Thyroid gland

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The thyroid gland is an important little endocrine organ in the anterior neck. It is not infrequently 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. It frustrates a significant number of pathologists, as the criteria for cancer are considered a bit wishy-washy.

Thyroid specimens

They come in 3 common varieties

  • 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.
  • FNA (fine needle aspiration).
    • done to r/o malignancy.

Gross pathology

  • White nodules - think:
    • Lymphoid tissue.
    • Papillary thyroid carcinoma - may be calcified.[1]

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 = metastatic PTC... even if it looks benign.
  • 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.

Diagnostic keys

The following should prompt careful examination:[2]

  • 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.[3]
    • CD31 is a marker for microvessel density.
  • Galectin-3 thought to be positive in papillary carcinoma.[3]
  • HBME-1 thought to be positive in papillary lesions.[4]

Parathyroid tissue

General:

  • Identification of normal can be tricky.

Features:[5]

  • Low power:
    • May vaguely resemble lymphoid tissue - may have hyperchromatic cytoplasm.
      • Does not have follicular centres like a lymph node.
    • May form gland-like structure and vaguely resemble the thyroid at low power.
    • Cytoplasm may be clear[6] - key feature.
    • Surrounded by a thin fibrous capsule.
  • High power:
    • Mixed cell population:[7]
      • Chief cells - predominant cell type, small, cytoplasm has variable staining (hyperchromatic-clear-eosinophilic).
      • Oxyphil cells (acid staining cells[8]) - abundant cytoplasm.
      • Adipocytes - increased with age, may be used to help differentiate from thyroid - key feature.


Name Staining (cytoplasm) Quantity of cells Cytoplasm (quantity) Function
(parathyroid) chief cells intense hyperchromatic to eosinophilic (see note) abundant moderate manufacture PTH
oxyphil cells moderate/light hyperchromatic to eosinophilic rare abundant ?

Notes:

  • Cytoplasmic staining varies considerably on H&E preparations - it may vary from hyperchromatic[9] to clear to eosinophilic[10].
  • Chief cells tend to stain more intensely than oxyphil cells.

Thyroid vs. parathyroid (see: parathyroid image):

  • Parathyroid cytoplasm:
    • Hyperchromatic.

Parathyroid vs. lymphoid tissue (see parathyroid image):

  • Parathyroid:
    • No germinal centres.
    • Gland-like/follicular-like arrangement -- much smaller than normal follicles of
    • Occasional cell with rim of clear cytoplasm (oxyphil?).

Images:

Parathyroid hyperplasia

  • Parathyroid hyperplasia - classically assoc. with renal failure.
  • Chief cell hyperplasia - associated with MEN I, MEN IIa.[11]

Parathryoid adenoma

  • One parathyroid is big... the others are small.
  • Associated with MEN I and MEN IIa/b (II/III).

MEN I:

MEN IIa/IIb (II/III):

Image: Parathyroid adenoma (med.utah.edu).[12]

Benign

Solid cell nest of thyroid

General

  • Embryonic remnants endodermal origin.[13]
  • Incidental finding.

Microscopic

Features:[13]

  • Solid or cystic cluster or variable size.
  • Cuboidal-to-columnar morphology.
  • Eosinophilic cytoplasm.
  • Round/ovoid nuclei with finely granular chromatin.
  • +/-Goblet cells (~30% of cases).[14]

Image:

DDx:[13]

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

IHC

Features:[13]

  • p63 +ve.
    • -ve in clear cells.
  • CEA +ve (polyconal).[14]
    • +ve also in clear cells.

Nodular hyperplasia

General

  • AKA 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.

Follicular adenoma

General

  • Most common neoplasm of thyroid.[15]
  • Encapusled lesion (surrounded by fibrous capsule).

Gross

  • Thick capsule.

Notes:

  • The entire capsule should be submitted.[16]
    • A good start for most thyroid specimens with a thick capsule is 10 blocks.

Microsopic

Features:

  • Cellular.

Negatives.

Graves disease

General

  • Often misspelled "Grave's disease".
  • Autoimmune disease leading to hyperthyroidism.
  • Eye problems not resolved with thyroid removal. (???)
  • Higher risk of papillary thyroid carcinoma.

Gross

Features:[17]

  • 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.

Granulomatous thyoiditis

General

  • AKA de Quervain disease, AKA subacute thyroiditis.[18]
  • Women > men.

Microscopic

Features:[19]

Ridel thyroiditis

General

Microscopic

Features:

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

DDx:

  • Anaplastic carcinoma - spindle cell variant.

Hashimoto's thyroiditis

General

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

Associations:[20]

  • Antimicrosomal (antithyroid peroxidase) +ve.
  • Antithyroglobulin +ve.
  • Increased risk of B-cell lymphoma.

Microscopic

Features:

  • Lymphocytic infiltrate.
  • Nuclear clearing common.
    • May confuse with papillary carcinoma.
  • Polymorphous lymphoplasmacytic infiltrate with germinal centres.[21]
  • +/-Oncocytic metaplasia.

Notes:

  • Histologically often not possible to separate from "nonspecific" thyroiditis.[22]

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:

  • Associated with radiation exposure.[23]

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.[24]

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.[25]
    • 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.

Subtypes of papillary thyroid carcinoma

There are many.

Tall cell variant

General

  • ~10% of PTC.

Microscopic

Features:[26]

  • 50% of cells with height 2x the width.[27][28]
    • There is some disagreement on these criteria;[28] SR believes height ought to be ~3x width, for 50% of the cells.[29]
  • 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.

Columnar cell variant

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 - key feature.
  • "Minimal" papillary features.
  • "Tall cells".
  • Clear-eosinophilic cytoplasm.
  • Mitoses common.

Image: Tall cell variant Pa ca (wiley.com).

Follicular variant

General

May be confused with follicular carcinoma or follicular adenoma.

Microscopic

Features:

  • Prominent follicles.

Cribriform-morular variant

General

Microscopic

Features:

  • Cribriform pattern.
  • Morules - balls of tissue.

Insular carcinoma

General

Features:[31]

  • 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:[31]

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

DDx:[32]

  • Medullary thyroid carcinoma.
  • Poorly differentiated thyroid carcinoma.

Follicular thyroid 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.[33]
        • 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.

Medullary thyroid carcinoma

General

  • Abbreviated MTC.

Medical school memory device - 3 M's:

Epidemiology:

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

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 (associated with familial forms of MTC).
    • C cells (AKA parafollicular cell): abundant cytoplasm - clear/pale.

IHC:[34]

  • Calcitonin +ve - it arises from C cells (which produce calcitonin).
  • Congo-red +ve (amyloid present) - mnemonic: CRAP -- congo red amyloid protein.
  • Neuroendocrine markers.
  • CEA +ve (often better staining than calcitonin).[35]

Image:

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.

IHC

  • Keratin (AE1/AE3).
  • Vimentin +ve, >90%.[36]
  • Thyroglobulin - rarely +ve (~15%).[36]
  • 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

General

  • AKA hyalinizing trabecular adenoma.
  • Considered by some (e.g. SL Asa) to be a variant of papillary thyroid carcinoma.[37]
  • Behaviour similar to papillary thyroid carcinoma - indolent.

Microscopic

Features:[38]

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

Image:

DDx:

  • Papillary thyroid carcinoma (if one believes this is a separate entity).
  • Medullary thyroid carcinoma.
  • Paraganglioma.[39]

IHC

  • Thyroglobulin +ve.
  • NSE +ve.

See also

References

  1. ↑ BEC. 20 October 2009.
  2. ↑ SR. 17 January 2011.
  3. ↑ 3.0 3.1 Rydlova, M.; Ludvikova, M.; Stankova, I. (Jun 2008). "Potential diagnostic markers in nodular lesions of the thyroid gland: an immunohistochemical study.". Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 152 (1): 53-9. PMID 18795075.
  4. ↑ Papotti, M.; Rodriguez, J.; De Pompa, R.; Bartolazzi, A.; Rosai, J. (Apr 2005). "Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential.". Mod Pathol 18 (4): 541-6. doi:10.1038/modpathol.3800321. PMID 15529186.
  5. ↑ http://www.medicalhistology.us/twiki/pub/Main/ChapterFourteenSlides/b56b_parathyroid_40x_he_labeled.jpg
  6. ↑ http://pathology.mc.duke.edu/research/Histo_course/parathyroid2.jpg
  7. ↑ http://www.bu.edu/histology/p/15002loa.htm
  8. ↑ http://dictionary.reference.com/search?q=oxyphil%20cell
  9. ↑ http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg
  10. ↑ http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm
  11. ↑ URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970475-2. Accessed on: 29 July 2010.
  12. ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/enfrm.html. Accessed on: 6 December 2010.
  13. ↑ 13.0 13.1 13.2 13.3 Reis-Filho JS, Preto A, Soares P, Ricardo S, Cameselle-Teijeiro J, Sobrinho-Simões M (January 2003). "p63 expression in solid cell nests of the thyroid: further evidence for a stem cell origin". Mod. Pathol. 16 (1): 43–8. doi:10.1097/01.MP.0000047306.72278.39. PMID 12527712. http://www.nature.com/modpathol/journal/v16/n1/full/3880708a.html.
  14. ↑ 14.0 14.1 Mizukami Y, Nonomura A, Michigishi T, et al. (February 1994). "Solid cell nests of the thyroid. A histologic and immunohistochemical study". Am. J. Clin. Pathol. 101 (2): 186–91. PMID 7509563.
  15. ↑ Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 51. ISBN 978-0443066856.
  16. ↑ SR. 17 January 2011.
  17. ↑ Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 30. ISBN 978-0443066856.
  18. ↑ SR. 17 January 2011.
  19. ↑ Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 559. ISBN 978-0781740517.
  20. ↑ Poropatich C, Marcus D, Oertel YC (1994). "Hashimoto's thyroiditis: fine-needle aspirations of 50 asymptomatic cases". Diagn. Cytopathol. 11 (2): 141–5. PMID 7813361. http://www3.interscience.wiley.com/journal/112701408/abstract?CRETRY=1&SRETRY=0.
  21. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 672. ISBN 978-1416025887.
  22. ↑ Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 560. ISBN 978-0781740517.
  23. ↑ Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 564. ISBN 978-0781740517.
  24. ↑ Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 565. ISBN 978-0781740517.
  25. ↑ Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 566. ISBN 978-0781740517.
  26. ↑ Urano M, Kiriyama Y, Takakuwa Y, Kuroda M (April 2009). "Tall cell variant of papillary thyroid carcinoma: Its characteristic features demonstrated by fine-needle aspiration cytology and immunohistochemical study". Diagn. Cytopathol.. doi:10.1002/dc.21086. PMID 19373912.
  27. ↑ http://pathologyoutlines.com/thyroid.html#tallcellvariant
  28. ↑ 28.0 28.1 Ghossein R, Livolsi VA (November 2008). "Papillary thyroid carcinoma tall cell variant". Thyroid 18 (11): 1179–81. doi:10.1089/thy.2008.0164. PMID 18925842.
  29. ↑ SR. 17 January 2011.
  30. ↑ Groen EJ, Roos A, Muntinghe FL, et al. (September 2008). "Extra-intestinal manifestations of familial adenomatous polyposis". Ann. Surg. Oncol. 15 (9): 2439–50. doi:10.1245/s10434-008-9981-3. PMC 2518080. PMID 18612695. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518080/?tool=pubmed.
  31. ↑ 31.0 31.1 Rufini V, Salvatori M, Fadda G, et al. (September 2007). "Thyroid carcinomas with a variable insular component: prognostic significance of histopathologic patterns". Cancer 110 (6): 1209–17. doi:10.1002/cncr.22913. PMID 17665497.
  32. ↑ Endo. fellow. 17 September 2009.
  33. ↑ SR. 17 January 2011.
  34. ↑ http://pathologyoutlines.com/thyroid.html#medullary
  35. ↑ SB. 7 January 2010.
  36. ↑ 36.0 36.1 Ordóñez NG, El-Naggar AK, Hickey RC, Samaan NA (July 1991). "Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases". Am. J. Clin. Pathol. 96 (1): 15–24. PMID 1712540.
  37. ↑ Cheung CC, Boerner SL, MacMillan CM, Ramyar L, Asa SL (December 2000). "Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics". Am. J. Surg. Pathol. 24 (12): 1622–6. PMID 11117782.
  38. ↑ URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675(06)71558-3. Accessed on: 17 January 2011.
  39. ↑ URL: http://path.upmc.edu/cases/case465/dx.html. Accessed on: 17 January 2011.
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