Thyroid gland

The thyroid gland is an important little endocrine organ in the anterior neck. It is frequently afflicted by cancer... but the common cancer has such a good prognosis there is debate about how aggressively it should be treated. The cytopathology of the thyroid gland is dealt with in the thyroid cytology article.

The gland frustrates a significant number of pathologists, as the criteria for cancer are considered a bit wishy-washy.

Thyroid specimens

They come in three common varieties

• FNA (fine needle aspiration).
  • Done to triage patients/rule-out malignancy - discussed in the article thyroid cytopathology.
• Hemithyroid.
  • Done to get a definitive diagnosis.
  • May be a "completion" - removal of the other half following definitive diagnosis.
• Total thyroid.
  • Done for malignancy or follicular lesion.

Gross pathology

• White nodules - think:
  • Lymphoid tissue.
  • Papillary thyroid carcinoma - may be calcified.

Diagnoses

Common

• Nodular hyperplasia -- most common.
• Lymphocytic thyroiditis.
• Papillary thyroid carcinoma (PTC) -- most common cancer.
• Follicular adenoma.
• Follicular thryoid carcinoma.
• Parathyroid tissue.

Pitfalls/weird stuff

• Thyroid tissue lateral to the jugular vein (often referred to as lateral aberrant thyroid tissue) is generally considered metastatic thyroid carcinoma (papillary thyroid carcinoma) even if it looks benign.
  • This dictum is disputed.
  • The level VI and VII lymph nodes are medial to the jugular.
• Hashimoto's disease may have so many lymphocytes that it mimics a lymph node -- may lead to misdiagnosis of PTC.
• Parasitic nodule: clump of thyroid that is attached by a thin thread... but looks like a separate nodule; may lead to misdiagnosis of PTC.

Image:

• Neck levels (radiopaedia.org).

Diagnostic keys

The following should prompt careful examination:

• Architecture: microfollicular, trabecular, solid, insular.
• Thick capsule.
• Necrosis - rare in the thyroid.

Thyroid IHC - general comments

• Not really useful.
• Papers with very small sample sizes abound.

Follicular thyroid carcinoma vs. papillary thyroid carcinoma

• CD31 more frequently positive in follicular lesions.
  • CD31 is a marker for microvessel density.
• Galectin-3 thought to be positive in papillary carcinoma.
• HBME-1 thought to be positive in papillary lesions.

Thyroid lesions per WHO

• Adapted from the Washington Manual of Surgical Pathology.

Adenoma

• Follicular adenoma.
• Hyalinizing trabecular tumour.

Carcinoma

• Papillary carcinoma.
• Follicular carinoma.
• Medullary carcinoma.
• Undifferentiated (anaplastic) carcinoma.

• Poorly differentiated carcinoma.
• Squamous cell carcinoma.
• Mucoepidermoid carcinoma.
• Sclerosing mucoepidermoid carcinoma with eosinophilia.
• Mucinous carcinoma.

• Mixed medullary and follicular carinoma.
• Spindle cell tumour with thymus-like differentiation.
• Carcinoma showing thymus-like differentiation.

Others

• Teratoma.
• Lymphoma.
• Ectopic thymoma.
• Angiosarcoma + other soft tissue lesions.
• Paraganglioma.
• Solitary fibrous tumour.
• Follicular dendritic cell tumour.
• Langerhans cell histiocytosis.
• Metastasis.

Parathyroid glands

Main article: Parathyroid glands

• May make an appearance in the context of thyroid surgery.

Benign

Solid cell nest of the thyroid gland

• AKA solid cell nest of thyroid.

General

• Embryonic remnants endodermal origin.
• Incidental finding.

Note:

• Hypothesized to have some relation to mucoepidermoid carcinoma of the thyroid gland; however, another study suspects a relationship with papillary thyroid carcinoma.

Microscopic

Features:

• Cellular solid or cystic cluster of variable size with:
  • Cuboidal cellular morphology.
    • May have columnar morphology.
  • Moderate-to-scant eosinophilic cytoplasm.
  • Round/ovoid nuclei with finely granular chromatin.
• +/-Goblet cells (~30% of cases).

Images:

• www:
  • Solid cell next (flickr.com).
  • Crappy B&W of solid cell nest (nature.com).
• WC:
  • Solid cell nest of the thyroid gland - intermed. mag. (WC).
  • Solid cell nest of the thyroid gland - very high mag. (WC).

DDx:

• C-cell hyperplasia.
• Medullary carcinoma.
• Squamous lesions.

IHC

Features:

• p63 +ve.
  • -ve in clear cells.
• CEA +ve (polyconal).
  • +ve also in clear cells.
• Chromogranin A +ve ~45% of cases.

Sign out

Solid cell nests of the thyroid gland are usually not reported.

Thyroid gland nodular hyperplasia

• AKA nodular hyperplasia.

General

• Clinical diagnosis: goitre, AKA sporadic goitre, AKA multinodular goitre (MNG).
• Most common diagnosis in the thyroid.
  • If you've seen a handful of thyroids you've seen this.

Notes:

• Large lesions may be clonal; however, this is clinically irrelevant.

Microscopic

Features:

• Follicles of variable size - key feature.
  • Should be obvious at low power, i.e. ~2.5x objective.
• Nodules maybe well circumscribed (on gross), but do not have a thick fibrous capsule.

Negatives:

• No nuclear features suggestive of malignancy (at lower power).
  • One should not look at high power.
• Not cellular.

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HEMITHYROID, RIGHT, HEMITHYROIDECTOMY:
- NODULAR HYPERPLASIA.
- NEGATIVE FOR MALIGNANCY.

Follicular thyroid adenoma

• AKA follicular adenoma, AKA thyroid follicular adenoma.

General

• Most common neoplasm of thyroid.
• Encapusled lesion (surrounded by fibrous capsule).

Gross

• Thick capsule.

Notes:

• The entire capsule should be submitted.
  • A good start for most thyroid specimens with a thick capsule is 10 blocks.

Microsopic

Features:

• Cellular.
• Thick capsule - key feature.

Negatives.

• No invasion of the capsule (see follicular thyroid carcinoma section).
• No nuclear features suggestive of papillary thyroid carcinoma.

DDx:

• Thyroid gland nodular hyperplasia with an encapsulated nodule - not as cellular.

Graves disease

General

• Often misspelled "Grave's disease".
• Autoimmune disease leading to hyperthyroidism.
• Eye problems not resolved with thyroid removal.^{[citation needed]}
• Higher risk of papillary thyroid carcinoma.

Clinical:

• TSH-receptor antibody +ve.

Gross

Features:

• Enlarged 50-150 g.
• "Beefy-red" appearance, looks like raw beef.

Microscopic

Features:

• Classic:
  • Hypercellular
  • Patchy lymphocytes.
  • Little colloid.
• Scalloping of colloid; colloid has undulating border.
  • Non-specific finding.
• +/-Nuclear clearing.
• +/-Papillae (may mimic papillary thyroid carcinoma in this respect).

Notes:

• Usually has an unimpressive appearance... as it is treated, i.e. history is important.
• Nuclear clearing and papillae are usu. diffuse in Graves disease - unlike in papillary thyroid carcinoma.

Image:

• Graves disease (med.utah.edu).

Idiopathic granulomatous thyroiditis

• AKA granulomatous thyroiditis - non-specific term; granulomas may be due a number of causes.
• AKA subacute thyroiditis.
• AKA de Quervain thyroiditis.
  • Should not be confused with de Quervain's disease (AKA gamer's thumb) something completely unrelated to the thyroid.

General

• Women > men.
• Etiology: possibly viral.

Microscopic

Features:

• Granulomas with multinucleated giant cells - usu. with engulfed colloid.
• Lymphocytes.
• Plasma cells.
• +/-Fibrosis.

DDx:

• Infectious granulomatous disease (fungal, microbacterial).
• Palpation thyroiditis.
• Sarcoidosis (classically intrafollicular distribution).

Images:

• Subacute thyroiditis - intermed. mag. (WC).
• Subacute thyroiditis - high mag. (WC).

Stains

• ZN -ve.
• GMS -ve.

Palpation thyroiditis

General

• Granulomatous inflammation due to palpation.
  • Incidence of granulomas higher in surgical thyroid specimens than autopsies.

Microscopic

Features:

• Granulomas involving the follicle.
  • Histiocytes within the colloid.

DDx:

• Idiopathic granulomatous thyroiditis.
• Sarcoidosis.
• Infectious granulomatous thyroiditis.

Stains

• ZN -ve.
• GMS -ve.

Riedel thyroiditis

• AKA invasive fibrous thyroiditis.

General

Clinical features:

• Extremely rare.
• Women > men.
• Usually smokers.
• May be associated with retroperitoneal fibrosis.
• May be hypothyroid.
• +/-Obstructive symptoms.

Microscopic

Features:

• Fibrosis.
• Specimen often fragmented as it was difficult to remove.

DDx:

• Anaplastic carcinoma, spindle cell variant.

Hashimoto thyroiditis

General

• This is a clinical diagnosis.
  • The histomorphologic findings, generally, are not diagnostic.

Etiology:

• Autoimmune disease leading to hypothyroidism.
  • Often genetic/part of a syndrome.

Clinical

Serology:

• Antimicrosomal (antithyroid peroxidase) +ve.
• Antithyroglobulin +ve.

Associated pathology:

• Increased risk of B-cell lymphoma; these are classically:
  • MALT lymphoma.
  • Diffuse large B cell lymphoma (DLBCL).

Microscopic

Features:

• Lymphocytic infiltrate - key feature.
• Nuclear clearing common.
  • May confuse with papillary thyroid carcinoma.
• Polymorphous lymphoplasmacytic infiltrate with germinal centres.
• +/-Oncocytic metaplasia.

Notes:

• Histologically often not possible to separate from "non-specific" thyroiditis.

DDx:

• Lymphocytic thyroiditis.
• Papillary thyroid carcinoma.
• MALT lymphoma.
• Diffuse large B cell lymphoma.

IHC

• Panel to exclude lymphoma may be required, e.g. CD3, CD20, CD10, BCL6, BCL2, kappa, lambda.

Molecular

• Occasionally done to exclude lymphoma - see MALT lymphoma and DLBCL.

C-cell hyperplasia

General

• Screening for C-cell hyperplasia/medullary thyroid carcinoma done with serum calcitonin level.

Gross

• Not visible.

Microscopic

Features:

• Location:
  • Mid portion of lobe to upper third of lobe.
    • Not at the poles.
    • Not in the isthmus.

• Definitions vary.

One definition - either of the following:

1. >50 C-cells per low-power field (x100).
   • This part of the definition suffers from LPFitis. The paper should have been rejected.
2. Confined to the thyroid gland and no larger than 10 mm in greatest dimension.

Another definition:

• Invasion of the basement membrane with stromal reaction.

A third definition:

• "Several clusters" of more than six C cells.

Images:

• Clear cell hyperplasia (forpath.org).

Malignant neoplasm

There are a bunch of 'em. The most common, by far, is papillary.

Papillary thyroid carcinoma

• Abbreviated PTC.

General

Medical school memory device P's:

• Palpable nodes.
• Popular (most common malignant neoplasm of the thyroid).
• Prognosis is good.
• Pre-Tx iodine scan.
• Post-Sx iodine scan.
• Psammoma bodies.

Notes:

• PTC is associated with radiation exposure.
• Papillary thyroid microcarcinoma is defined as a tumour with a maximal dimension of 1.0 cm or less.

Prognosis

Prognosis can be predicted by MAICS score. It which includes:

• Metastases.
• Age.
• Invasion of surround tissues.
• Ccompleteness of excision.
• Size of tumour.

Microscopic

Features:

• Nuclear changes - key feature.
  1. "Shrivelled nuclei"/"raisin" like nuclei, nuclei with a wavy nuclear membrane -- usu. easy to find.
  2. Nuclear inclusions - usu. harder to find; have high specificity.
  3. Nuclear grooves.
  4. Nuclear clearing (only on permanent section) - also known as "Orphan Annie eyes".
• Overlap of nuclei - "cells do not respect each other's borders" (easy to see at key feature at low power).
• Classically has papillae (nipple-like shape); papilla (definition): epithelium on fibrovascular core.
  • Absence of papillae does not exclude diagnosis.
• Psammoma bodies.
  • Circular, acellular, eosinophilic whorled bodies.
  • Not necessary to make diagnosis - but very specific in the context of a specimen labeled "thyroid".
  • Arise from infarction & calcification of papilla tips.

Notes:

• Psammoma bodies are awesome if you see 'em, i.e. useful for arriving at the diagnosis.
  • If there are no papillae structures -- you're unlikely to see psammoma bodies.
• At low power look for cellular areas/loss of follicles.
• Nuclear clearing seen in:
  • Hashimoto's and papillary thyroid carcinoma.
  • May be an artifact of fixation/processing.
• Nuclear overlapping is easy to see at lower power-- should be the tip-off to look at high power for nuclear features.
• Nuclear inclusions are quite rare and not required to make the diagnosis -- but a very convincing feature if seen.
• Papillae may be seen in Graves disease.

DDx:

• Lymphocytic thyroiditis:
  • Graves disease.
  • Hashimoto thyroiditis.
• Solid cell nest of thyroid.

Subtypes of papillary thyroid carcinoma

There are many.

Poor prognosis variants:

• Tall cell variant.
• Columnar cell variant.
• Solid variant.
• Diffuse sclerosing variant.

General

• ~10% of PTC.
• Often large > 6 cm.

Microscopic

Features:

• 50% of cells with height 2x the width.
  • There is some disagreement on these criteria; Raphael believes the height ought to be ~3x width, for 50% of the cells.
• Eosinophilic cytoplasm.
• Well-defined cell borders.
• Nucleus stratified; basal location, i.e. closer to the basement membrane.

Negative:

• Nuclei not pseudostratified, if pseudostratified consider columnar cell variant.

Images:

• PTC tall cell variant - intermed. mag. (WC).
• PTC tall cell variant - high mag. (WC).

General

Epidemiology:

• Poor prognosis.
• Very rare.

Microscopic

Features:

• Elongated nuclei (similar to colorectal adenocarcinoma) - key feature.
• +/-Pseudostratification of the nuclei (like in colorectal adenocarcinoma), differentiates from tall cell variant.
• Nuclear stratification - key feature.
• "Minimal" papillary features.
• "Tall cells".
• Clear-eosinophilic cytoplasm.
• Mitoses common.

Image: Columnar variant PTC (wiley.com).

General

• May be confused with follicular carcinoma or follicular adenoma.

Microscopic

Features:

• Prominent follicles.
• Typically have less nuclear pseudoinclusions than the conventional type.
• +/-Capsule.

General

• Associated with familial adenomatous polyposis (FAP).

Microscopic

Features:

• Cribriform architectural pattern.
• Morules - balls of tissue.

General

• Usually young adults, children.

Microscopic

Features:

• Papillae - usu. prominent.
• Squamous morules - key features.
• Lymphocytes - abundant.
• Fibrosis.

DDx:

• Lymphocytic thyroiditis (esp. Hashimoto's thyroiditis).

Papillary thyroid carcinoma warthin-like variant

• Resemble Warthin tumour.

Microscopic

Features:

• Eosinophilic cytoplasm.
• Lymphocytic thyroiditis.
• Papillae.

Papillary thyroid carcinoma solid variant

Features:

• Some studies suggest this has a poor prognosis.
• More common in children.
• Associated with Chernobyl nuclear accident.

Microscopic

Features:

• Solid sheets >50% of tumour mass.

IHC

Thyroid versus something else:

• Thyroglobulin +ve.
• TTF-1 (thyroid transcription factor-1) +ve.
• CD15 +ve.^{[citation needed]}

PTC versus benign:

• HBME-1 +ve (strong, diffuse).
• CK19 +ve (strong, diffuse).
• Galectin-3 +ve (strong, diffuse).

Molecular

• Currently not widely used in a diagnostic context.

Tabular summary

Molecular changes in papillary thyroid carcinoma as per Adeniran et al:

Molecular change	Frequency	Histology	Notes
BRAF point mutations	~ 40%	tall cell variant	poorer prognosis, older individuals
RET/PTC rearrangments	~ 20%	papillary architecture, psammoma bodies	younger individuals
RAS point mutations	~ 15%	exclusively follicular variant	-

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HEMITHYROID, RIGHT, COMPLETION OF TOTAL THYROIDECTOMY:
- PAPILLARY THYROID CARCINOMA, FOLLICULAR VARIANT.
-- TUMOUR SIZE: 4 MM (MAXIMAL).
-- ARCHITECTURE: FOLLICULAR.
-- CYTOMORPHOLOGY: CLASSICAL.
-- HISTOLOGIC GRADE: G1 (WELL DIFFERENTIATED).
-- NO TUMOUR CAPSULE.
-- NEGATIVE FOR LYMPHOVASCULAR INVASION.
-- NEGATIVE FOR PERINEURAL INVASION.
-- NEGATIVE FOR EXTRATHYROIDAL EXTENSION.
-- SURGICAL MARGINS NEGATIVE FOR MALIGNANCY.

Insular carcinoma

General

Features:

• Rare - approximately 5% of all thyroid carcinomas.
• Thought to be a separate tumour from papillary thyroid carcinoma and follicular thyroid carcinoma with a focal insular pattern.
• Some lump this entity with papillary carcinoma, i.e. consider it a variant of papillary thyroid carcinoma.

Microscopic

Features:

• Islands of cells - key feature.
• Scant cytoplasm.
• Nuclei monomorphic and round.

DDx:

• Medullary thyroid carcinoma.
• Poorly differentiated thyroid carcinoma.

Follicular thyroid carcinoma

• AKA follicular carcinoma.

Clinical

Medical school memory device 4 Fs:

• FNA NOT diagnosable.
• Far away mets (sometimes).
• Female predominant.
• Favourable prognosis.

Notes:

• Usu. has a hematologic spread.
  • PTC usu. spread via lymphatics.

Microscopic

Features:

• Defined by either:
  1. Invasion through the capsule:
     • Should be all the way through.
       • 1/2 does not count.
       • Fibrous reaction does not count.
       • "Above the contour" does not count.
  2. Vascular invasion (all of the following):
     1. In a small vein (not a capillary), that is outside of the tumour mass.
     2. Tumour adherent to the side of the vessel.
     3. Tumour must be re-endothelialized.

Notes:

• Impossible to differentiate from follicular adenoma on FNA (no cytologic differences).
• Described as "over-diagnosed" ... misdiagnoses: PTC follicular variant, follicular adenoma, multinodular goitre with a thick capsule.

Images:

• Follicular thyroid carcinoma - several images (upmc.edu).

Medullary thyroid carcinoma

• Abbreviated MTC.

General

Medical school memory device - 3 M's:

• aMyloid.
• Median node dissection done.
• MEN IIa syndrome/MEN IIb syndrome.
  • Medullary thyroid carcinoma.
  • Pheochromocytoma.
  • Parathyroid adenoma.

Epidemiology:

• Very rare.
• Poor prognosis.
• May be genetic (MEN IIa/b syndrome).
• Arises from C cells (which produce calcitonin).

Syndromic tumours - typically:

• Present in 30s or 40s.
• +/-Multifocal.
• +/-Bilateral.
• C-cell hyperplasia.

Gross

Features:

• Usu. well-circumscribed.
• White, gray or yellow.
• Gritty.
• Firm.

Image:

• MTC (nature.com).

Microscopic

Features:

• Nuclei with "neuroendocrine features".
  • Small, round nuclei.
  • Coarse chromatin (salt and pepper nuclei).
• +/-Amyloid deposits - fluffy appearing acellular eosinophilic material in the cytoplasm.
• +/-C-cell hyperplasia - seen with familial forms of MTC.
  • C cells (AKA parafollicular cell): abundant cytoplasm - clear/pale.

Note:

• The amyloid is formed from calcitonin.

Images:

• www:
  • Medullary thyroid carcinoma (bmj.com).
  • C cell hyperplasia (nature.com).
  • C cell (rutgers.edu).
  • Parafollicular cells (anatomyatlases.org).
• WC:
  • MTC - low mag. (WC).
  • MTC - high mag. (WC).
  • MTC and amyloid - high mag. (WC).

IHC

Features:

• Calcitonin +ve - it arises from C cells (which produce calcitonin).
• Congo-red +ve (amyloid present) - mnemonic: CRAP -- congo red amyloid protein.
• Neuroendocrine markers.
  • Chromogranin A.
  • Synaptophysin.
• CEA +ve (often better staining than calcitonin).
• Thyroglobulin usu. -ve.

EM

• Neurosecretory granules.
  • Feature seen in neuroendocrine tumours.

Images: Neurosecretory granules (ucsf.edu).

Anaplastic thyroid carcinoma

Epidemiology

• Very rare.
• Horrible prognosis.
• Often presents with obstruction.
• Typically there is a history of a thyroid mass.

Microscopic

Features:

• Cytologically malignant:
  • Huge NC ratio.
  • Mitoses.
• +/-Necrosis.

Notes:

• May have features of other thyroid carcinomas, e.g. psammoma bodies, papillae, nuclear changes of PTC.

Image: Anaplastic thyroid carcinoma with a component of papillary thyroid carcinoma (WC).

DDx:

• Poorly differentiated carcinoma.
• Squamous cell carcinoma.
• Medullary thyroid carcinoma.
• Sarcoma.

IHC

• Keratin (AE1/AE3) +ve.
• Vimentin +ve, >90%.
• Thyroglobulin - rarely +ve (~15%).
• CEA -ve, calcitonin -ve; to r/o medullary.
• p53 +ve.
• TTF-1 +ve.

Lymphomas of the thyroid

Main article: Lymphoma

General

• Rare.
• Increased risk with chronic inflammatory conditions.
• Fit in the the greater category of MALT lymphoma.

Microscopic

Features:

• Lymphoepithelial lesion - key feature.
• Plasma cells.
• "Overgrowth" - thyroid parenchyma displaced by lymphocytes.

Weird stuff

Hyalinizing trabecular tumour

• AKA hyalinizing trabecular adenoma.
• Abbreviated HTT.

General

• Considered by some (e.g. Silvia Asa) to be a variant of papillary thyroid carcinoma.
• Behaviour similar to papillary thyroid carcinoma - indolent.

Microscopic

Features:

• Trabecular arrangement of cells.
  • May have "curved" trabeculae.
• Extracellular space has hyaline material - key feature.
• Cytoplasm mimics hyaline material in the extracellular space.

Images:

• HTT (biomedcentral.com).
• HTT (ispub.com).

DDx:

• Papillary thyroid carcinoma (if one believes this is a separate entity).
• Medullary thyroid carcinoma - not trabecular, nuclei not PTC-like.
• Paraganglioma.

IHC

• Thyroglobulin +ve.
• NSE +ve.

Hürthle cell neoplasm

• AKA oncocytic neoplasm.
• Also spelled Hurthle cell neoplasm.

General

• Incidence: uncommon.
• This is a general category - includes:
  • Hürthle cell adenoma.
  • Hürthle cell carcinoma.

• Some advocate total thyroidectomy for all Hürthle cell neoplasms, as it is difficult to reliably differentiate adenomas and carcinomas.
• It can be understood as a special type of follicular neoplasm (including follicular thyroid adenoma and follicular thyroid carcinoma).

Adenoma vs. carcinoma

Suggestive for carcinoma:

• Male.
• >4 cm
  • Adenomas usu. <3 cm.

Definite for carcinoma:

• Lymphovascular invasion.
• Capsular invasion.

Gross

• Yellow.
• Encapsulated.

Microscopic

Features:

• Oncocytes >= 75% of cells:
  • Abundant granular, eosinophilic cytoplasm.
  • Round regular nucleus +/- prominent nucleolus.
• +/-Degenerative changes.

Negatives:

• Lack nuclear features of papillary thyroid carcinoma.
• Lack features of medullary thyroid carcinoma.

DDx:

• Papillary thyroid carcinoma oncocytic variant.
• Medullary thyroid carcinoma oncocytic variant.
• Others.

Minocycline associated thyroid pigmentation

• AKA minocycline thyroid.

General

• Benign pigmentation of the thyroid due to minocycline, an antibiotic.
  • Reported at other sites, e.g. heart valves, coronary arteries.

Gross

• Black thyroid.

Images:

• Pigmented thyroid gland (rheumatology.org).
• Minocycline thyroid - gross and microscopic (archivesofpathology.org).

Microscopic

Features:

• Granular yellow blobs:
  • Location:
    • Intracytoplasmic in the follicule-lining cells, i.e. follicular cells.
    • Intrafollicular.
  • Variable size ~0.5-4 micrometers.

Notes:

• Pigment described as lipofuscin-like.

Images:

• Pigmentation due to minocycline (flylib.com).
• Minocycline thyroid - gross and microscopic (archivesofpathology.org).

Stains

• Fontana-Masson stain +ve.

See also

• Thyroid cytopathology.
• Head and neck cytopathology.
• Salivary gland.
• Cytopathology.