This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

/pdf/consensus-guidelines-for-diagnosis-and-therapy-of-men-type-1-gitcnuak40.pdf

CONSENSUS: Guidelines for Diagnosis and Therapy of MEN Type 1 and Type 2

Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung’s disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype‐phenotype correlations to stratify mutations into three risk levels.

RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors.

BACKGROUND

Multiple endocrine neoplasia type 2B (MEN 2B) is an exceptional syndrome, for which the optimal age of thyroidectomy is poorly established and the course of medullary thyroid carcinoma (MTC) is ill-defined.



PATIENTS

All the 18 patients with a MEN 2B syndrome examined at the Institut Gustave Roussy were included in a single-center retrospective study.



RESULTS

There were 9 men and 9 women with a mean age of 13 years (range, 2–27 years) at diagnosis. The diagnosis of MTC was based on the presence of a thyroid nodule or involved neck lymph nodes and on dysmorphic features of MEN 2B in 60% and 40% of the cases, respectively. The classic M918T mutation in exon 16 was found in the 16 patients in whom it was investigated. At diagnosis, 2 patients had Stage I MTC, 15 patients had Stage III, and 1 patient had Stage IV disease. T1 MTC was found in 4 patients aged 2.1–3.7 years. However, two of these patients already had N1 disease. One patient with Stage I MTC, aged 3.4 years and 2 patients with Stage III disease, aged 14 and 25 years, had undetectable basal calcitonin (CT) after initial surgery. During follow-up, basal CT became detectable in one of three patients. Among the 15 other patients with an elevated postoperative CT level, metastases were demonstrated in 5 patients after a mean follow-up of 2 years. Five patients died, three of MTC, one of the MEN 2B syndrome, and one of intercurrent disease. Five- and 10-year overall survival rates were 85% and 75%, respectively.



CONCLUSIONS

This study confirms the need for early treatment of MTC in patients with the MEN 2B syndrome, preferably within the first 6 months of life. The phenotype of MTC occurring in the MEN 2B syndrome was not more aggressive than sporadic MTC or MTC occurring in other familial syndromes. Cancer 2002;94:44–50. © 2002 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.10205

Medullary thyroid carcinoma as part of a multiple endocrine neoplasia type 2B syndrome: influence of the stage on the clinical course.

BACKGROUND

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene, and is responsible for the development of endocrine neoplasia. Its prognosis is dependent on the appearance and spread of medullary thyroid carcinoma (MTC). Relatives at risk can be identified before clinical or biochemical signs of the disease become evident.



METHODS

Twenty-one families with MEN 2 (16 families with MEN 2A and 5 families with MEN 2B) were studied. Peripheral blood DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene exons 10, 11, and 16. Molecular analysis was carried out in all index patients as well as in 98 relatives of MEN 2A patients (60 juveniles, ages 6 months to 21 years, and 38 adults, ages 22 to 81 years) and in 13 relatives (6 juveniles ages 10 to 21 years, and 7 adults ages 41 to 66 years) from MEN 2B families.



RESULTS

Molecular studies showed a mutation at codon 634, exon 11 in all MEN 2A patients. All MEN 2B patients showed an ATG to ACG (Met918Thr) mutation. In MEN 2A families, 42 out of 98 relatives were affected. Total thyroidectomy was performed in 18 juvenile carriers ages 17 months to 21 years. Histopathologic studies of the glands revealed parafollicular cell (C-cell) hyperplasia in all of these carriers, medullary thyroid carcinoma in 15 carriers, and only one carrier with lymph node metastases.



CONCLUSIONS

The consistent finding of C-cell disease in all the juvenile carriers who underwent preventive thyroidectomy emphasizes the relevance of early screening in children at risk of developing MTC. The presence of MTC in the specimen of prophylactic thyroidectomy from a 17 month old girl highlights the importance of thyroidectomy as soon as the molecular diagnosis is confirmed. Cancer 2002;94:323–30. © 2002 American Cancer Society.

Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers.

Calcitonin (CT) is an important tumor marker for medullary thyroid carcinoma (MTC). Recent CT assays chiefly recognize the monomeric form of CT (mCT). It was the objective of this study to examine the consequences of the higher specificity of the assay for interpretation of the postoperative CT values in MTC patients. The postoperative mCT concentration was measured in 214 patients with differentiated thyroid carcinoma (MTC excepted; non-MTC patients) to determine a reference range of mCT in totally thyroidectomized patients. Monomeric CT was also determined with a two-site chemiluminescence immunoassay (Nichols) in 94 healthy subjects and in 68 MTC patients. The mCT concentrations were below the detection limit in all examined completely thyroidectomized non-MTC patients. Basal and stimulated mCT values were also below the detection limit in 32 of the 68 MTC patients. The biochemical and imaging diagnosis of the latter patients did not give any indication of tumor recurrence. We conclude that completely thyroidectomized patients with non-MTC do not show any measurable mCT concentrations. In comparison with an unspecific CT-RIA, the more specific mCT determination by immunoluminometric assay permits a more precise differentiation between postoperative normal and pathological values and an earlier diagnosis of recurrent MTC.

Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements.

Multiple endocrine neoplasia type 2 (MEN-2) is an inherited multiglandular disease with age-related penetrance and variable expression. The prognosis of MEN-2 is linked to the carcinological evolution of medullary thyroid cancer (MTC), which depends mainly on the stage of discovery, and to the incidents related to pheochromocytomas. The emphasizes the need for early diagnosis and management of MEN-2. Since 1993, mutations evidenced on the protooncogene RET have allowed subjects at risk to be identified, thus leading to a three-step management of these patients. (1) For all the potentially affected members of a MEN-2 family, screening by molecular genetics of the ret gene enables one to identify the subjects at risk who bear the mutation. When no mutation is observed, a linkage analysis study may be proposed. (2) In the subjects at risk, early screening for the various types of endocrine lesions may then start in childhood and be performed using specific biological markers of MTC, pheochromocytoma and primary hyperparathyroidism, and particularly, basal and pentagastrin-stimulated calcitonin measurement, which is known to be the most sensitive marker for the monitoring of MTC. (3) This step of biological investigations enables the earliest possible treatment of any endocrine lesion detected before it is expressed clinically, thus improving the prognosis of MEN-2. When genetic screening cannot be performed, only annual clinical and biological monitoring remain available in all members of a family affected with MEN-2.

Multiple Endocrine Neoplasia Type 2: Management of Patients and Subjects at Risk

But: etudier les resultats therapeutiques observes chez les patients operes precocement d'une forme familiale de cancer medullaire de la thyroide (CMT) et ayant avant intervention chirurgicale un taux de calcitonine (CT) < 150 pg/ml apres stimulation par la pentagastrine (Pg). Materiels et methodes: 36 patients (13 F, 23 H) ont ete selectionnes: 22 cas issus de 15 familles de NEM 2A, 13 cas issus de 8 familles de CMT isole (F-CMT) et un cas familial de NEM 2B. L'analyse genetique retrouvait une mutation du proto-oncogene RET dans tous les cas. La CT a ete mesuree par methode IRMA (Cis-Bioindustrie) avant et apres Pg. Les resultats des tests Pg avant et apres thyroidectomie, l'âge lors de l'intervention et les constatations anatomo-pathologiques ont ete analyses. Resultats: en pre-operatoire. le taux de CT stimulee etait a 82,5 ± 34,0 pg/ml (22-133); 16/36 patients avaient un taux de CT basale < 10 pg/ml; 2 d'entre-eux (F-CMT) avaient un taux de CT stimulee normal < 30 pg/ml. En pre-operatoire les cas de F-CMT se differenciaient des cas de NEM 2A par leur taux plus bas de CT stimulee (58,1 ± 24.0 vs 97,6 ± 31,3 pg/ml, p < 0,01) alors meme qu'ils etaient plus âges (20,4 ± 10,5 vs 11,6 ± 7.6 ans, p <0.01 par le test de Mann-Whitney). Une thyroidectomie totale a ete realisee chez tous les patients a un age moyen de 14,8 ± 9.8 ans (2,5-41,7) associee a un curage ganglionnaire dans 30 cas. Il n'existait pas de parallelisme entre le pic de CT sous Pg et les constatations anatomo-pathologiques: les deux cas de F-CMT ayant un test Pg normal presentaient un micro CMT; les autres patients presentaient un micro-CMT uni ou bilateral (dont 2 cas de NEM 2A et un cas de MEM 2B âges de moins de 5 ans) sauf4 patients ayant une hyperplasie des cellules C malgre un taux de CT basal eleve 3 fois sur 4. Il n'a pas ete retrouve d'envahissement metastatique ganglionnaire. Durant la surveillance post-operatoire, les derniers tests PG (n = 33) ont ete realises 27,5 mois (1-92) apres la thyroidectomie: la CT stimulee etait dans tous les cas < 10 pg/ml. En conclusion: la thyroidectomie doit etre proposee a un âge tres jeune chez les sujets porteurs d'une mutation sans tenir compte des resultats des tests Pg. Cette attitude, justifiee en cas de NEM 2A et 2B. est a nuancer en cas de formes peu agressives de F-CMT.

Early therapeutic management of patients genetically predisposed to medullary thyroid cancer

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Multiple Endocrine Neoplasia Type 2: Management of Patients and Subjects at Risk

Early therapeutic management of patients genetically predisposed to medullary thyroid cancer