Thyroid gland

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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).
  • 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.[1]

Diagnoses

Common

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.[2]
    • This dictum is disputed.[3]
    • 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:

Diagnostic keys

The following should prompt careful examination:[5]

  • 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.[6]
    • CD31 is a marker for microvessel density.
  • Galectin-3 thought to be positive in papillary carcinoma.[6]
  • HBME-1 thought to be positive in papillary lesions.[7]

Thyroid lesions per WHO

  • Adapted from the Washington Manual of Surgical Pathology.[8]

Adenoma

  • Follicular adenoma.
  • Hyalinizing trabecular tumour.

Carcinoma

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

Others

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.[9]
  • Incidental finding.

Note:

Microscopic

Features:[9]

  • 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).[12]

DDx:[9]

Images

  • Solid cell nest of the thyroid gland - intermed. mag. (WC)

  • Solid cell nest of the thyroid gland - high mag. (WC)

  • Solid cell nest of the thyroid gland - very high mag. (WC)

www:

IHC

Features:[9]

  • p63 +ve.
    • -ve in clear cells.
  • CEA +ve (polyconal).[12]
    • +ve also in clear cells.
  • Chromogranin A +ve ~45% of cases.[12]

Sign out

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

Thyroid gland 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.

Gross

Features:

  • Enlarge thyroid gland.
  • +/-Distinct (well-circumscribed) nodules.

Microscopic

Features:

  • Follicles of variable size - key feature.
    • Should be obvious at low power, i.e. with the 2.5x objective.
  • +/-Nodules.
    • Do not have a thick fibrous capsule.
    • May have a high cellularity.
    • Architecture: solid or microfollicular.[13]

Negatives:

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

DDx:

Sign out

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

HEMITHYROID, RIGHT, HEMITHYROIDECTOMY:
- CELLULAR ADENOMATOID NODULE ON A BACKGROUND OF NODULAR HYPERPLASIA.
- NEGATIVE FOR MALIGNANCY.

RIGHT THYROID, RIGHT HEMITHYROIDECTOMY:
- BENIGN NODULE WITH MICROFOLLICLES IN A BACKGROUND OF NODULAR HYPERPLASIA.
- NEGATIVE FOR MALIGNANCY.

Micro

The sections show thyroid gland with follicles of variable size and marked enlargement. A lymphocytic infiltrate is present. Focal germinal centre formation is present. Oncocytic changes and reactive changes are seen focally. No significant nuclear atypia is identified.

Alternate

The sections show thyroid gland with follicles of variable size and marked enlargement. A large nodule is present with microfollicles that are densely packed around the edge and few in the centre. The nuclei of the microfollicles are round. No significant nuclear membrane irregularities there are apparent. Very rare enlarged nuclei are present. Occasional nucleoli are seen. No nuclear overlap is readily apparent.

Follicular thyroid adenoma

  • AKA follicular adenoma, AKA thyroid follicular adenoma.

General

  • Most common neoplasm of thyroid.[14]
  • Encapusled lesion (surrounded by fibrous capsule).

Gross

  • Thick capsule.

Notes:

  • The entire capsule should be submitted.[15]
    • A good start for most thyroid specimens with a thick capsule is 10 blocks.

Microsopic

Features:

  • Cellular.
  • Thick capsule - key feature.

Negatives.

DDx:

Sign out

LEFT THYROID, SUPERIOR POLE, EXCISION:
- FOLLICULAR ADENOMA, MAXIMAL DIMENSION 5 MM.
- LYMPHOCYTIC THYROIDITIS.
- NODULAR HYPERPLASIA.
- NEGATIVE FOR MALIGNANCY.

Micro

The section shows a well-circumscribed lesion encapsulated by a thick fibrous capsule (~0.4 mm thick).

The lesions consists of microfollicles with a dense appearing colloid. The nuclei have round regular nuclear membranes. Small indistinct nucleoli are seen at high power.

Focally, the lesional cells overlap. However, the chromatin is not cleared. Nuclear grooves are not readily apparent and nuclear pseudoinclusions are not readily identified.

Graves disease

General

Clinical:

  • TSH-receptor antibody +ve.[16]

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.

Image:

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.[19]

Clinical:

Management:

  • Medical.
  • Rarely surgery.[21]

Microscopic

Features:[22][19]

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

DDx:

Images

  • Subacute thyroiditis - intermed. mag. (WC)

  • Subacute thyroiditis - high mag. (WC)

  • Subacute thyroiditis - very 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.[19]

Microscopic

Features:[19]

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

DDx:

Stains

  • ZN -ve.
  • GMS -ve.

Riedel thyroiditis

  • AKA invasive fibrous thyroiditis.[23]

General

Clinical features:[23]

  • 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:

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:[24]

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

Associated pathology:[24]

Microscopic

Features:

  • Lymphocytic infiltrate - key feature.
  • Nuclear clearing common.
  • Polymorphous lymphoplasmacytic infiltrate with germinal centres.[26]
  • +/-Oncocytic metaplasia.

Notes:

  • Histologically often not possible to separate from "non-specific" thyroiditis.[27]

DDx:

IHC

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

Molecular

C-cell hyperplasia

  • Abbreviated CCH.

General

Gross

  • Not visible.

Microscopic

Features:

  • Location:[29]
    • Mid portion of lobe to upper third of lobe.
      • Not at the poles.
      • Not in the isthmus.
  • Definitions vary.[30]

One definition - either of the following:[28]

  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

Malignant neoplasm

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

Papillary thyroid carcinoma

  • Abbreviated PTC.
Main article: Papillary thyroid carcinoma

Insular carcinoma

Main article: Insular 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.[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.

Images:

Medullary thyroid carcinoma

  • Abbreviated MTC.
Main article: Medullary thyroid carcinoma

Poorly differentiated thyroid carcinoma

Main article: Poorly differentiated thyroid carcinoma

Anaplastic thyroid carcinoma

Main article: Anaplastic thyroid carcinoma

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

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.

DDx:

Images

  • HHT - low mag. (WC)

  • HHT - intermed. mag. (WC)

  • HHT - high mag. (WC)

  • Thyroid gland - high mag. (WC)

  • HHT - intermed. mag. (WC)

  • HHT - high mag. (WC)

  • HHT - intermed. mag. (WC)

  • HHT - high mag. (WC)

  • HHT - very high mag. (WC)

www:

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.

Adenoma vs. carcinoma

Suggestive for carcinoma:[38]

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

Definite for carcinoma:[38]

  • Lymphovascular invasion.
  • Capsular invasion.

Gross

  • Yellow.
  • Encapsulated.

Microscopic

Features:[39]

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

Negatives:

DDx:[40]

  • 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.

Gross

Images:

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.[45]

Images

Stains

See also

References

  1. ↑ BEC. 20 October 2009.
  2. ↑ JOHNSON, RW.; SAHA, NC. (Jun 1962). "The so-called lateral aberrant thyroid.". Br Med J 1 (5293): 1668-9. PMC 1958877. PMID 14452106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1958877/.
  3. ↑ Escofet, X.; Khan, AZ.; Mazarani, W.; Woods, WG. (Jan 2007). "Lessons to be learned: a case study approach. Lateral aberrant thyroid tissue: is it always malignant?". J R Soc Promot Health 127 (1): 45-6. PMID 17319317.
  4. ↑ URL: http://radiopaedia.org/articles/lymph-node-levels-of-the-neck. Accessed on: 5 November 2012.
  5. ↑ SR. 17 January 2011.
  6. ↑ 6.0 6.1 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.
  7. ↑ 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.
  8. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 331. ISBN 978-0781765275.
  9. ↑ 9.0 9.1 9.2 9.3 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.
  10. ↑ Ozaki, O.; Ito, K.; Sugino, K.; Yasuda, K.; Yamashita, T.; Toshima, K.. "Solid cell nests of the thyroid gland: precursor of mucoepidermoid carcinoma?". World J Surg 16 (4): 685-8; discussion 688-9. PMID 1413837.
  11. ↑ Prichard, RS.; Lee, JC.; Gill, AJ.; Sywak, MS.; Fingleton, L.; Robinson, BG.; Sidhu, SB.; Delbridge, LW. (Feb 2012). "Mucoepidermoid carcinoma of the thyroid: a report of three cases and postulated histogenesis.". Thyroid 22 (2): 205-9. doi:10.1089/thy.2011.0276. PMID 22224821.
  12. ↑ 12.0 12.1 12.2 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.
  13. ↑ Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 36. ISBN 978-0443066856.
  14. ↑ Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 51. ISBN 978-0443066856.
  15. ↑ SR. 17 January 2011.
  16. ↑ Massart, C.; Gibassier, J.; d'Herbomez, M. (Sep 2009). "Clinical value of M22-based assays for TSH-receptor antibody (TRAb) in the follow-up of antithyroid drug treated Graves' disease: comparison with the second generation human TRAb assay.". Clin Chim Acta 407 (1-2): 62-6. doi:10.1016/j.cca.2009.06.033. PMID 19576193.
  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. ↑ URL: http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/enfrm.html. Accessed on: 4 December 2011.
  19. ↑ 19.0 19.1 19.2 19.3 Lloyd, Ricardo V. (2002). Endocrine Diseases (AFIP Atlas of Nontumor Pathology). Toronto: American Registry of Pathology. ISBN 978-1881041733. http://www.amazon.com/Endocrine-Diseases-Atlas-Nontumer-Pathology/dp/1881041735.
  20. ↑ Szczepanek-Parulska, E.; Zybek, A.; Biczysko, M.; Majewski, P.; Ruchała, M. (2012). "What might cause pain in the thyroid gland? Report of a patient with subacute thyroiditis of atypical presentation.". Endokrynol Pol 63 (2): 138-42. PMID 22538753.
  21. ↑ Volpé, R. (1993). "The management of subacute (DeQuervain's) thyroiditis.". Thyroid 3 (3): 253-5. PMID 8257868.
  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. 559. ISBN 978-0781740517.
  23. ↑ 23.0 23.1 Fatourechi, MM.; Hay, ID.; McIver, B.; Sebo, TJ.; Fatourechi, V. (Jul 2011). "Invasive fibrous thyroiditis (Riedel thyroiditis): the Mayo Clinic experience, 1976-2008.". Thyroid 21 (7): 765-72. doi:10.1089/thy.2010.0453. PMID 21568724.
  24. ↑ 24.0 24.1 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.
  25. ↑ Ohye, H.; Fukata, S.; Hirokawa, M. (Nov 2007). "[Malignant lymphoma of the thyroid].". Nihon Rinsho 65 (11): 2092-8. PMID 18018576.
  26. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 672. ISBN 978-1416025887.
  27. ↑ 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.
  28. ↑ 28.0 28.1 Machens A, Hoffmann F, Sekulla C, Dralle H (December 2009). "Importance of gender-specific calcitonin thresholds in screening for occult sporadic medullary thyroid cancer". Endocr. Relat. Cancer 16 (4): 1291–8. doi:10.1677/ERC-09-0136. PMID 19726541. http://erc.endocrinology-journals.org/cgi/content/full/16/4/1291.
  29. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Thyroid_11protocol.pdf. Accessed on: 7 April 2012.
  30. ↑ SR. 17 January 2011.
  31. ↑ Guyétant, S.; Josselin, N.; Savagner, F.; Rohmer, V.; Michalak, S.; Saint-André, JP. (Aug 2003). "C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients.". Mod Pathol 16 (8): 756-63. doi:10.1097/01.MP.0000081727.75778.0C. PMID 12920219.
  32. ↑ URL: http://www.forpath.org/workshops/0201/html/case_7.asp. Accessed on: 21 May 2013.
  33. ↑ SR. 17 January 2011.
  34. ↑ 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.
  35. ↑ URL: http://path.upmc.edu/cases/case465/dx.html. Accessed on: 17 January 2011.
  36. ↑ Baloch, ZW.; Puttaswamy, K.; Brose, M.; LiVolsi, VA. (2006). "Lack of BRAF mutations in hyalinizing trabecular neoplasm.". Cytojournal 3: 17. doi:10.1186/1742-6413-3-17. PMID 16867191.
  37. ↑ URL: http://www.ispub.com/journal/the-internet-journal-of-endocrinology/volume-2-number-1/hyalinizing-trabecular-neoplasm-of-the-thyroid-controversies-in-management.html. Accessed on: 1 January 2012.
  38. ↑ 38.0 38.1 38.2 Wasvary, H.; Czako, P.; Poulik, J.; Lucas, R. (Aug 1998). "Unilateral lobectomy for Hurthle cell adenoma.". Am Surg 64 (8): 729-32; discussion 732-3. PMID 9697901.
  39. ↑ 39.0 39.1 Thompson, Lester D. R. (2006). Endocrine Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 104. ISBN 978-0443066856.
  40. ↑ Montone KT, Baloch ZW, LiVolsi VA (August 2008). "The thyroid Hürthle (oncocytic) cell and its associated pathologic conditions: a surgical pathology and cytopathology review". Arch. Pathol. Lab. Med. 132 (8): 1241–50. PMID 18684023.
  41. ↑ 41.0 41.1 Sant'Ambrogio, S.; Connelly, J.; DiMaio, D.. "Minocycline pigmentation of heart valves.". Cardiovasc Pathol 8 (6): 329-32. PMID 10615019.
  42. ↑ Geria AN, Tajirian AL, Kihiczak G, Schwartz RA (2009). "Minocycline-induced skin pigmentation: an update". Acta Dermatovenerol Croat 17 (2): 123–6. PMID 19595269.
  43. ↑ Noble, JG.; Christmas, TJ.; Chapple, C.; Katz, D.; Milroy, EJ. (Jan 1989). "The black thyroid: an unusual finding during neck exploration.". Postgrad Med J 65 (759): 34-5. PMC 2429157. PMID 2780449. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2429157/.
  44. ↑ 44.0 44.1 Raghavan, R.; Snyder, WH.; Sharma, S. (Mar 2004). "Pathologic quiz case: tumor in pigmented thyroid gland in a young man. Papillary thyroid carcinoma in a minocycline-induced, diffusely pigmented thyroid gland.". Arch Pathol Lab Med 128 (3): 355-6. doi:10.1043/1543-2165(2004)128355:PQCTIP2.0.CO;2. PMID 14987144.
  45. ↑ Gordon, G.; Sparano, BM.; Kramer, AW.; Kelly, RG.; Iatropoulos, MJ. (Oct 1984). "Thyroid gland pigmentation and minocycline therapy.". Am J Pathol 117 (1): 98-109. PMC 1900569. PMID 6435454. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1900569/.
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