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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Research Article

Molecular Diagnosis and Treatment of Multiple Endocrine Neoplasia Type 2B in Ethnic Han Chinese

Author(s): Zhe-Wei Zhang, Xiao Guo* and Xiao-Ping Qi*

Volume 21, Issue 3, 2021

Published on: 10 September, 2020

Page: [534 - 543] Pages: 10

DOI: 10.2174/1871530320666200910112230

Price: $65

Abstract

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed.

Methods: This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported.

Results: All 5 patients initially presented MTC, but none had biochemically cured postoperatively. 2 also presented bilateral PHEO after adrenal-sparing surgery, 1 needed steroid replacement. Further, a total of 32 MEN 2B patients from literature were clustered with 28 available for analysis. 26 (92.8%) were diagnosed by endocrine-related symptoms; the remaining 2 (7.2%) due to RET testing and oral symptoms, respectively. 25 patients underwent thyroidectomy with/without neck lymph node dissection at the mean age of (23.3 ± 10.4) years. Histopathological examination revealed MTC (100%). Of them, 17 had definite TNM stage, with 1 in stage III and others in IV. Other information of MEN 2B-related symptoms included penetrance of PHEO (60.7%), constipation (32.1%), Hirschsprung disease (25%), alacrima (17.8%), mucosal ganglioneuroma (96.4%) and marfanoid habitus (71.4%). 19 patients were verified harboring RET-M918T (c.2753T>C), of whom 15 (78.9%) were de novo mutation. The other 9 were clinically diagnosed as MEN 2B.

Discussion & Conclusion: The initial diagnosis of MEN 2B is relatively later, and diagnosed by non-endocrine components is extremely lower. Recognition of MEN 2B and its non-endocrine-related components is still the utmost requirement for a Chinese physician. Combined RET screening and serum calcitonin detection can facilitate early diagnosis.

Keywords: Multiple endocrine neoplasia type 2B, medullary thyroid carcinoma, extra-endocrine signs, RET proto-oncogene, M918T mutation, Chinese.

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[1]
Mulligan, L.M.; Kwok, J.B.; Healey, C.S.; Elsdon, M.J.; Eng, C.; Gardner, E.; Love, D.R.; Mole, S.E.; Moore, J.K.; Papi, L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature, 1993, 363(6428), 458-460.
[http://dx.doi.org/10.1038/363458a0] [PMID: 8099202]
[2]
Treglia, G.; Aktolun, C.; Chiti, A.; Frangos, S.; Giovanella, L.; Hoffmann, M.; Iakovou, I.; Mihailovic, J.; Krause, B.J.; Langsteger, W.; Verburg, F.A.; Luster, M. EANM and the EANM Thyroid Committee. The 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma: the “evidence-based” refusal to endorse them by EANM due to the “not evidence-based” marginalization of the role of nuclear medicine. Eur. J. Nucl. Med. Mol. Imaging, 2016, 43(8), 1486-1490.
[http://dx.doi.org/10.1007/s00259-016-3404-7] [PMID: 27118126]
[3]
Wells, S. A., Jr; Asa, S. L.; Dralle, H.; Elisei, R.; Evans, D. B.; Gagel, R. F.; Lee, N.; Machens, A.; Moley, J. F.; Pacini, F.; Raue, F.; Frank-Raue, K.; Robinson, B.; Rosenthal, M. S.; Santoro, M.; Schlumberger, M.; Shah, M.; Waguespack, S. G. American Thyroid Association Guidelines Task Force on Medullary Thyroid C. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 2015, 25(6), 567-610.
[http://dx.doi.org/10.1089/thy.2014.0335] [PMID: 25810047]
[4]
Eng, C.; Smith, D.P.; Mulligan, L.M.; Nagai, M.A.; Healey, C.S.; Ponder, M.A.; Gardner, E.; Scheumann, G.F.; Jackson, C.E.; Tunnacliffe, A. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum. Mol. Genet., 1994, 3(2), 237-241.
[http://dx.doi.org/10.1093/hmg/3.2.237] [PMID: 7911697]
[5]
Castinetti, F.; Moley, J.; Mulligan, L.; Waguespack, S.G. A comprehensive review on MEN2B. Endocr. Relat. Cancer, 2018, 25(2), T29-T39.
[http://dx.doi.org/10.1530/ERC-17-0209] [PMID: 28698189]
[6]
Grey, J.; Winter, K. Patient quality of life and prognosis in multiple endocrine neoplasia type 2. Endocr. Relat. Cancer, 2018, 25(2), T69-T77.
[http://dx.doi.org/10.1530/ERC-17-0335] [PMID: 29066504]
[7]
Wells, S.A., Jr Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors. Endocr. Relat. Cancer, 2018, 25(2), T1-T13.
[http://dx.doi.org/10.1530/ERC-17-0325] [PMID: 29142004]
[8]
Eng, C.; Clayton, D.; Schuffenecker, I.; Lenoir, G.; Cote, G.; Gagel, R.F.; van Amstel, H.K.; Lips, C.J.; Nishisho, I.; Takai, S.I.; Marsh, D.J.; Robinson, B.G.; Frank-Raue, K.; Raue, F.; Xue, F.; Noll, W.W.; Romei, C.; Pacini, F.; Fink, M.; Niederle, B.; Zedenius, J.; Nordenskjöld, M.; Komminoth, P.; Hendy, G.N.; Mulligan, L.M. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA, 1996, 276(19), 1575-1579.
[http://dx.doi.org/10.1001/jama.1996.03540190047028] [PMID: 8918855]
[9]
Jasim, S.; Ying, A. K.; Waguespack, S. G.; Rich, T. A.; Grubbs, E. G.; Jimenez, C.; Hu, M. I.; Cote, G.; Habra, M. A. Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid, 2011, 21(2), 189-192.
[http://dx.doi.org/10.1089/thy.2010.0328] [PMID: 21186952]
[10]
Qi, X.P.; Peng, J.Z.; Yang, X.W.; Zao, Z.L.; Yu, X.H.; Fang, X.D.; Zhang, D.H.; Zhao, J.Q. The RET C611Y mutation causes MEN 2A and associated cutaneous. Endocr. Connect., 2018, 7(9), 998-1005.
[http://dx.doi.org/10.1530/EC-18-0220] [PMID: 30300539]
[11]
Edge, S.B.; Compton, C.C. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM In: Annals of surgical oncology; , 2010; 17, pp. 1471-1474.
[12]
Brauckhoff, M.; Machens, A.; Lorenz, K.; Bjøro, T.; Varhaug, J.E.; Dralle, H. Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective. Ann. Surg., 2014, 259(4), 800-806.
[http://dx.doi.org/10.1097/SLA.0b013e3182a6f43a] [PMID: 23979292]
[13]
Qi, X.P.; Zhao, J.Q.; Cao, Z.L.; Fu, E.; Li, F.; Zhao, Y.H.; Wang, G.P.; Li, P.F.; Ma, W.L.; Guo, J.; Jia, H. The clinical spectrum of multiple endocrine neoplasia type 2A with cutaneous lichen amyloidosis in Ethnic Han Chinese. Cancer Invest., 2018, 36(2), 141-151.
[http://dx.doi.org/10.1080/07357907.2018.1430813] [PMID: 29420094]
[14]
Gallagher, T.M.; Bucciarelli, M.; Kavalukas, S.L.; Baker, M.J.; Saunders, B.D. Attitudes toward genetic counseling and testing in patients with inherited endocrinopathies. Endocr. Pract., 2017, 23(9), 1039-1044.
[http://dx.doi.org/10.4158/EP171875.OR] [PMID: 28613942]
[15]
Griebeler, M. L.; Gharib, H.; Thompson, G. B. Medullary thyroid carcinoma Endocr. Pract., 2013, 19(4), 703-711.
[http://dx.doi.org/10.4158/EP12430.RA]
[16]
Makri, A.; Akshintala, S.; Derse-Anthony, C.; Del Rivero, J.; Widemann, B.; Stratakis, C.A.; Glod, J.; Lodish, M. Pheochromocytoma in children and adolescents with multiple endocrine neoplasia type 2B. J. Clin. Endocrinol. Metab., 2019, 104(1), 7-12.
[http://dx.doi.org/10.1210/jc.2018-00705] [PMID: 30113649]
[17]
Castinetti, F.; Waguespack, S.G.; Machens, A.; Uchino, S.; Hasse-Lazar, K.; Sanso, G.; Else, T.; Dvorakova, S.; Qi, X.P.; Elisei, R.; Maia, A.L.; Glod, J.; Lourenço, D.M., Jr; Valdes, N.; Mathiesen, J.; Wohllk, N.; Bandgar, T.R.; Drui, D.; Korbonits, M.; Druce, M.R.; Brain, C.; Kurzawinski, T.; Patocs, A.; Bugalho, M.J.; Lacroix, A.; Caron, P.; Fainstein-Day, P.; Borson Chazot, F.; Klein, M.; Links, T.P.; Letizia, C.; Fugazzola, L.; Chabre, O.; Canu, L.; Cohen, R.; Tabarin, A.; Spehar Uroic, A.; Maiter, D.; Laboureau, S.; Mian, C.; Peczkowska, M.; Sebag, F.; Brue, T.; Mirebeau-Prunier, D.; Leclerc, L.; Bausch, B.; Berdelou, A.; Sukurai, A.; Vlcek, P.; Krajewska, J.; Barontini, M.; Vaz Ferreira Vargas, C.; Valerio, L.; Ceolin, L.; Akshintala, S.; Hoff, A.; Godballe, C.; Jarzab, B.; Jimenez, C.; Eng, C.; Imai, T.; Schlumberger, M.; Grubbs, E.; Dralle, H.; Neumann, H.P.; Baudin, E. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol., 2019, 7(3), 213-220.
[http://dx.doi.org/10.1016/S2213-8587(18)30336-X] [PMID: 30660595]
[18]
Raue, F.; Dralle, H.; Machens, A.; Bruckner, T.; Frank-Raue, K. Long-term survivorship in multiple endocrine neoplasia type 2B diagnosed before and in the new millennium. J. Clin. Endocrinol. Metab., 2018, 103(1), 235-243.
[http://dx.doi.org/10.1210/jc.2017-01884] [PMID: 29077903]
[19]
Priya, S.R.; Dravid, C.S.; Digumarti, R.; Dandekar, M. Targeted therapy for medullary thyroid cancer: A review. Front. Oncol., 2017, 7, 238.
[http://dx.doi.org/10.3389/fonc.2017.00238] [PMID: 29057215]
[20]
Castinetti, F.; Qi, X.P.; Walz, M.K.; Maia, A.L.; Sansó, G.; Peczkowska, M.; Hasse-Lazar, K.; Links, T.P.; Dvorakova, S.; Toledo, R.A.; Mian, C.; Bugalho, M.J.; Wohllk, N.; Kollyukh, O.; Canu, L.; Loli, P.; Bergmann, S.R.; Biarnes Costa, J.; Makay, O.; Patocs, A.; Pfeifer, M.; Shah, N.S.; Cuny, T.; Brauckhoff, M.; Bausch, B.; von Dobschuetz, E.; Letizia, C.; Barczynski, M.; Alevizaki, M.K.; Czetwertynska, M.; Ugurlu, M.U.; Valk, G.; Plukker, J.T.; Sartorato, P.; Siqueira, D.R.; Barontini, M.; Szperl, M.; Jarzab, B.; Verbeek, H.H.; Zelinka, T.; Vlcek, P.; Toledo, S.P.; Coutinho, F.L.; Mannelli, M.; Recasens, M.; Demarquet, L.; Petramala, L.; Yaremchuk, S.; Zabolotnyi, D.; Schiavi, F.; Opocher, G.; Racz, K.; Januszewicz, A.; Weryha, G.; Henry, J.F.; Brue, T.; Conte-Devolx, B.; Eng, C.; Neumann, H.P. Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol., 2014, 15(6), 648-655.
[http://dx.doi.org/10.1016/S1470-2045(14)70154-8] [PMID: 24745698]
[21]
Lenders, J.W.; Duh, Q.Y.; Eisenhofer, G.; Gimenez-Roqueplo, A.P.; Grebe, S.K.; Murad, M.H.; Naruse, M.; Pacak, K.; Young, W.F., Jr; Endocrine, S. Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab., 2014, 99(6), 1915-1942.
[http://dx.doi.org/10.1210/jc.2014-1498] [PMID: 24893135]
[22]
Machens, A.; Dralle, H. Advances in risk-oriented surgery for multiple endocrine neoplasia type 2. Endocr. Relat. Cancer, 2018, 25(2), T41-T52.
[http://dx.doi.org/10.1530/ERC-17-0202] [PMID: 28883084]
[23]
Thosani, S.; Ayala-Ramirez, M.; Palmer, L.; Hu, M.I.; Rich, T.; Gagel, R.F.; Cote, G.; Waguespack, S.G.; Habra, M.A.; Jimenez, C. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J. Clin. Endocrinol. Metab., 2013, 98(11), E1813-E1819.
[http://dx.doi.org/10.1210/jc.2013-1653] [PMID: 24030942]
[24]
Altarescu, G.; Barenholz, O.; Renbaum, P.; Beeri, R.; Levy-Lahad, E.; Margalioth, E.J.; Brooks, B.; Varshaver, I.; Eldar-Geva, T. Preimplantation genetic diagnosis (PGD)--prevention of the birth of children affected with endocrine diseases. J. Pediatr. Endocrinol. Metab., 2011, 24(7-8), 543-548.
[http://dx.doi.org/10.1515/jpem.2011.262] [PMID: 21932595]
[25]
Rodrigues, K.C.; Toledo, R.A.; Coutinho, F.L.; Nunes, A.B.; Maciel, R.M.B.; Hoff, A.O.; Tavares, M.C.; Toledo, S.P.A.; Lourenço, D.M., Jr. Assessment of depression, anxiety, quality of life, and coping in long-standing multiple endocrine neoplasia type 2 patients. Thyroid, 2017, 27(5), 693-706.
[http://dx.doi.org/10.1089/thy.2016.0148] [PMID: 28276947]

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