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==Overview==
==Overview==
Development of medullary thyroid cancer is the result of genetic mutation of [[RET proto-oncogene]]. On gross pathology, well-circumscribed, gray, white, or yellow-colored masses are characteristic findings of medullary thyroid cancer. On microscopic histopathological analysis, polygonal to the spindle to small cells, [[interstitial edema]], and vascular hyalinized stroma are characteristic findings of medullary thyroid cancer.
Development of medullary thyroid cancer is the result of [[genetic mutation]] of [[RET proto-oncogene]]. On [[gross pathology]], well-circumscribed, gray, white, or yellow-colored [[Mass|masses]] are characteristic findings of medullary thyroid cancer. On microscopic [[Histopathological|histopathological analysis]], polygonal to the spindle to small cells, [[interstitial edema]], and vascular hyalinized stroma are characteristic findings of medullary thyroid cancer.
==Pathogenesis==
==Pathogenesis==
* Medullary thyroid cancer is a form of [[Thyroid cancer|thyroid carcinoma]] which originates from the [[parafollicular cell]]s (C cells), which produce the hormone [[calcitonin]].<ref name=hu>Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. [http://www.cancernetwork.com/cancer-management-11/chapter05/article/10165/1402668 "Thyroid and Parathyroid Cancers"] in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) [http://www.cancernetwork.com/cancer-management-11/ Cancer Management: A Multidisciplinary Approach]. 11 ed. 2008.</ref>
* Medullary thyroid cancer is a form of [[Thyroid cancer|thyroid carcinoma]] which originates from the [[parafollicular cell]]s (C cells), which produce the hormone [[calcitonin]].<ref name="hu">Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. [http://www.cancernetwork.com/cancer-management-11/chapter05/article/10165/1402668 "Thyroid and Parathyroid Cancers"] in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) [http://www.cancernetwork.com/cancer-management-11/ Cancer Management: A Multidisciplinary Approach]. 11 ed. 2008.</ref>
* Medullary thyroid cancer may be sporadic or hereditary as part of MEN type 2 A and B.<ref name="WellsAsa2015">{{cite journal|last1=Wells|first1=Samuel A.|last2=Asa|first2=Sylvia L.|last3=Dralle|first3=Henning|last4=Elisei|first4=Rossella|last5=Evans|first5=Douglas B.|last6=Gagel|first6=Robert F.|last7=Lee|first7=Nancy|last8=Machens|first8=Andreas|last9=Moley|first9=Jeffrey F.|last10=Pacini|first10=Furio|last11=Raue|first11=Friedhelm|last12=Frank-Raue|first12=Karin|last13=Robinson|first13=Bruce|last14=Rosenthal|first14=M. Sara|last15=Santoro|first15=Massimo|last16=Schlumberger|first16=Martin|last17=Shah|first17=Manisha|last18=Waguespack|first18=Steven G.|title=Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma|journal=Thyroid|volume=25|issue=6|year=2015|pages=567–610|issn=1050-7256|doi=10.1089/thy.2014.0335}}</ref><ref name="pmid15233908">{{cite journal |vauthors=Gertner ME, Kebebew E |title=Multiple endocrine neoplasia type 2 |journal=Curr Treat Options Oncol |volume=5 |issue=4 |pages=315–25 |date=August 2004 |pmid=15233908 |doi= |url=}}</ref>
*[[Mutations]] in the [[RET proto-oncogene|''RET'' proto-oncogene]] (REarranged during Transfection), located on [[chromosome 10]], lead to the [[gene expression|expression]] of a mutated [[receptor tyrosine kinase]] protein.
* Sporadic form accounts for 80% of the cases.  
*[[RET proto-oncogene|''RET'' proto-oncogene]] is involved in the regulation of cell growth and development and its [[germline mutation]] is responsible for nearly all cases of [[hereditary]] or familial medullary thyroid carcinoma.
* Medullary tumors are the third most common of all thyroid cancers.  
*[[Germline mutation]] of [[RET proto-oncogene|''RET'']] may also be responsible for the development of [[hyperparathyroidism]] and [[pheochromocytoma]].
* Medullary thyroid carcinoma is a subtype of thyroid cancer which accounts for 5-10% of all thyroid malignancies.  
* Medullary thyroid cancer may be sporadic or hereditary as part of [[MEN, type 2a|MEN type 2 A]] and [[MEN type IIb|B]].<ref name="WellsAsa2015">{{cite journal|last1=Wells|first1=Samuel A.|last2=Asa|first2=Sylvia L.|last3=Dralle|first3=Henning|last4=Elisei|first4=Rossella|last5=Evans|first5=Douglas B.|last6=Gagel|first6=Robert F.|last7=Lee|first7=Nancy|last8=Machens|first8=Andreas|last9=Moley|first9=Jeffrey F.|last10=Pacini|first10=Furio|last11=Raue|first11=Friedhelm|last12=Frank-Raue|first12=Karin|last13=Robinson|first13=Bruce|last14=Rosenthal|first14=M. Sara|last15=Santoro|first15=Massimo|last16=Schlumberger|first16=Martin|last17=Shah|first17=Manisha|last18=Waguespack|first18=Steven G.|title=Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma|journal=Thyroid|volume=25|issue=6|year=2015|pages=567–610|issn=1050-7256|doi=10.1089/thy.2014.0335}}</ref><ref name="pmid15233908">{{cite journal |vauthors=Gertner ME, Kebebew E |title=Multiple endocrine neoplasia type 2 |journal=Curr Treat Options Oncol |volume=5 |issue=4 |pages=315–25 |date=August 2004 |pmid=15233908 |doi= |url=}}</ref>
* It is characterized by consistent production of a hormonal marker called [[calcitonin]].
* Sporadic form accounts for 80% of the cases. This form usually occurs unilaterally.
* Medullary thyroid carcinoma is also characterized by calcification of both primary and metastatic sites. Metastatic involvement may be seen in up to 50% at the time of presentation.
* Medullary thyroid carcinoma is a subtype of [[thyroid cancer]] which accounts for 5-10% of all [[Thyroid Cancer|thyroid malignancies]].
* Approximately 25% of reported cases of medullary thyroid carcinoma are familial. Familial medullary thyroid carcinoma syndromes include [[multiple endocrine neoplasia type 2A]], [[multiple endocrine neoplasia type 2B]], and familial non-multiple endocrine neoplasia syndromes. Medullary thyroid carcinoma can secrete [[calcitonin]] and other peptide substances. Familial medullary thyroid carcinoma which constitute approximately 25% of medullary thyroid cancer is genetic in nature, caused by a mutation in the [[RET proto-oncogene]]. When medullary thyroid carcinoma occurs by itself it is termed sporadic medullary thyroid carcinoma.
* It is characterized by consistent production of a hormonal [[marker]] called [[calcitonin]].
* Medullary carcinoma usually presents as a hard mass and is often accompanied by [[blood vessel]] invasion. Medullary thyroid cancer occurs in two forms, sporadic and familial. In the sporadic form, the tumor is usually unilateral. In the familial form, the [[tumor]] is almost always bilateral. In addition, the familial form may be associated with benign or malignant tumors of other endocrine organs, commonly referred to as the multiple endocrine neoplasia syndromes.
*[[Metastatic]] involvement may be seen in up to 50% at the time of presentation.
* In these syndromes, there is an association with [[pheochromocytoma]] of the [[adrenal gland]] and [[parathyroid]] hyperplasia. Medullary carcinoma usually secretes [[calcitonin]], a hormonal marker for the [[tumor]], and may be detectable in [[blood]] even when the tumor is clinically occult. [[Metastases]] to regional [[lymph nodes]] are found in about 50% of cases. [[Prognosis]] depends on extent of disease at presentation, presence or absence of regional [[lymph node]] metastases, and completeness of the surgical resection.
* Approximately 25% of reported cases of medullary thyroid carcinoma are familial.
* Family members should be screened for calcitonin elevation to identify individuals who are at risk of developing familial medullary thyroid cancer. Multiple endocrine neoplasia 2A gene carrier status can be more accurately determined by analysis of mutations in the [[RET protooncogene|''RET'' gene]]. All patients with medullary carcinoma of the thyroid (whether familial or sporadic) should be tested for ''RET'' mutations, and, if they are positive, family members should also be tested. Family members who are gene carriers should undergo prophylactic thyroidectomy at an early age.
*Hereditary medullary thyroid cancer is inherited as an [[autosomal dominant]] trait.
*In the familial form, the [[tumor]] is almost always [[bilateral]].  
*In addition, the familial form may be associated with [[benign]] or [[malignant tumors]] of other endocrine organs, commonly referred to as the [[multiple endocrine neoplasia]] syndromes.
*Familial medullary thyroid carcinoma syndromes include:<ref name="pmid25810047">{{cite journal |vauthors=Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG |title=Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma |journal=Thyroid |volume=25 |issue=6 |pages=567–610 |date=June 2015 |pmid=25810047 |pmc=4490627 |doi=10.1089/thy.2014.0335 |url=}}</ref>
*[[Multiple endocrine neoplasia type 2A]]
*[[Multiple endocrine neoplasia type 2B]]
*familial non-multiple endocrine neoplasia syndromes
* Medullary carcinoma usually presents as a hard mass and is often accompanied by [[blood vessel]] invasion.
*[[Metastases]] to regional [[lymph nodes]] are found in about 50% of cases.
 
==Genetics==
==Genetics==
* Mutations in the [[RET proto-oncogene|''RET'' proto-oncogene]] (REarranged during Transfection), located on chromosome 10, lead to the [[gene expression|expression]] of a mutated [[receptor tyrosine kinase]] protein. [[RET proto-oncogene|''RET'' proto-oncogene]] is involved in the regulation of cell growth and development and its germline mutation is responsible for nearly all cases of hereditary or familial medullary thyroid carcinoma. Germline mutation of [[RET proto-oncogene|''RET'']] may also be responsible for the development of [[hyperparathyroidism]] and [[pheochromocytoma]]. Hereditary medullary thyroid cancer is inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50% probability of inheriting the mutant [[RET proto-oncogene|''RET'']] from the affected parent. DNA analysis makes it possible to identify children who carry the mutant gene. Hereditary medullary thyroid carcinoma or multiple endocrine neoplasia ([[Multiple endocrine neoplasia type 2|MEN2]]) accounts for approximately 25% of all medullary thyroid carcinomas.
* Medullary thyroid cancer is [[Association (statistics)|associated]] with  [[RET proto-oncogene|''RET'' proto-oncogene]] [[mutations]].<ref name="pmid9506724">{{cite journal |vauthors=Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Höppner W |title=A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue=3 |pages=770–4 |date=March 1998 |pmid=9506724 |doi=10.1210/jcem.83.3.4619 |url=}}</ref>
* Seventy-five percent of medullary thyroid carcinoma occurs in individuals without an identifiable family history and is assigned the term "sporadic". Individuals who develop sporadic medullary thyroid carcinoma tend to be older and have more extensive disease at the time of initial presentation than those with a family history  (screening is likely to be initiated at an early age in the hereditary form). Approximately 25-60% of sporadic medullary thyroid carcinomas have a somatic mutation (one that occurs within a single "parafollicular" cell) of the [[RET proto-oncogene|''RET'']].
 
==Associated Conditions==
==Associated Conditions==
* [[ Von Hippel-Lindau Disease]]
* Medullary thyroid cancer may be [[Association (statistics)|associated]] with:<ref name="ErcolinoLai2014">{{cite journal|last1=Ercolino|first1=Tonino|last2=Lai|first2=Roberta|last3=Giachè|first3=Valentino|last4=Melchionda|first4=Salvatore|last5=Carella|first5=Massimo|last6=Delitala|first6=Alessandro|last7=Mannelli|first7=Massimo|last8=Fanciulli|first8=Giuseppe|title=Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes|journal=Gene|volume=536|issue=2|year=2014|pages=332–335|issn=03781119|doi=10.1016/j.gene.2013.12.003}}</ref><ref name="KochBrouwers2006">{{cite journal|last1=Koch|first1=Christian A|last2=Brouwers|first2=Frederieke M|last3=Vortmeyer|first3=Alexander O|last4=Tannapfel|first4=Andrea|last5=Libutti|first5=Steven K|last6=Zhuang|first6=Zhengping|last7=Pacak|first7=Karel|last8=Neumann|first8=Hartmut PH|last9=Paschke|first9=Ralf|title=Somatic VHLgene alterations in MEN2-associated medullary thyroid carcinoma|journal=BMC Cancer|volume=6|issue=1|year=2006|issn=1471-2407|doi=10.1186/1471-2407-6-131}}</ref><ref name="RaueFrank-Raue2015">{{cite journal|last1=Raue|first1=Friedhelm|last2=Frank-Raue|first2=Karin|title=Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma|volume=204|year=2015|pages=61–90|issn=0080-0015|doi=10.1007/978-3-319-22542-5_3}}</ref>
* [[Neurofibromatosis type 1]]
**[[MEN 2a|MEN2A]]
**[[MEN 2B|MEN2B]]
**[[Pheochromocytoma]]
**[[Parathyroid adenoma]]
** Cutaneous lichen [[amyloidosis]]
** Mucosal neuroma
**[[Von Hippel-Lindau Disease]]
**[[Neurofibromatosis type 1]]


==Gross Pathology==
==Gross Pathology==
* Medullary thyroid cancer is usually a well circumscribed, gray, white, or yellow colored mass which is gritty to firm in consistency.
* Medullary thyroid cancer is usually a well circumscribed, gray, white, or yellow colored mass which is gritty to firm in consistency.<ref name="HusainShukla2014">{{cite journal|last1=Husain|first1=Nuzhat|last2=Shukla|first2=Saumya|last3=Awasthi|first3=NamrataP|title=Papillary variant of medullary carcinoma thyroid|journal=Indian Journal of Pathology and Microbiology|volume=57|issue=1|year=2014|pages=151|issn=0377-4929|doi=10.4103/0377-4929.130933}}</ref>
 
==Microscopic Pathology==
==Microscopic Pathology==
* Microscopic features of medullary thyroid cancer is as follows:
* On microscopic [[histopathological]] analysis, presence of [[amyloid]] is a characteristic finding of medullary thyroid cancer.<ref name="pmid2654432">{{cite journal |vauthors=Nelkin BD, de Bustros AC, Mabry M, Baylin SB |title=The molecular biology of medullary thyroid carcinoma. A model for cancer development and progression |journal=JAMA |volume=261 |issue=21 |pages=3130–5 |date=June 1989 |pmid=2654432 |doi= |url=}}</ref><ref name="ValentaMichel-Bechet1977">{{cite journal|last1=Valenta|first1=Lubomir J.|last2=Michel-Bechet|first2=Marc|last3=Mattson|first3=Joan C.|last4=Singer|first4=Frederick R.|title=Microfollicular thyroid carcinoma with amyloid rich stroma, resembling the medullary carcinoma of the thyroid (MCT)|journal=Cancer|volume=39|issue=4|year=1977|pages=1573–1586|issn=0008-543X|doi=10.1002/1097-0142(197704)39:4<1573::AID-CNCR2820390433>3.0.CO;2-A}}</ref>
===Cytoplasm and Nuclei===
* Other microscopic features associated with the [[diagnosis]] of medullary thyroid cancer include:
:* Nested with delicate vascular septa
** The majority of [[tumor]] cells are epithelioid, but spindle cells may be found as well.
:* Trabecular cells
** The nuclei demonstrate the characteristic granular appearance known as salt-and-pepper.
:* Tubular/glandular, pseudo-papillary cells
** The [[cytoplasm]] of [[Tumor cell|tumor cells]]  contains perinuclear calcitonin-containing azurophilic granules that are best seen in samples stained with the May–Grünwald–Giemsa stain.
:* Polygonal to spindle to small cells
:* Amphophilic, somewhat granular cytoplasm
:* [[Interstitial edema]]
:* [[Stroma]] may have [[amyloid]] deposits with fluffy appearing acellular eosinophilic material in the [[cytoplasm]]
:* [[Stroma]] is vascular and can show hemorrhage, hyalinised collagen, oedema or metaplastic bone
:* Coarse calcification and [[Psammoma body|psammoma bodies]] may be present
:* Nuclei with neuroendocrine features
:* Small, round nuclei.
:* Coarse chromatin (salt and pepper nuclei)
 
===Surrounding Thyroid===
:* +/- C-cell hyperplasia - seen with familial forms of medullary thyroid carcinoma
:* C cells (AKA parafollicular cell): abundant cytoplasm - clear/pale
{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
{| {{table}} cellpadding="4" cellspacing="0" style="border:#c9c9c9 1px solid; margin: 1em 1em 1em 0; border-collapse: collapse;"
| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|''' Medullary thyroid cancer'''}}
| align="center" style="background: #4479BA;" | {{fontcolor|#FFF|''' Medullary thyroid cancer'''}}
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|[[File:Thyroid MedullaryCarcinoma SpindleCell LP2 PA.JPG|thumb|none|250px| H&E stain, high power. Contributed in wikimedia.commons]]
|[[File:Thyroid MedullaryCarcinoma SpindleCell LP2 PA.JPG|thumb|none|250px| H&E stain, high power. Contributed in wikimedia.commons]]
|}
|}
* For more images of medullary thyroid cancer please [[Medullary thyroid cancer biopsy|click here]]
==Immunohistochemistry==
*[[Marker|Markers]] associated with medullary throid cancers include:<ref name="NakazawaCameselle-Teijeiro2014">{{cite journal|last1=Nakazawa|first1=Tadao|last2=Cameselle-Teijeiro|first2=José|last3=Vinagre|first3=João|last4=Soares|first4=Paula|last5=Rousseau|first5=Emmanuel|last6=Eloy|first6=Catarina|last7=Sobrinho-Simões|first7=Manuel|title=C-Cell-Derived Calcitonin-Free Neuroendocrine Carcinoma of the Thyroid|journal=International Journal of Surgical Pathology|volume=22|issue=6|year=2014|pages=530–535|issn=1066-8969|doi=10.1177/1066896914525228}}</ref><ref name="MendelsohnWells1984">{{cite journal|last1=Mendelsohn|first1=Geoffrey|last2=Wells|first2=Samuel A.|last3=Baylin|first3=Stephen B.|title=Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and virulent disseminated stages of disease|journal=Cancer|volume=54|issue=4|year=1984|pages=657–662|issn=0008-543X|doi=10.1002/1097-0142(1984)54:4<657::AID-CNCR2820540412>3.0.CO;2-V}}</ref><ref name="pmid2654432">{{cite journal |vauthors=Nelkin BD, de Bustros AC, Mabry M, Baylin SB |title=The molecular biology of medullary thyroid carcinoma. A model for cancer development and progression |journal=JAMA |volume=261 |issue=21 |pages=3130–5 |date=June 1989 |pmid=2654432 |doi= |url=}}</ref>
**[[Calcitonin]]
** [[Chromogranin]]
** [[CEA]]
** Calcitonin gene-related peptide (CGRP)
** [[Somatostatin]]
** [[Serotonin]]
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 14:27, 1 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Overview

Development of medullary thyroid cancer is the result of genetic mutation of RET proto-oncogene. On gross pathology, well-circumscribed, gray, white, or yellow-colored masses are characteristic findings of medullary thyroid cancer. On microscopic histopathological analysis, polygonal to the spindle to small cells, interstitial edema, and vascular hyalinized stroma are characteristic findings of medullary thyroid cancer.

Pathogenesis

Genetics

Associated Conditions

Gross Pathology

  • Medullary thyroid cancer is usually a well circumscribed, gray, white, or yellow colored mass which is gritty to firm in consistency.[9]

Microscopic Pathology

  • On microscopic histopathological analysis, presence of amyloid is a characteristic finding of medullary thyroid cancer.[10][11]
  • Other microscopic features associated with the diagnosis of medullary thyroid cancer include:
    • The majority of tumor cells are epithelioid, but spindle cells may be found as well.
    • The nuclei demonstrate the characteristic granular appearance known as salt-and-pepper.
    • The cytoplasm of tumor cells contains perinuclear calcitonin-containing azurophilic granules that are best seen in samples stained with the May–Grünwald–Giemsa stain.
Medullary thyroid cancer Image Image
  • Medullary thyroid carcinoma
H&E stain, low power. Contributed in wikimedia.commons
H&E stain, high power. Contributed in wikimedia.commons
  • Medullary thyroid cancer amyloid
H&E stain, medium power. Contributed in wikimedia.commons
H&E stain, high power. Contributed in wikimedia.commons
  • Thyroid MedullaryCarcinoma Comedonecrosis
H&E stain, medium power. Contributed in wikimedia.commons
H&E stain, high power. Contributed in wikimedia.commons
  • Medullary thyroid carcinoma spindle cell
H&E stain, low power. Contributed in wikimedia.commons
H&E stain, medium power. Contributed in wikimedia.commons
  • Medullary thyroid carcinoma spindle cell
H&E stain, low power. Contributed in wikimedia.commons
H&E stain, high power. Contributed in wikimedia.commons
  • For more images of medullary thyroid cancer please click here

Immunohistochemistry

References

  1. ↑ Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. "Thyroid and Parathyroid Cancers" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  2. ↑ Wells, Samuel A.; Asa, Sylvia L.; Dralle, Henning; Elisei, Rossella; Evans, Douglas B.; Gagel, Robert F.; Lee, Nancy; Machens, Andreas; Moley, Jeffrey F.; Pacini, Furio; Raue, Friedhelm; Frank-Raue, Karin; Robinson, Bruce; Rosenthal, M. Sara; Santoro, Massimo; Schlumberger, Martin; Shah, Manisha; Waguespack, Steven G. (2015). "Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma". Thyroid. 25 (6): 567–610. doi:10.1089/thy.2014.0335. ISSN 1050-7256.
  3. ↑ Gertner ME, Kebebew E (August 2004). "Multiple endocrine neoplasia type 2". Curr Treat Options Oncol. 5 (4): 315–25. PMID 15233908.
  4. ↑ Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG (June 2015). "Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma". Thyroid. 25 (6): 567–610. doi:10.1089/thy.2014.0335. PMC 4490627. PMID 25810047.
  5. ↑ Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Höppner W (March 1998). "A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A". J. Clin. Endocrinol. Metab. 83 (3): 770–4. doi:10.1210/jcem.83.3.4619. PMID 9506724.
  6. ↑ Ercolino, Tonino; Lai, Roberta; Giachè, Valentino; Melchionda, Salvatore; Carella, Massimo; Delitala, Alessandro; Mannelli, Massimo; Fanciulli, Giuseppe (2014). "Patient affected by neurofibromatosis type 1 and thyroid C-cell hyperplasia harboring pathogenic germ-line mutations in both NF1 and RET genes". Gene. 536 (2): 332–335. doi:10.1016/j.gene.2013.12.003. ISSN 0378-1119.
  7. ↑ Koch, Christian A; Brouwers, Frederieke M; Vortmeyer, Alexander O; Tannapfel, Andrea; Libutti, Steven K; Zhuang, Zhengping; Pacak, Karel; Neumann, Hartmut PH; Paschke, Ralf (2006). "Somatic VHLgene alterations in MEN2-associated medullary thyroid carcinoma". BMC Cancer. 6 (1). doi:10.1186/1471-2407-6-131. ISSN 1471-2407.
  8. ↑ Raue, Friedhelm; Frank-Raue, Karin (2015). "Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma". 204: 61–90. doi:10.1007/978-3-319-22542-5_3. ISSN 0080-0015.
  9. ↑ Husain, Nuzhat; Shukla, Saumya; Awasthi, NamrataP (2014). "Papillary variant of medullary carcinoma thyroid". Indian Journal of Pathology and Microbiology. 57 (1): 151. doi:10.4103/0377-4929.130933. ISSN 0377-4929.
  10. ↑ 10.0 10.1 Nelkin BD, de Bustros AC, Mabry M, Baylin SB (June 1989). "The molecular biology of medullary thyroid carcinoma. A model for cancer development and progression". JAMA. 261 (21): 3130–5. PMID 2654432.
  11. ↑ Valenta, Lubomir J.; Michel-Bechet, Marc; Mattson, Joan C.; Singer, Frederick R. (1977). "Microfollicular thyroid carcinoma with amyloid rich stroma, resembling the medullary carcinoma of the thyroid (MCT)". Cancer. 39 (4): 1573–1586. doi:10.1002/1097-0142(197704)39:4<1573::AID-CNCR2820390433>3.0.CO;2-A. ISSN 0008-543X.
  12. ↑ Nakazawa, Tadao; Cameselle-Teijeiro, José; Vinagre, João; Soares, Paula; Rousseau, Emmanuel; Eloy, Catarina; Sobrinho-Simões, Manuel (2014). "C-Cell-Derived Calcitonin-Free Neuroendocrine Carcinoma of the Thyroid". International Journal of Surgical Pathology. 22 (6): 530–535. doi:10.1177/1066896914525228. ISSN 1066-8969.
  13. ↑ Mendelsohn, Geoffrey; Wells, Samuel A.; Baylin, Stephen B. (1984). "Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and virulent disseminated stages of disease". Cancer. 54 (4): 657–662. doi:10.1002/1097-0142(1984)54:4<657::AID-CNCR2820540412>3.0.CO;2-V. ISSN 0008-543X.


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