)
─ Choriocarcinoma (HCG positive)
─ Teratoma with yolk sac tumor component (requires thorough sampling)
─ Papillary tumor of the pineal region (PTPR) (CK positive but AFP/Glypican-3 negative, different morphology)
─ Metastatic adenocarcinoma (e.g., hepatoid adenocarcinoma; clinical history, AFP may be positive but Glypican-3/SALL4 profile helps)

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Choriocarcinoma (of Pineal Region)

A highly malignant non-germinomatous germ cell tumor composed of both cytotrophoblastic and syncytiotrophoblastic cells, recapitulating placental trophoblastic tissue; extremely rare as a pure primary intracranial tumor
Clinical ─ Can occur in adolescents and young adults; highly aggressive with early hematogenous metastasis (especially to lungs and liver) and poor prognosis; often presents with symptoms of intracranial hemorrhage due to its vascularity, or increased intracranial pressure; marked elevation of serum and/or CSF HCG is characteristic; may cause precocious puberty in males due to HCG production
Macro ─ Typically a hemorrhagic and necrotic mass; may be relatively small but with extensive hemorrhage; can be infiltrative
Micro ─

─ Biphasic pattern composed of two distinct cell types:
─ Syncytiotrophoblastic cells: Large, multinucleated giant cells with abundant eosinophilic or amphophilic vacuolated cytoplasm and pleomorphic, hyperchromatic nuclei; these cells produce HCG and often surround clusters of cytotrophoblasts or line blood-filled spaces
─ Cytotrophoblastic cells: Smaller, mononucleated polygonal cells with clear or pale eosinophilic cytoplasm, distinct cell borders, and relatively uniform nuclei; arranged in sheets, nests, or cords, often capped by syncytiotrophoblasts
─ Extensive hemorrhage, necrosis, and vascular invasion are characteristic features
─ Often occurs as a component of a mixed germ cell tumor rather than in pure form

Ancillary studies ─

─ IHC (+)
─ HCG (Human Chorionic Gonadotropin): Strong and diffuse positivity in syncytiotrophoblastic cells (key marker)
─ Cytokeratins (AE1/AE3, CAM5.2): Positive in both cell types
─ SALL4 (nuclear): Positive in cytotrophoblasts and can be in syncytiotrophoblasts
─ GATA3: Can be positive, especially in cytotrophoblasts
─ Inhibin-alpha: May be positive in syncytiotrophoblasts
─ IHC (-)
─ AFP, Glypican-3 (unless mixed with yolk sac tumor)
─ OCT3/4 (usually negative in choriocarcinoma cells, though can be positive in associated germinoma or embryonal carcinoma components in a mixed GCT)
─ PLAP (usually negative or weak)
─ Serum/CSF Markers: HCG is markedly elevated

DDx ─

─ Other germ cell tumors with syncytiotrophoblastic giant cells (e.g., germinoma with STGCs, embryonal carcinoma with STGCs; in pure choriocarcinoma, both cytotrophoblasts and syncytiotrophoblasts are malignant and form the bulk of the tumor, not just scattered STGCs)
─ Metastatic choriocarcinoma (from gonadal or gestational primary; clinical history is crucial)
─ Pituitary adenoma with hemorrhage (pituitary hormone markers positive)
─ Highly vascular metastatic carcinoma with hemorrhage (e.g., renal cell carcinoma, melanoma; specific IHC markers for primary)

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Teratoma (of Pineal Region)

A type of germ cell tumor composed of a mixture of tissues differentiated along ectodermal, mesodermal, and endodermal lines, representing somatic differentiation from pluripotent germ cells; can be mature, immature, or with somatic-type malignancy
Clinical ─ Occurs in the pineal region, typically in children and young adults, with a male predominance; symptoms depend on size and location, often causing hydrocephalus, Parinaud syndrome, or endocrine disturbances; mature teratomas are generally benign, while immature teratomas and teratomas with somatic-type malignancy have a more aggressive course and higher risk of recurrence/malignant transformation
Macro ─ Appearance is often heterogeneous, reflecting the diverse tissue components; can be solid, cystic, or mixed; cysts may contain sebaceous material, hair, or serous fluid; areas of cartilage, bone, or fat may be grossly visible; immature teratomas are often softer and more necrotic, while those with somatic malignancy may show features of the specific cancer type
Micro ─

─ Mature Teratoma (WHO Grade 0):
─ Composed entirely of well-differentiated, mature tissues from two or three germ cell layers
─ Ectodermal derivatives: Squamous epithelium (skin with adnexa like hair follicles, sebaceous glands), neural tissue (glial cells, mature neurons, choroid plexus), teeth
─ Mesodermal derivatives: Cartilage, bone, adipose tissue, smooth muscle, striated muscle, fibrous connective tissue
─ Endodermal derivatives: Glandular structures resembling respiratory or gastrointestinal epithelium, pancreatic tissue, thyroid tissue
─ No immature (embryonal) tissues or malignant components

─ Immature Teratoma (WHO Grade 2 or 3, depending on amount of immature neuroepithelium):
─ Contains immature, embryonal-type tissues, most commonly immature neuroepithelium resembling fetal neural tube (primitive neuroblastic rosettes, tubules)
─ Other immature tissues (e.g., immature cartilage, mesenchyme) may be present
─ Grading is based on the quantity of immature neuroepithelium:
─ Grade 1 (mature): No or very rare immature neuroepithelium
─ Grade 2: Limited quantity of immature neuroepithelium (<1 low-power field [LPF, 40x objective] in any slide)
─ Grade 3: Moderate to large quantity of immature neuroepithelium (≥1 LPF in any slide)
─ Mitotic activity can be present in immature components

─ Teratoma with Somatic-Type Malignancy:
─ Development of a conventional somatic-type cancer within a teratoma (e.g., squamous cell carcinoma, adenocarcinoma, sarcoma like rhabdomyosarcoma or angiosarcoma, PNET-like tumors)
─ The malignant component overgrows or infiltrates the pre-existing teratomatous elements
─ Prognosis is dictated by the type and grade of the somatic malignancy

Ancillary studies ─

─ IHC (+)
─ Depends on the differentiated tissue types present (e.g., cytokeratins in squamous/glandular epithelium, GFAP in glial tissue, S100 in neural/cartilage/adipose tissue, desmin/myogenin in muscle)
─ Immature neuroepithelium: May be positive for neural stem cell markers (e.g., SOX2, Nestin) or synaptophysin in areas of differentiation
─ Malignant component in teratoma with somatic-type malignancy: Markers specific to that malignancy (e.g., p63 for squamous cell carcinoma, specific cytokeratins for adenocarcinoma)
─ IHC (-)
─ Pure mature teratomas are typically negative for germ cell markers like OCT3/4, PLAP, SALL4 in the differentiated somatic tissues (though SALL4 can be positive in some endodermal glands or immature elements)
─ AFP and HCG are usually negative unless there's an admixed yolk sac tumor or choriocarcinoma component, or very rarely produced by certain somatic malignancies
─ Serum/CSF Markers: Usually normal for AFP and HCG in pure mature teratomas; may be elevated if mixed with other GCT components or in some teratomas with somatic-type malignancy

DDx ─

─ Other germ cell tumors (Germinoma, Yolk Sac Tumor, Embryonal Carcinoma, Choriocarcinoma; distinguished by specific morphology and IHC markers; teratomas often occur in mixed GCTs)
─ Dermoid cyst (composed exclusively of skin and skin adnexa; a type of mature cystic teratoma focused on ectodermal elements)
─ Epidermoid cyst (lined only by keratinizing squamous epithelium)
─ Craniopharyngioma (adamantinomatous or papillary types; specific histological features and molecular markers,
CTNNB1 or BRAF mutations)
─ Hamartoma (disorganized but mature native tissues; rare in pineal, lacks foreign tissue types)
─ Metastatic carcinoma or sarcoma (if considering teratoma with somatic-type malignancy; clinical history, morphology)

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#Thyroid Gland

Normal Thyroid Histology & Developmental Anomalies

The thyroid gland is an endocrine gland in the neck responsible for producing thyroid hormones (thyroxine/T4 and triiodothyronine/T3) which regulate metabolism, and calcitonin which is involved in calcium homeostasis; developmental anomalies arise from aberrations in its embryological descent or differentiation
Clinical ─ Normal function is essential for metabolic balance across multiple organ systems; developmental anomalies can present as asymptomatic masses, cause obstructive symptoms, or lead to hypothyroidism/hyperthyroidism if thyroid tissue is malpositioned or insufficient/overactive
Macro ─ Normal: Butterfly-shaped gland with two lateral lobes connected by a central isthmus, located anterior to the trachea; reddish-brown, soft to firm, weighs ~15-25 grams. Developmental anomalies: Ectopic thyroid can be found anywhere along the descent path from foramen cecum to mediastinum; thyroglossal duct cysts are midline neck masses
Micro ─

Normal Thyroid Histology:
─ Composed of follicles of varying sizes, lined by a single layer of cuboidal to low columnar follicular epithelial cells (thyrocytes)
─ Follicles are filled with pink, amorphous colloid (stored thyroglobulin)
─ Follicular cells have round, basal nuclei and moderate amounts of cytoplasm
─ Parafollicular cells (C cells): Larger, pale cells located individually or in small clusters within the follicular basement membrane or in the interfollicular stroma; produce calcitonin; more numerous in the middle to upper thirds of the lateral lobes
─ Stroma is delicate, highly vascularized connective tissue
─ Lymphocytes may be sparsely present in normal stroma

Developmental Anomalies (General):
─ Agenesis/Hypoplasia: Complete or partial absence of thyroid tissue, leading to congenital hypothyroidism
─ Ectopic Thyroid: Presence of thyroid tissue outside its normal cervical location (see specific entry)
─ Thyroglossal Duct Cyst: Cystic remnant of the thyroglossal duct (see specific entry)
─ Branchial Cleft Anomalies presenting as cysts in neck (see specific entry)
─ Pyramidal Lobe: Common superior extension of thyroid tissue from the isthmus, a remnant of the distal thyroglossal duct
─ Lingual Thyroid: Most common form of ectopic thyroid, thyroid tissue at the base of the tongue (foramen cecum)
─ Struma Ovarii: Teratoma of the ovary composed predominantly of mature thyroid tissue; can rarely cause hyperthyroidism

Ancillary studies ─ (Normal Thyroid)

─ IHC (+)
─ Follicular cells: Thyroglobulin (Tg, cytoplasmic and intrafollicular), TTF-1 (thyroid transcription factor-1, nuclear), PAX8 (paired box gene 8, nuclear), Cytokeratins (e.g., CK7, CAM5.2)
─ C cells: Calcitonin, Chromogranin A, Synaptophysin, CEA (carcinoembryonic antigen); may be TTF-1 positive (often weaker than follicular cells)
─ IHC (-)
─ Follicular cells: Generally negative for calcitonin (though some cross-reactivity reported with certain antibodies if not specific), S100 (except occasional dendritic cells)
─ C cells: Negative for Thyroglobulin

DDx ─ (for normal histology, context dependent on sample type e.g. FNA, core biopsy, lobectomy)

─ Follicular nodular disease (variation in follicle size, colloid, +/- degenerative changes)
─ Follicular adenoma (encapsulated, different architecture, compression of adjacent normal)
─ Thyroiditis (inflammatory infiltrates, specific features depending on type)

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Solid Cell Nests (SCN)

Microscopic clusters of non-follicular, non-C cells found within the thyroid gland, considered remnants of the ultimobranchial body (ultimopharyngeal body) which contributes to thyroid development
Clinical ─ Asymptomatic, incidental microscopic findings; no known clinical significance or malignant potential on their own, but important to recognize and distinguish from neoplasms or metastatic carcinoma, especially on frozen section or small biopsies
Macro ─ Not grossly visible
Micro ─

─ Well-circumscribed, solid or cystic nests of polygonal to spindle-shaped cells with eosinophilic or clear cytoplasm
─ Nuclei are typically bland, round to oval, with smooth contours and inconspicuous nucleoli
─ May contain small follicle-like structures (microcysts) or show squamous metaplasia
─ Often located in the middle to upper portions of the thyroid lobes, in the vicinity of C cells (as both are derived from ultimobranchial body)
─ May be surrounded by a fibrous stroma or lymphoid infiltrate
─ No significant atypia, mitoses, or infiltrative growth

Ancillary studies ─

─ IHC (+)
─ p63, p40: Often positive, especially in areas with squamous features (strongest evidence of ultimobranchial body origin)
─ Cytokeratins (e.g., CK5/6, CK1, CK10, CK14 - squamous types; CK19): Variable positivity
─ PAX8: Can be positive
─ CEA (monoclonal): May be positive (a potential pitfall if C-cell lesions are considered)
─ Galectin-3: May be positive
─ IHC (-)
─ Thyroglobulin: Negative (key distinguishing feature from follicular cells)
─ Calcitonin: Negative (key distinguishing feature from C-cells/medullary carcinoma)
─ TTF-1: Often negative or weakly positive (in contrast to strong positivity in follicular cells and many C-cells)
─ S100

DDx ─

─ Papillary thyroid carcinoma (especially infiltrative follicular variant or micropapillary carcinoma; PTC shows nuclear features like grooves, inclusions, clearing; positive for thyroglobulin, TTF-1, PAX8; lacks p63/p40 expression in tumor cells)
─ Medullary thyroid carcinoma (calcitonin positive, amyloid may be present)
─ Squamous metaplasia in Hashimoto's thyroiditis (background of thyroiditis, thyroglobulin often positive in metaplastic cells)
─ Metastatic squamous cell carcinoma (marked atypia, infiltrative growth, clinical history)
─ Intrathyroidal thymic tissue/Thymoma (rare; thymic epithelial cells, Hassall's corpuscles, immature T-lymphocytes (TdT+))
─ Parathyroid tissue (intrathyroidal parathyroid; PTH positive, GATA3 positive, chromogranin positive; negative for thyroglobulin, calcitonin, p63)

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Ectopic Thyroid (including Lingual Thyroid)

Presence of thyroid tissue in any location outside its normal pre-tracheal position, resulting from aberrant migration of the thyroid anlage during embryogenesis
Clinical ─ Lingual thyroid (at the base of the tongue near foramen cecum) is the most common form (~90% of cases); other sites include lateral neck (often within lymph nodes, raising concern for metastasis if not recognized), mediastinum, trachea, esophagus, heart (struma cordis), adrenal gland, gallbladder; often asymptomatic, but can cause mass effects (dysphagia, dysphonia, airway obstruction), hypothyroidism (if it's the only functioning thyroid tissue and insufficient), or rarely hyperthyroidism; may undergo same pathological changes as normally sited thyroid (goiter, adenoma, carcinoma)
Macro ─ Variable size and appearance depending on location and any pathological changes; lingual thyroid appears as a nodular or lobulated mass at the base of the tongue
Micro ─

─ Histologically identical to normal thyroid gland tissue, composed of thyroid follicles lined by follicular cells and containing colloid
─ C-cells are generally absent or sparse in ectopic thyroid tissue, especially in lingual thyroid, as C-cells derive from the ultimobranchial body which fuses with the lateral thyroid lobes later in development
─ The tissue may be normal, hyperplastic (goitrous), or show neoplastic changes (adenoma, carcinoma)
─ Ectopic thyroid tissue in lymph nodes (benign thyroid inclusions) must be distinguished from metastatic well-differentiated thyroid carcinoma; benign inclusions are typically small, located in the lymph node capsule or peripheral sinuses, composed of normal-appearing follicles, and lack psammoma bodies, papillary architecture, or PTC nuclear features.

Ancillary studies ─

─ IHC (+) (for thyroid follicular cells within the ectopic tissue)
─ Thyroglobulin (Tg)
─ TTF-1 (nuclear)
─ PAX8 (nuclear)
─ IHC (-) (C-cell markers like calcitonin are usually sparse or absent)
─ Imaging: Thyroid scan (e.g., I-123 or Tc-99m pertechnetate scintigraphy) can confirm the thyroidal nature of the ectopic tissue and assess for normally sited thyroid gland

DDx ─ (Depends on location)

─ For neck masses: Thyroglossal duct cyst, branchial cleft cyst, lymphadenopathy, primary neck tumors
─ For lingual mass: Lymphoid hyperplasia of lingual tonsil, squamous cell carcinoma, salivary gland tumors
─ For thyroid tissue in lymph nodes: Metastatic well-differentiated thyroid carcinoma (PTC, follicular carcinoma; look for PTC nuclear features, infiltrative growth, psammoma bodies, Ki-67, BRAF/RAS mutations)
─ Struma ovarii (teratoma of ovary with thyroid tissue; ovarian location)

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Thyroglossal Duct Cyst

A congenital cyst that forms from persistent remnants of the thyroglossal duct, an embryologic tract formed during the descent of the thyroid gland from the foramen cecum to its final position in the neck
Clinical ─ Most common congenital neck mass in children, but can present at any age; typically presents as a painless, fluctuant, mobile midline or slightly off-midline neck mass, often inferior to the hyoid bone; may move with swallowing or protrusion of the tongue; can become infected, leading to pain, tenderness, and erythema; rarely, carcinoma (usually papillary thyroid carcinoma) can arise within the cyst
Macro ─ Smooth, well-circumscribed, unilocular cyst containing clear, mucoid, or turbid fluid; the cyst wall is usually thin unless chronically inflamed or infected
Micro ─

─ Cyst lining is variable:
─ Most commonly lined by pseudostratified columnar ciliated (respiratory-type) epithelium or stratified squamous epithelium
─ Cuboidal or simple columnar epithelium may also be seen
─ Transitional or urothelial-like epithelium has been reported
─ The cyst wall typically contains:
─ Thyroid follicles: Nests of normal-appearing thyroid follicles are found in the cyst wall in a significant percentage of cases (up to 60%) and are diagnostic when present
─ Inflammatory cells: Lymphocytes, plasma cells, macrophages are common, especially if the cyst has been inflamed or ruptured; lymphoid aggregates with germinal centers may be present
─ Fibrous connective tissue
─ Smooth muscle bundles may be seen in the wall
─ Squamous metaplasia of the lining is common, especially with chronic inflammation
─ Cholesterol clefts, foamy macrophages, and foreign body giant cells if there has been previous hemorrhage or rupture

Ancillary studies ─

─ IHC (+)
─ Epithelial lining: Cytokeratins (pattern depends on epithelial type)
─ Thyroid follicles in wall: Thyroglobulin, TTF-1, PAX8
─ IHC (-)
─ Malignancy markers (e.g., extensive Ki-67, p53 overexpression) unless carcinoma has arisen in the cyst

DDx ─

─ Branchial cleft cyst (typically lateral neck, different embryologic origin, often lined by squamous epithelium with abundant lymphoid tissue in the wall, lacks thyroid follicles)
─ Dermoid cyst / Epidermoid cyst (midline neck; dermoid contains skin adnexa like hair follicles and sebaceous glands; epidermoid lined by keratinizing squamous epithelium with granular layer; both lack thyroid follicles and respiratory epithelium)
─ Lymphadenopathy (reactive or neoplastic; solid, distinct lymphoid architecture)
─ Cystic hygroma (lymphangioma; endothelial-lined lymphatic channels)
─ Infected sebaceous cyst
─ Carcinoma arising in thyroglossal duct cyst (e.g., papillary thyroid carcinoma; look for diagnostic features of PTC within the epithelial component)

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Branchial Cleft Cyst

A congenital cyst arising from persistence of remnants of the embryonic branchial clefts or arches, typically located in the lateral aspect of the neck
Clinical ─ Usually presents as a painless, fluctuant mass in the lateral neck, anterior to the sternocleidomastoid muscle; most commonly from the second branchial cleft (90-95% of cases), typically located between the angle of the mandible and the clavicle; can occur at any age, often noted in late childhood or early adulthood; may become tender and enlarged if infected; fistulous tracts to the skin or pharynx can occur
Macro ─ Well-circumscribed, unilocular cyst filled with clear, mucoid, turbid, or purulent fluid (if infected); cyst wall is usually smooth but can be thickened if recurrently inflamed
Micro ─

─ Cyst lining:
─ Most commonly lined by stratified squamous epithelium (keratinizing or non-keratinizing), especially in second cleft cysts
─ Pseudostratified columnar ciliated (respiratory-type) epithelium can also be seen, particularly in cysts of first or third/fourth cleft origin, or mixed with squamous epithelium
─ Cuboidal or simple columnar epithelium may also occur
─ Cyst wall:
─ Characteristically contains abundant lymphoid tissue, often with reactive germinal centers; this lymphoid tissue is a key diagnostic feature
─ Fibrous connective tissue
─ Cholesterol clefts, foamy macrophages, and inflammatory cells (lymphocytes, plasma cells, neutrophils if acutely infected) are common
─ Muscle bundles may be present in the wall
─ Thyroid follicles are typically absent (helps distinguish from thyroglossal duct cyst if location is unusual)
─ Cartilage may rarely be present in the wall, especially in first branchial cleft cysts

Ancillary studies ─

─ IHC (+)
─ Epithelial lining: Cytokeratins (pattern depends on epithelial type, e.g., CK5/6 for squamous)
─ Lymphoid tissue: CD45, CD20 (B-cells), CD3 (T-cells)
─ IHC (-)
─ Thyroglobulin, TTF-1, PAX8 (in the cyst wall/lining, distinguishing from thyroglossal duct cyst or thyroid primaries)

DDx ─

─ Thyroglossal duct cyst (usually midline or paramedian, often associated with hyoid bone, contains thyroid follicles in the wall)
─ Lymphoepithelial cyst of salivary gland or oral mucosa (similar lining and lymphoid tissue, but location and association with salivary tissue helps)
─ Cystic metastatic carcinoma (especially squamous cell carcinoma from head and neck primary, or papillary thyroid carcinoma with cystic change; look for malignant cytological features, infiltrative growth, specific IHC markers like p16 for HPV-related SCC, or PTC features/markers)
─ Dermoid cyst / Epidermoid cyst (epidermoid lined by keratinizing squamous epithelium with granular layer; dermoid contains skin adnexa; lymphoid tissue is not a prominent feature)
─ Cystic hygroma (lymphangioma; endothelial-lined lymphatic channels)
─ Infected lymph node with cystic change (necrotic lymph node)
─ Parathyroid cyst (rare, PTH in fluid, parathyroid hormone positive cells if lining present)

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Bronchogenic Cyst

A congenital cyst resulting from abnormal budding or branching of the tracheobronchial tree during embryonic development; most commonly found in the mediastinum but can occur in the neck, lung parenchyma, or other locations
Clinical ─ Often asymptomatic and discovered incidentally; if symptomatic, presentation depends on location and size, and may include chest pain, cough, dyspnea, dysphagia, or recurrent respiratory infections if the cyst communicates with the airway or becomes infected; cervical bronchogenic cysts present as neck masses
Macro ─ Usually unilocular, smooth-walled cyst containing clear, serous, or mucoid fluid; occasionally can be filled with milky or gelatinous material; the wall is typically thin
Micro ─

─ Cyst lining:
─ Characteristically lined by pseudostratified columnar ciliated (respiratory-type) epithelium
─ Goblet cells are often present within the lining
─ Squamous metaplasia can occur, especially with inflammation
─ Cyst wall components (key diagnostic features, though not all may be present in every cyst):
─ Hyaline cartilage plates or islands (similar to tracheal/bronchial cartilage)
─ Smooth muscle bundles
─ Seromucinous bronchial-type glands
─ Fibrous connective tissue forms the outer layer of the wall
─ Inflammatory cells (lymphocytes, plasma cells) may be present, especially if inflamed or infected
─ Thyroid follicles are absent

Ancillary studies ─

─ IHC (+)
─ Epithelial lining: Cytokeratins (e.g., CK7 positive in respiratory epithelium)
─ Smooth muscle in wall: Smooth muscle actin (SMA), desmin
─ Cartilage: S100 protein may be positive in chondrocytes
─ IHC (-)
─ Thyroglobulin, TTF-1 (in lining cells, though TTF-1 can be positive in respiratory epithelium, pattern/intensity differs from thyroid follicular cells), PAX8
─ Calcitonin

DDx ─ (for cervical bronchogenic cyst)

─ Thyroglossal duct cyst (midline, thyroid follicles in wall, lacks cartilage and bronchial glands)
─ Branchial cleft cyst (lateral neck, prominent lymphoid tissue in wall, usually squamous or respiratory lining, lacks cartilage and bronchial glands)
─ Esophageal duplication cyst (lined by esophageal-type squamous or gastric/intestinal epithelium, often has two muscle layers)
─ Cystic hygroma (lymphangioma; endothelial lining)
─ Dermoid/Epidermoid cyst (keratinizing squamous epithelium +/- adnexa)
─ Thyroid cyst (arising within thyroid gland, lined by thyroid follicular cells or flattened epithelium)
─ Parathyroid cyst (rare, PTH in fluid)

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Follicular Nodular Disease (Multinodular Goiter, Adenomatoid Nodule)

A common benign condition characterized by diffuse or focal enlargement of the thyroid gland due to proliferation of follicular cells, forming multiple nodules of varying size and appearance; results from cycles of hyperplasia and involution
Clinical ─ Can be sporadic or endemic (iodine deficiency); more common in females and with increasing age; often asymptomatic, discovered as a palpable neck mass or incidentally on imaging; may cause compressive symptoms (dysphagia, dyspnea, hoarseness) if large; can be associated with hyperthyroidism (toxic multinodular goiter/Plummer disease) or hypothyroidism (less common); risk of malignancy within a nodular goiter is low but present
Macro ─ Enlarged, often asymmetric thyroid gland with a distorted architecture due to multiple nodules of varying sizes
─ Nodules can be solid, cystic, hemorrhagic, or calcified
─ Cut surface shows a variegated appearance: fleshy tan-brown nodules, gelatinous colloid-filled areas, cystic degeneration, hemorrhage, fibrosis, and calcification
─ Encapsulation of individual nodules is typically incomplete or absent, distinguishing them from true follicular adenomas, though some may appear well-circumscribed ("adenomatoid nodules")
Micro ─

─ Marked heterogeneity is characteristic, both between nodules and within nodules
─ Nodules are composed of thyroid follicles that vary widely in size, from microfollicles (small, back-to-back follicles with scant colloid) to macrofollicles (large, dilated follicles distended with abundant colloid)
─ Follicular cells may be flattened, cuboidal, or columnar (hypertrophic/hyperplastic)
─ Colloid can be abundant and pale, or scant and deeply eosinophilic with scalloping (if hyperactive)
─ Degenerative changes are common:
─ Cystic degeneration (fluid-filled spaces)
─ Hemorrhage (fresh or old, with hemosiderin-laden macrophages)
─ Fibrosis (interfollicular or forming thick bands)
─ Calcification (dystrophic, psammomatous bodies are rare in benign nodules)
─ Foamy macrophages, cholesterol clefts
─ Papillary hyperplasia (Sanderson polsters): Benign papillary infoldings of hyperplastic follicular epithelium into follicular lumens, lacking true fibrovascular cores and nuclear features of papillary carcinoma
─ Oncocytic (Hürthle cell) metaplasia can occur
─ Lymphocytic infiltrates may be present, sometimes resembling Hashimoto's thyroiditis focally
─ Intervening thyroid parenchyma between nodules may be compressed or also show hyperplastic changes

Ancillary studies ─

─ IHC (+) (follicular cells)
─ Thyroglobulin, TTF-1, PAX8
─ IHC (-)
─ Malignancy markers (e.g., BRAF V600E, RET/PTC rearrangements usually absent; however, neoplasms can arise within nodular goiter)
─ Ki-67 proliferation index: Generally low, but can be focally increased in hyperplastic areas

DDx ─

─ Follicular adenoma (solitary, well-encapsulated neoplasm with uniform architecture different from surrounding thyroid, compresses adjacent tissue)
─ Follicular carcinoma (capsular and/or vascular invasion required for diagnosis)
─ Papillary thyroid carcinoma (diagnostic nuclear features, true papillary structures with fibrovascular cores, psammoma bodies; can arise in a nodular goiter)
─ Hashimoto's thyroiditis (diffuse lymphocytic infiltrate with germinal centers, Hürthle cell metaplasia, follicular atrophy; can coexist with nodular disease)
─ Graves' disease (diffuse hyperplasia, colloid scalloping, lymphoid infiltrates; clinical hyperthyroidism)

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Acute Thyroiditis (Suppurative Thyroiditis, Infectious Thyroiditis)

A rare inflammatory condition of the thyroid gland caused by bacterial, fungal, or parasitic infection, leading to acute inflammation and often abscess formation
Clinical ─ Patients typically present with acute onset of severe neck pain (often unilateral), tenderness, fever, chills, dysphagia, and erythema over the thyroid; thyroid function is usually normal (euthyroid), but transient thyrotoxicosis or hypothyroidism can occur; predisposing factors include pre-existing thyroid disease (e.g., nodular goiter, Hashimoto's), immunosuppression, or pyriform sinus fistula (especially in children on the left side)
Macro ─ Thyroid gland may be enlarged, indurated, and tender; cut surface may show areas of liquefaction, abscess formation, or purulent exudate
Micro ─

─ Dense infiltration of the thyroid parenchyma by neutrophils (polymorphonuclear leukocytes) is the hallmark feature
─ Necrosis of thyroid follicles and interstitial tissue
─ Abscess formation (collections of neutrophils and necrotic debris)
─ Edema and vascular congestion
─ Presence of microorganisms may be demonstrable with special stains (e.g., Gram stain for bacteria, GMS or PAS for fungi) or by culture
─ Later stages may show granulation tissue, foamy macrophages, and fibrosis during healing

Ancillary studies ─

─ Special stains: Gram stain, Grocott-Gomori methenamine-silver (GMS), Periodic acid-Schiff (PAS) to identify bacteria or fungi
─ IHC: Not typically primary for diagnosis, but may show inflammatory cell markers (e.g., MPO for neutrophils)
─ Microbiology: Culture of fine-needle aspirate or tissue is crucial for identifying the causative organism and guiding antibiotic therapy
─ Blood tests: Elevated white blood cell count (leukocytosis) with neutrophilia, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

DDx ─

─ Subacute (granulomatous/De Quervain) thyroiditis (viral prodrome, granulomatous inflammation with multinucleated giant cells, less intense neutrophilic infiltrate, often thyrotoxic phase followed by hypothyroid phase)
─ Anaplastic thyroid carcinoma (can present with rapid neck mass and inflammation; highly malignant cells, necrosis, high mitotic rate)
─ Hashimoto's thyroiditis (lymphoplasmacytic infiltrate, Hürthle cells, germinal centers; usually chronic)
─ Hemorrhage into a thyroid nodule (can cause acute pain; hemosiderin, no primary infection)
─ Riedel's thyroiditis (dense fibrous tissue, "woody" thyroid; chronic inflammation)
─ Other causes of acute neck pain/swelling (e.g., infected branchial cleft cyst, cellulitis)

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Granulomatous (De Quervain) Thyroiditis (Subacute Thyroiditis)

A self-limited inflammatory condition of the thyroid gland, likely triggered by a viral infection, characterized by granulomatous inflammation and transient changes in thyroid function
Clinical ─ Typically preceded by an upper respiratory tract infection; presents with acute onset of neck pain (often radiating to jaw or ears), thyroid tenderness, fever, malaise, and fatigue; triphasic clinical course: initial hyperthyroid phase (due to follicle destruction and hormone release), followed by a hypothyroid phase, then usually return to euthyroid state within months; elevated ESR is characteristic; thyroid autoantibodies are usually negative or low titer
Macro ─ Gland may be unilaterally or bilaterally enlarged, firm, and tender; cut surface may appear yellowish-white and indurated in affected areas
Micro ─

─ Patchy, non-caseating granulomatous inflammation centered on disrupted thyroid follicles
─ Granulomas are composed of epithelioid histiocytes, multinucleated giant cells (often engulfing colloid), lymphocytes, and plasma cells
─ Early phase: Follicular destruction with neutrophilic infiltrate and colloid extravasation
─ Mid phase: Characteristic granulomas surrounding pools of colloid; follicular regeneration begins
─ Late phase: Resolution of inflammation, fibrosis, and return to more normal follicular architecture, though some fibrosis may persist
─ Affected areas are often sharply demarcated from uninvolved thyroid parenchyma

Ancillary studies ─

─ IHC: Not usually required for diagnosis
─ Histiocytes: CD68 positive
─ Lymphocytes: CD3, CD20
─ Special stains: Negative for microorganisms (e.g., AFB, GMS)
─ Fine Needle Aspiration (FNA): Shows multinucleated giant cells, epithelioid histiocytes, follicular cells (sometimes degenerated), colloid, and mixed inflammatory cells; helps distinguish from malignancy

DDx ─

─ Acute (suppurative) thyroiditis (predominantly neutrophilic infiltrate, abscess formation, bacterial/fungal organisms)
─ Hashimoto's thyroiditis (diffuse lymphoplasmacytic infiltrate, Hürthle cells, germinal centers, autoantibodies positive)
─ Palpation thyroiditis (focal, often asymptomatic, similar granulomatous reaction to colloid but usually less extensive and without systemic symptoms)
─ Riedel's thyroiditis (dense paucicellular fibrosis extending into adjacent tissues, "woody" thyroid)
─ Anaplastic thyroid carcinoma (can have inflammatory component and giant cells, but marked nuclear atypia, high mitotic rate, necrosis)
─ Sarcoidosis involving thyroid (rare; systemic sarcoidosis, non-caseating granulomas not necessarily centered on follicles)

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Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis, Autoimmune Thyroiditis)

An autoimmune disorder characterized by chronic inflammation of the thyroid gland, leading to progressive destruction of follicular cells and usually resulting in hypothyroidism; it is the most common cause of hypothyroidism in iodine-sufficient areas
Clinical ─ More common in women (10:1 to 20:1 female-to-male ratio), peak age 30-50 years; often presents with painless, diffuse thyroid enlargement (goiter) and symptoms of hypothyroidism (fatigue, weight gain, cold intolerance, constipation); may be associated with other autoimmune diseases; high titers of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies are typically present; increased risk of B-cell lymphoma (MALT lymphoma) of the thyroid
Macro ─ Gland is usually diffusely enlarged, firm, and pale tan-yellow or grayish-white on cut surface; lobulated appearance; capsule is intact
Micro ─

─ Diffuse, extensive infiltration of the thyroid parenchyma by lymphocytes and plasma cells, often forming lymphoid follicles with prominent germinal centers
─ Destruction and atrophy of thyroid follicles
─ Follicular epithelial cells often show oncocytic (Hürthle cell or Askanazy cell) metaplasia: large polygonal cells with abundant granular eosinophilic cytoplasm and prominent nucleoli
─ Variable degrees of interstitial fibrosis, which can be extensive in the fibrous variant of Hashimoto's thyroiditis
─ Squamous metaplasia of follicular epithelium can occur
─ Colloid is often scant or absent in atrophic follicles
─ Granulomatous reaction is uncommon

Ancillary studies ─

─ IHC (+)
─ Lymphoid infiltrate: CD20 (B-cells, prominent in germinal centers), CD3 (T-cells, interfollicular and within follicles), plasma cells (CD138, kappa/lambda to assess polyclonality)
─ Follicular/Hürthle cells: Thyroglobulin (may be weak or patchy in Hürthle cells), TTF-1, PAX8, Cytokeratins
─ IHC (-)
─ Hürthle cells: Calcitonin negative
─ Serology: Elevated anti-TPO and/or anti-Tg antibodies

DDx ─

─ Focal lymphocytic thyroiditis (milder, focal lymphoid infiltrate, lacks diffuse Hürthle cell change and follicular destruction)
─ Graves' disease (diffuse hyperplasia, scalloped colloid, lymphoid infiltrates often present but usually less extensive and without prominent Hürthle cell change; clinical hyperthyroidism, TSH receptor antibodies)
─ Subacute (De Quervain) thyroiditis (granulomatous inflammation, multinucleated giant cells)
─ Riedel's thyroiditis (dense paucicellular fibrosis, extends beyond thyroid capsule)
─ Thyroid lymphoma (usually MALT lymphoma arising in Hashimoto's; sheets of atypical lymphoid cells, lymphoepithelial lesions, monotypic light chain expression)
─ Follicular neoplasm with Hürthle cell features (adenoma or carcinoma; forms a discrete nodule, may show encapsulation or invasion for carcinoma)

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Riedel Thyroiditis (Invasive Fibrous Thyroiditis, Struma Fibrosa)

A rare chronic inflammatory condition of unknown etiology, characterized by extensive fibrosis that replaces thyroid parenchyma and extends into adjacent neck structures, leading to a hard, fixed thyroid mass
Clinical ─ Typically affects middle-aged women; presents with a slowly enlarging, painless, "woody" or rock-hard, fixed thyroid gland; may cause compressive symptoms (dyspnea, dysphagia, hoarseness, stridor) due to involvement of trachea, esophagus, or recurrent laryngeal nerves; often associated with hypothyroidism if thyroid tissue is extensively replaced; may be part of the spectrum of IgG4-related disease or occur as an isolated fibrosclerotic process
Macro ─ Thyroid gland is variably enlarged, extremely hard, and grayish-white; fibrosis obliterates normal architecture and adheres to surrounding tissues (strap muscles, trachea, esophagus, carotid sheath), making surgical resection difficult
Micro ─

─ Dense, paucicellular, hyalinized fibrous tissue replacing thyroid parenchyma and extending irregularly into adjacent soft tissues, skeletal muscle, and around vessels/nerves
─ The fibrous tissue is often "keloid-like"
─ Sparse inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and occasional macrophages; neutrophils are usually absent
─ Entrapped, atrophic thyroid follicles may be seen within the fibrous tissue
─ Vasculitis with vessel wall thickening and luminal obliteration (obliterative phlebitis) is often present, especially in IgG4-related cases
─ No significant atypia of fibroblasts or epithelial cells; malignancy is not a feature of Riedel's itself

Ancillary studies ─

─ IHC (+)
─ Plasma cells: CD138; staining for IgG and IgG4 can be performed. If IgG4-related, there will be an increased number of IgG4-positive plasma cells and an elevated IgG4/IgG ratio (>40%)
─ Fibroblasts: Vimentin
─ Entrapped follicular cells: Thyroglobulin, TTF-1 (may be weak or lost in atrophic follicles)
─ IHC (-)
─ Malignancy markers (e.g., anaplastic carcinoma markers like cytokeratins with bizarre pleomorphism)
─ Special stains: Trichrome stain highlights the dense collagenous fibrosis

DDx ─

─ Anaplastic thyroid carcinoma (highly malignant cells, pleomorphism, necrosis, high mitotic rate; can induce desmoplastic stroma but cellular atypia is key)
─ Paucicellular variant of anaplastic thyroid carcinoma (can be very fibrotic, but malignant cells are present)
─ Fibrosing variant of Hashimoto's thyroiditis (extensive fibrosis but usually confined to thyroid, prominent lymphoplasmacytic infiltrate with Hürthle cells and germinal centers)
─ Sarcoma of the thyroid (rare; atypical spindle cells, specific sarcoma markers)
─ Invasive well-differentiated thyroid carcinoma with desmoplasia (e.g., infiltrative PTC; shows diagnostic features of carcinoma)
─ Other fibrosing conditions of the neck (e.g., idiopathic cervical fibrosis, post-radiation fibrosis)

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Focal Lymphocytic Thyroiditis

A common incidental finding characterized by focal, non-destructive lymphocytic infiltrates in the thyroid gland, without the diffuse changes or clinical manifestations of Hashimoto's thyroiditis
Clinical ─ Usually asymptomatic and euthyroid; often discovered incidentally in thyroidectomy specimens removed for other reasons (e.g., nodular disease, neoplasms) or at autopsy; significance is uncertain, may represent an early stage or mild variant of autoimmune thyroiditis in some individuals, or a non-specific reactive change; thyroid autoantibodies (anti-TPO, anti-Tg) may be present in a subset of patients but often at lower titers than in Hashimoto's
Macro ─ Thyroid gland is usually grossly normal or may show unrelated nodularity; no specific macroscopic features for focal thyroiditis itself
Micro ─

─ Characterized by focal aggregates of lymphocytes and a few plasma cells within the thyroid parenchyma
─ The infiltrates are typically small and scattered, not diffuse
─ Germinal centers may occasionally be present but are not as prominent or widespread as in Hashimoto's thyroiditis
─ Minimal or no follicular destruction
─ Hürthle cell (oncocytic) metaplasia is usually absent or very focal and limited, unlike the extensive change in Hashimoto's
─ No significant fibrosis directly attributable to the focal inflammation

Ancillary studies ─

─ IHC: Not typically required for diagnosis
─ Lymphoid infiltrates: CD3, CD20 positive cells
─ Serology: Thyroid autoantibodies may or may not be elevated

DDx ─

─ Hashimoto's thyroiditis (diffuse and extensive lymphoplasmacytic infiltrate, prominent germinal centers, widespread Hürthle cell metaplasia, follicular destruction, and often clinical hypothyroidism or goiter)
─ Graves' disease (lymphoid infiltrates can be present but are usually accompanied by diffuse follicular hyperplasia, scalloped colloid, and clinical hyperthyroidism)
─ Non-specific reactive lymphoid infiltrates (e.g., adjacent to a neoplasm or resolving hemorrhage)
─ Intrathyroidal lymph node (organized lymphoid architecture with sinuses, distinct from parenchymal infiltrate)
─ Early or resolving subacute (De Quervain) thyroiditis (may have focal lymphoid infiltrates in later stages, but history and prior granulomatous phase are different)

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Postpartum Thyroiditis

A destructive autoimmune thyroiditis occurring in women within the first year after childbirth, characterized by transient hyperthyroidism, hypothyroidism, or both phases sequentially
Clinical ─ Affects ~5-10% of women postpartum; considered a variant of Hashimoto's thyroiditis; higher risk in women with pre-existing anti-TPO antibodies, Type 1 diabetes, or prior history of postpartum thyroiditis; typically presents 1-6 months postpartum with hyperthyroid phase (due to release of stored hormone from damaged follicles), followed by hypothyroid phase 3-9 months postpartum; most women recover normal thyroid function within 12-18 months, but some may develop permanent hypothyroidism
Macro ─ Thyroid gland may be normal in size or mildly diffusely enlarged and firm; no specific gross features distinct from other forms of lymphocytic thyroiditis
Micro ─

─ Histological features are similar to those of Hashimoto's thyroiditis and silent thyroiditis
─ Lymphocytic infiltration of thyroid parenchyma, which can be focal or diffuse
─ Formation of lymphoid follicles with germinal centers may occur
─ Disruption and destruction of thyroid follicles
─ Variable degrees of Hürthle cell (oncocytic) metaplasia of follicular cells
─ Fibrosis is usually not prominent unless it progresses to chronic Hashimoto's thyroiditis
─ The hyperthyroid phase shows more follicular damage and inflammation, while the hypothyroid phase shows more atrophy and fibrosis if it becomes chronic

Ancillary studies ─

─ IHC (+)
─ Lymphoid infiltrate: CD3, CD20 positive cells
─ Follicular/Hürthle cells: Thyroglobulin, TTF-1, PAX8
─ Serology: Anti-TPO antibodies are usually elevated; anti-Tg antibodies may also be present

DDx ─

─ Hashimoto's thyroiditis (histologically similar; postpartum thyroiditis is defined by its temporal relationship to pregnancy and often transient nature, though it can be the initial presentation of chronic Hashimoto's)
─ Silent (painless) thyroiditis (histologically identical, occurs in non-postpartum individuals of both sexes)
─ Graves' disease (can also occur postpartum; diffuse follicular hyperplasia, scalloped colloid, TSH receptor antibodies positive)
─ Subacute (De Quervain) thyroiditis (painful thyroid, granulomatous inflammation)
─ Focal lymphocytic thyroiditis (milder, focal infiltrates without significant destruction or clinical dysfunction)

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Silent Thyroiditis (Painless Thyroiditis, Lymphocytic Thyroiditis with Spontaneously Resolving Hyperthyroidism)

A form of self-limited autoimmune thyroiditis characterized by transient hyperthyroidism, often followed by hypothyroidism and then recovery, similar to postpartum thyroiditis but not associated with pregnancy
Clinical ─ Occurs in both sexes, but more common in women; can occur at any age; patients present with symptoms of mild to moderate hyperthyroidism (palpitations, fatigue, tremor, heat intolerance) but notably lack thyroid pain or tenderness; radioactive iodine uptake (RAIU) is characteristically low during the hyperthyroid phase; often a triphasic course: hyperthyroid (1-3 months), hypothyroid (1-3 months), then euthyroid; some patients may develop permanent hypothyroidism
Macro ─ Thyroid gland is usually normal in size or slightly enlarged and firm; no specific distinguishing gross features
Micro ─

─ Histological features are virtually identical to postpartum thyroiditis and often indistinguishable from Hashimoto's thyroiditis, especially the lymphocytic variant
─ Diffuse or focal lymphocytic infiltration of the thyroid parenchyma
─ Lymphoid follicles with germinal centers may be present
─ Disruption and damage to thyroid follicles with colloid depletion
─ Variable Hürthle cell (oncocytic) metaplasia
─ Minimal to mild fibrosis in most resolving cases

Ancillary studies ─

─ IHC (+)
─ Lymphoid infiltrate: CD3, CD20 positive cells
─ Follicular/Hürthle cells: Thyroglobulin, TTF-1, PAX8
─ Serology: Anti-TPO and/or anti-Tg antibodies are often elevated, though sometimes transiently or at lower levels than classic Hashimoto's

DDx ─

─ Graves' disease (hyperthyroidism with high RAIU, TSH receptor antibodies positive, diffuse follicular hyperplasia)
─ Subacute (De Quervain) thyroiditis (painful thyroid, granulomatous inflammation)
─ Hashimoto's thyroiditis (may be histologically identical; distinction often based on clinical course, especially the spontaneous resolution of hyperthyroidism and less likelihood of permanent severe goitrous hypothyroidism in silent thyroiditis, though overlap exists)
─ Factitious thyrotoxicosis (exogenous thyroid hormone intake; low RAIU, low serum thyroglobulin)
─ Struma ovarii with hyperthyroidism (thyroid tissue in an ovarian teratoma producing excess hormone; pelvic mass, low thyroid RAIU)

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Palpation Thyroiditis (Multifocal Granulomatous Folliculitis)

A focal, often incidental, granulomatous reaction in the thyroid gland, thought to be caused by mechanical injury or vigorous palpation leading to follicular rupture and colloid extravasation
Clinical ─ Usually asymptomatic and discovered as an incidental microscopic finding in thyroidectomy or biopsy specimens; rarely, it might be associated with prior fine-needle aspiration (FNA) or neck trauma; no significant thyroid dysfunction is typically associated
Macro ─ No specific gross abnormalities are usually attributable to palpation thyroiditis itself; the gland may show other pathology for which it was resected (e.g., nodules, carcinoma)
Micro ─

─ Focal, well-circumscribed microscopic lesions characterized by disrupted thyroid follicles with extravasated colloid into the stroma
─ Granulomatous inflammatory reaction surrounding the extruded colloid, composed of:
─ Multinucleated giant cells (foreign body type, often engulfing colloid)
─ Epithelioid histiocytes
─ Lymphocytes and plasma cells
─ Fibrosis may be present around the granulomas
─ The adjacent thyroid parenchyma is usually unremarkable or shows unrelated pathology
─ Neutrophils are generally sparse or absent unless there's superimposed acute inflammation from another cause
─ The lesions are typically small and multifocal

Ancillary studies ─

─ IHC: Not usually required for diagnosis
─ Histiocytes: CD68 positive
─ Special stains: Negative for microorganisms

DDx ─

─ Subacute (De Quervain) thyroiditis (more extensive, diffuse or widespread patchy involvement, associated with viral prodrome, neck pain, systemic symptoms, and triphasic thyroid function changes; palpation thyroiditis is focal and clinically silent)
─ Sarcoidosis involving the thyroid (rare; systemic sarcoidosis, non-caseating granulomas not necessarily centered on colloid)
─ Fungal or mycobacterial thyroiditis (specific organisms identified with special stains, usually in immunocompromised patients)
─ Foreign body reaction to suture material or other exogenous substances (history, presence of foreign material)
─ Granulomatous reaction associated with papillary thyroid carcinoma (occurs adjacent to or within some PTCs, but PTC features are present)

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Graves' Disease (Diffuse Toxic Goiter)

An autoimmune disorder characterized by hyperthyroidism due to circulating autoantibodies (TSH receptor antibodies, TRAb) that stimulate the TSH receptor on thyroid follicular cells, leading to diffuse thyroid hyperplasia and excessive thyroid hormone production
Clinical ─ Most common cause of hyperthyroidism; more common in women (5:1 to 10:1 female-to-male ratio), typically presenting between 20-50 years of age; symptoms include thyrotoxicosis (weight loss, heat intolerance, palpitations, anxiety, tremor, diarrhea), diffuse goiter, ophthalmopathy (exophthalmos, proptosis, diplopia), and sometimes dermopathy (pretibial myxedema); high serum T3/T4, low TSH, and positive TRAb (TSI - thyroid stimulating immunoglobulin - is a type of TRAb)
Macro ─ Thyroid gland is diffusely and symmetrically enlarged, firm, and highly vascular (beefy red appearance on cut surface); a thrill or bruit may be present over the gland; capsule is intact
Micro ─

─ Diffuse hyperplasia and hypertrophy of thyroid follicular cells
─ Follicular cells are tall columnar with abundant eosinophilic or amphophilic cytoplasm and enlarged, basally located nuclei
─ Papillary infoldings of the hyperplastic follicular epithelium into the follicular lumens are common (benign papillae, lacking true fibrovascular cores of PTC, but can be extensive)
─ Colloid is typically pale, scant, and shows prominent peripheral "scalloping" or "moth-eaten" appearance due to active resorption by follicular cells
─ Interstitial lymphoid infiltration is common, often with formation of lymphoid follicles with germinal centers (though usually not as extensive or destructive as in Hashimoto's thyroiditis)
─ Increased vascularity of the stroma
─ Hürthle cell change is generally not a prominent feature, unlike Hashimoto's

Ancillary studies ─

─ IHC (+)
─ Follicular cells: Thyroglobulin, TTF-1, PAX8, Cytokeratins
─ Lymphoid infiltrate: CD3, CD20 positive cells
─ Serology: Positive TSH receptor antibodies (TRAb/TSI) is diagnostic; anti-TPO and anti-Tg antibodies may also be present
─ Radioactive Iodine Uptake (RAIU): Diffusely increased uptake throughout the gland

DDx ─

─ Toxic multinodular goiter (hyperthyroidism with multiple autonomous nodules; variable follicle size, degenerative changes, areas of hyperplastic and quiescent nodules, RAIU shows patchy uptake)
─ Toxic adenoma (solitary hyperfunctioning ("hot") nodule with suppression of rest of gland; encapsulated follicular neoplasm)
─ Hashimoto's thyroiditis (can have transient hyperthyroid phase - "Hashitoxicosis"; prominent Hürthle cell metaplasia, follicular destruction, usually high anti-TPO/Tg, low TRAb)
─ Subacute (De Quervain) thyroiditis (painful, granulomatous inflammation, transient hyperthyroidism with low RAIU)
─ Silent/Postpartum thyroiditis (transient hyperthyroidism with low RAIU, lymphocytic infiltrate)
─ Diffuse hyperplasia of infancy (rare, due to activating TSH receptor mutations)

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Okay, here is "set 16", continuing with the Thyroid Gland. This set includes Radiation and Drug-Induced Changes, Follicular Adenoma, Follicular Adenoma with Papillary Architecture, and Oncocytic (Hürthle Cell) Adenoma, all within a single code block:

## **Radiation and Drug-Induced Changes (Thyroid)**

Alterations in thyroid morphology and function resulting from exposure to ionizing radiation or various medications  

Clinical ─ Radiation: Increased risk of benign nodules, thyroiditis, hypothyroidism, and thyroid carcinomas (especially papillary carcinoma) years after exposure, particularly in childhood (e.g_., post-Chernobyl, therapeutic radiation to head/neck). Drugs: Amiodarone (can cause hypothyroidism or thyrotoxicosis - Type 1 due to iodine load, Type 2 destructive thyroiditis), Lithium (can cause goiter, hypothyroidism, rarely hyperthyroidism), Interferon-alpha (can induce thyroiditis, hypo- or hyperthyroidism), Tyrosine Kinase Inhibitors (TKIs like Sunitinib, Sorafenib - can cause hypothyroidism or destructive thyroiditis), Immune checkpoint inhibitors (e_g_, Pembrolizumab, Nivolumab - can cause thyroiditis, hypo- or hyperthyroidism). Minocycline can cause black thyroid  

Macro ─ Radiation: Gland may be nodular, atrophic, or normal. Drug-induced: Variable; may be diffusely enlarged (goiter with lithium), normal, or show changes of thyroiditis. Black thyroid (minocycline): Gland appears dark brown to black  

Micro ─  

Radiation-Induced Changes:  

─ Atypia of follicular cells: Enlarged, hyperchromatic, pleomorphic nuclei; bizarre nuclear shapes; intranuclear cytoplasmic pseudoinclusions may be seen  

─ Follicular atrophy and interstitial fibrosis, often years after exposure  

─ Vascular changes: Thickening of vessel walls, endothelial atypia  

─ Increased risk of developing benign nodules (adenomatoid nodules, follicular adenomas) and carcinomas (predominantly PTC, often with specific genetic signatures like RET/PTC rearrangements)  

Drug-Induced Changes:  

─ Amiodarone:  

  ─ Type 1 (iodine-induced hyperthyroidism): May show features of diffuse hyperplasia or occur in glands with pre-existing nodules  

  ─ Type 2 (destructive thyroiditis): Follicular cell damage, disruption of follicles, histiocytic reaction, vacuolization of follicular cells, lymphocytic infiltrate; similar to subacute thyroiditis but usually without granulomas or giant cells  

─ Lithium: Follicular hyperplasia, colloid depletion, lymphocytic infiltrates, goiter formation  

─ Interferon-alpha/Immune checkpoint inhibitors: Can induce lymphocytic thyroiditis (similar to Hashimoto's, silent, or postpartum thyroiditis), follicular disruption, Hürthle cell change; granulomatous thyroiditis has also been reported with checkpoint inhibitors  

─ TKIs: Follicular atrophy, fibrosis, lymphocytic infiltration; destructive thyroiditis pattern can occur  

─ Minocycline (Black Thyroid): Accumulation of dark brown to black pigment (iron-containing lipofuscin-like material) within the cytoplasm of follicular cells; thyroid architecture is usually preserved, and function is typically normal  

Ancillary studies ─  

─ IHC (for specific changes):  

  ─ Drug-induced thyroiditis: CD3, CD20 for lymphocytes; CD68 for histiocytes  

─ Special stains:  

  ─ Minocycline-induced black thyroid: Iron stain (Perls' Prussian blue) may be positive on the pigment; Fontana-Masson may also stain the pigment  

DDx ─  

─ Radiation atypia vs. Papillary thyroid carcinoma (PTC): True PTC shows characteristic nuclear features throughout (clearing, grooves, pseudoinclusions), papillae with fibrovascular cores, psammoma bodies, and infiltrative growth or encapsulation. Radiation atypia can be bizarre but often lacks the full constellation or diffuse nature of PTC nuclear features. Molecular markers (*BRAF*, *RET/PTC*) aid in PTC diagnosis.  

─ Drug-induced thyroiditis vs. other forms of thyroiditis (clinical history of drug exposure, specific histologic patterns e.g., amiodarone effects on follicular cells, type of inflammatory infiltrate)  

─ Follicular nodular disease (distinguish from diffuse drug-induced goiter by nodularity and heterogeneity)  

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## **Follicular Adenoma**

A benign, encapsulated, neoplastic proliferation of thyroid follicular cells, showing a growth pattern different from the adjacent thyroid parenchyma, and lacking capsular or vascular invasion  

Clinical ─ Common thyroid neoplasm, presents as a solitary, painless thyroid nodule ("cold" nodule on scintigraphy as they usually don't concentrate iodine as avidly as normal thyroid); more frequent in women; usually euthyroid; risk of malignancy (follicular carcinoma) arising in an adenoma is very low, but distinction from follicular carcinoma relies on thorough examination of the capsule and vessels for invasion  

Macro ─ Solitary, well-circumscribed, encapsulated nodule, typically round to oval; cut surface is usually uniform, tan-brown, fleshy, or gelatinous, and may show hemorrhage, cystic change, fibrosis, or calcification; compresses adjacent normal thyroid tissue; capsule is usually thin and complete  

Micro ─  

─ Composed of well-differentiated follicular cells forming various architectural patterns that are different from the surrounding non-neoplastic thyroid:  

  ─ Microfollicular (fetal): Small, closely packed follicles with scant colloid (most common pattern)  

  ─ Normofollicular (simple): Follicles similar in size to normal thyroid  

  ─ Macrofollicular (colloid): Large follicles filled with abundant colloid (less common as a pure pattern, can overlap with colloid nodule)  

  ─ Trabecular/Solid/Embryonal: Cords or sheets of cells with minimal follicle formation  

─ Follicular cells are generally uniform, cuboidal, with round to oval nuclei, fine chromatin, and inconspicuous nucleoli  

─ Mitotic activity is usually scant; nuclear atypia is minimal  

─ Complete fibrous capsule is a key feature; tumor should be entirely encapsulated  

─ No evidence of capsular invasion (tumor cells breaching the full thickness of the capsule) or vascular invasion (tumor cells within endothelium-lined vascular spaces in or beyond the capsule) – extensive sampling of the capsule-tumor interface is crucial  

─ Degenerative changes (hemorrhage, cyst formation, fibrosis, calcification) can be present  

─ Oncocytic (Hürthle cell) change can occur focally or diffusely (see Oncocytic Adenoma)  

Ancillary studies ─  

─ IHC (+) (follicular cells)  

  ─ Thyroglobulin, TTF-1, PAX8  

─ IHC (-)  

  ─ Markers of papillary carcinoma (e.g., CK19 strong/diffuse, Galectin-3, HBME-1 may be variably expressed but without PTC nuclear features)  

  ─ Calcitonin  

─ Molecular ─  

  ─ Activating mutations in *TSHR*, *GNAS* (Gs alpha subunit), or *RAS* (N-, H-, K-RAS) oncogenes can be found in a subset of follicular adenomas; *PAX8/PPARγ* rearrangements are less common than in follicular carcinomas but can occur  

DDx ─  

─ Adenomatoid nodule (dominant nodule in follicular nodular disease; often lacks a complete, well-defined capsule, and surrounding tissue shows similar hyperplastic changes)  

─ Follicular carcinoma (requires demonstration of capsular and/or vascular invasion)  

─ Encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) / Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) (shows nuclear features of PTC, even if subtle and focal; NIFTP lacks invasion)  

─ Minimally invasive follicular carcinoma (difficult distinction, requires meticulous capsular/vascular assessment)  

─ Solid cell nests (p63/p40 positive, thyroglobulin negative)  

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## **Follicular Adenoma with Papillary Architecture (Follicular Adenoma with Papillary Hyperplasia)**

A variant of follicular adenoma characterized by the presence of significant papillary infoldings within the follicles, but importantly, lacking the characteristic nuclear features of papillary thyroid carcinoma (PTC)  

Clinical ─ Similar presentation to conventional follicular adenoma (solitary thyroid nodule); benign behavior; crucial to distinguish from papillary thyroid carcinoma, particularly the follicular variant  

Macro ─ Well-encapsulated nodule, similar to other follicular adenomas; may have a more complex or partially cystic cut surface due to papillary structures  

Micro ─  

─ Encapsulated follicular neoplasm  

─ Predominant architectural feature is the formation of papillae projecting into follicular lumens  

─ Papillae are lined by bland follicular cells with round to oval nuclei, fine chromatin, and inconspicuous nucleoli; **nuclear features of PTC (clearing, grooves, pseudoinclusions, overlapping, elongation) are absent** ─ Fibrovascular cores within the papillae may be delicate or more prominent but are generally less complex than in classical PTC  

─ The background architecture is often follicular (microfollicular, normofollicular)  

─ No capsular or vascular invasion  

─ Degenerative changes like cysts or hemorrhage may be present  

Ancillary studies ─  

─ IHC (+) (follicular cells)  

  ─ Thyroglobulin, TTF-1, PAX8  

─ IHC (-)  

  ─ Nuclear features of PTC are absent by definition, so IHC markers supporting PTC (e.g., strong diffuse CK19, Galectin-3, HBME-1) are typically negative or only focally/weakly positive in a pattern not typical for PTC. Careful correlation with morphology is key.  

─ Molecular ─  

  ─ Usually negative for *BRAF V600E* and *RET/PTC* rearrangements (hallmarks of classical PTC)  

  ─ May harbor *RAS* mutations or other alterations seen in follicular adenomas  

DDx ─  

─ Papillary thyroid carcinoma (classic or follicular variant; presence of characteristic PTC nuclear features is diagnostic, regardless of papillary architecture)  

─ Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) (has PTC-like nuclear features but is non-invasive; this entity requires strict criteria, and follicular adenoma with papillary architecture has bland nuclei)  

─ Follicular nodular disease with papillary hyperplasia (Sanderson polsters; lacks true encapsulation, part of a multinodular background, bland cytology)  

─ Hyalinizing trabecular tumor (trabecular architecture, hyalinized stroma, characteristic nuclear features including grooves and pseudoinclusions, but lacks true papillae of this type and usually lacks *RAS* but may have *PAX8/GLIS* fusions)  

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## **Oncocytic (Hürthle Cell) Adenoma**

A benign, encapsulated thyroid neoplasm composed predominantly (conventionally >75%) of oncocytic (Hürthle) cells, which are large polygonal follicular-derived cells with abundant granular eosinophilic cytoplasm due to mitochondrial accumulation  

Clinical ─ Presents as a solitary thyroid nodule, often "cold" on scintigraphy; more common in older individuals and females; usually euthyroid; distinction from oncocytic (Hürthle cell) carcinoma requires thorough examination for capsular and/or vascular invasion  

Macro ─ Typically a solid, well-circumscribed, encapsulated nodule; cut surface is characteristically tan-brown to mahogany brown, reflecting the eosinophilic cytoplasm of the cells; may show degenerative changes  

Micro ─  

─ Encapsulated neoplasm composed almost entirely of oncocytic (Hürthle) cells  

─ Oncocytic cells are large, polygonal, with abundant, deeply eosinophilic, granular cytoplasm (due to numerous mitochondria) and distinct cell borders  

─ Nuclei are typically large, round to oval, often eccentric, with prominent central nucleoli; nuclear pleomorphism and atypia can be seen and do not necessarily indicate malignancy in the absence of invasion  

─ Cells are arranged in various patterns: solid sheets, trabeculae, nests, or follicular structures (microfollicles or macrofollicles with scant colloid)  

─ Complete fibrous capsule must be present  

─ No capsular or vascular invasion (extensive sampling of capsule-tumor interface is essential)  

─ Mitotic figures are usually infrequent  

Ancillary studies ─  

─ IHC (+) (oncocytic cells)  

  ─ Thyroglobulin (Tg): Often positive, but can be weaker or more heterogeneous compared to non-oncocytic follicular cells  

  ─ TTF-1, PAX8: Nuclear positivity  

  ─ Mitochondrial markers (e.g., anti-mitochondrial antibody, COX subunit I): Strong cytoplasmic positivity confirming mitochondrial abundance  

  ─ Cytokeratins (CAM5.2)  

─ IHC (-)  

  ─ Calcitonin  

  ─ Markers of PTC (e.g., BRAF V600E usually negative; nuclear features of PTC are absent)  

─ Special Stains:  

  ─ PTAH (Phosphotungstic Acid Hematoxylin): Can highlight mitochondria (granular blue staining)  

─ Molecular ─  

  ─ May harbor *RAS* mutations  

  ─ Mitochondrial DNA mutations are common  

  ─ Somatic mutations in genes like *EIF1AX*, *TP53*, *NF1*, *CDKN1A* can be found but are more associated with progression to carcinoma  

DDx ─  

─ Oncocytic (Hürthle cell) carcinoma (requires demonstration of capsular and/or vascular invasion)  

─ Follicular adenoma with focal oncocytic change (<75% oncocytic cells)  

─ Oncocytic variant of papillary thyroid carcinoma (shows PTC nuclear features)  

─ Medullary thyroid carcinoma (some variants can have oncocytic features; calcitonin positive, Congo red for amyloid may be positive)  

─ Parathyroid adenoma or carcinoma with oncocytic features (PTH positive, thyroglobulin negative; rare to be intrathyroidal and mimic primary thyroid lesion perfectly)  

─ Hashimoto's thyroiditis or nodular goiter with extensive Hürthle cell metaplasia (metaplastic Hürthle cells in a background of thyroiditis or nodular hyperplasia, not a discrete encapsulated neoplasm; often polyclonal)  

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## **Hyalinizing Trabecular Tumor (HTT)**

A rare, typically benign thyroid neoplasm of follicular cell origin, characterized by a trabecular growth pattern, prominent hyalinization of stroma and cell membranes, and distinctive nuclear features that can mimic papillary thyroid carcinoma  

Clinical ─ Usually presents as a solitary, slow-growing, painless thyroid nodule; more common in adult women; most are benign, but rare cases with capsular/vascular invasion (termed malignant HTT or hyalinizing trabecular carcinoma) have been reported, though its malignant potential is debated and some consider it a tumor of uncertain malignant potential or low-grade carcinoma if invasive; often "cold" on scintigraphy  

Macro ─ Typically a well-circumscribed, solid, unencapsulated or partially encapsulated nodule; cut surface is firm, yellowish-tan to gray-white; larger tumors may show cystic change or hemorrhage  

Micro ─  

─ Characteristic trabecular, nested, or alveolar growth pattern of polygonal to spindle-shaped tumor cells  

─ Prominent extracellular hyalinization: Thick, eosinophilic, PAS-positive material surrounding trabeculae and individual tumor cells, often appearing as thickened "cell membranes" or within stroma  

─ Tumor cells have eosinophilic to amphophilic cytoplasm  

─ Nuclei show features that can overlap with papillary thyroid carcinoma:  

  ─ Elongated, oval, or irregular shapes  

  ─ Nuclear grooves (longitudinal) are common  

  ─ Intranuclear cytoplasmic pseudoinclusions can be present  

  ─ Chromatin is often fine or powdery, can appear clear or ground-glass focally  

  ─ Nucleoli are usually small  

─ Mitotic activity is typically low; necrosis is rare  

─ Psammoma bodies are generally absent  

─ Intracytoplasmic yellow-brown pigment (lipofuscin or melanin-like) can be seen in some tumor cells  

─ No true papillary structures with fibrovascular cores  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin: Positive (often weak or focal)  

  ─ TTF-1, PAX8: Nuclear positivity  

  ─ MIB-1 (Ki-67): Low proliferation index (usually <1-2%)  

  ─ Membranous staining with antibodies against cell adhesion molecules (e.g., E-cadherin, though this is not specific)  

  ─ Some cytokeratins (e.g., CAM5.2)  

─ IHC (Variable/Characteristic but not diagnostic alone)  

  ─ RET: Perimembranous or Golgi-like positivity (due to RET protein expression, not necessarily rearrangement)  

  ─ MUC1: Apical membranous positivity  

─ IHC (-)  

  ─ Calcitonin  

  ─ Congo Red (for amyloid): Negative (hyaline material is not amyloid)  

  ─ HBME-1, Galectin-3: Often negative or only focally positive (in contrast to PTC where they are more consistently positive)  

─ Molecular ─  

  ─ *PAX8/GLIS3* or *PAX8/GLIS1* gene fusions are characteristic and found in a majority of cases; these are generally absent in PTC and other follicular-derived neoplasms  

  ─ *BRAF V600E* and *RAS* mutations are typically absent  

  ─ *RET/PTC* rearrangements are absent  

DDx ─  

─ Papillary thyroid carcinoma (PTC), especially follicular or trabecular variants (PTC typically shows more diffuse and convincing nuclear clearing/overlapping/crowding, true papillae if classic type, psammoma bodies common; IHC profile with strong CK19, Galectin-3, HBME-1 more typical for PTC; *BRAF* or *RET/PTC* common in PTC, *PAX8/GLIS* fusions are absent)  

─ Medullary thyroid carcinoma (trabecular pattern can occur; calcitonin positive, Congo red positive for amyloid, thyroglobulin negative)  

─ Paraganglioma of thyroid (zellballen pattern, S100 positive sustentacular cells, synaptophysin/chromogranin positive chief cells, thyroglobulin negative)  

─ Follicular adenoma/carcinoma (trabecular variants exist but lack prominent hyalinization and PTC-like nuclear features of HTT)  

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## **Papillary Thyroid Carcinoma (PTC)**

The most common malignant endocrine neoplasm and the most common type of thyroid cancer, derived from thyroid follicular cells and characterized by distinctive nuclear features and often papillary architecture  

Clinical ─ More common in women and can occur at any age, with peak incidence in young to middle-aged adults; often presents as a palpable thyroid nodule or is detected incidentally on imaging; lymph node metastases (cervical) are common, but distant metastases are less frequent at presentation; overall prognosis is generally excellent, especially for smaller, localized tumors; risk factors include radiation exposure (especially in childhood), family history of thyroid cancer, and certain genetic syndromes (e.g., FAP, Cowden syndrome)  

Macro ─ Variable appearance: can be a well-circumscribed or infiltrative mass, solid or cystic, often grayish-white and firm; cut surface may show granular or papillary areas; calcification can be present; multifocality is common  

Micro ─  

General defining features:  

─ **Characteristic Nuclear Features (essential for diagnosis, even in absence of papillae):** ─ Nuclear enlargement, elongation, and overlapping (crowding)  

  ─ Irregular nuclear contours (raisinoid nuclei)  

  ─ Chromatin clearing ("Orphan Annie eye" nuclei – pale, ground-glass appearance)  

  ─ Nuclear grooves (longitudinal, coffee-bean appearance)  

  ─ Intranuclear cytoplasmic pseudoinclusions (cytoplasm invaginating into the nucleus)  

─ Papillary architecture: True papillae with fibrovascular cores lined by neoplastic cells (common but not required for diagnosis if nuclear features are present, e.g., in follicular variant)  

─ Psammoma bodies: Concentrically laminated calcifications, often within papillary stalks or stroma (highly characteristic but not present in all cases)  

─ Lymphocytic infiltration in the stroma is common  

─ Capsular invasion, vascular invasion, and extrathyroidal extension can occur and are important for staging  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8: Usually positive (confirm follicular cell origin)  

  ─ Cytokeratin 19 (CK19): Often strong and diffuse positivity  

  ─ Galectin-3: Often positive  

  ─ HBME-1 (Hector Battifora Mesothelial Epitope-1): Often positive (membranous/cytoplasmic)  

─ IHC (-)  

  ─ Calcitonin (rules out medullary carcinoma)  

─ Molecular ─  

  ─ *BRAF V600E* mutation: Most common genetic alteration, especially in classic and tall cell variants (associated with more aggressive features)  

  ─ *RAS* mutations (N-, H-, K-RAS): Common in follicular variant PTC and NIFTP  

  ─ *RET/PTC* rearrangements (e.g., *RET/PTC1*, *RET/PTC3*): More common in radiation-induced PTC and some classic variants  

  ─ *NTRK* gene fusions (rare, but targetable)  

  ─ *TERT* promoter mutations: Associated with older age, aggressive behavior, and poorer prognosis, often co-occurs with *BRAF* or *RAS* mutations  

DDx ─ (General, specific DDx depends on PTC variant)  

─ Benign papillary hyperplasia in follicular nodular disease (Sanderson polsters; lack PTC nuclear features)  

─ Follicular adenoma with papillary architecture (lacks PTC nuclear features)  

─ Hyalinizing trabecular tumor (trabecular pattern, hyalinization, *PAX8/GLIS* fusion, often lacks diffuse PTC immunoprofile)  

─ Solid cell nests (p63/p40 positive, thyroglobulin negative)  

─ Medullary thyroid carcinoma with papillary features (calcitonin positive)  

─ Metastatic carcinoma to thyroid (especially papillary renal cell carcinoma or lung adenocarcinoma; history, different IHC profile)  

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## **Classic PTC (Conventional Papillary Thyroid Carcinoma)**

The most common histological subtype of papillary thyroid carcinoma, characterized by a predominant (>50%) papillary architecture and typical PTC nuclear features  

Clinical ─ Presentation, risk factors, and general prognosis are similar to PTC overall; often presents with lymph node metastases  

Macro ─ Can be well-circumscribed or infiltrative, solid or cystic; cut surface often shows obvious papillary or granular areas; may be multifocal  

Micro ─  

─ Predominantly (>50% of the tumor) composed of true papillae: finger-like projections with fibrovascular cores, lined by neoplastic follicular cells  

─ Neoplastic cells exhibit the characteristic nuclear features of PTC:  

  ─ Nuclear enlargement, elongation, and overlapping  

  ─ Irregular nuclear contours  

  ─ Chromatin clearing ("Orphan Annie eye" nuclei)  

  ─ Nuclear grooves  

  ─ Intranuclear cytoplasmic pseudoinclusions  

─ Psammoma bodies are frequently found within papillary stalks or stroma  

─ Lymphocytic infiltration (often resembling Hashimoto's thyroiditis) can be prominent in the stroma surrounding the tumor or within fibrovascular cores  

─ Follicular areas may be present but constitute <50% of the tumor  

─ Encapsulation may be present or absent; invasion into capsule, surrounding thyroid, or extrathyroidal tissues can occur  

Ancillary studies ─  

─ IHC: Similar to general PTC (Thyroglobulin, TTF-1, PAX8, CK19, Galectin-3, HBME-1 positive)  

─ Molecular:  

  ─ *BRAF V600E* mutation is very common (up to 60-80% of cases)  

  ─ *RET/PTC* rearrangements are also seen, particularly in younger patients or radiation-associated cases  

  ─ *RAS* mutations are less common in classic PTC compared to follicular variant  

DDx ─  

─ Other variants of PTC (e.g., follicular variant, tall cell variant, diffuse sclerosing variant; distinguished by specific architectural or cytological features)  

─ Benign papillary hyperplasia in follicular nodular disease (lacks PTC nuclear features)  

─ Follicular adenoma with papillary architecture (lacks PTC nuclear features)  

─ Metastatic papillary carcinoma (history, IHC for primary site markers)  

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## **Papillary Thyroid Microcarcinoma (PTMC)**

A papillary thyroid carcinoma measuring ≤1.0 cm in greatest dimension, regardless of other histopathological features (e.g., variant, extrathyroidal extension, lymph node metastasis)  

Clinical ─ Very common, often discovered incidentally on imaging, at autopsy, or in thyroidectomy specimens removed for other reasons (e.g., benign nodular disease or Graves' disease); vast majority are indolent with excellent prognosis and extremely low rates of recurrence or mortality; however, a small subset can exhibit aggressive behavior, especially if associated with extrathyroidal extension, lymph node metastases at presentation, or aggressive histological variants (though less common in PTMC)  

Macro ─ Small nodule(s) ≤1.0 cm; may appear as a whitish, firm, irregular or scar-like area, or a small well-circumscribed nodule; often non-palpable  

Micro ─  

─ Meets all diagnostic criteria for papillary thyroid carcinoma (i.e., characteristic nuclear features, +/- papillary architecture, +/- psammoma bodies) but is ≤1.0 cm in maximum diameter  

─ Can be any histological variant of PTC (classic, follicular, tall cell, etc.), though classic and follicular variants are most common  

─ May be encapsulated or unencapsulated/infiltrative  

─ Multifocality can occur (multiple PTMCs)  

─ Minimal extrathyroidal extension (invading only sternothyroid muscle or perithyroidal soft tissue identified microscopically) can be seen and should be noted  

─ Lymphovascular invasion, if present, should be documented  

Ancillary studies ─  

─ IHC: Same as for larger PTCs (Thyroglobulin, TTF-1, PAX8, CK19, Galectin-3, HBME-1 often positive)  

─ Molecular:  

  ─ *BRAF V600E* mutation is common, similar to larger PTCs  

  ─ *RAS* mutations or *RET/PTC* rearrangements can also occur  

  ─ Presence of *TERT* promoter mutation (rare in PTMC) would be a concern for more aggressive potential  

DDx ─  

─ Benign lesions <1 cm (e.g., small adenomatoid nodule, follicular adenoma, solid cell nest; distinguished by absence of PTC nuclear features)  

─ Reactive atypia in follicular cells (e.g., adjacent to inflammation or hemorrhage; atypia is usually focal and lacks the full constellation of PTC nuclear changes)  

─ Importance of size criterion (≤1.0 cm) for classification as PTMC  

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## **Follicular Variant PTC (FVPTC)**

A variant of papillary thyroid carcinoma characterized by an almost exclusively follicular growth pattern, but with the diagnostic nuclear features of PTC; it is one of the most common variants of PTC  

Clinical ─ Similar clinical presentation and behavior to classic PTC, though some studies suggest infiltrative FVPTC may have a higher rate of distant metastasis and slightly worse prognosis than classic PTC, while encapsulated forms behave more indolently; often presents as a thyroid nodule  

Macro ─ Can be well-circumscribed or infiltrative; encapsulated forms appear as solid nodules, while infiltrative forms may be less defined; cut surface is usually fleshy, tan-to-pink  

Micro ─  

─ Predominantly (>99%) or exclusively follicular growth pattern (microfollicular, normofollicular, or macrofollicular)  

─ **Diagnostic nuclear features of PTC must be present and diffusely distributed:** ─ Nuclear enlargement, elongation, and overlapping  

  ─ Irregular nuclear contours  

  ─ Chromatin clearing ("Orphan Annie eye" nuclei)  

  ─ Nuclear grooves  

  ─ Intranuclear cytoplasmic pseudoinclusions (can be less frequent than in classic PTC)  

─ True papillae are absent or very rare (<1%)  

─ Psammoma bodies are uncommon  

─ Can be encapsulated or infiltrative:  

  ─ Infiltrative FVPTC: Tumor infiltrates into adjacent thyroid parenchyma or beyond the capsule; associated with a higher risk of recurrence and metastasis  

  ─ Encapsulated FVPTC: Tumor is surrounded by a fibrous capsule (see also NIFTP for non-invasive encapsulated forms)  

─ Lymphovascular invasion may be present  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8  

  ─ Markers like CK19, Galectin-3, HBME-1 may be positive but can be more variable or focal than in classic PTC  

─ IHC (-)  

  ─ Calcitonin  

─ Molecular ─  

  ─ *RAS* mutations (N-, H-, K-RAS) are common, especially in encapsulated forms  

  ─ *BRAF V600E* mutations are less common than in classic PTC, but can occur, particularly in infiltrative FVPTC  

  ─ *PAX8/PPARγ* rearrangements can occur, similar to follicular adenomas/carcinomas  

  ─ *RET/PTC* rearrangements are rare  

DDx ─  

─ Follicular adenoma (lacks PTC nuclear features; *RAS* mutations can overlap)  

─ Follicular carcinoma (lacks PTC nuclear features; requires capsular/vascular invasion)  

─ Classic PTC (has >1% well-formed papillae)  

─ Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) (a specific subtype of encapsulated, non-invasive FVPTC with stringent diagnostic criteria, reclassified to have very low malignant potential)  

─ Hyalinizing trabecular tumor (trabecular pattern, hyalinization, *PAX8/GLIS* fusions)  

─ Benign follicular nodule with nuclear atypia (focal atypia, lacks diffuse PTC nuclear features)  

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## **Encapsulated Follicular Variant PTC / Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP)**

NIFTP is a non-invasive, encapsulated or well-demarcated follicular-patterned thyroid neoplasm with PTC-like nuclear features, reclassified from encapsulated FVPTC to reflect its extremely low risk of adverse outcome when strict diagnostic criteria are met  

Clinical ─ Typically presents as a solitary thyroid nodule; patients are usually euthyroid; prognosis is excellent with surgical excision alone (lobectomy or thyroidectomy) if all diagnostic criteria for NIFTP are met; follow-up generally does not require radioactive iodine ablation  

Macro ─ Well-circumscribed or encapsulated nodule, usually solid, tan-white to tan-brown; cut surface is fleshy; no gross evidence of invasion  

Micro ─  

Strict diagnostic criteria for NIFTP include:  

─ **Inclusion Criteria:** ─ Encapsulation or clear demarcation from adjacent thyroid tissue  

  ─ Predominantly follicular growth pattern (papillae <1%; solid/trabecular/insular patterns <30%)  

  ─ PTC nuclear features (score 2-3 on a 3-point scale, indicating diffuse involvement of characteristic nuclear changes like enlargement, irregular contours, grooves, chromatin clearing, pseudoinclusions may be present but not required)  

─ **Exclusion Criteria (any of these features precludes NIFTP diagnosis):** ─ Presence of any true papillae (>1% of tumor)  

  ─ Psammoma bodies  

  ─ Tumor necrosis  

  ─ High mitotic activity (≥3 mitoses per 10 high-power fields)  

  ─ Any capsular or vascular invasion  

  ─ Presence of infiltrative growth pattern at the periphery  

  ─ Oncocytic (Hürthle cell) features >30%  

  ─ Any aggressive PTC variant histology (e.g., tall cell, hobnail, columnar cell, diffuse sclerosing)  

  ─ Distant or lymph node metastasis at presentation  

─ The entire tumor capsule and periphery must be meticulously examined to rule out invasion  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8  

  ─ CK19, Galectin-3, HBME-1 may be positive but are not required for diagnosis and can be variable  

─ Molecular ─  

  ─ *RAS* mutations (N-, H-, K-RAS) are the most common genetic alteration (40-60%)  

  ─ *PAX8/PPARγ* rearrangements can occur  

  ─ *BRAF V600E* mutations are characteristically absent or extremely rare; if present, a diagnosis of NIFTP should be questioned and alternative PTC variant considered  

  ─ *RET/PTC* rearrangements are typically absent  

  ─ *TERT* promoter mutations are absent  

DDx ─  

─ Follicular adenoma (lacks PTC nuclear features or has only focal/questionable nuclear changes not meeting NIFTP criteria)  

─ Follicular carcinoma (lacks PTC nuclear features, shows capsular/vascular invasion)  

─ Infiltrative Follicular Variant PTC (shows invasion, not NIFTP)  

─ Encapsulated Classic PTC or other encapsulated PTC variants (presence of papillae >1%, psammoma bodies, or other features excluded by NIFTP criteria)  

─ Minimally invasive follicular carcinoma (shows invasion)  

─ Hyalinizing trabecular tumor (different architecture, hyalinization, *PAX8/GLIS* fusions)  

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## **Diffuse Sclerosing Variant PTC (DSV-PTC)**

A rare, aggressive variant of papillary thyroid carcinoma characterized by diffuse involvement of one or both thyroid lobes, prominent squamous metaplasia, numerous psammoma bodies, dense fibrosis, and a heavy lymphocytic infiltrate  

Clinical ─ Typically occurs in younger patients (children and young adults), with a female predominance; often presents with a diffusely enlarged, firm (stony hard) thyroid gland (goitrous appearance) and frequently with extensive cervical lymph node metastases at diagnosis; distant metastases (especially pulmonary) can occur; prognosis may be worse than classic PTC of similar stage, though this is debated  

Macro ─ Thyroid gland is usually diffusely enlarged and very firm to hard; cut surface is grayish-white, fibrotic, and may show small cystic spaces or visible psammoma bodies; infiltrative borders, often without a dominant mass  

Micro ─  

─ Diffuse involvement of thyroid parenchyma, often bilateral  

─ Prominent papillary structures, often small and inconspicuous within a dense fibrotic stroma  

─ **Characteristic triad (though not all always present):** ─ Squamous metaplasia: Solid nests or morules of squamous-appearing cells are very common and a key feature  

  ─ Numerous psammoma bodies: Abundant, often large and coalescing  

  ─ Dense lymphocytic infiltrate: Prominent background lymphocytic thyroiditis, often with germinal centers, resembling Hashimoto's thyroiditis  

─ Dense stromal fibrosis (sclerosis) is extensive throughout the tumor  

─ Tumor cells exhibit typical PTC nuclear features (clearing, grooves, pseudoinclusions, overlapping)  

─ Extrathyroidal extension and extensive lymphovascular invasion are common  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8 (in tumor cells)  

  ─ Cytokeratins (e.g., CK19 strong and diffuse)  

  ─ Squamous metaplastic areas: p63, p40, high molecular weight cytokeratins  

  ─ Lymphoid infiltrate: CD3, CD20  

─ Molecular ─  

  ─ *RET/PTC* rearrangements (especially *RET/PTC1* and *RET/PTC3*) are very common (up to 70-80%)  

  ─ *BRAF V600E* mutations are relatively uncommon in DSV-PTC compared to classic PTC  

  ─ *NTRK* fusions have been reported  

DDx ─  

─ Hashimoto's thyroiditis with florid squamous metaplasia (Hashimoto's lacks true papillae with PTC nuclei, abundant psammoma bodies, and infiltrative growth typical of DSV-PTC, though it has lymphoid infiltrate and can have squamous metaplasia)  

─ Classic PTC with extensive fibrosis or lymphocytic stroma (DSV-PTC has a more diffuse growth pattern, more prominent squamous metaplasia, and usually more numerous psammoma bodies)  

─ Riedel's thyroiditis (dense paucicellular fibrosis, extends beyond thyroid; lacks malignant epithelial cells, papillae, psammoma bodies, and squamous metaplasia of DSV-PTC)  

─ Anaplastic thyroid carcinoma (can have squamous differentiation and fibrosis, but shows marked pleomorphism, high mitotic rate, necrosis, and loss of PTC nuclear features/thyroid markers)  

─ Chronic sclerosing sialadenitis (Küttner tumor) involving thyroid (IgG4-related; different primary process)  

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## **Tall Cell Variant PTC (TCV-PTC)**

An aggressive variant of papillary thyroid carcinoma defined by the presence of at least 30% (some use 50%) tall cells, which are tumor cells whose height is at least two to three times their width  

Clinical ─ Associated with older age at presentation, larger tumor size, higher rates of extrathyroidal extension, lymph node and distant metastases, increased recurrence, and poorer prognosis compared to classic PTC; often presents as a palpable thyroid mass  

Macro ─ Typically a solid, firm, grayish-white mass; may be large and show infiltrative borders or extrathyroidal extension  

Micro ─  

─ At least 30% (or 50% by some definitions) of tumor cells must qualify as "tall cells": cells whose height is at least 2-3 times their width, with eosinophilic, often granular cytoplasm, and basally located nuclei  

─ Tumor cells exhibit characteristic PTC nuclear features (clearing, grooves, pseudoinclusions, overlapping)  

─ Growth pattern is often papillary, but can be follicular or solid  

─ Hobnail features may coexist (see Hobnail Variant)  

─ Psammoma bodies may be present  

─ Mitotic activity can be increased, and necrosis may be seen in more aggressive examples  

─ Extrathyroidal extension and lymphovascular invasion are common  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8  

  ─ CK19, Galectin-3, HBME-1 (often strongly positive)  

─ Molecular ─  

  ─ *BRAF V600E* mutation is extremely common (up to 80-90% or higher)  

  ─ *TERT* promoter mutations are frequently co-existent with *BRAF V600E* in TCV-PTC and are associated with the most aggressive behavior and worst outcomes  

  ─ *RAS* mutations and *RET/PTC* rearrangements are uncommon  

DDx ─  

─ Classic PTC with focal tall cell features (<30% or <50% tall cells; distinction is based on proportion of tall cells)  

─ Oncocytic (Hürthle cell) variant of PTC (cells are oncocytic with granular eosinophilic cytoplasm due to mitochondria, but not necessarily meeting height:width ratio of tall cells; PTC nuclear features are present)  

─ Columnar cell variant PTC (cells are columnar with pseudostratified, hyperchromatic nuclei, often subnuclear vacuoles; different cytomorphology)  

─ Hobnail variant PTC (apical nuclei, surface blebs/hobnail appearance; can overlap with tall cell features)  

─ Poorly differentiated thyroid carcinoma (may arise from TCV-PTC; shows increased mitoses, necrosis, and loss of typical PTC architecture/nuclear features, forming solid/trabecular/insular patterns)  

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## **Columnar Cell Variant PTC**

A rare and aggressive variant of papillary thyroid carcinoma characterized by columnar cells with pseudostratified, hyperchromatic nuclei and often subnuclear or supranuclear cytoplasmic vacuoles, resembling colorectal adenocarcinoma  

Clinical ─ Typically affects older individuals; often presents as a large, invasive thyroid mass with extrathyroidal extension and distant metastases (especially lung and bone) at diagnosis; associated with a poor prognosis and high mortality rate, less responsive to conventional therapies for PTC  

Macro ─ Usually a large, solid, firm, infiltrative mass; grayish-white to tan on cut section; necrosis may be present  

Micro ─  

─ Predominantly composed of tall columnar cells (height at least 3-4 times their width) lining papillary structures or forming glands/cribriform patterns  

─ Nuclei are elongated, hyperchromatic, and characteristically pseudostratified (overlapping at different levels within the cell height), often losing typical PTC nuclear clearing and grooves in areas of high-grade transformation  

─ Subnuclear or supranuclear cytoplasmic vacuoles are a common and distinctive feature, pushing nuclei towards the apex or base respectively  

─ Mitotic activity is often increased, and atypical mitoses may be seen  

─ Tumor necrosis is common  

─ Lymphovascular invasion and extrathyroidal extension are frequently present  

─ May show areas with more conventional PTC nuclear features, but the columnar cell component with pseudostratification is dominant  

─ Can be encapsulated or widely infiltrative  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8: Usually positive, confirming thyroid origin, though expression can sometimes be reduced or lost in high-grade areas  

  ─ Cytokeratins (e.g., CAM5.2, CK7)  

  ─ CDX2: Can be aberrantly positive in some cases, contributing to confusion with metastatic colorectal adenocarcinoma  

─ IHC (-)  

  ─ Calcitonin  

  ─ Specific markers for colorectal adenocarcinoma (e.g., CK20 often negative or focal, though CDX2 can be a pitfall)  

─ Molecular ─  

  ─ *BRAF V600E* mutations are common  

  ─ *TERT* promoter mutations can occur and are associated with worse prognosis  

  ─ Alterations in *CTNNB1* (beta-catenin) or *APC* genes have been reported in some cases, potentially explaining the colorectal adenocarcinoma-like morphology  

  ─ *RET/PTC* rearrangements are less common  

DDx ─  

─ Metastatic adenocarcinoma, especially colorectal adenocarcinoma (critical distinction; colorectal mets are typically TTF-1/PAX8 negative, CK20 positive, CDX2 positive; clinical history is key)  

─ Tall cell variant PTC (tall cells with eosinophilic cytoplasm, but nuclei are usually basally located and lack prominent pseudostratification and subnuclear/supranuclear vacuoles of columnar cell variant; TCV cells are >2-3x height vs width, columnar cells are even more elongated)  

─ Solid variant PTC (predominantly solid growth, but lacks columnar cytology with pseudostratification)  

─ Poorly differentiated thyroid carcinoma (may show solid/trabecular growth, increased mitoses, necrosis; columnar cell variant is considered a specific high-grade variant of PTC, not necessarily dedifferentiated to PDTC unless it loses PTC features)  

─ Medullary thyroid carcinoma (some variants can have columnar cells; calcitonin positive)  

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## **Cribriform-Morular Variant PTC (CMV-PTC, Cribriform-Morular Thyroid Carcinoma)**

A rare and distinctive variant of papillary thyroid carcinoma, strongly associated with Familial Adenomatous Polyposis (FAP) and Gardner syndrome, but can also occur sporadically; characterized by a unique combination of cribriform, morular, and follicular patterns  

Clinical ─ Predominantly affects young women (often <30 years); may present as single or multiple thyroid nodules, often bilateral; when associated with FAP (due to germline *APC* mutations), it can be an early manifestation of the syndrome; generally has an indolent clinical course with a favorable prognosis, though lymph node and rare distant metastases can occur; sporadic cases also typically behave indolently  

Macro ─ Can be well-circumscribed or partially encapsulated nodules; tan to yellow, solid or with small cystic areas  

Micro ─  

─ Architectural heterogeneity is characteristic:  

  ─ Cribriform pattern: Back-to-back follicles or glandular structures lacking colloid, forming sieve-like spaces  

  ─ Follicular pattern: Microfollicles or macrofollicles  

  ─ Trabecular or solid areas may be present  

─ Morules: Distinctive, cohesive clusters of spindle to ovoid cells with bland, pale nuclei and eosinophilic cytoplasm, often showing nuclear clearing similar to biotin-rich optically clear nuclei (Brocchinia-type nuclei); these morules lack keratinization and are a hallmark of this variant  

─ Tumor cells lining follicles/cribriform structures often have typical PTC nuclear features (grooves, pseudoinclusions, clearing, overlapping), though they can be subtle or focal  

─ Papillary structures are usually absent or inconspicuous  

─ Peculiar "pac-man" or "cookie-cutter" like holes within colloid or stroma can be seen  

─ Psammoma bodies are rare  

─ Stromal hyalinization can be present  

Ancillary studies ─  

─ IHC (+)  

  ─ Tumor cells: Thyroglobulin, TTF-1, PAX8  

  ─ β-catenin: Strong nuclear and cytoplasmic positivity in tumor cells, especially prominent in morules (due to *APC* gene pathway dysregulation or *CTNNB1* mutations in sporadic cases)  

  ─ Estrogen Receptor (ER) and Progesterone Receptor (PR): Often positive  

  ─ CD10: Can be positive in morular cells  

─ IHC (variable)  

  ─ Cytokeratins, Galectin-3, HBME-1  

─ Molecular ─  

  ─ Germline *APC* gene mutations: Present in patients with FAP  

  ─ Somatic *APC* or *CTNNB1* (beta-catenin) gene mutations: Found in most sporadic cases, leading to Wnt/β-catenin pathway activation  

  ─ *BRAF V600E* and *RAS* mutations are typically absent  

DDx ─  

─ Other variants of PTC (lack the characteristic morules and diffuse nuclear/cytoplasmic β-catenin staining; different molecular profile)  

─ Hyalinizing trabecular tumor (trabecular, hyaline stroma, *PAX8/GLIS* fusion; β-catenin nuclear staining is not typical, morules absent)  

─ Solid cell nests (p63/p40 positive, thyroglobulin negative, lack β-catenin activation)  

─ Follicular adenoma/carcinoma (lack PTC nuclear features, morules, and diffuse β-catenin staining)  

─ Metastatic carcinoma with morular features (rare; e.g., from endometrium; clinical history, different IHC profile)  

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## **Hobnail Variant PTC**

A rare and aggressive variant of papillary thyroid carcinoma characterized by tumor cells with prominent apical nuclei and surface "hobnail" or "micropapillary" tufts, leading to a cobblestone-like appearance on the luminal surface  

Clinical ─ Associated with older age, larger tumor size, higher rates of extrathyroidal extension, lymph node and distant metastases (especially lung), increased recurrence, and significantly poorer prognosis compared to classic PTC; often resistant to conventional therapy  

Macro ─ Typically a large, infiltrative, firm, grayish-white mass; necrosis and hemorrhage may be present  

Micro ─  

─ Predominant (>30% of tumor, though some use >10%) hobnail cytomorphology:  

  ─ Tumor cells are cuboidal to polygonal, with high nuclear-to-cytoplasmic ratio  

  ─ Nuclei are located apically (towards the lumen), often bulging from the cell surface, creating a "hobnail" appearance  

  ─ Apical surface of cells may show small blebs, snouts, or tufts (micropapillary projections lacking fibrovascular cores)  

  ─ Loss of cellular polarity and cohesiveness is common  

─ Cells line follicles, papillae, or grow in solid sheets  

─ Background PTC nuclear features (grooves, pseudoinclusions, clearing) are usually present but can be obscured by hyperchromasia and atypia  

─ Marked nuclear pleomorphism, hyperchromasia, and prominent nucleoli are common  

─ Mitotic activity is often increased; atypical mitoses may be seen  

─ Necrosis, lymphovascular invasion, and extrathyroidal extension are frequent  

─ Can occur as a pure form or mixed with other PTC variants (e.g., tall cell)  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8: Usually positive, but can be focal or reduced in intensity  

  ─ CK19, Galectin-3, HBME-1: Often positive  

─ IHC (variable/emerging)  

  ─ p53: Overexpression may be seen in a subset, indicating genetic instability  

  ─ E-cadherin: Loss or aberrant expression may be seen, consistent with discohesive growth  

─ Molecular ─  

  ─ *BRAF V600E* mutation is very common (up to 80% or more)  

  ─ *TERT* promoter mutations are frequently found, often co-occurring with *BRAF V600E*, and are associated with the aggressive behavior  

  ─ *TP53* mutations can also occur  

  ─ *PIK3CA* mutations have been reported  

DDx ─  

─ Tall cell variant PTC (cells are tall with eosinophilic cytoplasm and basal nuclei; hobnail has apical nuclei and surface blebs; features can overlap, and mixed hobnail/tall cell tumors occur)  

─ Classic PTC with artifactual changes or tangential sectioning (can mimic hobnail features focally, but diffuse hobnail morphology is required for the variant diagnosis)  

─ Poorly differentiated thyroid carcinoma (may show discohesive cells and high-grade features; hobnail variant is considered a specific high-grade variant of PTC, retaining some PTC features)  

─ Anaplastic thyroid carcinoma (more pleomorphic, spindle cells, giant cells, loss of thyroid differentiation markers usually more profound)  

─ Metastatic adenocarcinoma with micropapillary or hobnail features (e.g., from lung, breast, ovary; clinical history, IHC for primary site markers; TTF-1 can be positive in lung primaries)  

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## **Solid Variant PTC**

A variant of papillary thyroid carcinoma characterized by a predominantly (>50%) solid, trabecular, or nested growth pattern of tumor cells that exhibit typical PTC nuclear features  

Clinical ─ Historically associated with radiation exposure (e.g., post-Chernobyl pediatric cases); can occur sporadically; behavior is generally similar to classic PTC of comparable stage, but some studies suggest it might be slightly more aggressive, especially if associated with extensive necrosis or high mitotic activity; often presents as a firm thyroid nodule  

Macro ─ Typically a solid, well-demarcated or infiltrative mass; grayish-white to tan on cut section  

Micro ─  

─ Predominantly (>50% of the tumor) solid, sheet-like, trabecular, or nested growth pattern  

─ Tumor cells exhibit the characteristic nuclear features of PTC:  

  ─ Nuclear enlargement, elongation, and overlapping  

  ─ Irregular nuclear contours  

  ─ Chromatin clearing ("Orphan Annie eye" nuclei)  

  ─ Nuclear grooves  

  ─ Intranuclear cytoplasmic pseudoinclusions  

─ Follicle formation is minimal (<10-20%) or absent in the solid areas; papillae are absent or very sparse  

─ Psammoma bodies may be present but are less common than in classic PTC  

─ Lymphocytic infiltrate can be variable  

─ Necrosis and increased mitotic activity can be seen, particularly in higher-grade examples or tumors transitioning to poorly differentiated carcinoma  

─ Encapsulation can be present or absent; infiltrative growth can occur  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8  

  ─ CK19, Galectin-3, HBME-1: Often positive  

─ Molecular ─  

  ─ *RET/PTC* rearrangements (especially *RET/PTC3*) are common in radiation-associated solid variant PTC  

  ─ *BRAF V600E* mutations can also occur, particularly in sporadic adult cases  

  ─ *NTRK* fusions have been reported  

DDx ─  

─ Poorly differentiated thyroid carcinoma (PDTC) (PDTC is defined by solid/trabecular/insular growth but also requires evidence of high-grade features like increased mitoses (≥3-5/10 HPF), tumor necrosis, and/or convoluted nuclei, often with partial loss of PTC nuclear features or reduced thyroglobulin expression; solid variant PTC retains typical PTC nuclei and generally has lower mitotic rates/less necrosis than PDTC)  

─ Medullary thyroid carcinoma (solid growth pattern common; calcitonin positive, Congo red for amyloid, thyroglobulin negative)  

─ Hyalinizing trabecular tumor (trabecular pattern but with prominent hyalinization and *PAX8/GLIS* fusions, different IHC profile for RET)  

─ Follicular carcinoma with solid areas (lacks PTC nuclear features)  

─ Solid cell nests (p63/p40 positive, thyroglobulin negative)  

─ Metastatic carcinoma with solid growth (history, specific IHC markers for primary)  

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## **Oncocytic (Hürthle Cell) Variant PTC**

A variant of papillary thyroid carcinoma in which the tumor cells lining papillae and/or follicles exhibit oncocytic (Hürthle cell) change (abundant granular eosinophilic cytoplasm) and possess the characteristic nuclear features of PTC  

Clinical ─ Behavior may be slightly more aggressive than classic PTC, with a higher propensity for lymph node and distant metastases, particularly when associated with extensive vascular invasion or extrathyroidal extension; occurs across a wide age range  

Macro ─ Typically a solid, tan-brown to mahogany-brown nodule, reflecting the oncocytic cytoplasm; may be encapsulated or infiltrative  

Micro ─  

─ Tumor cells show extensive oncocytic (Hürthle cell) metaplasia: large polygonal cells with abundant, granular, deeply eosinophilic cytoplasm (due to numerous mitochondria) and distinct cell borders  

─ These oncocytic cells line papillary structures with fibrovascular cores and/or form follicles  

─ **Diagnostic nuclear features of PTC must be present** in the oncocytic cells: nuclear enlargement, overlapping, irregular contours, chromatin clearing ("Orphan Annie eye"), nuclear grooves, and intranuclear pseudoinclusions  

─ Psammoma bodies can be present  

─ Background lymphocytic thyroiditis may be seen  

─ Invasion (capsular, vascular, extrathyroidal) should be assessed  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin (Tg): Often positive, but may be weaker or more heterogeneous than in non-oncocytic PTC  

  ─ TTF-1, PAX8: Nuclear positivity  

  ─ Mitochondrial markers (e.g., anti-mitochondrial antibody, COX subunit I): Strong cytoplasmic positivity confirming oncocytic nature  

  ─ Markers often positive in PTC (CK19, Galectin-3, HBME-1) can be expressed  

─ IHC (-)  

  ─ Calcitonin  

─ Molecular ─  

  ─ *BRAF V600E* mutations are less common than in classic PTC but can occur  

  ─ *RAS* mutations (N-, H-, K-RAS) may be more frequent than in classic PTC  

  ─ Mitochondrial DNA mutations are common in oncocytic cells  

  ─ *TERT* promoter mutations can occur and are associated with worse prognosis  

DDx ─  

─ Oncocytic (Hürthle cell) adenoma (lacks PTC nuclear features; benign)  

─ Oncocytic (Hürthle cell) carcinoma (lacks PTC nuclear features; defined by capsular/vascular invasion)  

─ Classic PTC with focal oncocytic change (oncocytic change is not predominant)  

─ Tall cell variant PTC (cells are tall with eosinophilic cytoplasm, but defined by height:width ratio ≥2-3:1 and basal nuclei; oncocytic cells are defined by granular cytoplasm due to mitochondria, not necessarily tall)  

─ Medullary thyroid carcinoma with oncocytic features (calcitonin positive)  

─ Parathyroid oncocytic adenoma/carcinoma (intrathyroidal; PTH positive, thyroglobulin negative)  

─ Hashimoto's thyroiditis with extensive Hürthle cell metaplasia (metaplastic, lacks true papillae and PTC nuclear features throughout a neoplastic proliferation)  

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## **Warthin-Like Variant PTC (Warthin-like Papillary Thyroid Carcinoma)**

A rare variant of papillary thyroid carcinoma characterized by papillary structures lined by oncocytic cells and a prominent lymphocytic infiltrate in the papillary stalks, resembling Warthin's tumor of the salivary gland  

Clinical ─ Typically occurs in patients with coexisting chronic lymphocytic thyroiditis (Hashimoto's thyroiditis); generally considered to have an indolent behavior and favorable prognosis, similar to or better than classic PTC; more common in women  

Macro ─ Usually a well-circumscribed, solid or cystic nodule; may be tan-brown due to oncocytic cells  

Micro ─  

─ Papillary architecture is a prominent feature  

─ Papillary fronds are lined by oncocytic (Hürthle) cells: large polygonal cells with abundant granular eosinophilic cytoplasm and distinct cell borders  

─ Tumor cell nuclei exhibit characteristic PTC features (enlargement, clearing, grooves, pseudoinclusions, overlapping)  

─ **Key diagnostic feature:** Dense lymphoplasmacytic infiltrate within the fibrovascular cores of the papillae, often forming lymphoid follicles with germinal centers  

─ The surrounding thyroid parenchyma frequently shows features of chronic lymphocytic (Hashimoto's) thyroiditis  

─ Psammoma bodies may be present  

─ Encapsulation may be present or absent  

Ancillary studies ─  

─ IHC (+)  

  ─ Oncocytic tumor cells: Thyroglobulin, TTF-1, PAX8, mitochondrial markers  

  ─ Lymphoid stroma: CD20 (B-cells), CD3 (T-cells), CD45  

  ─ Markers often positive in PTC (CK19, Galectin-3, HBME-1) can be expressed in tumor cells  

─ Molecular ─  

  ─ *BRAF V600E* mutations are common (similar to or slightly less frequent than classic PTC)  

  ─ *RET/PTC* rearrangements are less common  

  ─ Genetic alterations typical of Hashimoto's thyroiditis may be present in the background gland  

DDx ─  

─ Classic PTC with prominent lymphocytic stroma (Warthin-like variant specifically requires oncocytic cytology of the tumor cells lining the papillae in addition to the lymphoid stroma in the cores)  

─ Oncocytic (Hürthle cell) variant PTC (has oncocytic cells with PTC nuclei, but lacks the prominent lymphoplasmacytic infiltrate within papillary stalks that defines Warthin-like variant)  

─ Hashimoto's thyroiditis with papillary hyperplasia and Hürthle cell change (benign hyperplastic papillae lack true fibrovascular cores and consistent PTC nuclear features throughout the neoplastic cells)  

─ Lymphoepithelial cyst with papillary features (rare, different context)  

─ Metastatic Warthin's tumor to thyroid (extremely rare; history of salivary gland primary, specific salivary markers if any)  

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## **PTC with Fibromatosis/Fasciitis-like Stroma**

A rare variant of papillary thyroid carcinoma characterized by a prominent, reactive-appearing spindle cell stromal component resembling fibromatosis or nodular fasciitis, intermingled with neoplastic PTC elements  

Clinical ─ Can occur at any age; may present as a firm, fixed thyroid mass; behavior is generally considered similar to classic PTC of comparable stage, but the dense stroma may lead to adherence to adjacent structures; some reports suggest a potential for more aggressive local behavior due to the stromal component, but data are limited  

Macro ─ Typically a firm to hard, poorly circumscribed, grayish-white mass; infiltrative borders are common  

Micro ─  

─ Biphasic appearance:  

  1. Epithelial component: Consists of typical papillary thyroid carcinoma (classic, follicular, or other variants) with characteristic PTC nuclear features (clearing, grooves, pseudoinclusions, overlapping); often forms small nests, tubules, or individual cells entrapped within the stroma  

  2. Stromal component: Dominant feature; composed of bland-appearing spindle cells (fibroblasts/myofibroblasts) arranged in sweeping fascicles or a storiform pattern, set in a collagenous or myxoid matrix  

     ─ Spindle cells have elongated nuclei, fine chromatin, inconspicuous nucleoli, and scant cytoplasm  

     ─ Mitotic activity in the stromal cells is typically low; no significant atypia  

     ─ Resembles benign reactive processes like fibromatosis (desmoid-type) or nodular fasciitis (especially if more myxoid and cellular with a "tissue culture" appearance)  

─ Lymphocytic infiltrate may be present  

─ Extrathyroidal extension can occur  

Ancillary studies ─  

─ IHC (+)  

  ─ Epithelial (PTC) component: Thyroglobulin, TTF-1, PAX8, CK19  

  ─ Stromal spindle cells: Vimentin, Smooth Muscle Actin (SMA, often positive), Muscle Specific Actin (MSA), Calponin; may be focally desmin positive. Some cases show nuclear β-catenin in stromal cells (similar to fibromatosis)  

─ IHC (-)  

  ─ Stromal spindle cells: Thyroglobulin, TTF-1, PAX8, Cytokeratins (AE1/AE3, CAM5.2), S100, SOX10, CD34 (usually negative or only focally)  

  ─ Epithelial component: Negative for stromal markers  

─ Molecular (PTC component):  

  ─ *BRAF V600E* or other PTC-associated mutations may be present in the epithelial component  

─ Molecular (Stromal component):  

  ─ *CTNNB1* (beta-catenin) gene mutations have been reported in the stromal component of some cases with fibromatosis-like stroma, similar to desmoid fibromatosis  

DDx ─  

─ Anaplastic thyroid carcinoma with sarcomatoid differentiation (highly malignant epithelial and/or spindle cells, marked pleomorphism, high mitotic rate, necrosis; loss of thyroid markers in anaplastic component)  

─ Poorly differentiated thyroid carcinoma with desmoplastic stroma (epithelial component shows features of PDTC, not well-differentiated PTC)  

─ Solitary fibrous tumor of thyroid (CD34 positive, STAT6 nuclear positive stromal cells; entrapped benign follicles, not PTC)  

─ Primary sarcoma of the thyroid (e.g., fibrosarcoma, leiomyosarcoma; extremely rare; lacks epithelial PTC component; specific sarcoma immunoprofile)  

─ Riedel's thyroiditis (dense paucicellular fibrosis, extends beyond thyroid; lacks neoplastic PTC component and cellular spindle cell stroma of this variant)  

─ Nodular fasciitis involving thyroid (rare; lacks PTC component; usually more acute history, characteristic myxoid stroma and "tissue culture" like fibroblasts)  

─ Desmoid-type fibromatosis involving thyroid (lacks PTC component; β-catenin nuclear positive in spindle cells)  

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## **Follicular Thyroid Carcinoma (FTC)**

A malignant epithelial neoplasm derived from thyroid follicular cells, characterized by follicular differentiation and evidence of capsular and/or vascular invasion; it lacks the diagnostic nuclear features of papillary thyroid carcinoma  

Clinical ─ Second most common type of thyroid cancer after PTC (~10-15% of cases); more common in areas of iodine deficiency and in older individuals; often presents as a solitary thyroid nodule, which may be "cold" or "warm" on scintigraphy; hematogenous metastasis (to bone, lung) is more common than lymph node metastasis (in contrast to PTC); prognosis depends on extent of invasion (minimally invasive vs. widely invasive) and presence of distant metastases  

Macro ─ Typically a solitary, encapsulated or apparently well-circumscribed, solid nodule; cut surface is tan-brown, fleshy, and may show hemorrhage, necrosis, or fibrosis; widely invasive tumors may show gross infiltration into surrounding thyroid or extrathyroidal tissues  

Micro ─  

─ Composed of follicular cells arranged in various patterns: predominantly microfollicular, normofollicular, or trabecular/solid; colloid is often scant  

─ Tumor cells are generally uniform, cuboidal, with round to oval nuclei, fine chromatin, and inconspicuous nucleoli; **diagnostic nuclear features of PTC are absent** ─ **Diagnosis requires demonstration of invasion:** ─ Capsular invasion: Tumor cells breaching the full thickness of the tumor capsule (mushroom-like projections into or through the capsule); mere presence of tumor cells in an unlined capsular vessel is not sufficient, it needs to be true transgression of capsule. Requires extensive sampling of the capsule.  

  ─ Vascular invasion: Tumor cells invading into endothelium-lined vascular spaces within or beyond the tumor capsule; criteria include tumor thrombi adherent to endothelium, covered by endothelium, or admixed with fibrin. At least 4 vessels showing invasion is a common threshold in some systems, but any unequivocal vascular invasion can be significant.  

─ Classification based on extent of invasion:  

  ─ Minimally invasive FTC: Focal capsular invasion and/or limited vascular invasion (e.g., <4 vessels involved); generally good prognosis  

  ─ Widely invasive FTC: Extensive capsular invasion and/or extensive vascular invasion (e.g., ≥4 vessels involved); higher risk of recurrence and distant metastasis, poorer prognosis  

─ Mitotic activity is usually low in minimally invasive FTC, can be higher in widely invasive forms  

─ Oncocytic (Hürthle cell) change can occur but if predominant (>75%), it's classified as Oncocytic Carcinoma  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8 (confirm follicular cell origin)  

─ IHC (-)  

  ─ Calcitonin  

  ─ Markers of PTC (CK19, Galectin-3, HBME-1 are typically negative or only focally positive, and PTC nuclear features are absent)  

─ Molecular ─  

  ─ *RAS* mutations (N-, H-, K-RAS) are common (20-50%)  

  ─ *PAX8/PPARγ* rearrangements are found in a significant subset (25-40%)  

  ─ *PIK3CA* mutations can occur  

  ─ *TERT* promoter mutations can occur, especially in widely invasive FTC, and are associated with worse prognosis  

  ─ *BRAF V600E* mutations and *RET/PTC* rearrangements are typically absent  

DDx ─  

─ Follicular adenoma (lacks capsular or vascular invasion; molecular profile can overlap)  

─ Follicular variant of papillary thyroid carcinoma (FVPTC) (shows PTC nuclear features; different molecular profile typically, though *RAS* can overlap)  

─ Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) (PTC nuclear features, no invasion)  

─ Poorly differentiated thyroid carcinoma (may arise from FTC; shows increased mitoses, necrosis, solid/insular growth, often with loss of clear follicular differentiation)  

─ Medullary thyroid carcinoma (follicular pattern can occur; calcitonin positive)  

─ Metastatic carcinoma with follicular pattern (e.g., renal cell carcinoma; history, specific IHC markers like PAX8 (can be shared), CAIX, CD10 for renal)  

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## **Oncocytic (Hürthle Cell) Carcinoma**

A malignant epithelial neoplasm of the thyroid composed predominantly (>75%) of oncocytic (Hürthle) cells, characterized by capsular and/or vascular invasion; it is considered a distinct entity from non-oncocytic follicular carcinoma due to different molecular profiles and potentially more aggressive behavior  

Clinical ─ Less common than non-oncocytic FTC, accounts for ~3-5% of thyroid cancers; tends to occur in older individuals; often presents as a solitary thyroid nodule; less likely to concentrate iodine (often "cold" on scintigraphy); has a higher propensity for hematogenous metastasis (bone, lung) and lymph node metastasis compared to non-oncocytic FTC; overall prognosis may be worse than non-oncocytic FTC, particularly for widely invasive tumors  

Macro ─ Similar to non-oncocytic FTC but typically has a characteristic mahogany-brown or tan cut surface due to abundant mitochondria; encapsulated or infiltrative  

Micro ─  

─ Composed predominantly (>75%) of oncocytic (Hürthle) cells: large polygonal cells with abundant, granular, deeply eosinophilic cytoplasm and distinct cell borders; cytoplasm is packed with mitochondria  

─ Nuclei are large, round to oval, often eccentric, with prominent central nucleoli; nuclear pleomorphism and atypia can be significant but are not diagnostic of malignancy alone  

─ Growth patterns include solid, trabecular, nested, or follicular (microfollicular or macrofollicular with scant colloid)  

─ **Diagnosis of carcinoma requires unequivocal evidence of:** ─ Capsular invasion (full thickness breach)  

  ─ Vascular invasion (tumor in endothelium-lined spaces in/beyond capsule)  

─ Similar to FTC, classified as minimally invasive or widely invasive based on extent of invasion  

─ Mitotic activity can be variable; necrosis may be present in widely invasive tumors  

─ Nuclear features of PTC are absent (distinguishes from oncocytic variant of PTC)  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin (Tg): Often positive, but can be weaker or more heterogeneous than in non-oncocytic tumors  

  ─ TTF-1, PAX8: Nuclear positivity  

  ─ Mitochondrial markers (e.g., anti-mitochondrial antibody, COX subunit I): Strong cytoplasmic positivity  

─ IHC (-)  

  ─ Calcitonin  

  ─ Markers of PTC (if PTC nuclear features are absent)  

─ Molecular ─  

  ─ Characterized by widespread mitochondrial DNA mutations and complex chromosomal aberrations (aneuploidy, copy number alterations)  

  ─ Somatic mutations in genes like *EIF1AX*, *TP53*, *NF1*, *CDKN1A/B*, *ARID1A*, *DAXX/ATRX*, and alterations in histone methyltransferases (e.g., *KMT2C/D*) are common  

  ─ *RAS* mutations and *PAX8/PPARγ* rearrangements are less frequent than in non-oncocytic FTC  

  ─ *TERT* promoter mutations are associated with aggressive behavior  

  ─ *BRAF V600E* is typically absent  

DDx ─  

─ Oncocytic (Hürthle cell) adenoma (lacks capsular or vascular invasion)  

─ Oncocytic variant of papillary thyroid carcinoma (shows characteristic PTC nuclear features)  

─ Follicular carcinoma with extensive oncocytic change (if <75% oncocytic cells, though distinction is becoming less rigid if invasion present)  

─ Medullary thyroid carcinoma with oncocytic features (calcitonin positive)  

─ Parathyroid oncocytic adenoma/carcinoma (intrathyroidal; PTH positive, thyroglobulin negative)  

─ Hashimoto's thyroiditis or nodular goiter with extensive Hürthle cell metaplasia (metaplastic, not a discrete neoplasm with invasion; polyclonal)  

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## **Poorly Differentiated Thyroid Carcinoma / High-Grade Thyroid Carcinoma (PDTC/HGTC)**

A malignant epithelial neoplasm of follicular cell origin that is histologically and behaviorally intermediate between well-differentiated thyroid carcinomas (papillary, follicular) and anaplastic thyroid carcinoma; characterized by solid, trabecular, or insular growth, limited evidence of follicular differentiation, and high-grade features  

Clinical ─ Relatively uncommon (~5-10% of thyroid malignancies); typically affects older adults; often presents as a rapidly enlarging neck mass, may have symptoms of compression or invasion; aggressive clinical course with high rates of local recurrence, lymph node and distant metastases (lung, bone, brain), and significant mortality; may arise de novo or from pre-existing well-differentiated thyroid carcinoma  

Macro ─ Large, often infiltrative tumor, frequently with extrathyroidal extension; cut surface is fleshy, grayish-white or tan, commonly with areas of necrosis and hemorrhage  

Micro ─  

Diagnostic criteria (e.g., Turin consensus for PDTC):  

─ Follicular cell derivation (thyroid-specific IHC often positive)  

─ Solid, trabecular, or insular growth pattern as the predominant architecture  

─ Absence of conventional nuclear features of papillary carcinoma (or only focal/equivocal)  

─ At least one of the following high-grade features:  

  ─ Tumor necrosis (confluent, not single-cell)  

  ─ Increased mitotic activity (typically ≥3 or ≥5 mitoses per 10 high-power fields or per 2 mm²)  

  ─ Convoluted nuclei (not the typical PTC "raisinoid" nuclei, but more irregular and hyperchromatic, often with prominent nucleoli)  

─ High-Grade Thyroid Carcinoma (HGTC) is a broader term that may encompass tumors previously called PDTC and some high-grade follicular-derived carcinomas that don't fit neatly into PDTC by strict criteria but show high-grade features. This includes some PTC or FTC that have developed high-grade features.  

─ Cells are often monotonous or show moderate pleomorphism, with round to oval nuclei, coarse or vesicular chromatin, and prominent nucleoli; cytoplasm is scant to moderate  

─ Follicle formation is minimal or absent; colloid is sparse  

─ Vascular invasion is common  

Ancillary studies ─  

─ IHC (+)  

  ─ Thyroglobulin, TTF-1, PAX8: Usually positive, but expression may be reduced, focal, or heterogeneous compared to well-differentiated carcinomas (key for confirming thyroid origin)  

  ─ Cytokeratins (AE1/AE3, CAM5.2)  

  ─ Ki-67 proliferation index: Significantly elevated (often >10-20%)  

─ IHC (-)  

  ─ Calcitonin  

  ─ p63, p40 (unless squamous differentiation, which would lean towards anaplastic)  

─ Molecular ─  

  ─ Complex genetic alterations, often accumulating mutations seen in well-differentiated thyroid cancers along with additional "late" events  

  ─ *BRAF V600E* or *RAS* mutations are common (often as background from a preceding well-differentiated tumor)  

  ─ *TERT* promoter mutations are frequent and associated with aggressive behavior  

  ─ *TP53* mutations are common and indicate progression  

  ─ Mutations in genes like *PIK3CA*, *AKT1*, *PTEN*, and alterations in cell cycle regulators  

DDx ─  

─ Anaplastic thyroid carcinoma (more extreme pleomorphism, spindle cells, giant cells, often complete loss of thyroid differentiation markers, very high mitotic rate, extensive necrosis; PDTC is less anaplastic)  

─ Solid variant of papillary thyroid carcinoma (retains typical PTC nuclear features throughout, usually lower mitotic rate and less necrosis than PDTC)  

─ Widely invasive follicular or oncocytic carcinoma (may show focal solid growth or necrosis, but PDTC has predominant solid/trabecular/insular pattern and defining high-grade features more diffusely)  

─ Medullary thyroid carcinoma (solid/trabecular growth common; calcitonin positive, amyloid)  

─ Metastatic carcinoma (especially poorly differentiated neuroendocrine carcinoma from lung or elsewhere; clinical history, different IHC profile e.g., specific neuroendocrine markers not typical for thyroid origin, or markers of other primary sites)  

─ Non-Hodgkin lymphoma (sheets of atypical lymphoid cells, CD45 and specific lymphoid markers positive)  

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## **Anaplastic (Undifferentiated) Thyroid Carcinoma (ATC)**

A highly aggressive, undifferentiated malignant epithelial neoplasm of the thyroid gland, one of the most lethal human cancers, characterized by rapid growth, extensive local invasion, and early distant metastasis  

Clinical ─ Rare (<1-2% of thyroid cancers), but accounts for a disproportionately high mortality rate; typically affects elderly individuals (mean age 60-70 years), slight female predominance; often presents as a rapidly enlarging, firm, fixed neck mass causing compressive symptoms (dyspnea, dysphagia, hoarseness, stridor), pain, and skin changes; widespread metastases (lung, bone, brain, adrenal) are common at diagnosis or develop quickly; prognosis is dismal, with median survival of only a few months  

Macro ─ Large, infiltrative, often rock-hard mass that replaces thyroid tissue and extends widely into adjacent structures (muscle, trachea, esophagus, larynx, vessels, nerves); cut surface is typically fleshy, grayish-white or tan, with extensive necrosis and hemorrhage  

Micro ─  

─ Extreme cellular pleomorphism and anaplasia are hallmarks  

─ Common histological patterns (often mixed within the same tumor):  

  ─ Sarcomatoid (spindle cell): Fascicles of malignant spindle cells resembling fibrosarcoma or malignant fibrous histiocytoma  

  ─ Giant cell: Numerous bizarre, multinucleated or mononucleated malignant giant cells  

  ─ Squamoid/Epithelioid: Sheets or nests of large, pleomorphic epithelioid cells, sometimes with squamous differentiation (keratinization, intercellular bridges)  

  ─ Paucicellular variant: Extensive fibrosis with sparse, highly atypical tumor cells (can be diagnostically challenging)  

─ Nuclei are markedly atypical, hyperchromatic, irregular, with prominent and often bizarre nucleoli  

─ Mitotic activity is extremely high, with numerous atypical mitoses  

─ Extensive tumor necrosis is almost invariably present  

─ Vascular invasion and perineural invasion are common  

─ Often arises in a background of pre-existing well-differentiated thyroid carcinoma (PTC or FTC) or goiter, and areas of the precursor lesion may be identifiable  

─ Osteoclast-like giant cells (benign, reactive) may be present in stroma  

─ Inflammatory infiltrate can be prominent  

Ancillary studies ─  

─ IHC (+)  

  ─ Cytokeratins (AE1/AE3, CAM5.2, CK18): Often positive, but can be focal or lost in a subset of cases, especially sarcomatoid areas (key to prove epithelial origin if thyroid markers lost)  

  ─ PAX8: Positive in about 50-80% of cases (most specific thyroid lineage marker in ATC)  

  ─ p53: Overexpression (due to mutation) is very common (>70-80%)  

  ─ Ki-67 proliferation index: Very high (often >50-70%)  

─ IHC (Variable or Often Negative)  

  ─ Thyroglobulin (Tg): Usually negative or only very focally positive in rare cells (loss of differentiation)  

  ─ TTF-1: Often negative, or positive in a smaller percentage than PAX8  

  ─ Vimentin: Often co-expressed, especially in sarcomatoid areas  

  ─ S100, Desmin, SMA (may be positive in sarcomatoid areas, causing confusion with true sarcomas)  

─ IHC (-)  

  ─ Calcitonin (rules out medullary carcinoma)  

  ─ Lymphoid markers (CD45)  

─ Molecular ─  

  ─ Complex and numerous genetic alterations  

  ─ *TP53* mutations are nearly universal  

  ─ *TERT* promoter mutations are very common  

  ─ Mutations in *BRAF* (often V600E, if arising from PTC), *RAS* (if arising from FTC/FVPTC), *PIK3CA*, *PTEN*, *NF1*, *EIF1AX*, and genes involved in cell cycle regulation (e.g., *CDKN2A/B*) and chromatin remodeling are frequent  

  ─ High rates of chromosomal instability and aneuploidy  

DDx ─  

─ Poorly differentiated thyroid carcinoma (PDTC) (less pleomorphic, usually retains some thyroid IHC markers more consistently, lacks the extreme anaplasia/sarcomatoid/giant cell features of ATC)  

─ Primary thyroid sarcoma (extremely rare; true mesenchymal neoplasm, lacks epithelial markers like cytokeratins and PAX8; specific sarcoma immunoprofile)  

─ Metastatic undifferentiated carcinoma, sarcoma, or melanoma to thyroid (clinical history, specific IHC markers for primary site or lineage)  

─ Medullary thyroid carcinoma, anaplastic variant (rare; calcitonin may still be focally positive)  

─ Thyroid lymphoma, diffuse large B-cell type (CD45, B-cell markers positive; PAX8 negative)  

─ Riedel's thyroiditis (extensive fibrosis, but paucicellular inflammatory infiltrate, lacks malignant cells)  

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## **C-Cell Hyperplasia**

An increase in the number of parafollicular cells (C-cells) within the thyroid gland, which can be reactive (physiologic) or neoplastic (precursor to medullary thyroid carcinoma, especially in MEN2 syndromes)  

Clinical ─ Usually asymptomatic and an incidental microscopic finding; may be associated with conditions causing chronic hypercalcemia (reactive hyperplasia) or familial medullary thyroid carcinoma syndromes (MEN2A, MEN2B, FMTC due to germline *RET* mutations); elevated basal or stimulated serum calcitonin levels may be present in neoplastic hyperplasia  

Macro ─ No specific gross findings; thyroid gland is usually grossly normal or may show unrelated pathology  

Micro ─  

─ Increased number of C-cells, which can be focal or diffuse:  

  ─ C-cells are typically located within the basement membrane of thyroid follicles (intrafollicular) or in small clusters in the interfollicular stroma  

  ─ Normal C-cell distribution: More numerous in the middle to upper thirds of the lateral lobes; typically <10 cells per low power field (LPF) or <50 cells per 10 LPFs, depending on criteria. Generally, >50 C-cells in at least one LPF, or multiple large clusters, is considered hyperplasia.  

─ Neoplastic C-cell hyperplasia (associated with *RET* mutations/MEN2):  

  ─ Often multifocal and bilateral  

  ─ C-cells may form expansile nodules or sheets that distort and expand follicular architecture  

  ─ C-cells can be spindled or polygonal, with amphophilic cytoplasm and round to oval nuclei; atypia may be present  

  ─ May show extension beyond the follicular basement membrane into the interstitium  

  ─ Amyloid deposition is typically absent in hyperplasia (present in MTC)  

─ Reactive C-cell hyperplasia:  

  ─ Usually milder and more diffuse, without significant nodule formation or marked atypia  

  ─ Associated with hypercalcemic states (e.g., primary hyperparathyroidism, chronic renal failure) or chronic lymphocytic thyroiditis  

Ancillary studies ─  

─ IHC (+)  

  ─ C-cells: Calcitonin (strong and diffuse), Chromogranin A, Synaptophysin, CEA (carcinoembryonic antigen)  

  ─ TTF-1: Can be positive in C-cells (often weaker than in follicular cells)  

─ IHC (-)  

  ─ Thyroglobulin (C-cells are negative)  

─ Molecular ─  

  ─ Germline *RET* proto-oncogene mutations: Screening is crucial in patients with neoplastic C-cell hyperplasia to identify MEN2 or FMTC; specific codons affected determine risk and management (e.g., prophylactic thyroidectomy)  

DDx ─  

─ Normal thyroid gland with prominent C-cells (quantification and distribution are key; normal C-cells are less numerous and not forming expansile nodules)  

─ Medullary thyroid microcarcinoma (<1 cm MTC; neoplastic C-cell proliferation forming a discrete tumor nodule, may show invasion or desmoplasia; C-cell hyperplasia lacks a discrete tumor mass and invasion by definition)  

─ Medullary thyroid carcinoma (larger tumor, invasive growth, amyloid deposition common)  

─ Solid cell nests (p63/p40 positive, calcitonin negative, thyroglobulin negative)  

─ Tangential sectioning of follicles appearing as C-cell clusters (careful orientation)  

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## **Medullary Thyroid Microcarcinoma**

A medullary thyroid carcinoma (MTC) that measures ≤1.0 cm in greatest dimension; it is an early form of MTC  

Clinical ─ Often detected incidentally in thyroidectomy specimens removed for other reasons (e.g., nodular goiter, Graves' disease, C-cell hyperplasia in MEN2 patients undergoing prophylactic thyroidectomy), or via screening in MEN2 families (elevated calcitonin, *RET* mutation analysis); generally has an excellent prognosis, especially if confined to the thyroid and completely excised; lymph node metastases can occur even with small primary tumors  

Macro ─ Small nodule(s) ≤1.0 cm, often ill-defined or well-circumscribed; may be firm, grayish-white; frequently non-palpable and not visible on gross examination if very small (microscopic finding)  

Micro ─  

─ Neoplastic proliferation of C-cells forming a discrete tumor nodule ≤1.0 cm  

─ Tumor cells are similar to those in larger MTCs: polygonal, plasmacytoid, or spindle-shaped cells  

─ Cells are typically arranged in nests, trabeculae, or solid sheets, separated by fibrovascular stroma  

─ Amyloid deposition in the stroma (derived from calcitonin precursors) is common and characteristic, but may be absent in very small or early lesions  

─ Nuclei are round to oval, with stippled "salt-and-pepper" chromatin; nucleoli may be inconspicuous or small  

─ Cytoplasm is usually amphophilic or eosinophilic, often granular  

─ Minimal or no capsular structure; infiltrative growth into surrounding thyroid parenchyma may be seen  

─ Lymphovascular invasion should be assessed, as it can occur even in microcarcinomas  

─ May arise in a background of C-cell hyperplasia, especially in familial cases  

Ancillary studies ─  

─ IHC (+)  

  ─ Calcitonin: Strong and diffuse positivity in tumor cells (definitive marker)  

  ─ Chromogranin A, Synaptophysin: Positive (neuroendocrine differentiation)  

  ─ CEA (carcinoembryonic antigen, monoclonal): Often positive  

  ─ TTF-1: Can be positive (often weaker than in follicular cells)  

─ IHC (-)  

  ─ Thyroglobulin: Negative  

─ Special Stains:  

  ─ Congo Red: Positive for amyloid deposits (apple-green birefringence under polarized light) if amyloid is present  

─ Molecular ─  

  ─ Somatic *RET* mutations can be found in sporadic micro-MTCs  

  ─ Germline *RET* mutations if associated with MEN2/FMTC  

DDx ─  

─ C-cell hyperplasia (increased C-cells without a discrete tumor mass or stromal desmoplasia/amyloid characteristic of a formed tumor; micro-MTC shows a defined neoplastic proliferation)  

─ Solid cell nests (p63/p40 positive, calcitonin negative)  

─ Hyalinizing trabecular tumor (trabecular pattern, hyaline stroma, thyroglobulin positive, calcitonin negative, *PAX8/GLIS* fusions)  

─ Paraganglioma of thyroid (rare; S100 positive sustentacular cells, chief cells positive for chromogranin/synaptophysin but negative for calcitonin and thyroglobulin)  

─ Poorly differentiated thyroid carcinoma or solid variant PTC (calcitonin negative, thyroglobulin positive)  

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## **Medullary Thyroid Carcinoma (MTC)**

A neuroendocrine malignant neoplasm derived from the parafollicular cells (C-cells) of the thyroid gland, characterized by calcitonin production; accounts for ~3-5% of all thyroid malignancies  

Clinical ─ Can be sporadic (~75-80% of cases) or hereditary (~20-25%, associated with MEN2A, MEN2B, or Familial MTC [FMTC] due to germline *RET* proto-oncogene mutations); presents as a firm thyroid nodule or mass, often in the upper or middle portion of thyroid lobes; may cause compressive symptoms or dysphagia; diarrhea (due to calcitonin or other peptides) or Cushing syndrome (due to ectopic ACTH production by tumor) can occur; lymph node metastases (cervical, mediastinal) are common at presentation; distant metastases (liver, lung, bone) can occur; serum calcitonin and CEA are important tumor markers for diagnosis and follow-up  

Macro ─ Usually a solitary, firm, grayish-white to tan, unencapsulated or partially encapsulated tumor; typically solid, but may have areas of hemorrhage or necrosis; often located in the upper two-thirds of the thyroid lobes; infiltrative borders are common  

Micro ─  

─ Highly variable morphology, but cells generally show neuroendocrine features  

─ Common patterns:  

  ─ Solid sheets, nests, or trabeculae of tumor cells  

  ─ Follicular, papillary, pseudopapillary, or glandular patterns can occur, mimicking other thyroid neoplasms  

  ─ Spindle cell, plasmacytoid, oncocytic, small cell, giant cell, or clear cell variants exist  

─ Tumor cells are typically polygonal to spindle-shaped, with round to oval nuclei, stippled "salt-and-pepper" chromatin, and inconspicuous or small nucleoli  

─ Cytoplasm is usually amphophilic or eosinophilic, often granular  

─ **Amyloid deposition** in the stroma (derived from altered calcitonin molecules) is a characteristic feature in many cases, but not all (can be scant or absent, especially in some variants or early lesions)  

─ Fibrovascular stroma, often hyalinized  

─ C-cell hyperplasia is often present in the surrounding thyroid parenchyma, especially in hereditary cases  

─ Lymphovascular invasion is common  

─ Necrosis and mitotic activity are variable and can correlate with aggressiveness  

Ancillary studies ─  

─ IHC (+)  

  ─ Calcitonin: Strong and diffuse positivity (hallmark and most specific marker)  

  ─ Chromogranin A, Synaptophysin: Positive (confirm neuroendocrine differentiation)  

  ─ CEA (carcinoembryonic antigen, monoclonal): Often positive and can be a useful prognostic marker  

  ─ TTF-1: Can be positive (often weaker or more focal than in follicular-derived tumors)  

  ─ Other neuroendocrine peptides may be expressed (e.g., somatostatin, serotonin, VIP, ACTH)  

─ IHC (-)  

  ─ Thyroglobulin: Negative (crucial for distinguishing from follicular-derived carcinomas)  

─ Special Stains:  

  ─ Congo Red: Positive for amyloid deposits (apple-green birefringence under polarized light)  

─ Molecular ─  

  ─ *RET* proto-oncogene mutations: Somatic mutations (especially M918T in exon 16) are common in sporadic MTCs (>50%); germline *RET* mutations are present in all hereditary MTCs (specific codon mutations correlate with MEN2 subtypes and aggressiveness)  

  ─ *RAS* mutations (H-, K-, N-RAS) can occur in *RET*-negative sporadic MTCs (~20%)  

DDx ─  

─ Poorly differentiated or anaplastic thyroid carcinoma (thyroglobulin may be positive focally, calcitonin negative; different cytomorphology and IHC profile)  

─ Hyalinizing trabecular tumor (trabecular pattern, hyalinization; thyroglobulin positive, calcitonin negative, *PAX8/GLIS* fusions)  

─ Solid variant or follicular variant of papillary thyroid carcinoma (PTC nuclear features, thyroglobulin positive, calcitonin negative)  

─ Follicular carcinoma (follicular pattern, thyroglobulin positive, calcitonin negative)  

─ Paraganglioma of thyroid (S100 positive sustentacular cells, lacks calcitonin and amyloid, thyroglobulin negative)  

─ Metastatic neuroendocrine carcinoma (history of primary, different peptide profile, calcitonin usually negative unless primary is a calcitonin-producing NET from another site like lung - very rare)  

─ Solid cell nests (p63/p40 positive, calcitonin and thyroglobulin negative)  

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## **Mucoepidermoid Carcinoma (of thyroid)**

A rare malignant epithelial neoplasm of the thyroid gland characterized by a combination of mucin-producing cells, squamous cells, and intermediate cells; histologically similar to mucoepidermoid carcinoma of salivary glands  

Clinical ─ Can occur over a wide age range, but often in middle-aged to older adults; may present as a solitary thyroid nodule or mass; behavior is variable, ranging from indolent (low-grade) to aggressive with metastases (high-grade); often associated with a background of chronic lymphocytic thyroiditis (Hashimoto's)  

Macro ─ Typically a firm, unencapsulated or partially encapsulated mass; cut surface may be solid, grayish-white, and can show cystic areas filled with mucoid material  

Micro ─  

─ Composed of three main cell types in varying proportions:  

  ─ Mucous cells: Cuboidal to columnar cells with abundant pale, foamy, or vacuolated cytoplasm containing mucin; often line cysts or glandular structures  

  ─ Squamous cells (epidermoid cells): Polygonal cells with eosinophilic cytoplasm, distinct cell borders, intercellular bridges, and may show keratinization (individual cell or keratin pearls)  

  ─ Intermediate cells: Smaller, basaloid, or ovoid cells with scant cytoplasm, representing precursor cells that can differentiate into mucous or squamous cells; often form solid nests or line ducts  

─ Growth patterns include cystic spaces, glandular structures, solid nests, and sheets  

─ Stroma is often fibrous and may contain a lymphocytic infiltrate  

─ Grading (low, intermediate, high) is based on features like cystic component (<20% for high grade), neural invasion, necrosis, anaplasia, and mitotic rate, similar to salivary gland counterparts  

─ Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a distinct variant with prominent sclerosis and eosinophilia (covered separately if requested by user's ToC)  

Ancillary studies ─  

─ IHC (+)  

  ─ Squamous cells: p63, p40, CK5/6, high molecular weight cytokeratins  

  ─ Mucous cells: PAS-diastase (for mucin), Alcian blue, specific mucin stains (e.g., MUC1, MUC4, MUC5AC)  

  ─ Intermediate cells and glandular components: Pan-cytokeratin (AE1/AE3, CAM5.2), CK7, EMA  

  ─ PAX8: Often positive (supports thyroid origin or involvement if primary)  

  ─ TTF-1: Can be positive but may be focal or negative (less reliable than PAX8 for thyroid origin in this context)  

─ IHC (-)  

  ─ Thyroglobulin: Usually negative or only focally positive in entrapped benign follicles or rarely in tumor cells (a key point as these are not considered follicular cell derived despite PAX8/TTF-1 positivity)  

  ─ Calcitonin  

─ Molecular ─  

  ─ *MAML2* gene rearrangements (e.g., *CRTC1/3-MAML2* fusions) are characteristic and found in a significant proportion of cases, similar to salivary gland mucoepidermoid carcinoma; associated with better prognosis  

DDx ─  

─ Squamous cell carcinoma of thyroid (predominantly squamous differentiation, lacks mucous cells and intermediate cells; usually thyroglobulin negative)  

─ Papillary thyroid carcinoma with squamous metaplasia or mucinous differentiation (PTC shows characteristic nuclear features, thyroglobulin positive; mucinous change in PTC is usually extracellular, not intracellular like true mucous cells of MEC)  

─ Anaplastic thyroid carcinoma with squamous or glandular differentiation (marked pleomorphism, high mitotic rate, necrosis, often loss of thyroid markers)  

─ Metastatic mucoepidermoid carcinoma (from salivary gland or other sites; clinical history, different PAX8/TTF-1 profile)  

─ Solid cell nests with extensive squamous metaplasia and cystic change (p63/p40 positive, thyroglobulin negative; lacks true mucous cells and *MAML2* rearrangement)  

─ Thyroglossal duct cyst carcinoma (if arising in cyst; location, presence of benign cyst elements)  

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## **Secretory Carcinoma (of thyroid) (Mammary Analogue Secretory Carcinoma - MASC)**

A rare malignant epithelial neoplasm of the thyroid gland that is histologically, immunophenotypically, and molecularly identical to secretory carcinoma of the breast and salivary glands, characterized by an *ETV6-NTRK3* gene fusion  

Clinical ─ Affects adults, wide age range; may present as a painless thyroid nodule or mass; generally considered an indolent, low-grade malignancy with a favorable prognosis, though local recurrence and rare lymph node or distant metastases can occur  

Macro ─ Typically a well-circumscribed, firm, solid, or partially cystic nodule; grayish-white to tan on cut section  

Micro ─  

─ Histological features are similar regardless of site (breast, salivary, thyroid):  

  ─ Varied architectural patterns: Microcystic, macrocystic, glandular, cribriform, solid, and papillary (often with broad, hyalinized fibrovascular cores)  

  ─ Tumor cells are relatively uniform, polygonal to cuboidal, with eosinophilic, vacuolated, or clear cytoplasm  

  ─ Nuclei are round to oval, with fine chromatin and inconspicuous or small nucleoli; atypia is usually mild  

  ─ **Characteristic feature: Abundant eosinophilic, PAS-positive, diastase-resistant secretions** within glandular lumens, microcysts, or as intracellular globules (resembling thyroid colloid or zymogen granules)  

  ─ "Bubbly" or "foamy" appearance of cytoplasm and secretions is common  

  ─ Mitotic activity is typically low  

Ancillary studies ─  

─ IHC (+)  

  ─ S100 protein: Strong and diffuse positivity (characteristic)  

  ─ Mammaglobin: Often positive (characteristic)  

  ─ GCDFP-15: May be positive  

  ─ Pan-Trk (recognizing Trk proteins, including TrkC resulting from *ETV6-NTRK3* fusion): Often positive  

  ─ Cytokeratins (e.g., CAM5.2, CK7)  

  ─ PAX8: Can be positive (supporting thyroid involvement/origin if primary)  

  ─ TTF-1: Often positive but can be focal or negative  

─ IHC (-)  

  ─ Thyroglobulin: Typically negative or only very focally positive in entrapped follicles or rare tumor cells (tumor is not considered of follicular cell histogenesis despite PAX8/TTF-1 positivity)  

  ─ Calcitonin  

  ─ Estrogen Receptor (ER), Progesterone Receptor (PR), HER2: Usually negative (unlike many breast carcinomas)  

─ Molecular ─  

  ─ **Defining feature: *ETV6-NTRK3* gene fusion** (can be detected by FISH, RT-PCR, or next-generation sequencing)  

  ─ Other *NTRK* fusions may rarely occur  

DDx ─  

─ Papillary thyroid carcinoma, especially follicular variant or variants with clear cell/vacuolated features (PTC shows characteristic nuclear features, thyroglobulin usually strongly positive, S100/mammaglobin negative, lacks *ETV6-NTRK3* fusion)  

─ Follicular adenoma/carcinoma with clear cell change (lacks S100/mammaglobin, *ETV6-NTRK3* fusion)  

─ Metastatic secretory carcinoma from breast or salivary gland (indistinguishable histologically and molecularly; clinical history is paramount; PAX8/TTF-1 positivity in thyroid MASC favors thyroid primary if no other known primary)  

─ Mucoepidermoid carcinoma with clear cell features (presence of squamous and true mucous cells, *MAML2* fusion)  

─ Clear cell medullary thyroid carcinoma (rare; calcitonin positive)  

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## **Squamous Cell Carcinoma (of thyroid) (SCC)**

A rare, aggressive malignant epithelial neoplasm of the thyroid gland composed predominantly or exclusively of cells with squamous differentiation; its origin is debated, possibly arising from metaplastic follicular epithelium, remnants of thyroglossal duct or ultimobranchial body, or de novo  

Clinical ─ Typically affects older individuals (mean age >60 years); presents as a rapidly enlarging, firm, fixed neck mass, often with symptoms of invasion (dysphagia, dyspnea, hoarseness, pain); frequently associated with extrathyroidal extension and lymph node metastases at diagnosis; distant metastases are common; prognosis is generally poor, similar to or worse than poorly differentiated thyroid carcinoma but better than anaplastic carcinoma  

Macro ─ Large, infiltrative, firm, grayish-white mass, often with necrosis and hemorrhage; may invade adjacent structures  

Micro ─  

─ Composed of sheets, nests, or infiltrating cords of malignant squamous cells  

─ Squamous differentiation is evident by:  

  ─ Intercellular bridges  

  ─ Keratinization (individual cell keratinization, keratin pearls)  

  ─ Polygonal cells with abundant eosinophilic cytoplasm and distinct cell borders  

─ Tumor cells exhibit marked nuclear atypia, pleomorphism, hyperchromasia, and often prominent nucleoli  

─ Mitotic activity is usually brisk, and atypical mitoses may be seen  

─ Necrosis is common  

─ Vascular and perineural invasion may be present  

─ May arise in a background of chronic thyroiditis or multinodular goiter  

─ Must exclude extension from an adjacent head and neck primary SCC or metastasis  

─ A component of well-differentiated thyroid carcinoma (PTC or FTC) or anaplastic carcinoma may sometimes be identified, suggesting transformation  

Ancillary studies ─  

─ IHC (+)  

  ─ Squamous markers: p63, p40, CK5/6, high molecular weight cytokeratins (e.g., 34βE12)  

  ─ Pan-cytokeratin (AE1/AE3, CAM5.2)  

  ─ PAX8: May be positive in a subset (up to 50%), supporting thyroid origin if primary, but can also be positive in some SCCs from other sites (e.g., lung)  

  ─ TTF-1: Less frequently positive than PAX8, and if positive, raises possibility of metastasis from lung SCC or adenosquamous carcinoma  

─ IHC (-)  

  ─ Thyroglobulin: Usually negative (loss of follicular differentiation); if positive, consider adenosquamous carcinoma or PTC with extensive squamous metaplasia  

  ─ Calcitonin  

  ─ S100 (negative, rules out melanoma with squamous features)  

─ Molecular ─  

  ─ *TP53* mutations are common  

  ─ Other alterations similar to those in head and neck SCC or lung SCC may be found  

  ─ *BRAF* or *RAS* mutations may be present if arising from a pre-existing PTC or FTC  

DDx ─  

─ Metastatic squamous cell carcinoma (from head/neck, lung, esophagus, etc.; most common cause of SCC in thyroid region; clinical history, imaging, p16 status for HPV-related oropharyngeal origin)  

─ Anaplastic thyroid carcinoma with squamous differentiation (ATC is more pleomorphic, often with spindle/giant cells, rapid loss of markers; SCC is more uniformly squamous but high grade)  

─ Mucoepidermoid carcinoma (presence of mucous and intermediate cells, *MAML2* fusion)  

─ Papillary thyroid carcinoma with extensive squamous metaplasia (PTC nuclear features in non-squamous areas, thyroglobulin positive)  

─ SETTLE (Spindle Epithelial Tumor with Thymus-Like Elements) (biphasic, younger patients, specific IHC)  

─ Intrathyroidal thymic carcinoma (thymic-type histology, specific IHC like CD5)  

─ Thyroglossal duct cyst carcinoma with squamous differentiation (arising in cyst)  

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## **Thyroid Lymphomas**

Malignant neoplasms of lymphoid tissue arising primarily within the thyroid gland; most are non-Hodgkin lymphomas (NHL), predominantly of B-cell origin  

Clinical ─ Relatively uncommon, accounting for <5% of thyroid malignancies; typically affects older adults (median age 60-70 years), with a female predominance; strong association with pre-existing Hashimoto's thyroiditis (autoimmune thyroiditis provides a background of chronic inflammation and lymphoid proliferation); presents as a rapidly enlarging, painless or painful, firm thyroid mass, often causing compressive symptoms (dyspnea, dysphagia, hoarseness); B-symptoms (fever, night sweats, weight loss) may be present  

Types ─ Most common types:  

  ─ Diffuse Large B-Cell Lymphoma (DLBCL): Most frequent type, aggressive course  

  ─ Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma (Extranodal Marginal Zone Lymphoma): Indolent course, may remain localized for long periods, strongly associated with Hashimoto's  

  ─ Other less common types: Follicular lymphoma, Burkitt lymphoma, Hodgkin lymphoma (very rare)  

Macro ─ Diffuse enlargement of the thyroid gland or a discrete mass; cut surface is typically fleshy, homogenous, grayish-white or tan ("fish-flesh" appearance); necrosis may be present, especially in high-grade lymphomas  

Micro ─  

─ Diffuse infiltration and replacement of thyroid parenchyma by atypical lymphoid cells  

─ Thyroid follicles may be entrapped, destroyed, or show lymphoepithelial lesions (infiltration of follicular epithelium by neoplastic lymphocytes, characteristic of MALT lymphoma)  

─ Morphology depends on the lymphoma subtype:  

  ─ DLBCL: Sheets of large, atypical lymphocytes with vesicular nuclei, prominent nucleoli, and frequent mitoses; centroblastic, immunoblastic, or anaplastic variants  

  ─ MALT Lymphoma: Infiltrate of small to medium-sized lymphocytes with irregular nuclei (centrocyte-like cells), admixed with plasma cells, immunoblasts, and transformed large cells; follicular colonization (neoplastic cells infiltrating reactive germinal centers) may be seen  

─ Necrosis, vascular invasion can occur in high-grade lymphomas  

─ Background of Hashimoto's thyroiditis (lymphoid follicles, Hürthle cells, follicular atrophy) is often present  

Ancillary studies ─  

─ IHC (+) (markers depend on subtype)  

  ─ General lymphoid marker: CD45 (LCA)  

  ─ B-cell markers: CD20, CD79a, PAX5  

  ─ DLBCL: CD20, often MUM1, BCL6, CD10 (for subtyping into GCB vs non-GCB type), BCL2; Ki-67 high  

  ─ MALT Lymphoma: CD20, CD79a, BCL2 positive; often CD5-, CD10-, CD23-, Cyclin D1-  

  ─ Plasma cells (if prominent): CD138, kappa/lambda light chains (monoclonality in MALT lymphoma indicates plasmacytic differentiation)  

─ IHC (-)  

  ─ Cytokeratins (AE1/AE3, CAM5.2): Negative in lymphoma cells (highlights entrapped epithelial structures)  

  ─ Thyroglobulin, TTF-1, PAX8: Negative in lymphoma cells (positive in residual thyroid follicles)  

  ─ Calcitonin  

─ Flow Cytometry: Useful for immunophenotyping and demonstrating B-cell clonality (light chain restriction)  

─ Molecular ─  

  ─ Clonality studies (e.g., IgH gene rearrangements for B-cell lymphomas, TCR gene rearrangements for T-cell lymphomas - though T-cell lymphoma of thyroid is very rare)  

  ─ Specific translocations in some lymphoma types (e.g., t(11;18)(q21;q21) API2-MALT1 in MALT lymphoma, t(14;18)(q32;q21) IGH-BCL2 in follicular lymphoma, MYC rearrangements in Burkitt/high-grade DLBCL)  

DDx ─  

─ Hashimoto's thyroiditis (polyclonal lymphoid infiltrate, prominent germinal centers, Hürthle cells, lacks sheets of atypical monotonous lymphocytes and destructive infiltration seen in lymphoma; flow cytometry/molecular studies for clonality if uncertain)  

─ Anaplastic thyroid carcinoma (can have prominent inflammation or undifferentiated appearance; positive for cytokeratins and/or PAX8, negative for lymphoid markers)  

─ Poorly differentiated thyroid carcinoma (solid sheets of cells; positive for thyroid markers, negative for lymphoid markers)  

─ Medullary thyroid carcinoma, small cell variant (neuroendocrine markers positive, calcitonin positive)  

─ Intrathyroidal lymph node (normal architecture, reactive changes)  

─ Plasmacytoma (sheets of plasma cells; CD138 positive, monoclonal immunoglobulin, systemic workup for multiple myeloma)  

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## **Thyroblastoma**

An extremely rare, malignant biphasic or triphasic thyroid tumor of uncertain histogenesis, typically occurring in infants and young children, composed of epithelial elements (often resembling immature thyroid follicles or tubules) and a primitive mesenchymal or blastemal-like stromal component  

Clinical ─ Presents as a rapidly enlarging thyroid mass in infancy or early childhood; may cause compressive symptoms; highly aggressive with poor prognosis, frequent local recurrence, and distant metastases (lung, bone); some cases have been associated with DICER1 syndrome  

Macro ─ Large, poorly circumscribed, fleshy, grayish-white to tan mass, often with areas of necrosis and hemorrhage; may replace most of the thyroid gland and invade adjacent structures  

Micro ─  

─ Biphasic or triphasic appearance:  

  1. Epithelial component:  

     ─ Immature tubular or follicular structures lined by small, cuboidal to columnar epithelial cells with scant cytoplasm and hyperchromatic nuclei  

     ─ Solid nests or cords of epithelial cells  

     ─ Squamoid morules or clear cell change may be present  

     ─ Resembles developing thyroid tissue or nephroblastoma-like tubules  

  2. Mesenchymal (stromal) component:  

     ─ Primitive, undifferentiated small round blue cells (blastemal-like) with high N/C ratio, hyperchromatic nuclei, and frequent mitoses  

     ─ Spindle cell stroma, often myxoid or collagenous  

     ─ Rhabdomyoblastic differentiation (strap cells) may occur (triphasic)  

     ─ Cartilaginous or osseous differentiation is rare  

─ Mitotic activity is usually high in both epithelial and stromal components  

─ Necrosis and lymphovascular invasion are common  

Ancillary studies ─  

─ IHC (+)  

  ─ Epithelial component: Pan-cytokeratin (AE1/AE3, CAM5.2), EMA, PAX8; TTF-1 and Thyroglobulin may be focally positive in more differentiated tubular/follicular structures but often weak or negative in immature areas  

  ─ Mesenchymal (blastemal/spindle cell) component: Vimentin; may show focal desmin, myogenin if rhabdomyoblastic differentiation; CD99 can be positive  

  ─ SALL4: May be positive, indicating primitive nature  

─ IHC (-)  

  ─ Calcitonin  

  ─ S100 (usually negative in blastemal component)  

─ Molecular ─  

  ─ *DICER1* gene mutations (germline or somatic) are found in a significant proportion of cases, linking thyroblastoma to DICER1 syndrome (which includes pleuropulmonary blastoma, cystic nephroma, ovarian Sertoli-Leydig cell tumors, etc.)  

DDx ─  

─ Anaplastic thyroid carcinoma (usually elderly patients, different morphology often with giant/spindle cells, widespread loss of thyroid markers, PAX8 may be positive but lacks distinct biphasic pattern of thyroblastoma with immature tubules and blastema)  

─ Poorly differentiated thyroid carcinoma (older age group, more monotonous solid/trabecular growth, retains more consistent thyroid marker expression, lacks blastemal stroma)  

─ Teratoma with immature elements (contains tissues from all three germ layers, may include immature neuroepithelium but distinct from thyroblastoma's specific biphasic pattern)  

─ Synovial sarcoma (primary or metastatic; biphasic but with characteristic spindle cells and epithelial structures different from thyroblastoma; TLE1 positive, specific translocations like SS18-SSX)  

─ Metastatic blastoma from other sites (e.g., pleuropulmonary blastoma, nephroblastoma; clinical history, site-specific markers if any)  

─ SETTLE (Spindle Epithelial Tumor with Thymus-Like Elements) (biphasic, but different spindle and epithelial components, typically CD5 positive in epithelial component, older children/young adults)  

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## **Ultimobranchial Body Remnants/Cysts (UBB Remnants)**

Microscopic structures or small cysts within the thyroid gland derived from the embryonic ultimobranchial body (ultimopharyngeal body), which is the caudal portion of the last pharyngeal pouch complex that fuses with the developing thyroid and contributes C-cells and potentially other non-follicular elements  

Clinical ─ Asymptomatic, incidental microscopic findings with no known clinical significance; important for pathologists to recognize to avoid misinterpretation as a neoplastic or preneoplastic lesion, particularly solid cell nests which are considered a type of UBB remnant  

Macro ─ Not grossly visible; found microscopically within the thyroid parenchyma  

Micro ─  

─ Typically located in the middle to upper thirds of the thyroid lobes, consistent with the fusion site of the UBB  

─ Solid Cell Nests (SCN) are the most well-recognized form (see separate entry for SCN): clusters of polygonal to spindle cells, often with squamous features or microcysts, negative for thyroglobulin and calcitonin, positive for p63/p40  

─ Ultimobranchial body-related cysts:  

  ─ Small, microscopic cysts lined by various types of epithelium including squamous, cuboidal, columnar, or mucinous cells  

  ─ May contain proteinaceous material or cellular debris  

  ─ Sometimes referred to as "intrathyroidal cysts of ultimobranchial body origin"  

─ The remnants are usually well-circumscribed and integrated within the thyroid stroma, often near C-cell populations  

─ No atypia or infiltrative growth  

Ancillary studies ─  

─ (Primarily relevant for Solid Cell Nests, which are a form of UBB remnant)  

─ IHC (+) for SCN component: p63, p40, various cytokeratins (especially squamous types like CK5/6)  

─ IHC (-) for SCN component: Thyroglobulin, Calcitonin, TTF-1 (often negative or weak)  

─ For cystic structures, lining epithelium IHC depends on differentiation (e.g., cytokeratins)  

DDx ─  

─ Solid Cell Nests (are a type of UBB remnant; recognition is key)  

─ Small parathyroid glands or cysts (intrathyroidal; PTH positive, GATA3 positive)  

─ Thyroglossal duct remnants/cysts (can be intraparenchymal if duct extends into gland; may contain thyroid follicles, respiratory/squamous lining)  

─ Lymphoepithelial cyst (rare in thyroid; lymphoid stroma, epithelial lining)  

─ Cystic degeneration in a thyroid nodule (background nodular changes)  

─ Early/small neoplastic lesions (e.g., micropapillary carcinoma, foci of medullary carcinoma; distinguished by specific malignant features and IHC)  

─ Branchial cleft cyst elements (very rare to be truly intrathyroidal)  

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## **Thyroid Needle-Biopsy Site Changes (FNA Site Changes, WHAFFT)**

Reactive and reparative histological alterations in the thyroid gland occurring at the site of a previous fine-needle aspiration (FNA) biopsy or core needle biopsy; can sometimes mimic malignancy if the pathologist is unaware of the prior procedure  

Clinical ─ Usually asymptomatic; history of prior FNA is crucial for correct interpretation; changes typically develop within weeks to months after the procedure and can persist; "Worrisome Histologic Alterations Following Fine-Needle Aspiration of the Thyroid" (WHAFFT) describes features that can be particularly concerning if history is unknown  

Macro ─ May not be grossly visible if changes are small; can appear as a focal scar, induration, small hemorrhagic area, or a poorly defined nodule at the biopsy site  

Micro ─  

─ A spectrum of changes can be observed, often admixed:  

  ─ Hemorrhage (fresh or old with hemosiderin-laden macrophages)  

  ─ Granulation tissue and fibrosis (scar formation)  

  ─ Needle tract: A linear track of fibrosis, siderophages, and sometimes foreign material (e.g., cellulose from paper covering slides, ultrasound gel - rare)  

  ─ Follicular cell atypia/reactive changes: Enlarged nuclei, prominent nucleoli, cytoplasmic vacuolization, nuclear clearing, and even pseudoinclusions in follicular cells adjacent to the needle tract or area of repair; these reactive changes can be mistaken for PTC nuclear features  

  ─ Spindle cell proliferation: Bland fibroblastic/myofibroblastic proliferation as part of the repair process  

  ─ Papillary-like changes: Reactive papillary hyperplasia or infoldings of follicular epithelium, usually lacking true fibrovascular cores and diffuse PTC nuclei  

  ─ Vascular proliferation and damage (e.g., organizing thrombi, sideroticcysts)  

  ─ Histiocytic reaction, including foreign body giant cells (especially if colloid extravasation)  

  ─ Displacement of benign follicular cells into the needle tract, capsule, or adjacent soft tissue (pseudoinvasion) - very rare  

  ─ Cystic degeneration  

Ancillary studies ─  

─ IHC: Not usually primary for diagnosis, but can help in problematic cases  

  ─ Ki-67: May show focally increased proliferation in reparative areas but usually not as high or diffuse as in malignancy  

  ─ IHC for thyroid markers (Tg, TTF-1, PAX8) confirms follicular origin of atypical cells  

  ─ If PTC is suspected due to atypia, IHC for PTC markers (CK19, Galectin-3, HBME-1) might be performed, but reactive atypia usually doesn't show the strong diffuse pattern of true PTC. *BRAF V600E* testing might be considered in very difficult cases.  

DDx ─  

─ Papillary thyroid carcinoma (true PTC shows diffuse and convincing nuclear features, often true papillae, psammoma bodies, and may show infiltrative growth not confined to a linear tract; history of FNA is key to consider reactive changes)  

─ Follicular neoplasm (adenoma/carcinoma; well-circumscribed nodule, specific architectural patterns, invasion for carcinoma)  

─ Anaplastic thyroid carcinoma (if extensive atypia and spindle cells, but ATC has marked pleomorphism, high mitoses, necrosis beyond typical repair)  

─ Scar tissue from other causes (e.g., previous surgery, trauma)  

─ Organizing hematoma  

─ Palpation thyroiditis (granulomatous reaction to colloid, often multifocal, not necessarily linear tract)  

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# Parathyroid Glands

## **Normal Parathyroid Histology**

The parathyroid glands are small endocrine glands, typically four in number, located in the neck posterior to the thyroid gland, responsible for secreting parathyroid hormone (PTH) which regulates calcium and phosphorus homeostasis  

Clinical ─ PTH increases serum calcium by stimulating bone resorption, increasing renal calcium reabsorption, and increasing intestinal calcium absorption (via Vitamin D activation); dysregulation leads to hyperparathyroidism or hypoparathyroidism  

Macro ─ Typically 4 glands (2 superior, 2 inferior); small, ovoid or bean-shaped, yellowish-tan to reddish-brown; each measures ~3-6 mm in length, 2-4 mm in width, and 0.5-2 mm in thickness; total weight of all four glands is usually 120-140 mg; variable location due to embryologic migration  

Micro ─  

─ Composed mainly of two cell types arranged in nests, cords, or sheets, interspersed with adipose tissue and a rich capillary network:  

  ─ Chief cells: Most numerous cell type; small, polygonal cells with round, central, darkly staining nuclei and scant, clear to pale eosinophilic cytoplasm; synthesize and secrete PTH; cytoplasm contains glycogen (PAS positive, diastase sensitive) and small lipid droplets  

  ─ Oxyphil cells (Askanazy cells): Larger polygonal cells with abundant, granular, intensely eosinophilic cytoplasm (due to numerous mitochondria) and smaller, more condensed, often pyknotic nuclei; appear after puberty and increase with age; function is uncertain, may be effete or modified chief cells; generally do not secrete significant PTH  

  ─ Transitional oxyphil cells (pale oxyphils): Intermediate features between chief cells and oxyphil cells  

  ─ Water-clear cells: Rare in normal glands; large cells with optically clear cytoplasm due to abundant glycogen (historically associated with a rare form of hyperplasia)  

─ Adipose tissue (stromal fat): Constitutes a variable proportion of the gland volume, typically increasing with age (can be 10-50% or more in adults); amount varies between glands and individuals; generally decreased in hyperplasia or adenoma (relative to parenchymal cells)  

─ Delicate fibrovascular stroma supports the cells  

─ No true follicles like thyroid, but microcysts or acinar structures containing colloid-like material can occasionally be seen  

Ancillary studies ─  

─ IHC (+)  

  ─ Chief cells and Oxyphil cells: Parathyroid hormone (PTH, often more intense in chief cells), Chromogranin A, Synaptophysin (neuroendocrine markers)  

  ─ GATA3: Nuclear positivity (useful marker for parathyroid origin)  

  ─ PAX8: Can be positive (but also positive in thyroid, kidney, etc.)  

  ─ Cytokeratins (e_g_, CAM5.2): Can be positive  

─ IHC (-)  

  ─ Thyroglobulin, TTF-1 (negative, distinguishes from thyroid tissue)  

  ─ Calcitonin (negative, distinguishes from C-cells)  

─ Special Stains:  

  ─ PAS: Highlights glycogen in chief cells (diastase sensitive)  

  ─ Oil Red O (on frozen tissue): Highlights intracytoplasmic fat in chief cells  

DDx ─  

─ Thyroid tissue (follicles with colloid, thyroglobulin/TTF-1 positive)  

─ Lymph node (organized lymphoid architecture, CD45 positive)  

─ Thymic tissue (Hassall's corpuscles, mixture of epithelial cells and lymphocytes)  

─ Adipose tissue (if mostly fat with few parenchymal cells)  

─ Parathyroid adenoma or hyperplasia (alterations in cell composition, reduced stromal fat, specific architectural patterns)  

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## **Parathyroid Cysts**

Uncommon cystic lesions that can arise from remnants of pharyngeal pouch embryology, cystic degeneration of a parathyroid gland or adenoma, or from coalescence of microcysts within parathyroid tissue  

Clinical ─ Often asymptomatic and discovered incidentally on imaging or during neck surgery for other reasons; can occur at any age; may present as a painless neck mass, or rarely cause symptoms due to compression or hormonal activity (if functional cyst fluid containing PTH is rapidly absorbed or cyst ruptures); most are non-functional, but fluid PTH levels are typically elevated  

Macro ─ Usually unilocular, thin-walled cysts filled with clear, serous, or straw-colored fluid; can range from small (<1 cm) to very large (>10 cm); may be located in typical parathyroid positions or ectopically (e.g., mediastinum, within thyroid)  

Micro ─  

─ Cyst wall is typically thin and fibrous  

─ Lining epithelium is variable:  

  ─ Often composed of a single layer of flattened, cuboidal, or low columnar cells  

  ─ Squamous metaplasia can occur  

  ─ Atrophic parathyroid tissue (chief cells, oxyphil cells) may be present in the cyst wall or compressed at the periphery, which is key for diagnosis  

  ─ True epithelial lining may be absent in some cysts, especially pseudocysts formed by degeneration  

─ Cyst fluid is usually proteinaceous and acellular, or may contain hemosiderin-laden macrophages if there has been hemorrhage  

─ No evidence of malignancy (e.g., atypical cells, invasion) in benign cysts  

─ If arising from cystic degeneration of an adenoma, remnants of adenomatous tissue will be present in the wall  

Ancillary studies ─  

─ IHC (+) (for parathyroid tissue in cyst wall)  

  ─ PTH, Chromogranin A, GATA3 in residual parathyroid cells  

─ Fluid analysis:  

  ─ Elevated PTH level in cyst fluid (much higher than serum PTH) is diagnostic  

─ IHC (-)  

  ─ Thyroglobulin, TTF-1 (negative in parathyroid cells)  

DDx ─  

─ Thyroglossal duct cyst (midline, often contains thyroid follicles and respiratory/squamous lining)  

─ Branchial cleft cyst (lateral neck, squamous/respiratory lining, prominent lymphoid tissue in wall)  

─ Thyroid cyst (arising within thyroid gland, lined by thyroid follicular cells or flattened epithelium; PTH negative in fluid)  

─ Cystic hygroma (lymphangioma; endothelial-lined lymphatic channels)  

─ Dermoid/Epidermoid cyst (keratinizing squamous epithelium +/- adnexa)  

─ Cystic metastatic carcinoma (malignant cells, IHC for primary)  

─ Cystic degeneration of a parathyroid adenoma (adenomatous tissue in wall, often with atypia if atypical adenoma)  

─ Thymic cyst (may contain thymic tissue, Hassall's corpuscles)  

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## **Parathyroiditis**

A rare inflammatory condition of the parathyroid glands, which can be acute or chronic, and may be associated with autoimmune processes or infections  

Clinical ─ Can be asymptomatic or present with signs of hypoparathyroidism (hypocalcemia, tetany, paresthesias) due to glandular destruction, or rarely hyperparathyroidism if transient release of PTH occurs; may be associated with other autoimmune diseases (e.g., Hashimoto's thyroiditis, Addison's disease in autoimmune polyglandular syndromes) or occur in patients with DiGeorge syndrome; infectious parathyroiditis is extremely rare  

Macro ─ Glands may be normal, atrophic, or slightly enlarged and indurated depending on etiology and chronicity  

Micro ─  

─ Variable inflammatory infiltrates depending on the cause:  

  ─ Lymphocytic parathyroiditis (autoimmune): Most common form; infiltration of parathyroid parenchyma by lymphocytes and plasma cells, often forming lymphoid aggregates or follicles with germinal centers; associated with destruction and atrophy of chief cells; oxyphilic metaplasia may be prominent; fibrosis can occur in chronic stages  

  ─ Granulomatous parathyroiditis: Rare; presence of non-caseating granulomas, similar to those seen in sarcoidosis or other granulomatous diseases; may be idiopathic  

  ─ Suppurative (infectious) parathyroiditis: Extremely rare; neutrophilic infiltrate, abscess formation, necrosis (requires identification of causative organism)  

─ Fibrosis and parenchymal loss are common in chronic forms  

─ Amyloid deposition in parathyroid glands can occur in systemic amyloidosis and cause hypofunction, sometimes with associated inflammation  

Ancillary studies ─  

─ IHC (+)  

  ─ Lymphoid infiltrates: CD3, CD20, CD45  

  ─ Plasma cells: CD138  

  ─ Macrophages (in granulomatous type): CD68  

  ─ Residual parathyroid cells: PTH, Chromogranin A, GATA3  

─ Special stains: For microorganisms (Gram, GMS, AFB) if infection suspected; Congo Red for amyloid  

─ Serology: Parathyroid autoantibodies may be detectable in autoimmune cases  

DDx ─  

─ Normal parathyroid gland with focal lymphoid aggregates (inflammation in parathyroiditis is usually more extensive and destructive)  

─ Parathyroid atrophy (due to other causes like chronic hypercalcemia or post-surgery; inflammation may be minimal)  

─ Lymphoma involving parathyroid gland (neoplastic lymphoid infiltrate, monoclonal)  

─ Metastatic carcinoma to parathyroid (presence of malignant non-parathyroid cells)  

─ Parathyroid hyperplasia or adenoma with secondary inflammatory changes (primary lesion is neoplastic/hyperplastic)  

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## **Parathyroid Hyperplasia**

Enlargement of parathyroid glands due to an absolute increase in the number of parenchymal cells (chief cells, oxyphil cells, or water-clear cells), leading to excessive secretion of parathyroid hormone (PTH) and hyperparathyroidism; typically involves multiple glands  

Clinical ─ Primary Hyperplasia: Part of MEN1 or MEN2A syndromes, or sporadic; results in hypercalcemia, hypophosphatemia, nephrolithiasis, bone disease (osteitis fibrosa cystica). Secondary Hyperplasia: Compensatory response to chronic hypocalcemia (e.g., chronic renal failure, vitamin D deficiency, malabsorption); diffuse enlargement of all glands, high PTH, low/normal calcium. Tertiary Hyperplasia: Develops from longstanding secondary hyperplasia (usually in renal failure patients, post-transplant) where PTH secretion becomes autonomous despite correction of hypocalcemia; hypercalcemia and very high PTH  

Macro ─ All four glands are typically enlarged, but often asymmetrically; color is reddish-brown to tan; texture is soft to firm; combined weight of glands is increased (>120-140 mg, often significantly higher)  

Micro ─  

─ Diffuse or nodular proliferation of parathyroid parenchymal cells, involving multiple (usually all four) glands  

─ Reduction or absence of intraglandular stromal fat (adipose tissue) relative to parenchymal cells is a key feature, though some fat may persist, especially in nodular areas or between nodules  

─ Cell types involved:  

  ─ Chief cell hyperplasia: Most common; diffuse or nodular proliferation of chief cells, often forming sheets, cords, or acinar structures  

  ─ Oxyphil cell hyperplasia: Predominantly oxyphilic cells; less common  

  ─ Water-clear cell hyperplasia: Rare; diffuse replacement by large cells with optically clear cytoplasm (historically recognized, now very rare entity if it exists as a distinct form of primary hyperplasia)  

─ Architectural patterns:  

  ─ Diffuse hyperplasia: Uniform enlargement and hypercellularity of the glands  

  ─ Nodular hyperplasia: Multiple nodules of proliferating cells separated by fibrous bands or compressed stroma; nodules can vary in cell type and architecture; this pattern is common in both primary and secondary/tertiary hyperplasia  

─ Cellular atypia can be present but is usually mild and does not indicate malignancy  

─ Mitotic figures are generally infrequent  

Ancillary studies ─  

─ IHC (+) (parenchymal cells)  

  ─ PTH, Chromogranin A, GATA3  

  ─ Ki-67 proliferation index: Usually low (<1%), but can be slightly higher in some areas  

─ IHC (-)  

  ─ Thyroglobulin, TTF-1  

─ Molecular ─  

  ─ Primary hyperplasia: *MEN1* gene mutations in MEN1 syndrome; *RET* gene mutations in MEN2A; sporadic cases may involve mutations in genes like *CCND1* (cyclin D1, PRAD1 oncogene leading to overexpression) or genes regulating calcium sensing receptor (*CASR*) pathway  

DDx ─  

─ Parathyroid adenoma (typically involves a single gland, with the other glands being normal or atrophic; adenoma is usually a discrete, encapsulated nodule, though hyperplasia can be nodular making distinction difficult, especially on intraoperative frozen section. Loss of stromal fat is common to both. Multiple adenomas can occur but are less common than four-gland hyperplasia)  

─ Normal parathyroid gland (especially in younger individuals with less stromal fat; hyperplasia shows increased cellularity and gland weight)  

─ Parathyroid carcinoma (evidence of invasion - capsular, vascular, or into adjacent tissues - or metastasis; marked atypia, thick fibrous bands, increased and atypical mitoses are more suggestive of carcinoma but not definitive without invasion)  

─ Intrathyroidal parathyroid tissue undergoing hyperplasia (can mimic a thyroid nodule)  

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## **Parathyroid Adenoma**

A benign neoplastic proliferation of parathyroid parenchymal cells, typically involving a single gland, leading to autonomous overproduction of parathyroid hormone (PTH) and primary hyperparathyroidism  

Clinical ─ Most common cause of primary hyperparathyroidism; symptoms include hypercalcemia ("bones, stones, abdominal groans, and psychic moans" - bone pain/fractures, renal stones, constipation/peptic ulcers, depression/fatigue), hypophosphatemia; often detected incidentally by routine chemistry screening; more common in older adults and women; surgical excision of the adenoma is curative  

Macro ─ Typically a solitary, well-circumscribed, encapsulated, soft, tan to reddish-brown nodule; usually one gland is enlarged while the others are normal or atrophic (due to negative feedback from hypercalcemia); cystic changes or hemorrhage can occur; size and weight are variable (commonly 0.5-5 grams, but can be larger)  

Micro ─  

─ Composed predominantly of chief cells, but oxyphil cells, transitional oxyphil cells, and rarely water-clear cells can be present in varying proportions, forming different subtypes:  

  ─ **Chief Cell Adenoma:** Most common type (>80%); composed primarily of chief cells arranged in sheets, nests, cords, or follicular/acinar patterns; chief cells are polygonal with round, central nuclei and clear to eosinophilic cytoplasm; stromal fat is usually markedly reduced or absent within the adenoma (a key distinguishing feature from normal gland or hyperplasia on biopsy, though a thin rim of compressed normal parathyroid with fat may be seen peripherally)  

  ─ **Oxyphil Cell Adenoma:** Composed predominantly (>75-90%) of oxyphil cells (large cells with abundant granular eosinophilic cytoplasm and small, dense nuclei); less commonly functional (may be non-functioning or cause milder hyperparathyroidism)  

  ─ **Water-Clear Cell Adenoma:** Rare; composed of large cells with abundant, optically clear cytoplasm due to glycogen accumulation; historically associated with marked hyperparathyroidism (now extremely rare as a pure form)  

  ─ Mixed cell patterns are common  

─ Tumor cells are generally uniform, but focal nuclear pleomorphism, atypia, and enlarged hyperchromatic nuclei can be seen ("endocrine atypia") and do not necessarily indicate malignancy in the absence of definitive malignant features  

─ Mitotic figures are typically rare; if >5 mitoses/50 HPF or atypical mitoses are present, consider atypical adenoma or carcinoma  

─ A thin fibrous capsule usually surrounds the adenoma  

─ Compressed rim of normal or atrophic parathyroid tissue may be identifiable outside the capsule  

─ No capsular or vascular invasion (distinguishes from carcinoma)  

─ No invasion into adjacent non-parathyroid tissues  

Ancillary studies ─  

─ IHC (+) (tumor cells)  

  ─ PTH, Chromogranin A, Synaptophysin, GATA3  

  ─ Cyclin D1 (PRAD1): Overexpression (nuclear) is common in parathyroid adenomas (due to *CCND1* gene rearrangement or amplification) but can also be seen in hyperplasia and some carcinomas  

  ─ Parafibromin (*HRPT2* gene product): Retained nuclear expression is typical in adenomas (loss of expression is associated with parathyroid carcinoma and HPT-JT syndrome)  

  ─ Ki-67 proliferation index: Usually low (<1%, typically <5%)  

─ IHC (-)  

  ─ Thyroglobulin, TTF-1  

─ Special Stains:  

  ─ Oil Red O (on frozen tissue): Shows reduced intracytoplasmic fat in adenoma cells compared to normal suppressed chief cells  

─ Molecular ─  

  ─ *CCND1* (cyclin D1/PRAD1) gene rearrangements or overexpression in ~20-40%  

  ─ *MEN1* gene mutations (germline in MEN1 syndrome, somatic in some sporadic adenomas)  

  ─ Inactivating mutations of calcium-sensing receptor (*CASR*) gene are rare  

DDx ─  

─ Parathyroid hyperplasia (typically involves multiple glands, though can be nodular and asymmetric; stromal fat is diffusely reduced in hyperplastic glands; distinction from adenoma can be challenging with a single gland biopsy or if only one enlarged gland is identified at surgery without assessing others)  

─ Parathyroid carcinoma (requires unequivocal capsular invasion, vascular invasion, invasion into adjacent tissues, or metastases; marked atypia, thick fibrous bands, increased/atypical mitoses, and loss of parafibromin are suggestive but not diagnostic alone)  

─ Atypical parathyroid adenoma (features suspicious for but not diagnostic of carcinoma; see separate entry)  

─ Normal parathyroid gland (especially if hypercellular or from a young individual; adenoma shows a discrete nodule with compression of any adjacent normal rim and more pronounced loss of stromal fat)  

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## **Parathyroid Lipoadenoma (Parathyroid Hamartoma)**

A rare benign lesion of the parathyroid gland characterized by an admixture of mature adipose tissue and parathyroid parenchymal cells (chief cells, oxyphil cells), forming a discrete, often encapsulated mass  

Clinical ─ Usually non-functional or associated with mild hyperparathyroidism; can occur at any age, often presents as an asymptomatic neck mass or is found incidentally; some consider it a hamartoma rather than a true adenoma due to the mixture of mature tissues  

Macro ─ Typically a solitary, well-circumscribed, encapsulated mass; larger than typical adenomas, can be several centimeters; cut surface is characteristically yellowish and lobulated due to abundant adipose tissue, interspersed with tan-brown parathyroid tissue  

Micro ─  

─ Composed of an intimate admixture of mature adipocytes (representing 30-90% of the tumor volume) and clusters, nests, or trabeculae of parathyroid parenchymal cells  

─ Parathyroid cells are predominantly chief cells, but oxyphil cells and transitional forms can also be present  

─ The parathyroid cells are cytologically bland, similar to those in normal gland or typical adenoma  

─ The adipose tissue is mature, without atypia  

─ The lesion is usually well-encapsulated or well-demarcated  

─ Fibrous stroma may be present, sometimes forming septa that divide the lesion into lobules  

─ No evidence of invasion  

Ancillary studies ─  

─ IHC (+) (parathyroid cells)  

  ─ PTH, Chromogranin A, GATA3  

─ IHC (-) (adipocytes)  

  ─ S100 protein positive in adipocytes  

─ Special Stains:  

  ─ Oil Red O (on frozen tissue): Highlights abundant stromal and intracytoplasmic fat  

DDx ─  

─ Normal parathyroid gland with abundant stromal fat (especially in older individuals; lipoadenoma forms a discrete, larger, encapsulated mass and the fat is an integral part of the lesion, not just background stroma)  

─ Parathyroid adenoma with entrapped stromal fat (fat is usually less abundant and more peripheral in typical adenomas)  

─ Parathyroid hyperplasia with increased stromal fat (hyperplasia involves multiple glands, fat is often less organized and prominent than in lipoadenoma)  

─ Lipoma or other benign mesenchymal tumor involving the parathyroid region (would lack the distinct admixture of parathyroid parenchymal cells throughout)  

─ Infiltrating adipose tissue into an atrophic parathyroid gland  

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## **Atypical Parathyroid Adenoma / Atypical Parathyroid Tumor**

A parathyroid neoplasm that exhibits some worrisome histologic features suggestive of, but not diagnostic for, parathyroid carcinoma; it represents a borderline category where definitive classification as benign adenoma or carcinoma is challenging due to lack of unequivocal invasion or metastasis  

Clinical ─ Patients usually present with primary hyperparathyroidism, often with more severe hypercalcemia and higher PTH levels than typical adenomas; risk of recurrence or progression to carcinoma is low but higher than for typical adenomas; complete surgical excision with clear margins is important  

Macro ─ Typically a solitary, enlarged gland, often larger and firmer than typical adenomas; may show adherence to surrounding tissues or a thickened capsule, but no gross invasion  

Micro ─  

─ Exhibits some, but not all, features suggestive of parathyroid carcinoma, falling short of a definitive malignant diagnosis. These features may include several of the following:  

  ─ Fibrous bands: Thick, hyalinized fibrous septa traversing the tumor  

  ─ Trabecular growth pattern: Cells arranged in thickened trabeculae  

  ─ Adherence to or involvement of the tumor capsule (but not unequivocal full-thickness transgression or invasion into adjacent soft tissue)  

  ─ Mitotic activity: Increased mitotic figures (e.g., >1 mitosis per 10 HPF, but generally <5 per 50 HPF without atypical forms, though thresholds vary and are not absolute)  

  ─ Significant nuclear atypia/pleomorphism (beyond typical endocrine atypia)  

  ─ Areas of sheet-like or solid growth with diminished stromal fat  

  ─ Necrosis (small foci)  

─ **Crucially, unequivocal capsular invasion into adjacent non-parathyroid tissue, vascular invasion (into vessels outside the capsule or large intratumoral vessels with tumor thrombi), perineural invasion, or metastases are ABSENT** (their presence would define carcinoma)  

Ancillary studies ─  

─ IHC (+)  

  ─ PTH, Chromogranin A, GATA3  

  ─ Ki-67 proliferation index: May be elevated (e.g., >1% and often <5%, but can be higher) compared to typical adenomas, but variable and not diagnostic alone  

  ─ Parafibromin (*HRPT2* gene product): Complete loss of nuclear expression (in >10-15% of tumor cells) is more suggestive of carcinoma or HPT-JT syndrome association, but can rarely be lost in atypical adenomas; retained expression is more common  

  ─ APC (adenomatous polyposis coli): Loss of expression has been linked to aggressive behavior in some studies  

─ Molecular ─  

  ─ Somatic mutations in *CDC73* (formerly *HRPT2*, encoding parafibromin) can occur  

DDx ─  

─ Parathyroid carcinoma (requires unequivocal invasion or metastasis; often shows more pronounced atypia, higher mitotic rate with atypical forms, extensive fibrous bands, and more consistent loss of parafibromin)  

─ Parathyroid adenoma (lacks the combination of worrisome features seen in atypical adenoma; typical adenomas have bland cytology, low mitoses, and usually no prominent fibrous bands or adherence)  

─ Parathyroid hyperplasia (multiglandular disease, though can be nodular)  

─ Difficult cases often require extensive sampling of the tumor-capsule-soft tissue interface and careful correlation of all histologic and immunohistochemical findings. Clinical follow-up is essential.  

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## **Parathyroid Carcinoma**

A rare malignant neoplasm of parathyroid parenchymal cells, characterized by local invasion, recurrence, and potential for distant metastasis, leading to severe primary hyperparathyroidism  

Clinical ─ Accounts for <1% to 5% of cases of primary hyperparathyroidism; often presents with more severe hypercalcemia (e.g., >14 mg/dL), markedly elevated serum PTH levels, and palpable neck mass compared to benign parathyroid disease; may involve bone (osteitis fibrosa cystica), kidneys (nephrocalcinosis, stones), and other organs; higher risk in Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome (germline *CDC73/HRPT2* mutation); prognosis is variable, with 5-year survival rates around 50-85%, depending on stage and resectability; recurrence is common, and death often results from complications of uncontrolled hypercalcemia rather than tumor burden itself  

Macro ─ Typically a solitary, large (>2-3 cm), firm, grayish-white to tan, lobulated, and often irregular mass; may show adherence or gross invasion into adjacent structures (thyroid, recurrent laryngeal nerve, esophagus, soft tissues); a thick, fibrous capsule is common; areas of necrosis or hemorrhage may be visible  

Micro ─  

─ Diagnosis relies on unequivocal evidence of invasion or metastasis:  

  ─ **Capsular invasion:** Full-thickness penetration of the tumor capsule by neoplastic cells (not just tumor cells within capsular vessels)  

  ─ **Vascular invasion:** Tumor cells within endothelium-lined spaces in or beyond the capsule, often forming thrombi attached to vessel walls  

  ─ **Invasion into adjacent tissues:** Infiltration of thyroid gland, skeletal muscle, adipose tissue, nerve  

  ─ **Metastases:** To regional lymph nodes or distant sites (lung, liver, bone)  

─ Histologic features suggestive of, but not independently diagnostic of, carcinoma (can also be seen in atypical adenomas or even some adenomas):  

  ─ Trabecular or sheet-like growth pattern  

  ─ Thick, hyalinized fibrous bands traversing the tumor  

  ─ Increased mitotic activity (e.g., >5 mitoses per 50 high-power fields [HPF] or presence of atypical mitoses)  

  ─ Marked nuclear atypia, pleomorphism, and prominent nucleoli (can be more pronounced than in adenomas)  

  ─ Tumor cell necrosis (comedo-like or diffuse)  

  ─ Perineural invasion  

─ Tumor cells are usually chief cells, but oxyphilic or clear cell differentiation can occur  

Ancillary studies ─  

─ IHC (+)  

  ─ PTH, Chromogranin A, GATA3 (confirm parathyroid origin)  

  ─ Ki-67 proliferation index: Often elevated (>5%), but variable and not diagnostic alone; higher values correlate with worse prognosis  

  ─ Parafibromin (*CDC73/HRPT2* gene product): Complete loss of nuclear expression (in the majority of tumor cells) is a strong indicator of carcinoma or HPT-JT syndrome, found in ~70-80% of carcinomas; retained expression does not exclude carcinoma  

  ─ APC (adenomatous polyposis coli): Loss of expression reported in some carcinomas  

─ IHC (-)  

  ─ Thyroglobulin, TTF-1 (to exclude thyroid origin if invading thyroid)  

─ Molecular ─  

  ─ Somatic or germline inactivating mutations of the *CDC73* (formerly *HRPT2*) tumor suppressor gene are common (~70% of sporadic carcinomas, and defines HPT-JT syndrome)  

  ─ Other genetic alterations (e.g., *PIK3CA*, *TP53*, copy number alterations) may occur, especially in advanced/metastatic disease  

DDx ─  

─ Atypical parathyroid adenoma (features suspicious for carcinoma but lacks unequivocal invasion or metastasis; parafibromin may or maynot be lost; Ki-67 often intermediate)  

─ Parathyroid adenoma (lacks invasive features and usually has blander cytology and lower Ki-67; parafibromin retained)  

─ Parathyroid hyperplasia (multiglandular disease)  

─ Metastatic carcinoma to parathyroid or neck (rare; history of primary, different IHC profile)  

─ Thyroid carcinoma invading parathyroid (thyroid markers positive)  

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## **Parathyromatosis**

A rare condition characterized by the presence of multiple nodules of benign (usually hyperfunctioning) parathyroid tissue scattered throughout the neck and/or mediastinum, typically occurring after surgical spillage and implantation of parathyroid cells during parathyroidectomy for adenoma or hyperplasia  

Clinical ─ Usually presents as recurrent or persistent primary hyperparathyroidism after previous parathyroid surgery; can be difficult to manage due to diffuse nature of the implanted tissue; imaging studies may show multiple small foci of uptake or nodules; re-operation is challenging  

Macro ─ Multiple small, seed-like nodules or ill-defined infiltrates of parathyroid tissue scattered in soft tissues of the neck, often in surgical bed, strap muscles, or along dissection planes; individual nodules are typically small (millimeters)  

Micro ─  

─ Multiple, discrete or coalescing nodules of benign parathyroid tissue (chief cells, oxyphil cells) dispersed in fibrous scar tissue, adipose tissue, or skeletal muscle  

─ The parathyroid tissue itself is cytologically bland, resembling normal parathyroid tissue, hyperplasia, or adenoma (depending on the original pathology that was spilled)  

─ Individual nodules are often not encapsulated or have very thin capsules  

─ No features of malignancy (e.g., marked atypia, high mitotic rate, definitive invasion from individual nodules into surrounding stroma beyond simple entrapment)  

─ Chronic inflammation and foreign body giant cell reaction may be present in the surrounding stroma due to surgical manipulation and spillage  

─ It is crucial to distinguish from parathyroid carcinoma with multiple invasive foci or lymph node metastases; parathyromatosis nodules are cytologically benign and represent implantation of benign tissue  

Ancillary studies ─  

─ IHC (+) (parathyroid nodules)  

  ─ PTH, Chromogranin A, GATA3 (confirm parathyroid origin of nodules)  

  ─ Ki-67 proliferation index: Usually low within the nodules, similar to benign parathyroid tissue  

  ─ Parafibromin: Retained nuclear expression is expected (as it's implantation of benign tissue)  

─ IHC (-)  

  ─ Thyroglobulin, TTF-1  

DDx ─  

─ Multiple parathyroid adenomas (synchronous or metachronous development of distinct adenomas in normal gland locations, rather than diffuse seeding in soft tissue)  

─ Parathyroid hyperplasia involving ectopic or supernumerary glands (hyperplastic changes within anatomically distinct glands)  

─ Metastatic parathyroid carcinoma (malignant cytological features, infiltrative growth, potential for parafibromin loss; parathyromatosis nodules are benign cytologically)  

─ Non-parathyroid nodules in the neck (e.g., lymph nodes, thyroid nodules, metastatic carcinoma from other sites; distinguished by morphology and IHC)  

─ Sarcoidosis or other granulomatous diseases with neck involvement (granulomatous inflammation, not parathyroid nodules)  

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# Adrenal Glands

## **Normal Adrenal Histology (Cortex and Medulla)**

The adrenal glands are paired endocrine organs located superior and medial to the kidneys, composed of an outer cortex and an inner medulla, which differ in embryologic origin, histology, and function  

Clinical ─ Cortex produces corticosteroids (glucocorticoids, mineralocorticoids, adrenal androgens); Medulla produces catecholamines (epinephrine, norepinephrine); essential for stress response, metabolism, electrolyte balance, and blood pressure regulation  

Macro ─ Each gland is pyramidal or crescent-shaped, weighing ~4-6 grams in adults; yellow cortex surrounds a gray-tan medulla. Superiorly, they are capped by adipose tissue. Right adrenal is often more pyramidal, left more crescentic. Vasculature is prominent.  

Micro ─  

**Adrenal Cortex:** (Mesodermal origin; ~80-90% of gland volume)  

─ Organized into three distinct concentric zones, based on cell morphology and primary steroid product:  

  ─ Zona Glomerulosa (outermost zone, ~15% of cortex):  

    ─ Cells arranged in rounded clusters or arcades, surrounded by capillaries  

    ─ Cells are relatively small, polygonal, with scant eosinophilic cytoplasm and round, dark nuclei  

    ─ Produces mineralocorticoids (primarily aldosterone), regulated by renin-angiotensin system and potassium  

    ─ May contain "clear cells" which are lipid-depleted stem/progenitor cells  

  ─ Zona Fasciculata (middle zone, ~75% of cortex, thickest layer):  

    ─ Cells arranged in long, straight cords or columns, one to two cells thick, separated by sinusoidal capillaries  

    ─ Cells are large, polygonal, with abundant, pale, foamy, or vacuolated cytoplasm due to numerous lipid droplets (cholesterol for steroid synthesis) - "clear cells" or spongiocytes  

    ─ Nuclei are central, vesicular  

    ─ Produces glucocorticoids (primarily cortisol) and some adrenal androgens, regulated by ACTH  

    ─ Inner portion may blend with zona reticularis and contain more compact, eosinophilic cells  

  ─ Zona Reticularis (innermost zone, ~10% of cortex, adjacent to medulla):  

    ─ Cells arranged in irregular, anastomosing cords or networks  

    ─ Cells are smaller, more compact than fasciculata cells, with eosinophilic (less lipid-rich) cytoplasm and often lipofuscin pigment (brownish)  

    ─ Nuclei may be more hyperchromatic  

    ─ Produces adrenal androgens (DHEA, androstenedione) and some glucocorticoids, regulated by ACTH  

**Adrenal Medulla:** (Neuroectodermal origin; ~10-20% of gland volume)  

─ Composed of chromaffin cells (pheochromocytes), sustentacular cells, and autonomic ganglion cells  

─ Chromaffin cells:  

  ─ Large, polygonal or pleomorphic cells arranged in nests, alveoli ("Zellballen"), or short cords, intimately associated with sinusoidal blood vessels  

  ─ Abundant basophilic or amphophilic granular cytoplasm (granules store catecholamines)  

  ─ Nuclei are round to oval, vesicular, with prominent nucleoli  

  ─ Synthesize and secrete catecholamines (epinephrine and norepinephrine)  

  ─ Exhibit chromaffin reaction (turn brown when exposed to chromium salts due to catecholamine oxidation)  

─ Sustentacular cells: Spindle-shaped or stellate support cells, located at the periphery of chromaffin cell nests; S100 positive  

─ Autonomic ganglion cells: Large neurons with prominent nucleoli, scattered individually or in small clusters  

─ Rich vascular network and sympathetic nerve fibers  

Ancillary studies ─  

─ Adrenal Cortex:  

  ─ IHC (+): Melan-A, Inhibin-alpha, Calretinin, Synaptophysin (can be weak/focal), SF-1 (Steroidogenic Factor 1, nuclear). Cytokeratins (e.g., CAM5.2) can be positive.  

  ─ Specific enzymes for steroidogenesis (e.g., CYP11B1 for cortisol, CYP11B2 for aldosterone synthase - zona specific)  

─ Adrenal Medulla (Chromaffin cells):  

  ─ IHC (+): Chromogranin A, Synaptophysin (strong neuroendocrine markers), Tyrosine hydroxylase, Phenylethanolamine N-methyltransferase (PNMT, for epinephrine-producing cells). S100 highlights sustentacular cells. Ganglion cells are positive for neuronal markers.  

  ─ IHC (-): Cytokeratins (chromaffin cells usually negative or weak, distinguishing from cortical cells or metastatic carcinoma if CK is a consideration)  

DDx ─ (depending on sample)  

─ Adrenocortical adenoma/carcinoma (neoplastic proliferation of cortical cells)  

─ Pheochromocytoma (neoplasm of chromaffin cells)  

─ Metastatic carcinoma (especially renal cell carcinoma to adrenal, or lung carcinoma; IHC profile is key)  

─ Normal kidney (glomeruli, tubules) if sample is from retroperitoneum without clear adrenal origin  

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## **Adrenal Rests (Heterotopia, Accessory Adrenal Tissue)**

Presence of adrenal cortical tissue (rarely medullary tissue) in ectopic locations outside the main adrenal glands, resulting from aberrant migration or fragmentation of adrenocortical primordia during embryogenesis  

Clinical ─ Usually asymptomatic and discovered incidentally during surgery for other conditions, imaging, or at autopsy; common sites include retroperitoneum near kidneys or main adrenal glands, celiac axis, broad ligament, spermatic cord, epididymis, testis, ovary, liver, lung (very rare); typically small (<1 cm); can rarely undergo hyperplasia or neoplastic transformation (adenoma, carcinoma) similar to orthotopic adrenal tissue, potentially causing endocrine syndromes  

Macro ─ Small, well-circumscribed, yellowish nodules, often resembling miniature adrenal glands or cortical nodules  

Micro ─  

─ Composed of adrenal cortical tissue, typically showing zonation (glomerulosa, fasciculata, reticularis), though zonation may be imperfect or absent, especially in smaller rests  

─ Zona fasciculata-like cells (clear, lipid-rich cells) are often the most prominent component  

─ A surrounding fibrous capsule may be present  

─ Medullary tissue is rarely present in ectopic rests  

─ The histological appearance is that of normal or hyperplastic adrenal cortex  

─ No evidence of malignancy if it is just a rest; neoplastic changes would be classified as ectopic adenoma/carcinoma  

Ancillary studies ─  

─ IHC (+) (for cortical cells)  

  ─ Melan-A, Inhibin-alpha, Calretinin, SF-1, Synaptophysin (focal)  

  ─ Cytokeratins (CAM5.2)  

─ IHC (-)  

  ─ Markers of other tissues depending on location (e.g., renal markers if near kidney, germ cell markers if in gonad)  

DDx ─ (Depends on location and if it forms a mass)  

─ Metastatic carcinoma (e.g., clear cell renal cell carcinoma if near kidney and composed of clear cells; metastatic tumors show atypia, infiltrative growth, and specific IHC for primary)  

─ Paraganglioma (if composed of neuroendocrine-like cells; chromogranin/synaptophysin strongly positive, S100 positive sustentacular cells, lacks cortical markers)  

─ Adrenocortical adenoma or carcinoma arising in a rest (shows neoplastic features beyond simple rest architecture)  

─ Xanthogranulomatous inflammation (sheets of foamy histiocytes, CD68 positive, lacks cortical markers)  

─ Sebaceous lesions (if in skin/adnexal regions where rests can occur; different histology)  

─ Leydig cell tumor or Sertoli cell tumor (if in testis/ovary; specific gonadal markers like inhibin (shared), calretinin (shared), SF-1 (shared), but also SOX9, FOXL2, etc.)  

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## **Adrenal Cysts**

Uncommon lesions of the adrenal gland, which can be classified based on their lining and pathogenesis into endothelial cysts, epithelial cysts (true cysts), parasitic cysts, and pseudocysts (most common)  

Clinical ─ Often asymptomatic and found incidentally on imaging; larger cysts can cause abdominal pain, flank pain, or gastrointestinal symptoms due to mass effect; rarely, can be associated with hypertension (if compressing renal artery or if functional tissue in wall - very rare) or hemorrhage; most are benign and non-functional  

Macro ─ Variable size, from small to very large; usually unilocular, but can be multilocular; cyst fluid can be serous, hemorrhagic, or murky; wall thickness varies  

Micro ─  

─ **Endothelial Cysts (Lymphangiomatous or Angiomatous Cysts):** (~40-45%)  

  ─ Lined by flattened endothelial cells  

  ─ Cyst wall is composed of lymphatic or blood vascular channels, often with smooth muscle and fibrous tissue  

  ─ May contain lymphoid aggregates  

  ─ Positive for endothelial markers (CD31, CD34, D2-40 for lymphatic)  

─ **Epithelial Cysts (True Cysts):** (~5-10%)  

  ─ Lined by a true epithelium, which can be cuboidal, columnar, flattened, or rarely glandular (mesothelial, Mullerian, or adrenal cortical origin debated for some)  

  ─ May arise from entrapped mesothelial cells, Mullerian remnants, or cystic change in adrenal cortical adenomas or mesonephric rests  

  ─ Positive for cytokeratins in epithelial lining  

─ **Parasitic Cysts:** (Rare in non-endemic areas, ~5-7%)  

  ─ Most commonly *Echinococcus granulosus* (hydatid cyst)  

  ─ Lined by parasitic membranes (laminated outer layer, inner germinal layer with scolices); host inflammatory reaction with fibrosis and calcification in the wall  

─ **Pseudocysts:** (Most common type, ~40-50%)  

  ─ Lack a true cellular lining  

  ─ Cyst wall is composed of dense fibrous connective tissue, often with evidence of old hemorrhage (hemosiderin, cholesterol clefts, calcification), inflammation, and hyalinization  

  ─ Thought to result from hemorrhage into normal adrenal tissue, an adrenal tumor (adenoma, pheochromocytoma, metastasis), or a pre-existing true cyst  

Ancillary studies ─  

─ Dependent on suspected cyst type:  

  ─ Endothelial cysts: CD31, CD34, D2-40 (for lining)  

  ─ Epithelial cysts: Cytokeratins (for lining)  

  ─ Parasitic cysts: Special stains for parasitic elements (e.g., PAS for cyst wall), serology for echinococcosis  

  ─ Pseudocysts: IHC not specific for the wall (fibrous tissue); underlying adrenal tissue or tumor in the wall would stain with relevant markers  

DDx ─  

─ Cystic adrenal neoplasms (e.g., cystic adrenocortical adenoma/carcinoma, cystic pheochromocytoma, cystic metastasis; solid neoplastic components usually present in the wall, specific IHC markers for the tumor type)  

─ Renal cyst (if location is ambiguous; renal epithelial markers like PAX8 (shared), but different morphology and context)  

─ Pancreatic pseudocyst (if extending to adrenal region; history of pancreatitis, amylase-rich fluid)  

─ Other retroperitoneal cystic lesions (e.g., lymphocele, urachal cyst)  

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## **Adrenalitis**

Inflammation of the adrenal gland, which can be caused by autoimmune processes, infections (bacterial, fungal, viral), hemorrhage, or systemic inflammatory diseases; can lead to adrenal insufficiency (Addison's disease if bilateral and extensive)  

Clinical ─ Autoimmune adrenalitis: Most common cause of primary adrenal insufficiency (Addison's disease) in developed countries; associated with other autoimmune disorders (autoimmune polyglandular syndromes APS-1, APS-2); anti-21-hydroxylase antibodies are often present. Infectious adrenalitis: Can occur in disseminated infections (e.g., tuberculosis, fungal infections like histoplasmosis/cryptococcosis, CMV in immunocompromised patients); symptoms may relate to sepsis or specific infection, plus adrenal insufficiency if severe. Hemorrhagic adrenalitis (Waterhouse-Friderichsen syndrome): Often due to severe sepsis (e.g., meningococcemia) leading to bilateral adrenal hemorrhage and acute adrenal crisis  

Macro ─ Autoimmune: Glands are often small, atrophic, and fibrotic in late stages; may be enlarged in early active phase. Infectious: Glands may be enlarged, necrotic, hemorrhagic, or contain abscesses/granulomas. Hemorrhagic: Glands are massively enlarged, hemorrhagic, and necrotic  

Micro ─  

─ **Autoimmune Adrenalitis:** ─ Lymphoplasmacytic infiltrate predominantly in the adrenal cortex, often with lymphoid aggregates and germinal centers  

  ─ Progressive destruction and atrophy of cortical cells (all three zones can be affected, but often starts in outer zones)  

  ─ Medulla is typically spared or only minimally involved  

  ─ Residual cortical cells may show hypertrophy or atypia  

  ─ Fibrosis increases with chronicity  

─ **Infectious Adrenalitis:** ─ Dependent on the organism:  

    ─ Bacterial: Neutrophilic infiltrate, abscess formation, necrosis  

    ─ Tuberculous: Caseating granulomas with Langhans giant cells, acid-fast bacilli (AFB)  

    ─ Fungal: Granulomas (caseating or non-caseating) or diffuse infiltrate of fungal organisms (e.g., yeast, hyphae, identifiable with GMS or PAS stains)  

    ─ Viral (e.g., CMV): Characteristic viral inclusions (cytomegalic cells with large intranuclear and smaller cytoplasmic inclusions), necrosis, inflammation  

─ **Hemorrhagic Adrenalitis / Adrenal Infarction:** ─ Extensive hemorrhage and necrosis throughout the gland, often starting in the medulla and inner cortex and extending outwards  

  ─ Loss of normal architecture, fibrin thrombi in small vessels may be seen  

  ─ Minimal inflammatory response initially, later organization with macrophages and fibrosis if patient survives  

Ancillary studies ─  

─ Autoimmune adrenalitis:  

  ─ IHC: CD3, CD20, CD45 for lymphocytes; CD138 for plasma cells. Anti-21-hydroxylase antibody staining on tissue (if available) or serum testing.  

─ Infectious adrenalitis:  

  ─ Special stains: Gram, AFB (Ziehl-Neelsen), GMS, PAS for microorganisms  

  ─ IHC for specific viral antigens (e.g., CMV)  

  ─ Culture of tissue if available  

DDx ─  

─ Lymphoma involving adrenal gland (neoplastic lymphoid infiltrate, monoclonal, specific lymphoma markers; autoimmune adrenalitis has polyclonal infiltrate)  

─ Metastatic carcinoma with prominent inflammation (malignant epithelial cells present, specific carcinoma markers)  

─ Adrenal cortical hyperplasia or neoplasm with secondary inflammation/hemorrhage (primary lesion is hyperplastic/neoplastic)  

─ Idiopathic cortical atrophy (loss of cortical cells, fibrosis, minimal inflammation)  

─ Drug-induced adrenal injury (e.g., mitotane, ketoconazole; specific history, may show necrosis/atrophy)  

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## **Adrenal Cortical Hyperplasia**

A condition characterized by an increase in the volume of the adrenal cortex, resulting from an increase in cell number and/or cell size, leading to excessive production of adrenocortical hormones or sometimes being non-functional  

Clinical ─ Manifestations depend on the specific hormones produced in excess: Cushing's syndrome (excess cortisol), Conn's syndrome/primary hyperaldosteronism (excess aldosterone), or virilization/feminization (excess adrenal androgens/estrogens); can be congenital or acquired, diffuse or nodular, ACTH-dependent or ACTH-independent  

Macro ─ Adrenal glands are often bilaterally enlarged, though a unilateral presentation can occur with some nodular forms; weight and appearance vary with subtype (diffusely thickened cortex, multiple nodules, or micronodules)  

Micro ─  

─ Increased cortical thickness and/or cellularity  

─ Can be diffuse (involving entire cortex more or less uniformly) or nodular (forming discrete or ill-defined nodules)  

─ Cell types involved depend on the zone affected and the underlying cause (e.g., zona fasciculata cells in ACTH-dependent hyperplasia, zona glomerulosa cells in some forms of hyperaldosteronism)  

─ Cells may appear normal, hypertrophic (enlarged with more cytoplasm), or show lipid depletion (compact, eosinophilic cells) or lipid richness (clear, foamy cells)  

─ Specific patterns include diffuse hyperplasia, micronodular hyperplasia, macronodular hyperplasia, and congenital adrenal hyperplasia with specific zonal changes  

Ancillary studies ─  

─ IHC (for cell types and to exclude neoplasm):  

  ─ Markers for cortical cells: Melan-A, Inhibin-alpha, Calretinin, SF-1  

  ─ Ki-67: Usually low, but can be slightly increased in some hyperplasias  

─ Specific enzyme IHC (e.g., for CYP11B1, CYP11B2) can help delineate zones or defects in CAH  

─ Molecular: Genetic testing for *CYP* gene mutations in CAH, *MEN1* or *APC* mutations in certain syndromic hyperplasias, or genes involved in ACTH-independent macronodular hyperplasia (e.g., *ARMC5*)  

DDx ─  

─ Adrenocortical adenoma (usually a solitary, discrete, encapsulated nodule; hyperplasia is often bilateral and more diffuse or multifocal/nodular without a dominant encapsulated mass)  

─ Adrenocortical carcinoma (malignant features, invasion, higher Ki-67, necrosis)  

─ Normal adrenal gland (especially if at upper limit of size/weight or with stress-related lipid depletion)  

─ Metastatic carcinoma (atypical cells, IHC for primary site)  

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## **Congenital Adrenal Hyperplasia (CAH)**

A group of autosomal recessive disorders caused by inherited deficiencies in enzymes required for cortisol biosynthesis in the adrenal cortex, leading to decreased cortisol production, compensatory ACTH overproduction, and consequent adrenal hyperplasia with overproduction of precursor steroids and androgens  

Clinical ─ Most common form (~95%) is 21-hydroxylase deficiency (CYP21A2 mutations), followed by 11β-hydroxylase deficiency (CYP11B1 mutations); clinical presentation varies with the specific enzyme defect and its severity:  

  ─ Classic CAH (severe): Neonatal salt-wasting crisis (hyponatremia, hyperkalemia, dehydration due to aldosterone deficiency) and virilization of female infants (ambiguous genitalia); males may appear normal at birth or show penile enlargement.  

  ─ Simple virilizing CAH (moderate): Androgen excess leading to precocious puberty in males, virilization in females, rapid growth, advanced bone age.  

  ─ Non-classic CAH (mild/late-onset): Presents later in childhood or adulthood with hirsutism, acne, menstrual irregularities, infertility.  

Laboratory: Low cortisol, high ACTH, elevated precursor steroids (e.g., 17-hydroxyprogesterone in 21-hydroxylase deficiency); electrolyte imbalances in salt-wasting forms.  

Macro ─ Adrenal glands are bilaterally enlarged, often markedly, with a cerebriform or convoluted cortical surface; cut surface is typically thickened, brown (due to lipid depletion and ACTH effect), and may show focal nodularity  

Micro ─  

─ Diffuse bilateral cortical hyperplasia, predominantly affecting the zona fasciculata and reticularis, which are thickened and composed of compact, eosinophilic, lipid-depleted cells (due to chronic ACTH stimulation)  

─ Zona glomerulosa may be normal, hyperplastic, or atrophic depending on the specific enzyme defect and its effect on aldosterone synthesis (e.g., hyperplastic in some salt-wasting forms, atrophic if aldosterone precursors are shunted)  

─ Cells are often arranged in disorganized cords and nests  

─ Nuclear atypia can be present but is not indicative of malignancy  

─ Medulla is usually normal but may appear compressed or relatively inconspicuous due to cortical expansion  

─ Longstanding CAH can lead to development of adrenocortical nodules or even neoplasms (myelolipomas, adenomas)  

─ Testicular adrenal rest tumors (TARTs) can occur in males with CAH due to ACTH stimulation of ectopic adrenal cells in testes  

Ancillary studies ─  

─ IHC:  

  ─ Cortical cells positive for usual adrenal cortical markers (Melan-A, Inhibin, SF-1)  

  ─ IHC for specific steroidogenic enzymes can demonstrate absence or mislocalization of the deficient enzyme  

─ Molecular: Genetic testing for mutations in causative genes (e.g., *CYP21A2*, *CYP11B1*) is diagnostic  

DDx ─  

─ Other forms of adrenal cortical hyperplasia (e.g., ACTH-dependent Cushing's, macronodular hyperplasia; distinguished by clinical context, hormone profiles, specific genetic defects, and different zonal involvement patterns)  

─ Adrenocortical neoplasms (adenoma, carcinoma; usually unilateral, may be functional but different hormone profile and morphology than diffuse hyperplasia of CAH)  

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## **Diffuse Adrenocortical Hyperplasia**

Bilateral enlargement of the adrenal cortex characterized by a relatively uniform thickening of one or more cortical zones, typically due to excessive ACTH stimulation or, less commonly, other factors  

Clinical ─ Most commonly seen in ACTH-dependent Cushing's syndrome (due to pituitary corticotroph adenoma - Cushing's disease, or ectopic ACTH production by a non-pituitary tumor); results in cortisol excess. Less commonly, can be seen in primary hyperaldosteronism (idiopathic hyperaldosteronism - IHA, if zona glomerulosa is diffusely hyperplastic, though often nodular).  

Macro ─ Both adrenal glands are symmetrically or asymmetrically enlarged and heavier than normal; cortex is diffusely thickened, often yellow (lipid-rich if ACTH effect is not chronic/overwhelming) or brownish (lipid-depleted with chronic ACTH).  

Micro ─  

─ Diffuse thickening of the adrenal cortex, primarily the zona fasciculata and/or reticularis in ACTH-dependent Cushing's syndrome  

─ Zona fasciculata cells are often enlarged, with clear, lipid-rich cytoplasm (spongiocytes), or may become compact and eosinophilic (lipid-depleted) with prolonged, intense ACTH stimulation  

─ Zona reticularis may also be prominent and composed of compact, eosinophilic cells  

─ Zona glomerulosa may be normal or atrophic in ACTH-dependent Cushing's; in idiopathic hyperaldosteronism due to diffuse hyperplasia, the zona glomerulosa shows diffuse or focal hyperplasia of aldosterone-producing cells, which may be subtle.  

─ No discrete, encapsulated nodules like an adenoma, though micronodules (<1 cm) may be present within the diffusely thickened cortex  

─ Medulla is usually unremarkable  

Ancillary studies ─  

─ IHC:  

  ─ Cortical cells positive for Melan-A, Inhibin, SF-1  

  ─ Zona-specific enzyme IHC (e.g., CYP11B2 for glomerulosa, CYP17A1 for fasciculata/reticularis) can highlight zonal involvement  

─ Clinical correlation with ACTH levels and specific hormone profiles is crucial  

DDx ─  

─ Congenital adrenal hyperplasia (specific enzyme defects, characteristic zonal changes, often more cerebriform gross appearance, earlier onset)  

─ Micronodular or macronodular adrenal hyperplasia (presence of distinct nodules, though diffuse hyperplasia can have superimposed micronodules)  

─ Early or subtle adrenocortical adenoma (adenoma is a discrete neoplasm, usually unilateral with contralateral atrophy if cortisol-producing)  

─ Normal adrenal gland (especially in response to stress which can cause some lipid depletion and apparent compactness; gland weight and cortical thickness are key)  

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## **Nodular Adrenocortical Disease (NAD)**

A heterogeneous group of conditions characterized by the presence of single or multiple nodules within the adrenal cortex, which may or maynot be associated with hormonal overproduction; encompasses various specific entities with different underlying pathologies and clinical presentations  

Clinical ─ Can be functional (causing Cushing's syndrome, hyperaldosteronism, or rarely androgen excess) or non-functional (incidentalomas); may be unilateral or bilateral; can be sporadic or associated with genetic syndromes (e.g., MEN1, Carney complex, McCune-Albright syndrome)  

Macro ─ Adrenal glands show one or more grossly visible nodules, varying in size from micronodules (<1 cm) to macronodules (≥1 cm); nodules can be yellow, brown, or black (pigmented); inter-nodular cortex may be normal, atrophic, or hyperplastic  

Micro ─  

─ Presence of distinct nodules of adrenocortical cells, which may be well-circumscribed but are typically unencapsulated or have incomplete capsules (distinguishing from most adenomas)  

─ Nodules can be composed of clear cells (lipid-rich, resembling zona fasciculata), compact eosinophilic cells (lipid-poor, resembling zona reticularis), or less commonly, cells resembling zona glomerulosa  

─ Some specific forms of NAD include:  

  ─ Sporadic non-functioning nodules (incidentalomas)  

  ─ ACTH-independent macronodular adrenal hyperplasia (AIMAH) / Bilateral macronodular adrenal hyperplasia (BMAH)  

  ─ Primary pigmented nodular adrenocortical disease (PPNAD)  

  ─ Isolated micronodular adrenal disease (iMAD)  

─ The internodular cortex may show atrophy (if nodules are autonomously producing cortisol), hyperplasia, or be relatively normal  

─ (Specific microscopic features will be detailed under the respective subtypes)  

Ancillary studies ─  

─ IHC and molecular studies depend on the specific subtype of NAD suspected  

─ Clinical evaluation of hormonal function is crucial  

DDx ─  

─ Adrenocortical adenoma(s) (typically solitary and encapsulated, though multiple adenomas can occur, especially in syndromes like MEN1)  

─ Adrenocortical carcinoma (malignant features, invasion, usually a dominant large mass)  

─ Metastatic carcinoma (atypical cells, IHC for primary site)  

─ Pheochromocytoma (if nodule is medullary or involves medulla; chromaffin cell markers positive)  

─ Diffuse adrenal hyperplasia (lacks dominant nodularity, though can have micronodules)  

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## **Sporadic NAD (Non-functioning) (Adrenocortical Incidentaloma)**

Non-hyperfunctioning adrenocortical nodules discovered incidentally on imaging studies performed for unrelated reasons; most are benign adrenocortical adenomas or non-neoplastic nodules of hyperplasia  

Clinical ─ Usually asymptomatic and do not secrete clinically significant amounts of hormones; found in ~1-10% of adults undergoing abdominal imaging, prevalence increases with age; require endocrinological workup to exclude subclinical hormone excess (e.g., subclinical Cushing's syndrome, pheochromocytoma, primary aldosteronism) and imaging follow-up or intervention if >1 cm or suspicious features, to rule out malignancy  

Macro ─ Typically solitary or multiple well-circumscribed nodules, usually <4 cm; yellowish (lipid-rich) or brown/red (lipid-poor); may show cystic change, hemorrhage, or calcification  

Micro ─  

─ Histology is variable, reflecting the underlying nature of the nodule(s):  

  ─ Most commonly represent benign adrenocortical adenomas (see separate entry for adenoma features - typically composed of clear, lipid-rich cells resembling zona fasciculata, or compact, eosinophilic cells)  

  ─ Can be nodules of focal hyperplasia (nodular hyperplasia) without features of a discrete adenoma; these are often unencapsulated or poorly encapsulated, composed of lipid-rich or lipid-poor cortical cells, sometimes with mixed cell types or disorganized architecture  

  ─ Less commonly, other benign lesions like myelolipoma, cyst, or ganglioneuroma  

  ─ Rarely, an early adrenocortical carcinoma, pheochromocytoma, or metastasis might present as an incidentaloma  

─ The term "Sporadic NAD (Non-functioning)" in the context of nodular hyperplasia often refers to incidental nodules that are not part of a specific syndrome or known cause of bilateral hyperplasia, and lack hormone overproduction. These are often architecturally similar to adenomatoid nodules seen in multinodular goiter of the thyroid.  

─ Internodular cortex is usually normal or atrophic if there's subclinical cortisol secretion from a nodule  

Ancillary studies ─  

─ IHC (for typical non-functioning cortical nodules/adenomas):  

  ─ Melan-A, Inhibin-alpha, Calretinin, SF-1: Positive  

  ─ Ki-67: Low (<2-5%)  

─ Extensive hormonal workup is primary to define "non-functioning" status  

DDx ─  

─ Functional adrenocortical adenoma (requires clinical/biochemical correlation)  

─ Adrenocortical carcinoma (larger size, necrosis, hemorrhage, high mitotic rate, atypical mitoses, invasion, specific IHC like high Ki-67, loss of some differentiation markers possible)  

─ Pheochromocytoma (if arising in medulla or as composite tumor; chromaffin markers positive)  

─ Metastatic carcinoma (history of primary, atypical cytology, IHC for primary site)  

─ Other specific forms of nodular adrenal disease (e.g., PPNAD, AIMAH; distinguished by specific clinical, genetic, and histological features)  

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## **Primary Pigmented Nodular Adrenocortical Disease (PPNAD)**

A rare cause of ACTH-independent Cushing's syndrome, characterized by bilateral, small to normal-sized adrenal glands with multiple small, often pigmented (brown or black) cortical micronodules; frequently associated with Carney complex  

Clinical ─ Usually presents in children or young adults with signs and symptoms of Cushing's syndrome (e.g., weight gain, growth retardation, moon facies, hypertension); paradoxical increase in cortisol secretion with Liddle's test (dexamethasone suppression test); strong association with Carney complex (an autosomal dominant disorder characterized by myxomas, spotty skin pigmentation, and other endocrine tumors, due to *PRKAR1A* gene mutations) but can occur sporadically  

Macro ─ Adrenal glands are typically normal in size or slightly enlarged, weighing <12 grams combined; cut surface reveals multiple small (<5 mm, usually 1-3 mm), discrete, darkly pigmented (brown, black, or reddish) or non-pigmented nodules studding the cortex; internodular cortex is atrophic  

Micro ─  

─ Multiple, discrete, unencapsulated cortical micronodules, often bilateral  

─ Nodules are composed of large, eosinophilic, granular (lipid-poor) cortical cells, sometimes with clear cell components  

─ Cells within nodules often show enlarged, hyperchromatic, pleomorphic nuclei (endocrine atypia)  

─ Lipofuscin pigment (golden-brown) is variably present within the cytoplasm of nodular cells, contributing to the dark gross appearance (but pigment may be scant or absent in some nodules - "unpigmented PPNAD")  

─ Internodular cortex is atrophic, composed of thin cords of lipid-depleted cells, due to suppression by cortisol produced by the nodules  

─ Mitotic activity is very low within nodules  

─ No significant fibrosis or inflammation typically  

Ancillary studies ─  

─ IHC (+) (nodular cells)  

  ─ Melan-A, Inhibin-alpha, SF-1, Synaptophysin (may be more prominent than in normal fasciculata)  

─ IHC (-)  

  ─ Chromogranin A (typically negative or weak in cortical cells, helps distinguish from pheochromocytoma if pigment is confusing)  

─ Special Stains:  

  ─ PAS: May highlight lipofuscin pigment (diastase resistant)  

  ─ Fontana-Masson: Can stain lipofuscin (melanin-like properties)  

─ Molecular ─  

  ─ Germline inactivating mutations of *PRKAR1A* (protein kinase A regulatory subunit 1-alpha) gene are found in most patients with Carney complex and PPNAD  

  ─ Other genes in cAMP pathway can be involved in sporadic cases  

DDx ─  

─ Bilateral Macronodular Adrenocortical Hyperplasia (AIMAH) (macronodules >1 cm, different genetic basis, internodular cortex not always atrophic initially)  

─ Other forms of ACTH-independent Cushing's (e.g., cortisol-producing adenoma - usually unilateral, or carcinoma)  

─ Congenital adrenal hyperplasia (diffuse hyperplasia, specific enzyme defects, different clinical picture)  

─ Adrenal cortical adenoma(s) with pigmentation (if unilateral or dominant pigmented nodule, need to assess bilaterality and nodule size/characteristics)  

─ Metastatic melanoma to adrenal (rare; S100, HMB-45, SOX10 positive; lacks adrenal cortical markers)  

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## **Bilateral Micronodular Adrenocortical Disease (i-MAD)**

A group of rare disorders causing ACTH-independent Cushing's syndrome due to bilateral adrenal micronodules (<1 cm); Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is the classic and most well-characterized form of i-MAD, often associated with Carney Complex. The term i-MAD can also encompass other rare non-PPNAD forms.  

Clinical ─ Similar to PPNAD, presents with ACTH-independent Cushing's syndrome, often in children or young adults. If not PPNAD/Carney Complex, genetic causes can include phosphodiesterase (PDE) gene mutations (e.g., *PDE11A*, *PDE8B*).  

Macro ─ Adrenal glands are usually normal in size or slightly enlarged, with multiple small cortical nodules (typically <1 cm, often <0.5 cm). Pigmentation may or may not be present, depending on whether it is PPNAD or another form of i-MAD. Internodular cortex is atrophic due to cortisol secretion by the nodules.  

Micro ─  

─ Characterized by multiple, bilateral, unencapsulated micronodules of adrenocortical cells.  

─ **If PPNAD type:** Nodules are composed of large, eosinophilic, granular (lipid-poor) cells, often with nuclear atypia and variable lipofuscin pigment. Internodular cortex is atrophic. (See PPNAD entry for more detail).  

─ **Non-PPNAD forms of i-MAD (e.g., related to *PDE* mutations):** Nodules may be composed of clear, lipid-rich cells (fasciculata-like) or eosinophilic cells. Pigmentation is typically absent. Internodular cortex is atrophic.  

─ Nodules are generally well-demarcated but not truly encapsulated.  

─ Low mitotic activity.  

Ancillary studies ─  

─ IHC (nodular cells):  

  ─ Melan-A, Inhibin-alpha, SF-1, Synaptophysin  

─ Molecular:  

  ─ *PRKAR1A* mutations for PPNAD/Carney Complex.  

  ─ Mutations in genes like *PDE11A* or *PDE8B* for other forms of i-MAD.  

DDx ─  

─ Primary Pigmented Nodular Adrenocortical Disease (PPNAD) (is a subtype of i-MAD; distinguished by pigmentation and *PRKAR1A* association if syndromic)  

─ Diffuse ACTH-dependent hyperplasia with micronodularity (ACTH levels are high or normal-inappropriately high, internodular cortex is hyperplastic, not atrophic)  

─ Congenital adrenal hyperplasia (specific enzyme defects, different clinical and biochemical profile)  

─ Early ACTH-independent macronodular adrenal hyperplasia (AIMAH) (nodules will become >1cm; different genetic basis)  

─ Incidental non-functioning micronodules (no Cushing's syndrome, internodular cortex not atrophic)  

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## **Bilateral Macronodular Adrenocortical Disease (AIMAH / BMAH)**

(ACTH-Independent Macronodular Adrenal Hyperplasia / Bilateral Macronodular Adrenal Hyperplasia)  

A rare form of ACTH-independent Cushing's syndrome characterized by bilateral enlargement of adrenal glands due to multiple macronodules (typically ≥1 cm)  

Clinical ─ Usually presents in older adults (5th-6th decade) with insidious onset of Cushing's syndrome, often subclinical or mild initially, but can become overt; ACTH levels are suppressed; nodules may aberrantly express G-protein coupled receptors (GPCRs) leading to cortisol production in response to non-ACTH ligands (e.g., vasopressin, beta-blockers, LH, GIP - "food-dependent Cushing's"); can be sporadic or familial (e.g., associated with *ARMC5* germline mutations)  

Macro ─ Both adrenal glands are massively enlarged (can weigh hundreds of grams), with numerous large nodules (≥1 cm, often much larger, up to several cm); nodules are typically yellowish (lipid-rich) but can be brown (lipid-poor) or mixed; internodular cortex is often atrophic or compressed, but can sometimes appear hyperplastic or normal early on  

Micro ─  

─ Multiple, large, unencapsulated or poorly encapsulated nodules replacing most of the adrenal cortex bilaterally  

─ Nodules are composed predominantly of large, clear, lipid-rich cells resembling zona fasciculata (spongiocytes), but areas of compact, eosinophilic, lipid-poor cells (reticularis-like) can also be present, especially in larger nodules or with longer duration of disease  

─ Cells within nodules are generally bland, with round nuclei and abundant cytoplasm; mild nuclear atypia ("endocrine atypia") can be seen  

─ Mitotic activity is low  

─ Internodular cortex is typically atrophic due to ACTH suppression by autonomous cortisol production from nodules, but can be variable, especially in earlier stages or if aberrant receptor expression is patchy  

─ Fibrous septa may separate nodules  

─ Cystic change, hemorrhage, or myelolipomatous change can occur within nodules  

Ancillary studies ─  

─ IHC (+) (nodular cells)  

  ─ Melan-A, Inhibin-alpha, SF-1, Synaptophysin  

  ─ Expression of aberrant GPCRs may be demonstrable by specialized IHC or molecular techniques if clinically suspected  

─ Molecular ─  

  ─ Germline or somatic mutations in *ARMC5* (armadillo repeat containing 5) gene are found in a significant proportion of cases (especially familial or severe forms)  

  ─ Other genetic alterations (e.g., *GNAS*, *PRKACA*, *PDE11A*, *PDE8B*) can be involved in subsets or in the development of nodules expressing aberrant receptors  

DDx ─  

─ Multiple bilateral adrenocortical adenomas (can occur, e.g., in MEN1 or Carney Complex, but AIMAH nodules are typically less well-encapsulated and glands are usually more massively and diffusely nodular; genetic context differs)  

─ Congenital adrenal hyperplasia with macronodular change (CAH has specific enzyme defects, high ACTH, different primary morphology)  

─ ACTH-dependent Cushing's disease with secondary nodular hyperplasia (ACTH is high or inappropriately normal; internodular cortex is hyperplastic, not atrophic)  

─ Bilateral adrenocortical carcinoma (extremely rare; malignant cytological features, invasion, high Ki-67, necrosis; AIMAH nodules are benign)  

─ Metastatic carcinoma to adrenals (bilateral involvement can occur; atypical cells, IHC for primary site)  

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## **Adrenocortical Adenoma**

A benign neoplastic proliferation of adrenal cortical cells, which can be functional (hormone-producing) or non-functional (clinically silent, often incidentalomas)  

Clinical ─ Functional adenomas: Cushing's syndrome (cortisol-producing), Conn's syndrome/primary hyperaldosteronism (aldosterone-producing), rarely virilization or feminization (androgen/estrogen-producing). Non-functional adenomas: Most common type, usually discovered incidentally; generally small (<4 cm). Most are sporadic; can be associated with MEN1 or McCune-Albright syndrome (cortisol-producing, *GNAS* mutations)  

Macro ─ Typically solitary, well-circumscribed, encapsulated nodule, usually <5 cm and <50 grams (larger size raises concern for carcinoma); cut surface is often uniformly yellow (lipid-rich, especially cortisol-producing) or less commonly tan-brown (lipid-poor, e.g., some aldosterone-producing or oncocytic); black adenomas are dark brown/black due to lipofuscin. Contralateral adrenal gland and adjacent cortex may be atrophic if adenoma is cortisol-producing.  

Micro ─  

─ Composed of adrenal cortical cells arranged in nests, alveoli, or broad sheets, supported by a rich capillary network  

─ Cells typically resemble those of the normal adrenal cortex, predominantly zona fasciculata-like (clear, lipid-rich cells) or zona reticularis-like (compact, eosinophilic, lipid-poor cells), or a mixture  

─ Capsule is usually present, though may be thin  

─ Nuclear atypia ("endocrine atypia" - enlarged, hyperchromatic, pleomorphic nuclei) can be present but is not necessarily indicative of malignancy in the absence of other worrisome features  

─ Mitotic activity is generally low (e.g., <5 mitoses per 50 HPF); atypical mitoses are absent  

─ Necrosis is typically absent or very focal (if due to hemorrhage/infarction)  

─ No evidence of capsular invasion, vascular invasion, or invasion into surrounding adrenal parenchyma or soft tissue  

Subtypes/Variants:  

─ **Cortisol-producing adenoma:** Often composed of lipid-rich clear cells (fasciculata-like); adjacent cortex and contralateral gland are atrophic.  

─ **Aldosterone-producing adenoma (Aldosteronoma):** Often smaller; may be composed of clear cells, compact eosinophilic cells (resembling glomerulosa or reticularis cells), or hybrid cells. Spironolactone bodies (eosinophilic, laminated cytoplasmic inclusions) may be seen in surrounding non-neoplastic zona glomerulosa cells of patients treated with spironolactone.  

─ **Non-functioning adenoma:** Histologically variable, often lipid-rich fasciculata-like cells.  

─ **Oncocytic adenoma:** Composed predominantly (>75%) of large polygonal cells with abundant granular eosinophilic cytoplasm (oncocytes, due to mitochondrial accumulation) and prominent nucleoli; must lack invasion.  

─ **Black adenoma:** Contains abundant lipofuscin pigment within tumor cells, imparting a dark color; usually non-functional or cortisol-producing.  

Ancillary studies ─  

─ IHC (+)  

  ─ Melan-A, Inhibin-alpha, Calretinin, SF-1 (Steroidogenic Factor 1, nuclear): Confirm adrenocortical origin  

  ─ Synaptophysin: Can be positive (often focal/weak in cortex, stronger in medulla/pheochromocytoma)  

  ─ Cytokeratins (e.g., CAM5.2): Can be positive  

  ─ For aldosterone-producing adenomas: CYP11B2 (aldosterone synthase) IHC may highlight tumor cells, while CYP11B1 (11β-hydroxylase for cortisol) is typically weak or negative in these cells.  

─ IHC (-)  

  ─ Chromogranin A (usually negative or very weak in cortical cells, distinguishes from pheochromocytoma)  

  ─ PAX8 (negative, helps distinguish from renal cell carcinoma if metastatic)  

─ Ki-67 proliferation index: Typically low (<2-5%)  

DDx ─  

─ Adrenocortical carcinoma (larger size, necrosis, hemorrhage, high mitotic rate, atypical mitoses, broad fibrous bands, diffuse growth, capsular/vascular invasion, specific Weiss score criteria)  

─ Adrenocortical nodular hyperplasia (often bilateral, multiple nodules, less distinct encapsulation, inter-nodular cortex may be hyperplastic or atrophic depending on type)  

─ Pheochromocytoma (arises from medulla, chromaffin markers positive, S100 positive sustentacular cells)  

─ Metastatic carcinoma (especially clear cell renal cell carcinoma, lung adenocarcinoma; history of primary, atypical cytology, IHC for primary site markers like PAX8 for renal, TTF-1 for lung)  

─ Adrenal cyst or myelolipoma (distinct histology)  

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## **Adrenocortical Carcinoma (ACC)**

A rare, highly malignant epithelial neoplasm arising from the adrenal cortex, often characterized by large size, aggressive behavior, and poor prognosis; can be functional (hormone-producing) or non-functional  

Clinical ─ Can occur at any age, bimodal peaks (childhood and 4th-5th decades); functional ACCs can cause Cushing's syndrome, virilization/feminization, or mixed syndromes; non-functional ACCs often present late with abdominal mass, pain, weight loss, or symptoms of metastases (lung, liver, bone, lymph nodes); associated with certain genetic syndromes (e.g., Li-Fraumeni syndrome - *TP53* mutations, Beckwith-Wiedemann syndrome, MEN1 rarely); overall 5-year survival is poor (~30-40%)  

Macro ─ Typically large (>5-6 cm, often >100 grams, but size alone is not diagnostic), unilateral mass; cut surface is often variegated, with fleshy tan-yellow to brown tissue, extensive necrosis, hemorrhage, and cystic change; infiltrative borders, invasion into adrenal vein, vena cava, or adjacent organs may be evident; satellite nodules can occur  

Micro ─  

─ Diagnosis often relies on a combination of architectural and cytological features, often assessed using scoring systems (e.g., Weiss score, modified Weiss score, Lin-Weiss-Bisceglia system for pediatric cases). Features suggestive of malignancy include:  

  ─ Diffuse growth pattern (loss of normal nested/alveolar architecture in >1/3 of tumor)  

  ─ High nuclear grade (Fuhrman grade 3 or 4 equivalent; large, pleomorphic, vesicular nuclei with prominent nucleoli)  

  ─ High mitotic rate (e.g., >5 mitoses per 50 HPF in Weiss system)  

  ─ Atypical mitotic figures  

  ─ Tumor necrosis (confluent, not just focal)  

  ─ Capsular invasion (tumor cells extending through the capsule into periadrenal fat)  

  ─ Vascular invasion (tumor cells within endothelium-lined spaces, especially large veins)  

  ─ Sinusoidal invasion (tumor cells within intratumoral sinusoidal spaces)  

─ Tumor cells can resemble normal cortical cells (clear, eosinophilic, or mixed) but usually show more pleomorphism and atypia than adenomas  

─ Broad fibrous bands traversing the tumor are common  

Histologic Variants:  

─ **Conventional ACC:** Most common, showing typical features described above.  

─ **Oncocytic ACC:** Composed predominantly (>75%) of malignant oncocytic cells with granular eosinophilic cytoplasm; must show invasion or meet other criteria for malignancy (e.g., high Weiss score if oncocytic features specifically addressed by scoring system).  

─ **Myxoid ACC:** Significant (>10-25%) myxoid stroma; often associated with aggressive behavior.  

─ **Sarcomatoid ACC:** Biphasic tumor with carcinomatous and sarcomatoid (spindle cell, pleomorphic) components; very aggressive.  

─ **Pediatric ACC:** May have different histologic features and prognostic implications; often associated with *TP53* mutations.  

Ancillary studies ─  

─ IHC (+)  

  ─ Melan-A, Inhibin-alpha, Calretinin, SF-1: Usually positive, confirming adrenocortical origin, but expression can be reduced, focal, or lost in poorly differentiated/sarcomatoid areas  

  ─ Synaptophysin: Can be positive  

  ─ Cytokeratins (CAM5.2): Can be positive  

  ─ Ki-67 proliferation index: Significantly elevated (often >10-20%, a Weiss criterion if >5%)  

  ─ p53: Overexpression (due to mutation) is common  

─ IHC (-)  

  ─ Chromogranin A (helps exclude pheochromocytoma)  

  ─ PAX8 (helps exclude renal cell carcinoma)  

─ Molecular ─  

  ─ *TP53* mutations (somatic or germline in Li-Fraumeni) are common  

  ─ Alterations in Wnt/β-catenin pathway (*CTNNB1* mutations)  

  ─ IGF2 overexpression  

  ─ Copy number alterations, chromosomal instability are frequent  

  ─ *TERT* promoter mutations can occur  

DDx ─  

─ Adrenocortical adenoma (smaller, lacks high Weiss score features, no invasion/metastasis)  

─ Pheochromocytoma (chromaffin markers positive)  

─ Metastatic carcinoma (most important DDx; history of primary, IHC profile specific to primary site e.g., PAX8/CAIX for renal, TTF-1/Napsin A for lung, GATA3 for breast)  

─ Renal cell carcinoma directly invading adrenal (PAX8 positive, distinct morphology)  

─ Hepatocellular carcinoma directly invading adrenal (HepPar-1, Arginase-1 positive)  

─ Lymphoma (CD45, lymphoid markers)  

─ Sarcoma (primary or metastatic; specific sarcoma markers, lack of adrenocortical markers)  

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## **Adrenal Myelolipoma**

A rare, benign mesenchymal tumor of the adrenal gland composed of mature adipose tissue (myelo-) and hematopoietic elements (-lipo), resembling bone marrow  

Clinical ─ Usually asymptomatic and discovered incidentally on imaging ("incidentaloma"); can occur at any age, most common in middle-aged to older adults; typically non-functional; rarely, can cause symptoms due to large size (abdominal or flank pain), spontaneous hemorrhage/rupture (leading to acute retroperitoneal bleed), or association with endocrine disorders (e.g., Cushing's, Conn's, CAH - though direct causal link is debated, may be reactive to chronic stimulation or stress)  

Macro ─ Usually unilateral, solitary, well-circumscribed, unencapsulated or thinly encapsulated mass; size varies greatly (few mm to >30 cm); cut surface is characteristically variegated, with yellowish (fatty) areas admixed with reddish-brown (hematopoietic) areas; consistency is soft and greasy  

Micro ─  

─ Composed of an intimate mixture of two main components:  

  1. Mature adipose tissue: Sheets of mature adipocytes with univacuolated clear cytoplasm and small, eccentric nuclei; indistinguishable from normal fat  

  2. Hematopoietic elements: Nests and clusters of hematopoietic cells of all three lineages (erythroid precursors, granulocytic precursors, and megakaryocytes) in varying proportions and stages of maturation, similar to normal bone marrow  

     ─ Myeloid:Neutrophils, eosinophils, myelocytes, metamyelocytes  

     ─ Erythroid: Normoblasts at various stages  

     ─ Megakaryocytes: Large, multinucleated cells  

─ No significant cytologic atypia in either component  

─ Mitotic activity is very low, consistent with normal hematopoietic turnover  

─ Foci of hemorrhage, calcification, or ossification may be present  

─ Entrapped normal adrenal cortical cells or nodules may be seen at the periphery or intermingled, especially in smaller lesions  

Ancillary studies ─  

─ IHC (not usually required for diagnosis if histology is classic)  

  ─ Adipocytes: S100 protein positive  

  ─ Hematopoietic cells:  

    ─ Myeloperoxidase (MPO): Highlights granulocytic lineage  

    ─ Glycophorin A/C or E-cadherin (CDH1): Highlights erythroid lineage  

    ─ CD61 or CD42b: Highlights megakaryocytes  

    ─ CD34: May highlight hematopoietic progenitors and endothelial cells  

─ IHC (-)  

  ─ Adrenocortical markers (Melan-A, Inhibin) are negative in the myelolipomatous components but positive in any entrapped adrenal cortex  

  ─ Cytokeratins (negative in myelolipomatous components)  

DDx ─  

─ Retroperitoneal lipoma or liposarcoma involving adrenal gland (lipoma lacks hematopoietic elements; liposarcoma shows atypical adipocytes/lipoblasts, increased cellularity, mitoses, specific molecular alterations e.g., *MDM2* amplification for well-differentiated liposarcoma)  

─ Extramedullary hematopoiesis (can occur in various organs in response to chronic anemia or marrow failure; if in adrenal, may be diffuse rather than forming a discrete mass, often associated with known hematologic disorder)  

─ Angiomyolipoma (composed of abnormal blood vessels, smooth muscle, and adipose tissue; HMB-45 positive in smooth muscle component; rare in adrenal)  

─ Teratoma (contains derivatives of all three germ layers, not just fat and marrow elements)  

─ Adrenocortical neoplasm with fatty change or osseous metaplasia (primary lesion is adrenocortical, lacks trilineage hematopoiesis)  

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## **Adrenal Sex Cord Stromal Tumor**

A very rare primary tumor of the adrenal gland that morphologically resembles sex cord-stromal tumors of the gonads (e.g., granulosa cell tumor, Sertoli-Leydig cell tumor); of uncertain histogenesis but presumed to arise from pluripotential stromal cells or ectopic gonadal rests within the adrenal  

Clinical ─ Can occur at any age, slight female predominance; may be non-functional or produce hormones (estrogens, androgens, rarely corticosteroids), leading to endocrine symptoms (e.g., virilization, feminization, precocious puberty); behavior is variable, most are benign, but malignant cases with recurrence or metastasis have been reported  

Macro ─ Usually a well-circumscribed, solid, unilateral mass; cut surface can be yellow, tan, white, or variegated; size is variable  

Micro ─  

─ Histologic appearance is diverse, recapitulating various patterns seen in gonadal sex cord-stromal tumors:  

  ─ Granulosa cell tumor-like pattern: Nests, cords, or diffuse sheets of cells with scant cytoplasm and grooved "coffee-bean" nuclei; Call-Exner bodies (small follicle-like structures with eosinophilic material) may be present  

  ─ Sertoli cell tumor-like pattern: Tubules, cords, or hollow follicle-like structures lined by columnar cells  

  ─ Leydig cell tumor-like pattern: Sheets of large polygonal cells with abundant eosinophilic cytoplasm and Reinke crystals (rarely identified)  

  ─ Thecomatous/fibromatous pattern: Spindle cells in a collagenous stroma  

  ─ Mixed patterns are common  

─ Cytologic atypia, mitotic activity, necrosis, and infiltrative growth suggest malignancy, but criteria for malignancy are not well-established due to rarity  

Ancillary studies ─  

─ IHC (+) (variable depending on differentiation)  

  ─ Inhibin-alpha: Often positive (key marker for sex cord-stromal differentiation)  

  ─ Calretinin: Often positive  

  ─ SF-1 (Steroidogenic Factor 1): Can be positive  

  ─ CD99: Can be positive  

  ─ Vimentin: Positive in stromal components  

  ─ Cytokeratins (CAM5.2, AE1/AE3): Can be positive in epithelial-like components (e.g., Sertoli-like areas)  

  ─ Estrogen Receptor (ER), Progesterone Receptor (PR), Androgen Receptor (AR): May be positive  

─ IHC (-)  

  ─ Melan-A: Usually negative or only focally positive (helps distinguish from adrenocortical neoplasms, though some overlap exists with SF-1/Inhibin in adrenocortical tumors)  

  ─ Chromogranin A, Synaptophysin (negative, rules out pheochromocytoma/neuroendocrine)  

  ─ PAX8 (negative, rules out renal/Mullerian origin if metastatic)  

DDx ─  

─ Adrenocortical adenoma/carcinoma (Melan-A strongly positive; inhibin/calretinin can be positive in ACC, making distinction challenging if morphology overlaps; specific sex cord patterns like Call-Exner bodies absent in ACC)  

─ Metastatic sex cord-stromal tumor from gonad (clinical history of gonadal primary is crucial)  

─ Metastatic carcinoma (e.g., renal cell, lung; specific IHC for primary site)  

─ Pheochromocytoma (neuroendocrine markers positive)  

─ Other rare primary adrenal mesenchymal tumors (e.g., leiomyoma, sarcoma)  

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## **Adenomatoid Tumor of Adrenal**

An extremely rare, benign neoplasm of presumed mesothelial origin occurring in the adrenal gland, histologically identical to adenomatoid tumors found more commonly in the male and female genital tracts  

Clinical ─ Usually an asymptomatic, incidental finding during imaging or surgery for other reasons; affects adults; no known endocrine function; benign clinical course with no recurrence or metastasis reported after excision  

Macro ─ Typically a small (<2-3 cm), well-circumscribed, solid, firm, grayish-white nodule, often located within the adrenal capsule or subcapsular region, but can be intra-parenchymal  

Micro ─  

─ Characterized by gland-like or slit-like spaces, tubules, cords, and nests of flattened, cuboidal, or vacuolated mesothelial-like cells, embedded in a fibrous or fibromuscular stroma  

─ Glandular spaces may appear empty or contain scant eosinophilic material  

─ Cells have bland, oval to flattened nuclei, inconspicuous nucleoli, and eosinophilic or clear/vacuolated cytoplasm (signet-ring like cells can be seen due to cytoplasmic vacuoles, but are mucin-negative)  

─ No significant atypia, mitotic activity, or necrosis  

─ Lymphoid aggregates may be present in the stroma  

Ancillary studies ─  

─ IHC (+) (tumor cells)  

  ─ Mesothelial markers: Calretinin (strong nuclear and cytoplasmic), WT1 (Wilms Tumor 1 protein, nuclear), D2-40 (podoplanin, membranous), Cytokeratin 5/6 (CK5/6)  

  ─ Pan-cytokeratin (AE1/AE3, CAM5.2)  

─ IHC (-)  

  ─ Adrenocortical markers: Melan-A, Inhibin-alpha, SF-1  

  ─ Endothelial markers: CD31, CD34 (negative in tumor cells, highlights stromal vessels)  

  ─ CEA, Ber-EP4, MOC31 (helps distinguish from metastatic adenocarcinoma)  

  ─ PAS-diastase (negative for intracytoplasmic mucin in vacuolated cells)  

DDx ─  

─ Adrenal cyst (endothelial or epithelial; different lining cells and IHC profile)  

─ Lymphangioma or Angioma (endothelial markers CD31/CD34 positive)  

─ Metastatic adenocarcinoma (especially signet-ring cell carcinoma; malignant cytology, positive for CEA or other adenocarcinoma markers, negative for calretinin/WT1)  

─ Adrenocortical adenoma/carcinoma (adrenocortical markers positive, mesothelial markers negative)  

─ Pheochromocytoma (neuroendocrine markers positive)  

─ Mesothelioma (if suspicion of metastatic disease from pleura/peritoneum, though primary adrenal mesothelioma is exceptionally rare; history, more aggressive features if malignant)  

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## **Adrenal Medullary Hyperplasia**

An increase in the volume of the adrenal medulla due to an increase in the number and/or size of chromaffin cells; can be diffuse or nodular, and may be a precursor to pheochromocytoma, especially in hereditary syndromes  

Clinical ─ Often asymptomatic; may be found incidentally or in patients with MEN2A or MEN2B syndromes (due to germline *RET* mutations), von Hippel-Lindau (VHL) disease, neurofibromatosis type 1 (NF1), or other familial pheochromocytoma/paraganglioma syndromes; can sometimes cause symptoms similar to pheochromocytoma (hypertension, palpitations, anxiety) if associated with increased catecholamine production, but often biochemically subtle or silent; bilateral involvement is common in syndromic cases  

Macro ─ Adrenal medulla may appear normal, diffusely thickened, or contain ill-defined nodules; the cortico-medullary junction may be obscured or irregular; gland weight may be normal or slightly increased  

Micro ─  

─ Increased mass of medullary tissue relative to cortical tissue (normal medulla is ~10-20% of total adrenal volume or has a medullary:cortical ratio of ~1:10)  

─ **Diffuse hyperplasia:** Generalized increase in medullary cells, expanding the medulla and extending into the cortex in a tongue-like fashion  

─ **Nodular hyperplasia:** Formation of discrete, unencapsulated nodules of chromaffin cells within the medulla, often multiple and bilateral; nodules may vary in size  

─ Chromaffin cells in hyperplastic areas are similar to normal medullary cells: polygonal cells with granular basophilic/amphophilic cytoplasm, round nuclei, and stippled chromatin; some cellular atypia or nuclear pleomorphism can be seen but is not indicative of malignancy  

─ Sustentacular cells are present at the periphery of cell nests  

─ The distinction between prominent normal medulla, hyperplasia, and early/small pheochromocytoma can be challenging, especially on small biopsies or if nodules are <1 cm. An increased medullary width (e.g., >1 mm or >3x normal width) or medulla comprising >30% of the gland's cross-sectional area has been suggested.  

Ancillary studies ─  

─ IHC (+) (hyperplastic chromaffin cells)  

  ─ Chromogranin A, Synaptophysin (strong and diffuse)  

  ─ Tyrosine hydroxylase, PNMT (for epinephrine-producing cells)  

  ─ S100 protein: Highlights sustentacular cells surrounding nests of chromaffin cells  

─ IHC (-)  

  ─ Cytokeratins (negative in chromaffin cells)  

  ─ Adrenocortical markers (Melan-A, Inhibin)  

─ Molecular ─  

  ─ Germline mutations in *RET*, *VHL*, *NF1*, *SDHx* genes should be considered if syndromic features or family history present  

DDx ─  

─ Pheochromocytoma (especially small or early; pheochromocytoma is typically a discrete, often larger, encapsulated or well-circumscribed tumor with expansile growth, more pronounced cytological atypia possible, and often loss of the organized Zellballen pattern with sustentacular cells uniformly surrounding nests; hyperplasia is more diffuse or forms smaller, less discrete nodules within medullary architecture)  

─ Normal adrenal medulla (especially if prominent or in a tangentially sectioned gland; quantitative assessment and comparison to normal ratios can be helpful)  

─ Composite pheochromocytoma-ganglioneuroma (presence of ganglion cells and Schwannian stroma)  

─ Adrenocortical nodule compressing medulla (can give false impression of medullary hyperplasia)  

─ Metastatic neuroendocrine carcinoma (atypical cells, higher Ki-67, different clinical context, may lack S100+ sustentacular network)  

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## **Pheochromocytoma**

A catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla; paragangliomas are related tumors arising from extra-adrenal chromaffin cells (covered separately or as part of paraganglioma/pheochromocytoma spectrum)  

Clinical ─ "Rule of 10s" (traditionally: ~10% bilateral, ~10% extra-adrenal [paragangliomas], ~10% malignant, ~10% pediatric, ~10% familial - though familial proportion is now known to be higher, ~25-40%); presents with classic triad of episodic headaches, sweating, and tachycardia (palpitations), often associated with sustained or paroxysmal hypertension; other symptoms include anxiety, tremor, pallor, chest pain, nausea; diagnosis confirmed by elevated plasma or urinary levels of catecholamines (epinephrine, norepinephrine) and their metabolites (metanephrines, normetanephrines, VMA); ~25-40% are associated with hereditary syndromes (MEN2A/2B - *RET*, VHL disease - *VHL*, NF1 - *NF1*, familial paraganglioma syndromes - *SDHA/B/C/D/AF2*)  

Macro ─ Typically a well-circumscribed, pseudoencapsulated or encapsulated, solid mass within the adrenal medulla; size varies greatly (few cm to >10 cm); cut surface is often tan-gray, reddish-brown, or hemorrhagic, may show cystic degeneration or necrosis, especially in larger tumors; turns dark brown ("dusky") on exposure to dichromate fixatives (Zenker's) due to chromaffin reaction (oxidation of catecholamines)  

Micro ─  

─ Composed of polygonal to spindle-shaped tumor cells (chromaffin cells/pheochromocytes) arranged in characteristic nests or alveoli ("Zellballen"), separated by a rich sinusoidal vascular network  

─ Tumor cells have abundant granular cytoplasm (basophilic, amphophilic, or eosinophilic) due to catecholamine storage granules  

─ Nuclei are usually round to oval, with stippled "salt-and-pepper" chromatin (neuroendocrine appearance); nucleoli can be prominent  

─ Significant nuclear pleomorphism, atypia, and bizarre multinucleated cells can be present ("endocrine atypia") but do not reliably predict malignancy  

─ Sustentacular cells (S100 positive) are typically present at the periphery of Zellballen, though may be sparse or difficult to identify in some tumors  

─ Intracytoplasmic hyaline globules (PAS positive) may be seen  

─ Vascular invasion, capsular invasion, and necrosis can occur but are not definitive for malignancy in absence of metastases  

─ Malignancy is defined by the presence of metastases to sites where chromaffin tissue is normally absent (e.g., lymph nodes, liver, lung, bone); there are no universally accepted histologic criteria to reliably predict metastatic potential in the absence of metastases. Scoring systems (e.g., PASS - Pheochromocytoma of the Adrenal gland Scaled Score, GAPP - Grading system for Adrenal Pheochromocytoma and Paraganglioma) attempt to stratify risk but have limitations.  

Ancillary studies ─  

─ IHC (+) (tumor cells)  

  ─ Chromogranin A: Strong and diffuse positivity (key neuroendocrine marker)  

  ─ Synaptophysin: Strong and diffuse positivity  

  ─ Neuron-Specific Enolase (NSE)  

  ─ Tyrosine hydroxylase (enzyme for catecholamine synthesis)  

  ─ PNMT (Phenylethanolamine N-methyltransferase): Positive in epinephrine-producing tumors (most adrenal pheochromocytomas produce both epinephrine and norepinephrine)  

  ─ S100 protein: Highlights sustentacular cells at periphery of nests (loss or paucity of sustentacular cells has been associated with more aggressive behavior in some studies)  

─ IHC (-)  

  ─ Cytokeratins (AE1/AE3, CAM5.2): Usually negative in tumor cells (helps distinguish from adrenocortical carcinoma or metastatic carcinoma)  

  ─ Adrenocortical markers (Melan-A, Inhibin-alpha, SF-1)  

─ Molecular ─  

  ─ Genetic testing for mutations in susceptibility genes (*RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX*) is recommended, especially in young patients, bilateral tumors, family history, or extra-adrenal location, as ~40% may have a germline mutation. *SDHB* mutations are associated with higher risk of malignancy/metastasis.  

DDx ─  

─ Adrenocortical carcinoma (adrenocortical markers positive, chromaffin markers negative, different morphology)  

─ Adrenal medullary hyperplasia (diffuse or micronodular proliferation, lacks discrete large tumor mass, maintains more organized architecture)  

─ Metastatic neuroendocrine carcinoma (history of primary, different peptide profile, may lack S100+ sustentacular network, Ki-67 often higher)  

─ Metastatic melanoma (S100 positive in tumor cells, HMB-45/SOX10 positive, lacks chromogranin/synaptophysin)  

─ Ganglioneuroma/Ganglioneuroblastoma (presence of mature ganglion cells, Schwannian stroma +/- neuroblasts)  

─ Alveolar soft part sarcoma (rare in adrenal; ASPSCR1-TFE3 fusion, characteristic PAS-D positive crystals, different IHC)  

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## **Paraganglioma (Sympathetic and Parasympathetic)**

Neuroendocrine tumors arising from chromaffin cells of extra-adrenal sympathetic and parasympathetic paraganglia; closely related to adrenal pheochromocytomas. Sympathetic paragangliomas typically produce catecholamines, while parasympathetic paragangliomas (often in head/neck, e.g., carotid body, jugulotympanic) are usually non-functional or produce other peptides.  

Clinical ─ Sympathetic Paragangliomas (functional): Located along sympathetic chains in thorax, abdomen (e.g., organ of Zuckerkandl), pelvis; often secrete norepinephrine, leading to sustained hypertension, headaches, sweating. Parasympathetic Paragangliomas (often non-functional or "chemodectomas"): Commonly in head and neck (carotid body tumor, glomus jugulare, glomus tympanicum, glomus vagale); present as slow-growing masses, cranial nerve palsies, tinnitus, hearing loss; rarely secrete catecholamines. Approximately 35-40% are hereditary (mutations in *SDHx* genes (especially *SDHB*, *SDHD*), *VHL*, *RET*, *NF1*, *TMEM127*, *MAX*). Malignancy is defined by metastases (to lymph nodes, bone, liver, lung), more common with *SDHB* mutations and larger/sympathetic tumors.  

Macro ─ Well-circumscribed, encapsulated or pseudoencapsulated, fleshy, reddish-brown to tan masses; size varies greatly; may be highly vascular. Head and neck paragangliomas are often intimately associated with nerves and vessels.  

Micro ─  

─ Histologically identical to pheochromocytoma, regardless of location or functional status.  

─ Composed of polygonal to spindle-shaped tumor cells (chief cells/chromaffin cells) arranged in characteristic nests or alveoli ("Zellballen").  

─ Zellballen are surrounded by a delicate fibrovascular stroma and supported by S100-positive sustentacular cells at the periphery of nests (though sustentacular cells can be sparse).  

─ Tumor cells have abundant granular cytoplasm (basophilic, amphophilic, or eosinophilic) and round to oval nuclei with stippled "salt-and-pepper" chromatin.  

─ Nuclear pleomorphism and atypia ("endocrine atypia") can be prominent but do not predict malignancy.  

─ Intracytoplasmic hyaline globules may be present.  

─ Vascular invasion, capsular invasion (if encapsulated), and necrosis can occur but are not definitive for malignancy without metastases.  

─ Specific histologic features for malignancy are lacking; risk stratification scores (e.g., GAPP score) consider factors like tumor type (sympathetic vs. parasympathetic), cellularity, comedonecrosis, vascular/capsular invasion, mitotic rate, Ki-67 index, and catecholamine type.  

Ancillary studies ─  

─ IHC (+) (tumor cells)  

  ─ Chromogranin A, Synaptophysin, Neuron-Specific Enolase (NSE) (strong neuroendocrine markers)  

  ─ Tyrosine hydroxylase  

  ─ CD56  

  ─ S100 protein: Highlights sustentacular cells (loss/paucity may indicate more aggressive potential)  

  ─ Specific catecholamine synthesizing enzymes (e.g., PNMT usually negative in extra-adrenal paragangliomas as they primarily make norepinephrine)  

  ─ GATA3: Can be positive in paragangliomas, especially head and neck.  

─ IHC (-)  

  ─ Cytokeratins (AE1/AE3, CAM5.2): Usually negative (helps distinguish from metastatic carcinoma or some neuroendocrine carcinomas)  

  ─ Adrenocortical markers (Melan-A, Inhibin)  

  ─ TTF-1 (unless metastatic from lung NET, which is rare scenario for primary PGL site)  

─ Molecular ─  

  ─ Genetic testing for germline mutations in susceptibility genes (*SDHx*, *VHL*, *RET*, *NF1*, *TMEM127*, *MAX*, *EPAS1/HIF2A*) is crucial, especially in young patients, multiple tumors, family history, or metastatic disease. *SDHB* mutations are associated with higher risk of malignancy. Somatic mutations in these genes can also occur.  

DDx ─  

─ Metastatic neuroendocrine carcinoma (history of primary, often higher Ki-67, may lack clear Zellballen or prominent S100+ sustentacular network)  

─ Melanoma (S100 positive in tumor cells, SOX10/HMB-45/Melan-A positive, lacks chromogranin/synaptophysin)  

─ Alveolar soft part sarcoma (ASPSCR1-TFE3 fusion, characteristic PAS-D positive crystals, different IHC)  

─ Carotid body hyperplasia (in response to chronic hypoxia; diffuse enlargement, preserved lobular architecture, not a discrete tumor)  

─ Schwannoma or other neural tumors (if in head/neck; S100 diffusely positive in tumor cells, different morphology)  

─ Meningioma (if near skull base; EMA positive, SSTR2A positive)  

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## **Composite Pheochromocytoma/Paraganglioma**

A rare tumor of the adrenal medulla or extra-adrenal paraganglia that contains an intimate admixture of conventional pheochromocytoma/paraganglioma elements and elements of a neuroblastic tumor (ganglioneuroma, ganglioneuroblastoma, or neuroblastoma)  

Clinical ─ Symptoms may relate to catecholamine excess from the pheochromocytoma component, or be due to mass effect; may occur sporadically or in association with syndromes like NF1 or MEN2; behavior is generally dictated by the most malignant component (i.e., neuroblastoma or ganglioneuroblastoma component if present and aggressive, or metastatic potential of pheochromocytoma component)  

Macro ─ Usually a relatively well-circumscribed mass, often larger than typical pheochromocytoma; cut surface may be heterogeneous, with areas typical of pheochromocytoma (tan-brown, hemorrhagic) and firmer, grayish-white areas corresponding to the neuroblastic component  

Micro ─  

─ Two distinct but intimately intermingled components:  

  1. Pheochromocytoma/Paraganglioma component: Typical Zellballen architecture of polygonal chromaffin cells with granular cytoplasm, supported by sustentacular cells, and positive for chromogranin/synaptophysin.  

  2. Neuroblastic tumor component:  

     ─ Ganglioneuroma: Mature ganglion cells (large cells with vesicular nuclei, prominent nucleoli, abundant Nissl substance) within a Schwannian stromal background (spindle cells, wavy nuclei).  

     ─ Ganglioneuroblastoma: Admixture of mature ganglion cells, Schwannian stroma, and immature neuroblasts (small round blue cells, high N/C ratio, Homer Wright rosettes may be present). Can be intermixed or nodular.  

     ─ Neuroblastoma: Predominantly composed of primitive neuroblasts with scant cytoplasm, hyperchromatic nuclei, often forming Homer Wright rosettes, set in a scant neuropil-rich stroma.  

─ The proportion of each component varies widely  

─ The pheochromocytoma component usually appears benign cytologically  

Ancillary studies ─  

─ IHC: Useful to highlight the different components:  

  ─ Pheochromocytoma component: Chromogranin A, Synaptophysin positive; S100 highlights sustentacular cells.  

  ─ Ganglioneuroma component: Ganglion cells positive for synaptophysin, neurofilament protein (NFP), Class III beta-tubulin; Schwannian stroma S100 positive.  

  ─ Neuroblastoma/Ganglioneuroblastoma component: Neuroblasts positive for synaptophysin, PGP9.5, NB84a, CD56; may show focal chromogranin. Homer Wright rosettes are synaptophysin positive in fibrillary centers. S100 positive in Schwannian stroma if present. Ki-67 may be high in neuroblastic areas.  

─ IHC (-)  

  ─ Cytokeratins (negative in all neural components)  

DDx ─  

─ Pure pheochromocytoma/paraganglioma (lacks neuroblastic elements)  

─ Pure neuroblastic tumor (lacks pheochromocytoma component)  

─ Collision tumor (two separate, distinct tumors abutting, not intermingled; very rare)  

─ Adrenocortical carcinoma with neuroendocrine differentiation (rare; adrenocortical markers positive)  

─ Metastatic carcinoma with neuroendocrine features involving adrenal medulla (history, IHC for primary)  

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## **Neuroblastoma (Adrenal)**

A malignant embryonal tumor of the sympathetic nervous system arising from primitive neuroblasts derived from the neural crest; adrenal medulla is the most common primary site, but can occur anywhere along the sympathetic chain  

Clinical ─ Primarily a tumor of early childhood (median age ~18 months, >90% diagnosed by age 5); presents as an abdominal mass, pain, fever, weight loss, or symptoms related to metastases (bone pain, periorbital ecchymoses - "raccoon eyes", skin nodules - "blueberry muffin baby"); may produce catecholamines (elevated urinary VMA/HVA); staging (INSS or INRGSS) and biologic factors (age, MYCN amplification, ploidy, histology) are crucial for prognosis and treatment stratification; prognosis varies widely from spontaneous regression (especially in infants with Stage MS/4S) to aggressive disease  

Macro ─ Variable size, often large, lobulated, soft, friable mass; cut surface is typically grayish-tan or pink, often with extensive hemorrhage, necrosis, and calcification; may infiltrate surrounding structures  

Micro ─  

─ Composed of sheets of small, round, blue tumor cells (neuroblasts) with scant cytoplasm, indistinct cell borders, and round to oval, hyperchromatic nuclei with fine, stippled chromatin  

─ **Homer Wright rosettes** are characteristic (but not always present): neuroblasts arranged around a central fibrillary core of neuropil (axonal processes)  

─ Neuropil (eosinophilic, fibrillar material) is often present between tumor cells  

─ Mitotic activity and karyorrhexis (apoptosis) are often prominent  

─ Degree of differentiation (Shimada classification - favorable vs. unfavorable histology based on differentiation, Schwannian stroma, MKI):  

  ─ Undifferentiated: Sheets of primitive neuroblasts, no neuropil or rosettes  

  ─ Poorly differentiated: Predominantly neuroblasts, some neuropil, +/- Homer Wright rosettes  

  ─ Differentiating: >5% of tumor cells show features of ganglion cell differentiation (larger cells with more cytoplasm, vesicular nuclei, visible nucleoli)  

─ Schwannian stromal development: Amount of Schwann cell-rich stroma (paucicellular to abundant) is a key prognostic factor  

─ Calcification is common  

─ Lymphovascular invasion may be seen  

Ancillary studies ─  

─ IHC (+) (neuroblasts)  

  ─ Synaptophysin: Often diffuse positivity in cytoplasm and neuropil  

  ─ Neuron-Specific Enolase (NSE)  

  ─ PGP9.5 (Protein Gene Product 9.5)  

  ─ CD56 (NCAM)  

  ─ NB84a (specific for neuroblastoma)  

  ─ Tyrosine hydroxylase, Chromogranin A (can be focal)  

  ─ Phox2b: Nuclear positivity  

─ IHC (-)  

  ─ Cytokeratins, CD45 (LCA), Desmin, Myogenin (to exclude other small round blue cell tumors)  

  ─ S100 protein: Highlights any Schwannian stroma present (stroma-rich tumors have better prognosis); negative in neuroblasts  

─ Molecular ─  

  ─ **MYCN amplification:** Strong adverse prognostic factor, assessed by FISH or other methods  

  ─ Chromosomal abnormalities (e.g., deletion of 1p, 11q, gain of 17q)  

  ─ DNA ploidy (hyperdiploidy associated with better prognosis in infants)  

DDx ─  

─ Other small round blue cell tumors of childhood:  

  ─ Ewing sarcoma/PNET (CD99 positive, FLI1 positive, *EWSR1* fusions; typically osseous or soft tissue)  

  ─ Rhabdomyosarcoma (Desmin, Myogenin, MyoD1 positive; specific morphology like strap cells)  

  ─ Lymphoma/Leukemia (CD45 positive, specific lymphoid/hematopoietic markers)  

  ─ Wilms tumor (if renal/retroperitoneal; triphasic histology - blastemal, epithelial, stromal)  

─ Ganglioneuroblastoma (contains mature ganglion cells and Schwannian stroma in addition to neuroblasts)  

─ Ganglioneuroma (fully mature, composed of ganglion cells and Schwannian stroma, no neuroblasts)  

─ Pheochromocytoma (older age group, Zellballen pattern, lacks primitive neuroblasts)  

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## **Ganglioneuroblastoma (Intermixed, Nodular)**

A neuroblastic tumor composed of a mixture of mature ganglion cells, Schwannian stroma, and immature neuroblasts; it represents an intermediate stage of differentiation between neuroblastoma (primitive) and ganglioneuroma (fully mature). It is subclassified into intermixed and nodular types.  

Clinical ─ Primarily occurs in children (median age slightly older than neuroblastoma, often >18 months to 5 years); adrenal gland and posterior mediastinum are common sites; clinical presentation varies with location, size, and catecholamine production (less frequent than neuroblastoma); prognosis depends on subtype (nodular is generally more aggressive than intermixed), age, stage, and MYCN status.  

Macro ─ Tumors are typically encapsulated or well-circumscribed, but can be infiltrative; cut surface is often heterogeneous, with firm, grayish-white areas (stroma-rich) and softer, tan, hemorrhagic, or necrotic areas (neuroblastic component). Nodular GNB shows distinct nodules of neuroblastoma within a ganglioneuroma-like background.  

Micro ─  

─ Composed of three cell types in varying proportions:  

  1. Ganglion cells: Mature or maturing large neurons with abundant eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and Nissl substance.  

  2. Schwannian stroma: Spindle cells with wavy nuclei and fibrillar cytoplasm, forming a supportive stroma; can be paucicellular to abundant.  

  3. Neuroblasts: Primitive small round blue cells with scant cytoplasm, hyperchromatic nuclei, and high N/C ratio; may form Homer Wright rosettes or be diffusely arranged.  

─ **Subtypes based on distribution of components (International Neuroblastoma Pathology Classification - INPC/Shimada system):** ─ **Ganglioneuroblastoma, Intermixed (Favorable Histology by INPC if stroma-rich):** ─ Neuroblasts are randomly intermingled with mature ganglion cells and Schwannian stroma throughout the tumor.  

    ─ Neuroblastic component is usually focal, forming microscopic nests or scattered individual cells.  

    ─ Schwannian stroma is typically abundant (stroma-rich).  

    ─ Mitosis-karyorrhexis index (MKI) of the neuroblastic component is assessed (low/intermediate MKI is favorable).  

  ─ **Ganglioneuroblastoma, Nodular (Unfavorable Histology by INPC, regardless of age or MKI):** ─ Macroscopic or microscopic distinct nodule(s) of neuroblastoma within a background that is predominantly ganglioneuroma or stroma-rich/stroma-dominant ganglioneuroblastoma, intermixed.  

    ─ The neuroblastic nodule(s) are often poorly differentiated or undifferentiated, with high MKI, and may show *MYCN* amplification.  

    ─ The ganglioneuromatous component is mature.  

    ─ This subtype implies clonal divergence and more aggressive behavior due to the neuroblastic nodules.  

Ancillary studies ─  

─ IHC:  

  ─ Neuroblastic component: Synaptophysin, PGP9.5, CD56, NB84a positive. Ki-67 high in neuroblastic areas.  

  ─ Ganglion cells: Synaptophysin, Neurofilament Protein (NFP), Class III beta-tubulin positive.  

  ─ Schwannian stroma: S100 protein positive.  

─ Molecular:  

  ─ *MYCN* amplification status is crucial, especially in the neuroblastic nodules of GNB, Nodular (amplification confers unfavorable prognosis).  

  ─ Ploidy and segmental chromosomal aberrations are also assessed for risk stratification.  

DDx ─  

─ Neuroblastoma (predominantly primitive neuroblasts, minimal or no ganglion cell differentiation or Schwannian stroma beyond neuropil; stroma-poor by INPC).  

─ Ganglioneuroma (fully mature, composed only of ganglion cells and Schwannian stroma, no neuroblasts).  

─ Composite pheochromocytoma-ganglioneuroblastoma (presence of pheochromocytoma component, chromogranin/synaptophysin positive in Zellballen).  

─ Other pediatric small round blue cell tumors (if neuroblastic component is predominant and poorly differentiated; requires IHC panel to exclude lymphoma, rhabdomyosarcoma, Ewing sarcoma).  

─ Desmoplastic small round cell tumor (if intra-abdominal; characteristic polyphenotypic IHC, *EWSR1-WT1* fusion).  

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## **Ganglioneuroma (Adrenal)**

A benign, fully mature neuroblastic tumor of the sympathetic nervous system, composed of mature ganglion cells, Schwannian stroma, and nerve fibers; it represents the most differentiated end of the neuroblastic tumor spectrum  

Clinical ─ Can occur at any age, but common in older children, adolescents, and young adults; adrenal medulla and posterior mediastinum are common sites; usually asymptomatic and discovered incidentally, or may cause symptoms due to mass effect; rarely produces hormones (e.g., VIP leading to watery diarrhea syndrome, or catecholamines if arising from or admixed with chromaffin cells); excellent prognosis, surgical excision is curative; malignant transformation is exceptionally rare  

Macro ─ Typically a solitary, well-circumscribed, encapsulated, firm, rubbery mass; size varies greatly (can be very large); cut surface is grayish-white or yellowish-tan, often with a whorled or lobulated appearance due to abundant fibrous stroma; calcification may be present  

Micro ─  

─ Composed of three mature elements:  

  1. Ganglion cells: Large, mature neurons with abundant eosinophilic cytoplasm containing Nissl substance, eccentric vesicular nuclei, and prominent nucleoli; often scattered individually or in small clusters within the Schwannian stroma; binucleated or multinucleated forms can be seen; no atypia or mitoses.  

  2. Schwannian stroma: Predominant component; composed of well-differentiated Schwann cells (spindle cells with elongated, wavy nuclei and pale eosinophilic cytoplasm) arranged in interlacing fascicles or a loose, myxoid matrix; resembles schwannoma or neurofibroma.  

  3. Nerve fibers: Axonal processes, often seen within the Schwannian stroma.  

─ **No neuroblasts, primitive cells, or significant mitotic activity should be present** (their presence would indicate ganglioneuroblastoma or neuroblastoma).  

─ Lymphocytic infiltrates are common.  

─ Blood vessels may be prominent and hyalinized.  

─ Calcification can occur.  

Ancillary studies ─  

─ IHC (+)  

  ─ Ganglion cells: Synaptophysin, Neurofilament Protein (NFP), Class III beta-tubulin, Chromogranin A (can be positive), NeuN (nuclear).  

  ─ Schwannian stroma: S100 protein (strong and diffuse), SOX10, GFAP (can be focally positive).  

─ IHC (-)  

  ─ Neuroblastic markers if truly pure ganglioneuroma (e.g., minimal Ki-67).  

  ─ Cytokeratins (negative in neural elements).  

─ Molecular:  

  ─ *MYCN* amplification is absent.  

DDx ─  

─ Ganglioneuroblastoma, intermixed (stroma-rich) (presence of scattered microscopic nests of neuroblasts; thorough sampling is important to exclude).  

─ Schwannoma (composed purely of Schwann cells, Antoni A/B areas, Verocay bodies; lacks ganglion cells).  

─ Neurofibroma (mixture of Schwann cells, perineurial-like cells, fibroblasts, and axons, often with wavy collagen; ganglion cells are not a primary component, though can be entrapped if arising near a ganglion).  

─ Composite pheochromocytoma-ganglioneuroma (presence of pheochromocytoma component).  

─ Mature teratoma (contains derivatives of other germ cell layers, not just neural elements).  

─ Leiomyoma or other benign mesenchymal tumor (different histology and IHC).  

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