Section 4 -

De Novo Mulitiple Endocrine Neoplasia 2B Robert Yoshiyuki Osamura Tokai University School of Medicine Kanagawa, Japan

Case 1 Diagnosis:  de novo mulitiple endocrine neoplasia 2B Bilateral adrenal pheochromocytoms Medullary thyroid carcinoma(MTC) Rectal ganglioneuroma Case History A 31 year-old male was admitted to the hospital because of noncardiogenic pulmonary edema. He lacked marfanoid habitus but thickened lips and tongue neuroma were present. Chroniic constipation had been present since childhood, and the patent had a two-year history of untreated hypertension. Non-caciogenic pulmonary edema and toxic megacolon were noted, and the abdominal CT scan revealed bilateral adrenal tumors. Ultrasonograph of the thyroid showed two mass lesions. Intubation and mechanical ventilation were performed because of severe hypoxemia. Endocrinological examinations showed high levels of serum and urinary fractionaed catecholamines, serum calcitonin, serum carcinoembryouic antigen(CEA), and serum intact parathyroid hormone. High catecholamine level was thought to be the cause of pulmonary edema. RET gene analysis showed a codon 918 mutation in exon 16 resulting in an ATG(methionine) to ACG(threonine) substitution, but analysis of the patient's parent's showed the wild type. Therefore, the patient was diagnosed as having de novo MEN2B. He underwent laparoscopic bilateral adrenalectomy. However, the values of serum calcitonin and CEA did not return to normal ranges. Micrometastases were suspected. Pathological Diagnosis Bilateral adrenal pheochromocytomas Medullary carcinoma of thyroid(MCT) Gaglioneuromatosis, rectum Molecular Endocrine Pathology Genetic and molecular analysis(germline mutation) RET gene analysis on genomic DNA from the blood cells Germline mutation:heterozygous point mutation, ATG to ACG Resulting in substitution of methionine by threonine at codon 918 in exon 16 RET gene analysis on somatic DNA from the paraffin sections(somatic mutation) From bilateral pheochromocytomas and MCT Showed the same point mutation at codon 918 Discussion Multiple endocrine neoplasia type 2 MEN2 is an autosomal dominant inherited cancer syndrome. Predisposition to MEN2 is caused by germline mutations of the RET proto-oncogene on chromosome 10q11.2. There are three clinically distinct forms of MEN2 syndrome-MEN2A,familial medullary thyroid carcinoma(FMTC), and MEN2B. In all of these subtypes, medullary thyroid carcinoma(MTC)is a key. MEN2A is the most common subtype of MEN2. Clinical features of the MEN2A syndrome include MTC,and/or C-cell hyperplasia(CCH) in almost all affected individuals, pheochromocytoma(approximately 50%) and hyperparathyroidism(HPT(15-30%). MEN2B is the most aggressive of the MEN2 variants and accounts for approximately 5% of all cases of MEN2. MEN2B is similar to MEN2A but is characterized by the earlier onset of the disease and by developmental abonormalities. In FMTC, the third form of MEN2, MTC is the only clinical feature. Introduced in recent years and still developing genetic testingof individuals at highest hereditary risk of MEN2 syndrome holds the possibility of early detection and improved treatment and prognosis. Brauckhoff et al.(2004) reported 21 cases of of ME2B syndrome due to codon 918T mutation of the RET protooncongene. More than 50% of patients with typical MEN2B have a de novo M918T germline mutation. Mean age at MEN2B diagnosis was 14.2years (range 1-31 years).. All patients had MTC. Severe intestinal manifestation occurred more aften in the group of early onset. They suggested an additional pathological process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET mutation. Elder et al. reported the higher frequency of various syndrome in pheochromocytomas and suggested revision of the "10% rule tumors". Firstly, a larger proportion of these tumors are today discovered in normotensive patients during imaging carried out for other reasons than suspicion of pheochromocytoma. Secondly, although the differential diagnosis between malignant and benign tumors remains a challenge, the risk of malignancy well exceeds the classical 10% in patients with extra-adrenal disease, and/or carriers of germ-line SDHB mutations. Finally, up to a third of patients carry a germ-line mutation in a gene predisposing to pheochromocytoma and/or paraganglioma. Identification of a constitutional mutation in RET, VHL, SDHD, or SDHB has implications for clinical screening and follow-up for both the patient and for relatives at risk who can be identified by screening for the same mutation. Genetic testing in apparently sporadic cases is therefore regarded as beneficial, especially in patients diagnosed before 50 years of age, and in patients with bilateral, multifocal, malignant and/or extra-adrenal disease. Massoll and Mazzaferri emphasized that all patients who have MTC should be tested for RET mutations, including putative sporadic cases. He concluded MTC cases should be tested for MEN type1, Germline Schlling et al. examined the mutation of codon 918 in the blood samples(germline mutation) and in the tumor tissue embedded in FFPE blocks(somatic mutation). They showed that in the sporadic medullary thyroid carcinoma 918 mutation patients followed more aggressive development of distant metastases during follow-up with decreased metastses-free survival. In their series, 918mt patients had a significantly lower survival rate than 918we pteitns. These data show that the RET colon 918 mutation has a pgognostic impact on patients with sporadic MTC whch may influence follow-up treatment. References: Peczkowska M and Januszewicz A.;Mutiple endocrine neoplasia type 2. Familial Cancer 4:25-36, 2005. Brauckhoff M.et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation:clinical manifestation and course in early and late onset disease. World J Surg 28:1305-11, Epub 2004. Elder EE,Elder G,Larsson C.:Pheochromocytoma and functioning paraganglioma syndrome:no longer the 10% tumor. J Sug Oncol 89:193-201,2005. Massoll N.Mazzaferri EL.:Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med 24:49-83,2004. Schilling T. et al. Prognostic value of codon 918(ATG-ACG) RET proto-oncogene mutatations in sporadic medullary thyroid carcinoma. Int J Caner 95:62-66, 2001. Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol 183:257-265.