The endocrine system regulates the homeostasis of the human body through small molecules named “hormones”. For appropriate function of the endocrine system, the following regulatory mechanisms should function properly: appropriate production and secretion of hormones, transport of hormones through the blood stream, sensing of hormones and exertion of physiologic effects in target organs, and hormone metabolism. To better understand the physiopathology of endocrine tumors, this review describes the basic features of the endocrine system.

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[in Japanese]

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Pheochromocytoma occurs in MEN2. Lethal complications may develop if the existence of pheochromocytoma is unknown, when MEN2 patients undergo surgical procedures. The surgical treatment of medullary thyroid carcinoma precedes that of pheochromocytoma in MEN2 patients, and it is necessary to check for the presence of pheochromocytoma before thyroidectomy. The probability of pheochromocytoma was reported as 50% in MEN2, but this is based on old data before the advent of gene diagnosis and early thyroidectomy for medullary thyroid carcinoma. If medullary thyroid carcinoma is treated early, the life expectancy might increase, consequently, the probability of pheochromocytoma may rise. There is a report in which pheochromocytoma was responsible for 2/3 of the causes of death in patients with MEN2 who developed pheochromocytoma. During the follow-up of MEN2 patients after total thyroidectomy for medullary thyroid carcinoma, there exists much controversy in the treatment of pheochromocytoma: when pheochromocytoma should be treated surgically, what should the surgical procedure be, total adrenalectomy or partial adrenalectomy, etc.

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The RET gene is a causative gene of multiple endocrine neoplasia type 2A（MEN 2A）, 2B（MEN 2B）, and familial medullary thyroid carcinoma（FMTC）. In this study, we examined RET gene mutation in 98 cases of medullary thyroid carcinomas（MTC）. These patients consisted of 44 familial MTC cases from 23 families, and 54 sporadic MTC cases. RET gene mutations in exons 10, 11 and 13–16 from peripheral blood leukocytes were analyzed by PCR and subsequent automated DNA sequencing. RET gene mutations were found in 23 cases, and mutations were found in codon 611 in 2, 618 in 2, 620 in 3, 634 in 12, 768 in 1, 804 in 2 and 891 in 1, respectively. Seven of 61（11%） apparently sporadic MTC revealed RET gene mutation, which is newly discovered as hereditary MTC. Four of the 7 patients had mutations in exons 13–15, and this region is considered a hotspot occurring in relatively milder MTC. The characteristics of hereditary MTC were younger age at onset of MTC, multiple carcinomas in the thyroid gland, and the association of pheochromocytoma or parathyroid hyperplasia. In conclusion, RET gene screening is a sensitive, specific, and useful method for discriminating gene carriers and non-gene carriers. We recommend RET gene screening for all MTC patients or MTC-suspected patients. Exons 13–15 should be examined in addition to exons 10, 11 and 16.

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MEN type 1 is an autosomal dominant syndrome associated with neoplasms in multiple endocrine organs （e.g., parathyroid, endocrine pancreas, and anterior pituitary）. Primary hyperparathyroidism is part of the phenotype with the highest frequency of MEN1, followed in order by pancreatic endocrine tumor and pituitary tumors. In addition, tumor of the adrenal cortex, thyroid tumor, and carcinoid have been reported. Treatment of MEN1 has a specific therapeutic method compared to that of the non-MEN neoplasms in each endocrine organ. Total parathyroidectomy with autoplantation is performed the patients with primary hyperparathyroidism associated with MEN1; for pancreatic tumor, nucleation, partial resection of the pancreas and total duodenalectomy with preserved pancreatic head is performed. Most pituitary tumors associated with MEN1 are followed and medicated without surgical treatment. There is a relationship with genotype and phenotype of RET in MEN2, but there is no correlation in MEN1. And prophylactic resection in the each organ involved by MEN1 is not performed based on the findings of MEN1 gene test, because cancer does not necessarily occur in MEN1, but total pancreatectomy would decreuse QOL. However, the MEN1 gene test also might contribute to early stage detection and allow the patient to avoid surgery such as the pituitary tumor. Although the most significant prognostic factor of MEN1 is the outcome of pancreatic tumor, it is controversial whether conservative treatment to preserve QOL or early aggressive resection of the pancreas should be performed. An increase in MEN1 cases will be expected in the future, and counseling for the long-term survivors will become important.

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Nevoid basal cell carcinoma syndrome （NBCCS; Gorlin syndrome）, an autosomal dominant disorder caused by mutations in PTCH1, is characterized by minor anomalies and a high incidence of tumors such as basal cell carcinoma（BCC）and medulloblastoma. We have identified PTCH1 mutations in 21 out of 24 cases with NBCCS. More than half of the mutations comprised insertion/deletion of 1–4 nucleotides, resulting in frameshifts in coding. We also found splicing mutations and whole PTCH1 deletions which were intractable to detect with conventional methods. The early genetic testing of suspected cases of NBCCS is advisable in the light of the following reasons: First, many symptoms develop with age, and it is not always easy to diagnose patients at an early age. Second, after radiation therapy for medulloblastoma, NBCCS patients develop secondary cancers in the irradiated areas; therefore, omitting or limiting radiation therapy should be considered. Third, a proper diagnosis with genetic testing helps in the early detection of medulloblastoma and also lessens the risk of developing BCCs by reducing ultraviolet radiation. Finally, emerging small molecule inhibitors of hedgehog signaling may be useful for treating patients with NBCCS-related tumors if potential adverse effects on embryonic and post-natal development are avoided.

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