Difference between revisions of "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 aggresively 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.
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.   


==Thyroid specimens==  
The gland frustrates a significant number of pathologists, as the criteria for cancer are considered a bit wishy-washy.
They come in 3 common varieties:
 
=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.
*Hemithyroid.
**Done to get a definitive diagnosis.
**Done to get a definitive diagnosis.
Line 8: Line 12:
*Total thyroid.
*Total thyroid.
**Done for malignancy or follicular lesion.
**Done for malignancy or follicular lesion.
*FNA (fine needle aspiration).
**done to r/o malignancy.


Gross pathology:
==Gross pathology==
*White nodules - think:
*White nodules - think:
**Lymphoid tissue.
**Lymphoid tissue.
**Papillary thyroid carcinoma - may be calcified.<ref>BEC. 20 October 2009.</ref>
**Papillary thyroid carcinoma - may be calcified.<ref>BEC. 20 October 2009.</ref>


==Common diagnoses==
=Diagnoses=
*Nodular hyperplasia.
==Common==
*Lymphocytic thyroiditis.
*[[Thyroid gland nodular hyperplasia|Nodular hyperplasia]] -- most common.
*Papillary thyroid carcinoma -- most common cancer.
*[[Lymphocytic thyroiditis]].
*Papillary thyroid carcinoma (PTC) -- most common cancer.
**[[Papillary thyroid carcinoma follicular variant]].
*[[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.<ref name=pmid14452106>{{Cite journal  | last1 = JOHNSON | first1 = RW. | last2 = SAHA | first2 = NC. | title = The so-called lateral aberrant thyroid. | journal = Br Med J | volume = 1 | issue = 5293 | pages = 1668-9 | month = Jun | year = 1962 | doi =  | PMID = 14452106 | PMC = 1958877 }}</ref>
**This dictum is disputed.<ref name=pmid17319317>{{Cite journal  | last1 = Escofet | first1 = X. | last2 = Khan | first2 = AZ. | last3 = Mazarani | first3 = W. | last4 = Woods | first4 = WG. | title = Lessons to be learned: a case study approach. Lateral aberrant thyroid tissue: is it always malignant? | journal = J R Soc Promot Health | volume = 127 | issue = 1 | pages = 45-6 | month = Jan | year = 2007 | doi =  | PMID = 17319317 }}</ref>
**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:
*[http://images.radiopaedia.org/images/26383/ad505c78a87e71180792049299f5cd_big_gallery.jpg Neck levels (radiopaedia.org)].<ref>URL: [http://radiopaedia.org/articles/lymph-node-levels-of-the-neck http://radiopaedia.org/articles/lymph-node-levels-of-the-neck]. Accessed on: 5 November 2012.</ref>
 
==Diagnostic keys==
The following should prompt careful examination:<ref>SR. 17 January 2011.</ref>
*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.<ref name=pmid18795075>{{Cite journal  | last1 = Rydlova | first1 = M. | last2 = Ludvikova | first2 = M. | last3 = Stankova | first3 = I. | title = Potential diagnostic markers in nodular lesions of the thyroid gland: an immunohistochemical study. | journal = Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub | volume = 152 | issue = 1 | pages = 53-9 | month = Jun | year = 2008 | doi =  | PMID = 18795075 }}</ref>
**CD31 is a marker for microvessel density.
*Galectin-3 thought to be positive in papillary carcinoma.<ref name=pmid18795075/>
*HBME-1 thought to be positive in papillary lesions.<ref name=pmid15529186>{{Cite journal  | last1 = Papotti | first1 = M. | last2 = Rodriguez | first2 = J. | last3 = De Pompa | first3 = R. | last4 = Bartolazzi | first4 = A. | last5 = Rosai | first5 = J. | title = Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential. | journal = Mod Pathol | volume = 18 | issue = 4 | pages = 541-6 | month = Apr | year = 2005 | doi = 10.1038/modpathol.3800321 | PMID = 15529186 }}</ref>
 
==Thyroid lesions per WHO==
*Adapted from the ''Washington Manual of Surgical Pathology''.<ref name=Ref_WMSP331>{{Ref WMSP|331}}</ref>
===Adenoma===
*Follicular adenoma.
*Follicular adenoma.
*Follicular thryoid carcinoma.
*Hyalinizing trabecular tumour.
*Parathyroid tissue.


===Parathyroid tissue===
===Carcinoma===
General:
*[[Papillary thyroid carcinoma|Papillary carcinoma]].
*Identification of normal can be tricky.
*[[Follicular thyroid carcinoma|Follicular carinoma]].
*[[Medullary thyroid carcinoma|Medullary carcinoma]].
*[[Anaplastic thyroid carcinoma|Undifferentiated (anaplastic) carcinoma]].


Features:<ref>[http://www.medicalhistology.us/twiki/pub/Main/ChapterFourteenSlides/b56b_parathyroid_40x_he_labeled.jpg http://www.medicalhistology.us/twiki/pub/Main/ChapterFourteenSlides/b56b_parathyroid_40x_he_labeled.jpg]</ref>
*[[Poorly differentiated thyroid carcinoma|Poorly differentiated carcinoma]].
*Low power:
*[[Squamous cell carcinoma]].
**May vaguely resemble lymphoid tissue - may have hyperchromatic cytoplasm.
*[[Mucoepidermoid carcinoma]].
***Does ''not'' have follicular centres like a lymph node.
*Sclerosing mucoepidermoid carcinoma with eosinophilia.
**May form gland-like structure and vaguely resemble the thyroid at low power.
*Mucinous carcinoma.
**Cytoplasm may be clear<ref>[http://pathology.mc.duke.edu/research/Histo_course/parathyroid2.jpg http://pathology.mc.duke.edu/research/Histo_course/parathyroid2.jpg]</ref> - '''key feature'''.
**Surrounded by a thin fibrous capsule.
*High power:
**Mixed cell population:<ref>[http://www.bu.edu/histology/p/15002loa.htm http://www.bu.edu/histology/p/15002loa.htm]</ref>
***Chief cells - predominant cell type, small, cytoplasm has variable staining (hyperchromatic-clear-eosinophilic).
***Oxyphil cells (''acid staining'' cells<ref>[http://dictionary.reference.com/search?q=oxyphil%20cell http://dictionary.reference.com/search?q=oxyphil%20cell]</ref>) - abundant cytoplasm.
***Adipocytes - increased with age, may be used to help differentiate from thyroid - '''key feature'''.


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


{| class="wikitable"
===Others===
| '''Name''' || '''Staining (cytoplasm)''' || '''Quantity of cells''' ||  '''Cytoplasm (quantity)''' || '''Function'''
*[[Teratoma]].
|-
*[[Lymphoma]].
| (parathyroid) chief cells  || intense hyperchromatic to eosinophilic (see note) || abundant || moderate || manufacture PTH
*Ectopic thymoma.
|-
*[[Angiosarcoma]] + other [[soft tissue lesions]].
| oxyphil cells  || moderate/light hyperchromatic to eosinophilic || rare || abundant || ?
*[[Paraganglioma]].
|}
*[[Solitary fibrous tumour]].
Notes:
*[[Follicular dendritic cell tumour]].
*Cytoplasmic staining varies considerably on H&E preparations - it may vary from hyperchromatic<ref>[http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg]</ref> to clear to eosinophilic<ref>[http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm http://instruction.cvhs.okstate.edu/Histology/HistologyReference/hrendo.htm]</ref>.
*[[Langerhans cell histiocytosis]].
*Chief cells tend to stain more intensely than oxyphil cells.
*[[Metastasis]].


Thyroid vs. parathyroid (see: [http://instruction.cvhs.okstate.edu/Histology/HistologyReference/imagesco/parathyroid2F.jpg parathyroid image]):
=Parathyroid glands=
*Parathyroid cytoplasm:
{{Main|Parathyroid glands}}
**Hyperchromatic.
*May make an appearance in the context of thyroid surgery.


Parathyroid vs. lymphoid tissue (see [http://www.deltagen.com/target/histologyatlas/atlas_files/endocrine/parathyroid_and_thyroid_glands_20x.jpg parathyroid image]):
=Benign=
*Parathyroid:
==Solid cell nest of the thyroid gland==
**No germinal centres.
*[[AKA]] ''solid cell nest of thyroid''.
**Gland-like/follicular-like arrangement -- much smaller than normal follicles of
===General===
**Occasional cell with rim of clear cytoplasm (oxyphil?).
*Embryonic remnants endodermal origin.<ref name=pmid12527712>{{cite journal |author=Reis-Filho JS, Preto A, Soares P, Ricardo S, Cameselle-Teijeiro J, Sobrinho-Simões M |title=p63 expression in solid cell nests of the thyroid: further evidence for a stem cell origin |journal=Mod. Pathol. |volume=16 |issue=1 |pages=43–8 |year=2003 |month=January |pmid=12527712 |doi=10.1097/01.MP.0000047306.72278.39 |url=http://www.nature.com/modpathol/journal/v16/n1/full/3880708a.html}}</ref>
*Incidental finding.


Images:
Note:
*[http://library.med.utah.edu/WebPath/ENDOHTML/ENDO031.html Parathyroid - med.utah.edu].
*Hypothesized to have some relation to [[mucoepidermoid carcinoma]] of the thyroid gland;<ref name=pmid1413837>{{Cite journal  | last1 = Ozaki | first1 = O. | last2 = Ito | first2 = K. | last3 = Sugino | first3 = K. | last4 = Yasuda | first4 = K. | last5 = Yamashita | first5 = T. | last6 = Toshima | first6 = K. | title = Solid cell nests of the thyroid gland: precursor of mucoepidermoid carcinoma? | journal = World J Surg | volume = 16 | issue = 4 | pages = 685-8; discussion 688-9 | month =  | year =  | doi =  | PMID = 1413837 }}</ref> however, another study suspects a relationship with [[papillary thyroid carcinoma]].<ref name=pmid22224821>{{Cite journal  | last1 = Prichard | first1 = RS. | last2 = Lee | first2 = JC. | last3 = Gill | first3 = AJ. | last4 = Sywak | first4 = MS. | last5 = Fingleton | first5 = L. | last6 = Robinson | first6 = BG. | last7 = Sidhu | first7 = SB. | last8 = Delbridge | first8 = LW. | title = Mucoepidermoid carcinoma of the thyroid: a report of three cases and postulated histogenesis. | journal = Thyroid | volume = 22 | issue = 2 | pages = 205-9 | month = Feb | year = 2012 | doi = 10.1089/thy.2011.0276 | PMID = 22224821 }}</ref>
*[http://pathology.mc.duke.edu/research/PTH225.html Histology - several images. - pathology.mc.duke.edu].
 
===Microscopic===
Features:<ref name=pmid12527712/>
*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).<ref name=pmid7509563>{{cite journal |author=Mizukami Y, Nonomura A, Michigishi T, ''et al.'' |title=Solid cell nests of the thyroid. A histologic and immunohistochemical study |journal=Am. J. Clin. Pathol. |volume=101 |issue=2 |pages=186–91 |year=1994 |month=February |pmid=7509563 |doi= |url=}}</ref>


===Parathyroid hyperplasia===
DDx:<ref name=pmid12527712/>
*Chief cell hyperplasia - associated with MEN I, MEN IIa.<ref>URL: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970475-2 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970475-2]. Accessed on: 29 July 2010.</ref>
*[[C-cell hyperplasia]].
*[[Medullary thyroid carcinoma|Medullary carcinoma]].
*Squamous lesions.


==Benign==
====Images====
===Nodular hyperplasia===
<gallery>
*Very common benign diagnosis.
Image:Solid_cell_nest_of_the_thyroid_gland_-_intermed_mag.jpg | Solid cell nest of the thyroid gland - intermed. mag. (WC)
**If you've seen a handful of thyroids you've seen this.
Image:Solid_cell_nest_of_the_thyroid_gland_-_high_mag.jpg | Solid cell nest of the thyroid gland - high mag. (WC)
*Follicles of variable size.
Image:Solid_cell_nest_of_the_thyroid_gland_-_very_high_mag.jpg | Solid cell nest of the thyroid gland - very high mag. (WC)
*Nodules maybe well circumscribed (on gross), but do not have a thick fibrous capsule.
</gallery>
*Negatives:
www:
**No nuclear features suggestive of malignancy (papillary carcinoma).
*[http://farm6.static.flickr.com/5143/5685400518_c4f506d370.jpg Solid cell next (flickr.com)].
**Not cellular.
*[http://www.nature.com/modpathol/journal/v16/n1/fig_tab/3880708f1.html#figure-title Crappy B&W of solid cell nest (nature.com)].


===Follicular adenoma===
===IHC===
*Most common neoplasm of thyroid<ref>{{Ref EP|51}}</ref>
Features:<ref name=pmid12527712/>
*Encapusled lesion (surrounded by fibrous capsule).
*p63 +ve.
*Cellular.
**-ve in clear cells.
*Negatives
*[[CEA]] +ve (polyconal).<ref name=pmid7509563>{{cite journal |author=Mizukami Y, Nonomura A, Michigishi T, ''et al.'' |title=Solid cell nests of the thyroid. A histologic and immunohistochemical study |journal=Am. J. Clin. Pathol. |volume=101 |issue=2 |pages=186–91 |year=1994 |month=February |pmid=7509563 |doi= |url=}}</ref>
**No nuclear features suggestive of papillary carcinoma.
**+ve also in clear cells.
*Chromogranin A +ve ~45% of cases.<ref name=pmid7509563/>


===Graves disease===
===Sign out===
*Often misspelled "Grave's disease".
Solid cell nests of the thyroid gland are usually not reported.
*Hyperthyroidism.
*Etiology: autoimmune.
*Gross:<ref>{{Ref EP|30}}</ref>
**Enlarged 50-150 g.
**"Beefy-red" appearance, looks like raw beef.


===Granulomatous thyoiditis===
==Thyroid gland nodular hyperplasia==
Features:<ref>Sternberg P.559</ref>
*[[AKA]] ''[[nodular hyperplasia]]''.
*AKA ''de Quervain disease''.
*[[AKA]] ''adenomatoid nodule''.
*Women > men.
{{Main|Thyroid gland nodular hyperplasia}}


===Ridel thyroiditis===
==Follicular thyroid adenoma==
*Fibrosis.
*[[AKA]] follicular adenoma, [[AKA]] thyroid follicular adenoma.
*Specimen often fragmented as it was difficult to remove.
{{Main|Follicular thyroid adenoma}}
*Thought to be related to ''[[retroperitoneal fibrosis]]''.


==Hashimoto's thyroiditis==
==Graves disease==
===Clinical===
{{Main|Graves' disease}}
Presentation:
*Hypothyroid


Associations:<ref name=pmid7813361 >{{cite journal |author=Poropatich C, Marcus D, Oertel YC
==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.


|title=Hashimoto's thyroiditis: fine-needle aspirations of 50 asymptomatic cases |journal=Diagn. Cytopathol. |volume=11
===General===
*Women > men.
*Etiology: possibly viral.<ref name=llyod/>


|issue=2 |pages=141–5 |year=1994 |pmid=7813361 |doi=  
Clinical:
*Tenderness.<ref name=pmid22538753>{{Cite journal  | last1 = Szczepanek-Parulska | first1 = E. | last2 = Zybek | first2 = A. | last3 = Biczysko | first3 = M. | last4 = Majewski | first4 = P. | last5 = Ruchała | first5 = M. | title = What might cause pain in the thyroid gland? Report of a patient with subacute thyroiditis of atypical presentation. | journal = Endokrynol Pol | volume = 63 | issue = 2 | pages = 138-42 | month =  | year = 2012 | doi = | PMID = 22538753 }}</ref>


|url=http://www3.interscience.wiley.com/journal/112701408/abstract?CRETRY=1&SRETRY=0}}</ref>
Management:
*Antimicrosomal (antithyroid peroxidase) +ve.
*Medical.
*Antithyroglobulin +ve.
*Rarely surgery.<ref>{{Cite journal  | last1 = Volpé | first1 = R. | title = The management of subacute (DeQuervain's) thyroiditis. | journal = Thyroid | volume = 3 | issue = 3 | pages = 253-5 | month =  | year = 1993 | doi =  | PMID = 8257868 }}</ref>
*Increased risk of B-cell lymphoma.


===Etiology===
===Microscopic===
*Autoimmune.
Features:<ref name=Ref_Sternberg4_559>{{Ref Sternberg4|559}}</ref><ref name=llyod>{{cite book |title=Endocrine Diseases (AFIP Atlas of Nontumor Pathology) |last= Lloyd |first = Ricardo V. |authorlink= |coauthors= |year= 2002 |publisher= American Registry of Pathology |location= Toronto |isbn=978-1881041733 |page= |pages= |url=http://www.amazon.com/Endocrine-Diseases-Atlas-Nontumer-Pathology/dp/1881041735 |accessdate=}}</ref>
**Often genetic/part of a syndrome.
*[[Granulomas]] with multinucleated giant cells - usu. with engulfed colloid.
*Lymphocytes.
*Plasma cells.
*+/-Fibrosis.


===Diagnosis===
DDx:
*Histologically often not possible to separate from "nonspecific" thyroiditis.<ref>Sternberg P.560.</ref>
*Infectious granulomatous disease (fungal, microbacterial).
*Nuclear clearing common - ergo may confuse with papillary carcinoma.
*[[Palpation thyroiditis]].
*Polymorphous lymphoplasmacytic infiltrate with germinal centres.<ref>APBR P.672.</ref>
*[[Sarcoidosis]] (classically intrafollicular distribution).


==Malignant neoplasm==
====Images====
There are a bunch of 'em. The most common, by far, is papillary.
<gallery>
Image:Subacute_thyroiditis_-_intermed_mag.jpg | Subacute thyroiditis - intermed. mag. (WC)
Image:Subacute_thyroiditis_-_high_mag.jpg | Subacute thyroiditis - high mag. (WC)
Image:Subacute_thyroiditis_-_very_high_mag.jpg | Subacute thyroiditis - very high mag. (WC)
</gallery>


==Papillary==
===Stains===
===Clinical===  
*ZN -ve.
Basic clinican knowledge - P's:
*GMS -ve.
*Palpable nodes.
*Popular (most common malignant neoplasm of the thyroid).
*Prognosis is good.
*Pre-Tx iodine scan.
*Post-Sx iodine scan.
*[[Psammoma bodies]].


Notes:
==Palpation thyroiditis==
*Associated with radiation exposure.<ref>Sternberg P.564</ref>
===General===
*Granulomatous inflammation due to palpation.
**Incidence of granulomas higher in surgical thyroid specimens than autopsies.<ref name=llyod/>


===Histology===
===Microscopic===
*The '''key diagnostic features''' are nuclear changes.
Features:<ref name=llyod>{{cite book |title=Endocrine Diseases (AFIP Atlas of Nontumor Pathology) |last= Lloyd |first = Ricardo V. |authorlink= |coauthors= |year= 2002 |publisher= American Registry of Pathology |location= Toronto |isbn=978-1881041733 |page= |pages= |url=http://www.amazon.com/Endocrine-Diseases-Atlas-Nontumer-Pathology/dp/1881041735 |accessdate=}}</ref>
**"Shrivelled nuclei"/"raisin" like nuclei, nuclei with a wavy nuclear membrane.
*[[Granuloma]]s involving the follicle.
**Nuclear grooves.
**Histiocytes within the colloid.
**Nuclear inclusions.
**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).
**Absence of papillae does not exclude diagnosis.
*[[Psammoma bodies]].  
**Circular, acellular, eosinophilic whorled bodies.
**Not necessary to make diagnosis.
**Arise from infarction & calcification of papilla tips.<ref>Sternberg P.565</ref>


Notes:
DDx:
*Psammoma bodies are awesome if you see 'em, i.e. useful for arriving at the diagnosis.
*[[Idiopathic granulomatous thyroiditis]].
**If there are no papillae structures -- you're unlikely to see psammomas.
*[[Sarcoidosis]].
*At low power look for cellular areas/loss of follicles.
*Infectious granulomatous thyroiditis.
*Nuclear clearing seen in:
**Hashimoto's and papillary thyroid carcinoma.<ref>Sternberg P.566</ref>
**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.


===Subtypes if papillary===
===Stains===
There are many.
*ZN -ve.
*GMS -ve.


===Tall cell variant===
==Riedel thyroiditis==
Features:<ref name=pmid19373912>{{cite journal |author=Urano M, Kiriyama Y, Takakuwa Y, Kuroda M |title=Tall cell variant of papillary thyroid carcinoma: Its characteristic features demonstrated by fine-needle aspiration cytology and immunohistochemical study |journal=Diagn. Cytopathol. |volume= |issue= |pages= |year=2009 |month=April |pmid=19373912 |doi=10.1002/dc.21086 |url=}}</ref>
*[[AKA]] ''invasive fibrous thyroiditis''.<ref name=pmid21568724>{{Cite journal | last1 = Fatourechi | first1 = MM. | last2 = Hay | first2 = ID. | last3 = McIver | first3 = B. | last4 = Sebo | first4 = TJ. | last5 = Fatourechi | first5 = V. | title = Invasive fibrous thyroiditis (Riedel thyroiditis): the Mayo Clinic experience, 1976-2008. | journal = Thyroid | volume = 21 | issue = 7 | pages = 765-72 | month = Jul | year = 2011 | doi = 10.1089/thy.2010.0453 | PMID = 21568724 }}</ref>
*50% of cells with height 2x the width.<ref>[http://pathologyoutlines.com/thyroid.html#tallcellvariant http://pathologyoutlines.com/thyroid.html#tallcellvariant]</ref><ref name=pmid18925842>{{cite journal |author=Ghossein R, Livolsi VA |title=Papillary thyroid carcinoma tall cell variant |journal=Thyroid |volume=18 |issue=11 |pages=1179–81 |year=2008 |month=November |pmid=18925842 |doi=10.1089/thy.2008.0164 |url=}}</ref>
{{Main|Riedel thyroiditis}}
**There is some disagreement on these criteria.<ref name=pmid18925842/>
*Eosinophilic cytoplasm.
*Well-defined cell borders.
*Nucleus stratified; basal location, i.e. closer to the basement membrane.


Negative:
==Hashimoto thyroiditis==
*Nuclei ''not'' pseudostratified, if pseudostratified consider ''columnar cell variant''.
{{Main|Hashimoto's thyroiditis}}


===Columnar cell variant===
==C-cell hyperplasia==
Epidemiology:
*Abbreviated ''CCH''.
*Poor prognosis.
{{Main|C-cell hyperplasia}}


Features:
==Adenolipoma of the thyroid==
*Elongated nuclei (similar to colorectal adenocarcinoma) - '''key feature'''.
{{Main|Adenolipoma of the thyroid}}
*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: [http://www3.interscience.wiley.com/cgi-bin/fulltext/75000320/nfig003a?CRETRY=1&SRETRY=0 Tall cell variant Pa ca (wiley.com)].
===Follicular variant===
May be confused with follicular carcinoma or follicular adenoma.


Features:
=Malignant neoplasm=
*Prominent follicles.
There are a bunch of 'em.  The most common, by far, is papillary.


===Cribriform-morular variant===  
==Papillary thyroid carcinoma==
Features:
*Abbreviated ''PTC''.
*Cribriform pattern.
{{Main|Papillary thyroid carcinoma}}
*Morules - balls of tissue.


==Insular carcinoma==
==Insular carcinoma==
General:<ref name=pmid17665497>{{cite journal |author=Rufini V, Salvatori M, Fadda G, ''et al.'' |title=Thyroid carcinomas with a variable insular component: prognostic significance of histopathologic patterns |journal=Cancer |volume=110 |issue=6 |pages=1209–17 |year=2007 |month=September |pmid=17665497 |doi=10.1002/cncr.22913 |url=}}</ref>
{{Main|Insular thyroid carcinoma}}
*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.


Features:<ref name=pmid17665497/>
==Follicular thyroid carcinoma==
*Islands of cells - '''key feature'''.
*[[AKA]] ''follicular carcinoma''.
*Scant cytoplasm.
{{Main|Follicular thyroid carcinoma}}
*Nuclei monomorphic and round.


DDx:<ref>Endo. fellow. 17 September 2009.</ref>
==Medullary thyroid carcinoma==
*Medullary thyroid carcinoma.
*Abbreviated ''MTC''.
*Poorly differentiated thyroid carcinoma.
{{Main|Medullary thyroid carcinoma}}


==Follicular thyroid carcinoma==
==Poorly differentiated thyroid carcinoma==
===Clinical===
{{Main|Poorly differentiated thyroid carcinoma}}
*FNA NOT diagnosable.
*Far away mets (sometimes).
*Female predominant.
*Favourable prognosis.


===Histology===
==Anaplastic thyroid carcinoma==
*IMPOSSIBLE to differentiate from ''follicular adenoma'' on FNA (no cytologic differences).
{{Main|Anaplastic thyroid carcinoma}}
*Defined by invasion through the capsule.


==Medullary thyroid carcinoma==
==Lymphomas of the thyroid==
{{Main|Lymphoma}}
===General===
===General===
*Abbreviated ''MTC''.
*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.


===Clinical===
=Weird stuff=
3 M's:
==Hyalinizing trabecular tumour==
*[[amyloid|aMyloid]].
*[[AKA]] ''hyalinizing trabecular adenoma''.
*Median node dissection done.
*Abbreviated ''HTT''.
*[[MEN IIa syndrome]]/[[MEN IIb syndrome]].
{{Main|Hyalinizing trabecular tumour}}
**Medullary thyroid carcinoma.
**[[Pheochromocytoma]].
**[[Parathyroid adenoma]].


===Epidemiology===
==Hürthle cell neoplasm==
*Very rare.
*[[AKA]] ''oncocytic neoplasm''.
*Poor prognosis.
*Also spelled ''Hurthle cell neoplasm''.
*May be genetic (MEN IIa/b syndrome).
{{Main|Hürthle cell neoplasm}}
*Arises from C cells (which produce calcitonin).


===Histology===
==Minocycline associated thyroid pigmentation==
Features:
*[[AKA]] ''minocycline thyroid''.
*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:<ref>[http://pathologyoutlines.com/thyroid.html#medullary http://pathologyoutlines.com/thyroid.html#medullary]</ref>
===General===
*[[Calcitonin]] +ve - it arises from C cells (which produce calcitonin).
*Benign pigmentation of the thyroid due to ''minocycline'', an antibiotic.
*Congo-red +ve (amyloid present) - mnemonic: ''CRAP'' -- congo red amyloid protein.
**Reported at other sites, e.g. [[heart valves]],<ref name=pmid10615019/> [[skin]],<ref name=pmid19595269>{{cite journal |author=Geria AN, Tajirian AL, Kihiczak G, Schwartz RA |title=Minocycline-induced skin pigmentation: an update |journal=Acta Dermatovenerol Croat |volume=17 |issue=2 |pages=123–6 |year=2009 |pmid=19595269 |doi= |url=}}</ref> coronary arteries.
*Neuroendocrine markers.
**[[Chromogranin A]].
**[[Synaptophysin]].
*CEA +ve (often better staining than calcitonin).<ref>SB. 7 January 2010.</ref>


Image:
===Gross===
*[http://jcp.bmj.com/content/vol57/issue3/images/large/cp8474.f16.jpeg Medullary thyroid carcinoma (bmj.com)].
*Black thyroid.<ref name=pmid2780449>{{Cite journal  | last1 = Noble | first1 = JG. | last2 = Christmas | first2 = TJ. | last3 = Chapple | first3 = C. | last4 = Katz | first4 = D. | last5 = Milroy | first5 = EJ. | title = The black thyroid: an unusual finding during neck exploration. | journal = Postgrad Med J | volume = 65 | issue = 759 | pages = 34-5 | month = Jan | year = 1989 | doi =  | PMID = 2780449 | PMC = 2429157 }}</ref>
*[http://www.nature.com/ki/journal/v70/n11/fig_tab/5001888f2.html C cell hyperplasia (nature.com)].
*[http://lifesci.rutgers.edu/~babiarz/Review3/Lp6/scope8.htm C cell (rutgers.edu)].
*[http://www.anatomyatlases.org/MicroscopicAnatomy/Images/Plate287.jpg Parafollicular cells (anatomyatlases.org)].


==Anaplastic thyroid carcinoma==
Images:
===Epidemiology===
*[http://images.rheumatology.org/viewphoto.php?albumId=89099&imageId=5231272 Pigmented thyroid gland (rheumatology.org)].
*Very rare.
*[http://www.archivesofpathology.org/doi/full/10.1043/1543-2165(2004)128%3C355:PQCTIP%3E2.0.CO;2 Minocycline thyroid - gross and microscopic (archivesofpathology.org)].<ref name=pmid14987144>{{Cite journal  | last1 = Raghavan | first1 = R. | last2 = Snyder | first2 = WH. | last3 = Sharma | first3 = S. | title = Pathologic quiz case: tumor in pigmented thyroid gland in a young man. Papillary thyroid carcinoma in a minocycline-induced, diffusely pigmented thyroid gland. | journal = Arch Pathol Lab Med | volume = 128 | issue = 3 | pages = 355-6 | month = Mar | year = 2004 | doi = 10.1043/1543-2165(2004)128355:PQCTIP2.0.CO;2 | PMID = 14987144 }}</ref>
*Horrible prognosis.


===Histology===
===Microscopic===
Features:
Features:
*Cytologically malignant:  
*Granular yellow blobs:
**Huge NC ratio.
**Location:
**Mitoses.
***Intracytoplasmic in the follicule-lining cells, i.e. follicular cells.
**+/-Necrosis.
***Intrafollicular.
**Variable size ~0.5-4 micrometers.
 
Notes:
*Pigment described as ''lipofuscin-like''.<ref name=pmid6435454>{{Cite journal  | last1 = Gordon | first1 = G. | last2 = Sparano | first2 = BM. | last3 = Kramer | first3 = AW. | last4 = Kelly | first4 = RG. | last5 = Iatropoulos | first5 = MJ. | title = Thyroid gland pigmentation and minocycline therapy. | journal = Am J Pathol | volume = 117 | issue = 1 | pages = 98-109 | month = Oct | year = 1984 | doi =  | PMID = 6435454 | PMC = 1900569 }}</ref>


==IHC==
====Images====
*Keratin (AE1/AE3).
*[http://www.archivesofpathology.org/doi/full/10.1043/1543-2165(2004)128%3C355:PQCTIP%3E2.0.CO;2 Minocycline thyroid - gross and microscopic (archivesofpathology.org)].<ref name=pmid14987144>{{Cite journal | last1 = Raghavan | first1 = R. | last2 = Snyder | first2 = WH. | last3 = Sharma | first3 = S. | title = Pathologic quiz case: tumor in pigmented thyroid gland in a young man. Papillary thyroid carcinoma in a minocycline-induced, diffusely pigmented thyroid gland. | journal = Arch Pathol Lab Med | volume = 128 | issue = 3 | pages = 355-6 | month = Mar | year = 2004 | doi = 10.1043/1543-2165(2004)128355:PQCTIP2.0.CO;2 | PMID = 14987144 }}</ref>
*Vimentin +ve, >90%.<ref name=pmid1712540>{{cite journal |author=Ordóñez NG, El-Naggar AK, Hickey RC, Samaan NA |title=Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases |journal=Am. J. Clin. Pathol. |volume=96 |issue=1 |pages=15–24 |year=1991 |month=July |pmid=1712540 |doi= |url=}}</ref>
*Thyroglobulin - rarely +ve (~15%).<ref name=pmid1712540/>
*CEA -ve, calcitonin -ve; to r/o medullary.


==Thyroid IHC - general comments==
===Stains===
*Not really useful.
*[[Fontana-Masson stain]] +ve.<ref name=pmid10615019>{{Cite journal  | last1 = Sant'Ambrogio | first1 = S. | last2 = Connelly | first2 = J. | last3 = DiMaio | first3 = D. | title = Minocycline pigmentation of heart valves. | journal = Cardiovasc Pathol | volume = 8 | issue = 6 | pages = 329-32 | month = | year = | doi =  | PMID = 10615019 }}</ref>
*Papers with very small sample sizes abound.
 
==Sclerosing mucoepidermoid carcinoma with eosinophilia==
===Follicular thyroid carcinoma vs. papillary thyroid carcinoma===
{{Main|Sclerosing mucoepidermoid carcinoma with eosinophilia}}
*CD31 more frequently positive in follicular lesions.<ref name=pmid18795075>{{Cite journal  | last1 = Rydlova | first1 = M. | last2 = Ludvikova | first2 = M. | last3 = Stankova | first3 = I. | title = Potential diagnostic markers in nodular lesions of the thyroid gland: an immunohistochemical study. | journal = Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub | volume = 152 | issue = 1 | pages = 53-9 | month = Jun | year = 2008 | doi =  | PMID = 18795075 }}</ref>
**CD31 is a marker for microvessel density.
*Galectin-3 thought to be positive in papillary carcinoma.<ref name=pmid18795075/>
*HBME-1 thought to be positive in papillary lesions.<ref name=pmid15529186>{{Cite journal  | last1 = Papotti | first1 = M. | last2 = Rodriguez | first2 = J. | last3 = De Pompa | first3 = R. | last4 = Bartolazzi | first4 = A. | last5 = Rosai | first5 = J. | title = Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential. | journal = Mod Pathol | volume = 18 | issue = 4 | pages = 541-6 | month = Apr | year = 2005 | doi = 10.1038/modpathol.3800321 | PMID = 15529186 }}</ref>


==See also==
=See also=
*[[Thyroid cytopathology]].
*[[Thyroid cytopathology]].
*[[Head and neck cytopathology]].
*[[Head and neck cytopathology]].
Line 310: Line 307:
*[[Cytopathology]].
*[[Cytopathology]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}


[[Category:Endocrine pathology]]
[[Category:Endocrine pathology]]

Latest revision as of 03:43, 20 March 2018

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

Main article: Thyroid gland nodular hyperplasia

Follicular thyroid adenoma

  • AKA follicular adenoma, AKA thyroid follicular adenoma.
Main article: Follicular thyroid adenoma

Graves disease

Main article: Graves' disease

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.[13]

Clinical:

Management:

  • Medical.
  • Rarely surgery.[15]

Microscopic

Features:[16][13]

  • 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.[13]

Microscopic

Features:[13]

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

DDx:

Stains

  • ZN -ve.
  • GMS -ve.

Riedel thyroiditis

  • AKA invasive fibrous thyroiditis.[17]
Main article: Riedel thyroiditis

Hashimoto thyroiditis

Main article: Hashimoto's thyroiditis

C-cell hyperplasia

  • Abbreviated CCH.
Main article: C-cell hyperplasia

Adenolipoma of the thyroid

Main article: Adenolipoma of the thyroid

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.
Main article: Follicular thyroid carcinoma

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.
Main article: Hyalinizing trabecular tumour

Hürthle cell neoplasm

  • AKA oncocytic neoplasm.
  • Also spelled Hurthle cell neoplasm.
Main article: Hürthle cell neoplasm

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.[22]

Images

Stains

Sclerosing mucoepidermoid carcinoma with eosinophilia

Main article: Sclerosing mucoepidermoid carcinoma with eosinophilia

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. ↑ 13.0 13.1 13.2 13.3 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.
  14. ↑ 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.
  15. ↑ Volpé, R. (1993). "The management of subacute (DeQuervain's) thyroiditis.". Thyroid 3 (3): 253-5. PMID 8257868.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 18.0 18.1 Sant'Ambrogio, S.; Connelly, J.; DiMaio, D.. "Minocycline pigmentation of heart valves.". Cardiovasc Pathol 8 (6): 329-32. PMID 10615019.
  19. ↑ Geria AN, Tajirian AL, Kihiczak G, Schwartz RA (2009). "Minocycline-induced skin pigmentation: an update". Acta Dermatovenerol Croat 17 (2): 123–6. PMID 19595269.
  20. ↑ 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/.
  21. ↑ 21.0 21.1 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.
  22. ↑ 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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