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{{Multiple endocrine neoplasia type 2}}
{{Multiple endocrine neoplasia type 2}}
{{CMG}}; {{AE}} {{Ammu}}
{{CMG}}; {{AE}} {{Ammu}}
==Overview==
==Overview==
[[Surgery operation|Surgery]] is the mainstay of treatment for multiple endocrine neoplasia type 2. Management of multiple endocrine neoplasia type 2 [[Patient|patients]] includes [[thyroidectomy]] including [[cervical]], central, and [[bilateral]] [[lymph node]]s dissection for [[medullary thyroid carcinoma]], unilateral [[adrenalectomy]] for unilateral [[pheochromocytoma]] or bilateral [[adrenalectomy]] when both [[gland]]s are involved, and selective resection of pathologic [[parathyroid gland]]s for [[primary hyperparathyroidism]].
==Surgery==
==Surgery==
Management of multiple endocrine neoplasia type 2 patients includes thyroidectomy including cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.
Management of multiple endocrine neoplasia type 2 [[Patient|patients]] includes [[thyroidectomy]] including [[cervical]], central, and [[bilateral]] [[lymph node]]s dissection for [[medullary thyroid carcinoma]], unilateral [[adrenalectomy]] for unilateral [[pheochromocytoma]] or bilateral [[adrenalectomy]] when both [[gland]]s are involved, and selective resection of pathologic [[parathyroid gland]]s for [[primary hyperparathyroidism]].
===Medullary Thyroid Cancer===
===Medullary Thyroid Cancer===
====Conventional Therapy====
* The treatment of choice for primary [[medullary thyroid carcinoma]], both sporadic or [[hereditary]], is total [[thyroidectomy]] with [[Systematics|systematic]] [[Dissection (medical)|dissection]] of all [[lymph node]]s of the central compartment. Total [[thyroidectomy]] is necessary as [[medullary thyroid carcinoma]] is multicentric in 65–90% of [[Patient|patients]] in multiple endocrine neoplasia type 2 and extensive central [[lymph node]] [[Dissection (medical)|dissection]] has been reported to improve survival and recurrence rates compared to less aggressive procedures. [[Lymph node]] dissection of laterocervical compartments is not performed on principle but only when the neck [[ultrasound]] suggests the presence of [[Metastatic Cancer of Unknown Primary Site|metastatic]] nodes.<ref name="pmid17665245">{{cite journal| author=Machens A, Hauptmann S, Dralle H| title=Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer. | journal=World J Surg | year= 2007 | volume= 31 | issue= 10 | pages= 1960-5 | pmid=17665245 | doi=10.1007/s00268-007-9185-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17665245  }}</ref><ref name="pmid6128962">{{cite journal| author=Russell CF, Van Heerden JA, Sizemore GW, Edis AJ, Taylor WF, ReMine WH et al.| title=The surgical management of medullary thyroid carcinoma. | journal=Ann Surg | year= 1983 | volume= 197 | issue= 1 | pages= 42-8 | pmid=6128962 | doi= | pmc=PMC1352852 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6128962  }} </ref><ref name="AnZhang2017">{{cite journal|last1=An|first1=Changming|last2=Zhang|first2=Xiwei|last3=Wang|first3=Shixu|last4=Zhang|first4=Zongmin|last5=Yin|first5=Yulin|last6=Xu|first6=Zhengang|last7=Tang|first7=Pingzhang|last8=Li|first8=Zhengjiang|title=Efficacy of Superselective Neck Dissection in Detecting Metastasis in Patients with cN0 Papillary Thyroid Carcinoma at High Risk of Lateral Neck Metastasis|journal=Medical Science Monitor|volume=23|year=2017|pages=2118–2126|issn=1643-3750|doi=10.12659/MSM.900273}}</ref>
* [[Endoscopic]] adrenal-sparing [[surgery]] has become the method of choice for the [[Surgery operation|surgical therapy]] of [[pheochromocytoma]].<ref name="pmid18784938">{{cite journal| author=Walz MK, Alesina PF| title=Single access retroperitoneoscopic adrenalectomy (SARA)--one step beyond in endocrine surgery. | journal=Langenbecks Arch Surg | year= 2009 | volume= 394 | issue= 3 | pages= 447-50 | pmid=18784938 | doi=10.1007/s00423-008-0418-z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18784938  }} </ref>
* Among [[Patient|patients]] with an asynchronous development of [[pheochromocytoma]], the [[adrenal gland]] without [[pheochromocytoma]] can be preserved, but the [[patient]] must be aware that the probability to repeat the surgical treatment in the near future is very high. The advantage of a unilateral [[adrenal]] [[surgery]] is the possibility to avoid substitute [[therapy]] until the second [[surgery]] is performed.<ref name="pmid18784938" />
* The [[parathyroid gland]]s are frequently found to be enlarged at the time of the [[thyroidectomy]] for [[medullary thyroid carcinoma]] and should, therefore, be carefully evaluated. The goal in multiple endocrine neoplasia type 2 patients with [[primary hyperparathyroidism]] (PHPT) is to excise the enlarged [[gland]]s and to leave at least one apparently normal [[parathyroid]] [[gland]] intact. If all [[gland]]s are enlarged, a subtotal [[parathyroidectomy]] or total [[parathyroidectomy]] with [[autotransplantation]] should be performed.


====Prophylactic or Precocious Thyroidectomy in RET Gene Carrier====
====Prophylactic or Precocious Thyroidectomy in RET Gene Carrier====
* Prophylactic thyroidectomy is advised in gene carriers to guarantee a definitive cure in these subjects. Four different risk levels (from A, the lowest, to D the highest) for RET mutations have been suggested by the American Thyroid Association task force, which developed the most recent guidelines for the management of MTC patients.<ref name="pmid19469690">{{cite journal| author=American Thyroid Association Guidelines Task Force. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF et al.| title=Medullary thyroid cancer: management guidelines of the American Thyroid Association. | journal=Thyroid | year= 2009 | volume= 19 | issue= 6 | pages= 565-612 | pmid=19469690 | doi=10.1089/thy.2008.0403 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19469690  }} </ref> According to these guidelines, these levels of risk, which are related to the clinical aggressiveness of the corresponding MTC, should be taken into consideration when planning surgical treatment. In particular patients with a level D, RET mutation (i.e., Met918Thr) should be treated as soon as possible in the first year of life; patients with level B and C mutations (located in exons 10, 11, 13, 14, and 15) should be operated on before 5 years of age; only for patients with a level A mutation (exon 8 and 5 mutations), total thyroidectomy can be delayed after five years of age or until the CT positivity.
* [[Prophylactic]] [[thyroidectomy]] is advised in [[gene]] carriers to guarantee a definitive cure in these subjects.  
* Recently, some evidences in big series of RET gene carriers demonstrated that gene carriers with undetectable levels of basal CT have an almost null risk to have already developed the MTC.<ref name="pmid19801688">{{cite journal| author=Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK et al.| title=Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing. | journal=Hong Kong Med J | year= 2009 | volume= 15 | issue= 5 | pages= 326-31 | pmid=19801688 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19801688  }} </ref><ref name="pmidhttp://dx.doi.org/10.1210/jc.2010-1234">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1210/jc.2010-1234 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref> Moreover, a serum Ct <30–40 pg/mL is always associated to an intrathyroidal micro-MTC without any evidence of lymph node metastases. Taking into account these observation, Elisei et al. <ref name="pmidhttp://dx.doi.org/10.1210/jc.2011-2046">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=http://dx.doi.org/10.1210/jc.2011-2046 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }} </ref> designed a study in which they operated on only RET gene carriers on the basis of basal and stimulated CT. According to their results, the time of surgical treatment could be personalized and safely planned when the stimulated serum CT becomes positive at the annual control, independently from the type of RET mutation and its associated level of risk. Of course, both cysteine RET mutations and older age are risk factors for having an earlier positive result for either basal or Pg-stimulated serum CT. For these reasons, the follow-up controls should be more or less frequent in cysteine or noncysteine RET-mutated gene carriers, respectively. This strategy obviously implies a high compliance of theRET gene carriers to the scheduled followup with the advantage that young children can be treated later, sometime even after the puberty, close to the adulthood.
* In 1999, during the Seventh International Multiple Endocrine Neoplasia Meeting in Gubbio, the risk of [[MTC]] has been stratified in three [[categories]] according to the [[Mutation|mutations]] of c-''[[RET gene|RET]]'' as following:
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
|+'''''Prophylactic Thyroidectomy'''''
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Gene}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Risk}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Treatment}}
|-
! style="background: #F5F5F5;" | Children with MEN2B and/or c-RET codon 883, 918,
922<ref name="MariniFalchetti2006">{{cite journal|last1=Marini|first1=Francesca|last2=Falchetti|first2=Alberto|last3=Del Monte|first3=Francesca|last4=Carbonell Sala|first4=Silvia|last5=Tognarini|first5=Isabella|last6=Luzi|first6=Ettore|last7=Brandi|first7=Maria|journal=Orphanet Journal of Rare Diseases|volume=1|issue=1|year=2006|pages=45|issn=17501172|doi=10.1186/1750-1172-1-45}}</ref>
! style="background: #F5F5F5;" | Highest risk of aggressive [[medullary thyroid carcinoma]]
! style="background: #F5F5F5;" |  Total [[thyroidectomy]] with
central node dissection, within the first six months.
|-
! style="background: #F5F5F5;" | Children with any c-[[RET gene|RET]] [[Genetic code|codon]] 611, 618, 620 or 634
[[Mutation|mutations]]<ref name="WellsPacini2013">{{cite journal|last1=Wells|first1=Samuel A.|last2=Pacini|first2=Furio|last3=Robinson|first3=Bruce G.|last4=Santoro|first4=Massimo|title=Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update|journal=The Journal of Clinical Endocrinology & Metabolism|volume=98|issue=8|year=2013|pages=3149–3164|issn=0021-972X|doi=10.1210/jc.2013-1204}}</ref>
! style="background: #F5F5F5;" | High risk of [[medullary thyroid carcinoma]]
! style="background: #F5F5F5;" |  Total [[thyroidectomy]] should be performed before age of
five years, with or without [[central]] node [[Dissection (medical)|dissection]].
|-
! style="background: #F5F5F5;" | Children with c-[[RET gene|RET]] [[Genetic code|codon]] 609, 768, 790, 791, 804
and 891 [[Mutation|mutations]]<ref name="İmge AydoğanYüksel2016">{{cite journal|last1=İmge Aydoğan|first1=Berna|last2=Yüksel|first2=Bağdagül|last3=Tuna|first3=Mazhar Müslüm|last4=Navdar Başaran|first4=Mehtap|last5=Akkurt Kocaeli|first5=Ayşen|last6=Ertörer|first6=Melek Eda|last7=Aydın|first7=Kadriye|last8=Güldiken|first8=Sibel|last9=Şimşek|first9=Yasin|last10=Cihan Karaca|first10=Züleyha|last11=Yılmaz|first11=Merve|last12=Aktürk|first12=Müjde|last13=Anaforoğlu|first13=İnan|last14=Kebapçı|first14=Nur|last15=Duran|first15=Cevdet|last16=Taşlıpınar|first16=Abdullah|last17=Kulaksızoğlu|first17=Mustafa|last18=Gürsoy|first18=Alptekin|last19=Dağdelen|first19=Selçuk|last20=Erdoğan|first20=Murat Faik|title=Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey|journal=Journal of Clinical Research in Pediatric Endocrinology|volume=8|issue=1|year=2016|pages=13–20|issn=13085727|doi=10.4274/jcrpe.2219}}</ref>
! style="background: #F5F5F5;" | Less aggressive and slowly growing [[medullary thyroid carcinoma]]
! style="background: #F5F5F5;" |  Operated at a later stage
|}
* Recently, some evidences in big series of [[RET gene|''RET'' gene]] carriers demonstrated that [[gene]] carriers with undetectable levels of basal [[calcitonin]] (Ct) have an almost null risk to have already developed the [[medullary thyroid carcinoma]].<ref name="pmid19801688">{{cite journal| author=Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK et al.| title=Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing. | journal=Hong Kong Med J | year= 2009 | volume= 15 | issue= 5 | pages= 326-31 | pmid=19801688 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19801688  }} </ref><ref>Prognostic Factors of Disease-Free Survival after Thyroidectomy in 170 Young Patients with a RET Germline Mutation: A Multicenter Study of the Groupe Français d'Etude des Tumeurs Endocrines. Endocrine Society (30.09,2015)http://press.endocrine.org/doi/abs/10.1210/jc.2010-1234 accessed on October, 2015</ref>
* Moreover, a [[serum]] Ct <30–40 pg/mL is always associated to an intrathyroidal micro-[[medullary thyroid carcinoma]] without any evidence of [[lymph node]] [[metastases]]. Moreover, a serum Ct <30–40 pg/mL is always associated to an intrathyroidal [[Micro-|micro]][[Medullary carcinoma of the thyroid|-medullary thyroid carcinoma]] without any evidence of [[lymph node]] [[metastases]].
* The following flowchart depicts the surgical management of [[medullary thyroid cancer]]:
[[File:Medullary thyroid cancer.png|thumb|center|500px|ESMO clinical practice guidelines for treatment of medullary cell carcinoma]]
[[File:Medullary thyroid cancer.png|thumb|center|500px|ESMO clinical practice guidelines for treatment of medullary cell carcinoma]]
=====Post Surgery=====
=====Post Surgery=====
* Thyroid should supplemented be supplemented for patients undergoing total thyroidectomy.<ref name="pmid22997443">{{cite journal| author=Pacini F, Castagna MG, Brilli L, Pentheroudakis G, ESMO Guidelines Working Group| title=Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2012 | volume= 23 Suppl 7 | issue=  | pages= vii110-9 | pmid=22997443 | doi=10.1093/annonc/mds230 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22997443  }} </ref>
* [[Thyroxine]] should be supplemented for patients undergoing total [[thyroidectomy]].<ref name="pmid22997443">{{cite journal| author=Pacini F, Castagna MG, Brilli L, Pentheroudakis G, ESMO Guidelines Working Group| title=Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2012 | volume= 23 Suppl 7 | issue=  | pages= vii110-9 | pmid=22997443 | doi=10.1093/annonc/mds230 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22997443  }} </ref>
* Serum calcitonin and CEA DT are measured during post surgical follow-up.
*[[Serum]] [[calcitonin]] and [[carcinoembryonic antigen]] doubling time (CEA DT) are measured during post surgical follow-up.
* Provacative pentagastrin or calcium test is administered and serum calcitonin level is measured.
* Provacative [[pentagastrin]] or [[calcium]] test is administered and [[serum]] [[calcitonin]] level is measured.
* If there is no significant elevation in serum calcitonin level, serum calcitonin is measured every 6 months for 2-3 years and then yearly.
* If there is no significant elevation in serum [[calcitonin]] level, [[serum]] [[calcitonin]] is measured every 6 months for 2-3 years and then yearly.
* If the calcitonin is below 150 pg/ml, USG neck is recommended.
* If the [[calcitonin]] is below 150 pg/ml, [[Ultrasound-enhanced systemic thrombolysis|ultrasound]] [[neck]] is recommended.
* If the basal serum calcitonin is above 150 pg/ml, screening for distant metastasis is recommeneded.
* If the basal [[serum]] [[calcitonin]] is above 150 pg/ml, screening for distant [[metastasis]] is recommended.
* The following flowchart depicts the post [[Surgery|surgical]] management of [[medullary thyroid cancer]]:
[[File:Post surgical follow up MEN 2.png|thumb|center|500px|ESMO clinical practice guidelines for treatment of medullary cell carcinoma]]
 
==References==
{{reflist|2}}
 
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Latest revision as of 11:50, 21 June 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

Surgery is the mainstay of treatment for multiple endocrine neoplasia type 2. Management of multiple endocrine neoplasia type 2 patients includes thyroidectomy including cervical, central, and bilateral lymph nodes dissection for medullary thyroid carcinoma, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.

Surgery

Management of multiple endocrine neoplasia type 2 patients includes thyroidectomy including cervical, central, and bilateral lymph nodes dissection for medullary thyroid carcinoma, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for primary hyperparathyroidism.

Medullary Thyroid Cancer

Conventional Therapy

Prophylactic or Precocious Thyroidectomy in RET Gene Carrier

  • Prophylactic thyroidectomy is advised in gene carriers to guarantee a definitive cure in these subjects.
  • In 1999, during the Seventh International Multiple Endocrine Neoplasia Meeting in Gubbio, the risk of MTC has been stratified in three categories according to the mutations of c-RET as following:
Prophylactic Thyroidectomy
Gene Risk Treatment
Children with MEN2B and/or c-RET codon 883, 918,

922[5]

Highest risk of aggressive medullary thyroid carcinoma Total thyroidectomy with

central node dissection, within the first six months.

Children with any c-RET codon 611, 618, 620 or 634

mutations[6]

High risk of medullary thyroid carcinoma Total thyroidectomy should be performed before age of

five years, with or without central node dissection.

Children with c-RET codon 609, 768, 790, 791, 804

and 891 mutations[7]

Less aggressive and slowly growing medullary thyroid carcinoma Operated at a later stage
ESMO clinical practice guidelines for treatment of medullary cell carcinoma
Post Surgery
ESMO clinical practice guidelines for treatment of medullary cell carcinoma

References

  1. ↑ Machens A, Hauptmann S, Dralle H (2007). "Increased risk of lymph node metastasis in multifocal hereditary and sporadic medullary thyroid cancer". World J Surg. 31 (10): 1960–5. doi:10.1007/s00268-007-9185-1. PMID 17665245.
  2. ↑ Russell CF, Van Heerden JA, Sizemore GW, Edis AJ, Taylor WF, ReMine WH; et al. (1983). "The surgical management of medullary thyroid carcinoma". Ann Surg. 197 (1): 42–8. PMC 1352852. PMID 6128962.
  3. ↑ An, Changming; Zhang, Xiwei; Wang, Shixu; Zhang, Zongmin; Yin, Yulin; Xu, Zhengang; Tang, Pingzhang; Li, Zhengjiang (2017). "Efficacy of Superselective Neck Dissection in Detecting Metastasis in Patients with cN0 Papillary Thyroid Carcinoma at High Risk of Lateral Neck Metastasis". Medical Science Monitor. 23: 2118–2126. doi:10.12659/MSM.900273. ISSN 1643-3750.
  4. ↑ 4.0 4.1 Walz MK, Alesina PF (2009). "Single access retroperitoneoscopic adrenalectomy (SARA)--one step beyond in endocrine surgery". Langenbecks Arch Surg. 394 (3): 447–50. doi:10.1007/s00423-008-0418-z. PMID 18784938.
  5. ↑ Marini, Francesca; Falchetti, Alberto; Del Monte, Francesca; Carbonell Sala, Silvia; Tognarini, Isabella; Luzi, Ettore; Brandi, Maria (2006). Orphanet Journal of Rare Diseases. 1 (1): 45. doi:10.1186/1750-1172-1-45. ISSN 1750-1172. Missing or empty |title= (help)
  6. ↑ Wells, Samuel A.; Pacini, Furio; Robinson, Bruce G.; Santoro, Massimo (2013). "Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update". The Journal of Clinical Endocrinology & Metabolism. 98 (8): 3149–3164. doi:10.1210/jc.2013-1204. ISSN 0021-972X.
  7. ↑ İmge Aydoğan, Berna; Yüksel, Bağdagül; Tuna, Mazhar Müslüm; Navdar Başaran, Mehtap; Akkurt Kocaeli, Ayşen; Ertörer, Melek Eda; Aydın, Kadriye; Güldiken, Sibel; Şimşek, Yasin; Cihan Karaca, Züleyha; Yılmaz, Merve; Aktürk, Müjde; Anaforoğlu, İnan; Kebapçı, Nur; Duran, Cevdet; Taşlıpınar, Abdullah; Kulaksızoğlu, Mustafa; Gürsoy, Alptekin; Dağdelen, Selçuk; Erdoğan, Murat Faik (2016). "Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey". Journal of Clinical Research in Pediatric Endocrinology. 8 (1): 13–20. doi:10.4274/jcrpe.2219. ISSN 1308-5727.
  8. ↑ Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK; et al. (2009). "Prophylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing". Hong Kong Med J. 15 (5): 326–31. PMID 19801688.
  9. ↑ Prognostic Factors of Disease-Free Survival after Thyroidectomy in 170 Young Patients with a RET Germline Mutation: A Multicenter Study of the Groupe Français d'Etude des Tumeurs Endocrines. Endocrine Society (30.09,2015)http://press.endocrine.org/doi/abs/10.1210/jc.2010-1234 accessed on October, 2015
  10. ↑ Pacini F, Castagna MG, Brilli L, Pentheroudakis G, ESMO Guidelines Working Group (2012). "Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Ann Oncol. 23 Suppl 7: vii110–9. doi:10.1093/annonc/mds230. PMID 22997443.


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