Biomedicine & Pharmacotherapy 58 (2004) 348–350 www.elsevier.com/locate/biopha
Dossier: Thyroid tumors
Clinical manifestations of familial medullary thyroid carcinoma Kaori Kameyama a,*, Hiroko Okinaga b, Hiroshi Takami c a
Division of Diagnostic Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan b Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan c Department of Surgery, Teikyo University School of Medicine, Kaga, Itabayashi-ku, Tokyo, Japan Received 31 March 2004 Available online 07 June 2004
Abstract We conducted a large-scale nation-wide questionnaire survey to ascertain the status of familial medullary thyroid carcinoma (MTC) in Japan in 2002. Out of a total of 271 MTC cases (male to female ratio 1:1.4), multiple endocrine neoplasia (MEN) 2A accounted for 83 cases (30.6%), familial MTC (FMTC) for 14 cases (5.1%), MEN for 11 cases (4.1%), and sporadic MTC for 163 cases (60.1%). Mean age at the time of diagnosis was 35.6 in MEN2A, 34.6 in FMTC, 30.5 in MEN2B, and 47.6 in sporadic MTC. Forty-five percent of MEN2A patients had pheochromocytoma and 11% of MEN2A patients had parathyroid disorders when MTC was diagnosed. Finally, the RET oncogene test yielded the largest number of initial findings that led to diagnosis of familial MTC. © 2004 Elsevier SAS. All rights reserved. Keywords: Medullary thyroid carcinoma; Familial cancer; RET protooncogene
2. Patients and methods
Medullary thyroid carcinoma (MTC) is classified into inherited and sporadic types, and the former is classified as multiple endocrine neoplasia (MEN) type 2A and type 2B, and familial non-MEN (FMTC). MEN2A is characterized by MTC, pheochromocytoma, and adenoma and/or hyperplasia of one or more parathyroid glands. FMTC is characterized by the presence of MTC in at least four members of affected families and the absence of adrenal and parathyroid tumors. In MEN2B, MTC is associated with pheochromocytoma, mucosal neuroma, and ganglioneuromatosis of the gut, and a marfanoid habitus is present [1,2]. Serum calcitonin measurement used to be the most reliable marker for diagnosing MTC, prior to the RET-era. After the relationships of mutations in the RET protooncogene to MEN2A and 2B were established in 1993 [3,4] and 1994 , MTC cases discovered on the basis of the RET protooncogene began to accumulate. In this survey, we show the current of familial MTC in Japan since the dawn of the RET-era.
We prepared a questionnaire to collect clinical and laboratory data on all patients with MTC and sent it to all member institutions of the Japanese Society of Thyroid Surgery. The period of investigation is 1995–2002, and 271 patients with histologically proved MTC were registered. 3. Results and discussion 3.1. Proportions The proportions of the four categories of MTC are shown in Fig. 1. Among the 271 cases, 83 (30.6%) had MEN2A; 14 (5.1%) FMTC; 11 (4.1%) MEN2B, and 163 (60.1%) sporadic MTC. The familial form of MTC reportedly accounts for up to 25% of all cases [6–8]. Among the familial forms, MEN2A is the most common, followed by FMTC, and MEN2B. This distribution is as same as that of other groups [6,8,9] reporting before the RET-era. The ratio of familial cases did not increase despite genetic screening. 3.2. Annual number of cases
* Corresponding author. E-mail address: [email protected]
(K. Kameyama). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2004.05.002
The numbers of patients with each of the disease categories according to year are shown in Fig. 2. The number of
K. Kameyama et al. / Biomedicine & Pharmacotherapy 58 (2004) 348–350
Fig. 1. The proportions of the four categories of MTC. Fig. 4. Initial findings that led to diagnosis of familial MTC.
The mean age of familial cases was younger than that of the sporadic cases, and MEN2B patients were the youngest. The order of mean age in each category was same as that of our previous study, conducted in 1996 . However, especially in familial cases other than MEN2B, mean age was younger than in 1996 (40.3 in MEN2A, 43.0 in FMTC, 26.5 in MEN2B, and 48.5 in sporadic MTC). This result reflects the increased percentage diagnosed by RET screening rather than by clinical symptoms (data shown below). Fig. 2. Annual number of each of the disease categories.
annually reported MTC cases was 30–40, and the proportions of each category also had a similar distribution. 3.3. Gender The male to female ratio was 1:1.8 overall; 1:1.4, in MEN2A, 1:0.8 in MEN2B; and 1:2.3 in sporadic MTC (Fig. 3). Begholm et al.  reported a 1:1.3 ratio in sporadic MTC and 1:0.9 in familial cases. Raue et al.  reported a 1:1.4 ratio in sporadic cases and 1:1.1 in familial cases. These reports and our study revealed familial MTC to have a closer sex distribution. These results may depend on the autosomal dominant having with high penetrance . 3.4. Age Mean age at the time of diagnosis was 35.6 years in MEN2A; 34.6 years in FMTC; 30.5 years in MEN2B; and 47.6 years in sporadic MTC.
3.5. Pheochromocytoma The incidence of pheochromocytoma in familial MTC was 45% in MEN2A, 0% in FMTC, and 0% in MEN2B. Frank-Raue et al.  reported that pheochromocytoma occurred in 46% of MEN2A patients, which is consistent with our results. They indicated systemic biochemical screening to be required because clinical symptoms of pheochromocytoma are frequently modest or absent in MEN2 patients. 3.6. Parathyroid disorders The incidence of parathyroid disorders in familial MTC was 11% in MEN2A, 0% in FMTC, and 0% in MEN2B. The proportions with parathyroid disorders in MEN2A patients were similar to those reported by Schuffenecker et al.  (19%) and Block et al.  (17%). 3.7. The initial findings The initial findings were RET protooncogene mutations (45 patients), neck mass (39 patients), elevated nonstimulated serum calcitonin (10 cases), elevated serum CEA (three cases), and other findings (14 cases) including adrenal tumor, abdominal mass, bone disorders, etc. (Fig. 4). While neck mass remains the most common initial finding of MTC to date [9,10,14], RET protooncogene mutation has now been revealed as a reliable means of diagnosis in this study. The RET test has completely revolutionized the diagnosis of MTC. Acknowledgements
Fig. 3. Gender of each of the disease categories.
We would like to express our sincere gratitude to the members of Japanese Society of Thyroid Surgery for their
K. Kameyama et al. / Biomedicine & Pharmacotherapy 58 (2004) 348–350
cooperation in conducting the questionnaire which served as the basis of this study.
References   
Schimk RN. Genetic aspects of multiple endocrine neoplasia. Ann Rev Med 1984;35:25–31. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. J Am Med Assoc 1996;276: 1575–9. Mulligan LM, Kwok JBJ, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 1993;363:458–60. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN2A and FMTC. Nat Genet 1994;6:70–4. Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary carcinoma and in a family with FMTC. Oncogene 1995;10: 509–13. Raue F, Kotzerke J, Reinwein D, et al. Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German medullary thyroid cancer register. Clin Invest 1993;71:7–12.
Calmettes C, Chaventre A, Feingold N, Franc B, Guliana JM. Screening for medullary thyroid cancer in France: a national effort. Henry Ford Hosp Med J 1989;37:120–1. Begholm U, Adami HO, Bergstrom R, et al. Clinical characteristics in sporadic and familial medullary thyroid carcinoma: a nationwide study of 249 patients in Sweden from 1959 through 1981. Cancer 1989;63:1196–204. Saad MF, Ordonez NG, Rashid RK, Guido JJ, Hill Jr CS, Hickey RC, et al. Medullary carcinoma of the thyroid: a study of the clinical features and prognostic factors in 161 patients. Medicine 1984;65:319–42. Takami H, Hosoda Y. Current status of inherited medullary thyroid carcinoma in Japan. Oncol Rep 1996;3:943–6. Frank-Raue K, Kratt T, Hoppner W, Buhr H, Ziegler R, Raue F. Diagnosis and management of pheochromocyomas in patients with multiple endocrine neoplasia type 2—relevance of specific mutations in the RET proto-oncogene. Eur J Endocrinol 1996;135:222–5. Schuffenecker I, Virally-Monad M, Brohet R, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET protooncogene. J Clin Endocrinol Metab 1998;83:487–91. Block MA, Jackson CE, Greenwald KA, et al. Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Arch Surg 1980;115:695–704. Gharib H, McConahey WM, Tiegs RD, et al. Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970. Mayo Clin Proc 1992; 67:934–40.