Multiple endocrine neoplasias

Several inherited cancer syndromes are also known to result from mutations in proto-oncogenes. An example is given by the RET proto-oncogene. Depending on the type of mutation and on which part of the gene is affected, RET mutations can lead to multiple endocrine neoplasia 2A or 2B or familial medullary thyroid carcinoma. These familial cancers are inherited in autosomal dominant fashion. A second example is the CDK4 proto-oncogene, which when mutated can cause familial melanoma. 

A. Although all of the conditions can present as an asymptomatic nodule in the thyroid, the marked hypercalcemia in this patient makes hyperparathyroidism the probable diagnosis. Carcinomas of the thyroid are common, and outcomes are improved with early diagnosis. Medullary carcinoma and hyperparathyroidism caused by hyperplasia may be inherited and are associated with the multiple endocrine neoplasia syndromes. 

C. Eng. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung s disease. Seminars in medicine of the Beth Israel Hospital, Boston. NEn J Med, 335 (13), 943-951, 1996. 

MEN, multiple endocrine neoplasias, including thyroid carcinomas and tumours of the adrenal medulla, (phaeochromocytoma). 

Muscle weakness and diffuse myalgia were reported in a 17-year-old man with multiple endocrine neoplasia syndrome type 1 taking ketoconazole for oral candidiasis. The electromyogram showed a distinct myopathic pattern. Withdrawal of the ketoconazole was followed by rapid improvement (SEDA-17, 323). 

Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Reiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 1999 340 1872-9. 

Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, et al. Pheochromocy-tomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J CUn Endocrinol Metab 2001 86 1999-2008. 

Multiple endocrine neoplasia type I with pituitary and pancreatic tumors... 

Multiple endocrine neoplasia type II with medullary thyroid carcinoma and pheochroniocytoma Malignancy... 

Calcitonin is secreted by the parafollicular or C cells, which arise from the neural crest and are distributed throughout the thyroid gland. These cells are included in the APUD (cmine precursor uptake and decarboxylation) family, which explains the association of medullary thyroid carcinoma (a tumor of the C cells) and other tumors of the APUD family in multiple endocrine neoplasia type 2A and -2B (MEN-2A and MEN-2B). Release of calcitonin is stimulated by calcium, and it has been used pharmacologically as an inhibitor of bone resorption. 

Decker RA, Peacock ML, Borst MJ, Sweet JD, Thompson NW. Progress in genetic screening of multiple endocrine neoplasia type 2A is calcitonin testing obsolete Surgery 1995 118 257-64. 

Gagel RE. Multiple endocrine neoplasia type II and familial medullary thyroid carcinoma impact of genetic screening on management. Cancer Treat Res 1997 89 421-41. 

Kaplan MM, Stall GM, Cmnmings T, MacAulay A, MacAulay A, Motte P, Wolfe HJ, et al. High-sensitivity serum calcitonin assays applied to screening for thyroid C-celi disease in multiple endocrine neoplasia type 2A. Henry Ford Hosp Med J 1992 40 227-31. 

Wells SA Jr, Donis-Keller H. Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrmol Metab Clin North Am 1994 23 215-8. 

Primary hyperparathyroidism results from hyperplasia, adenoma, or carcinoma of the parathyroid glands and from ectopic production of the hormone by squamous cell carcinoma of the lung or by adenocarcinoma of the kidney. In about 10% of hyperparathyroidism, hyperplasia or tumors of the parathyroid glands occur due to familial disorders known as multiple endocrine neoplasia (MEN). MEN syndromes consist of three subtypes (I, IIA, IIB) and are... 

J. R. Hansford and L. M. Mulligan Multiple endocrine neoplasia type 2 and RET from neoplasia to neurogenesis. Journal of Medical Genetics 37, 817 (2000). 

R. V. Thakker Editorial Multiple endocrine neoplasia-syndromes of the twentieth century. Journal of Clinical Endocrinology and Metabolism 83, 2617(1998). 

There is epidemiologic evidence to suggest an increased prevalence of duodenal ulcers in patients with certain chronic diseases, but the pathophysiologic mechanisms of these associations are uncertain. A strong association exists in patients with systemic mastocytosis, multiple endocrine neoplasia type 1, chronic pulmonary diseases, chronic renal failure, kidney stones, hepatic cirrhosis, and ai-antitrypsin deficiency. An association may exist in patients with cystic fibrosis, chronic pancreatitis, Crohn s disease, coronary artery disease, polycythemia vera, and hyperparathyroidism. 

Multiple endocrine neoplasia type 2 RET proto-oncogene... 

Lee, A. K., DeLellis, R. A., Blount, M., Nunnemacher, G., and Wolfe, H. J. (1982). Pituitary proliferative lesions in aging male Long-Evans rats. A model of mixed multiple endocrine neoplasia syndrome. Lab Invest 47, 595-602. 

Kambouris M, Jackson CE, Eeldman GL. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTG] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat. 1996 8 64-70. 

Kovacs CS, Mase RM, Kovacs K, et al. Thyroid medullary carcinoma with thyroglobulin immunoreactivity in sporadic multiple endocrine neoplasia type 2-B. Cancer. 1994 74 928-932. 

FIGURE 10.20 C-cell hyperplasia from a patient with multiple endocrine neoplasia 2A. This immunoperoxidase stain for calcitonin is strongly positive in the C cells, whereas the follicular cells are negative. 

C cells in normal glands have an exclusive intrafollicular topography and are concentrated at the junctions of the upper and middle thirds of the lobes (Fig. 10.19). In patients with multiple endocrine neoplasia, type 2 (MEN2), C-cell hyperplasia has been recognized as the precursor of medullary thyroid carcinoma. Detailed immunohistochemical studies have shown that C-cell hyperplasia is characterized by increased numbers of C cells within the follicles in the same regions of the gland where C cells normally predominate (Fig. 10.20). These relationships are maintained in areas of more advanced C-cell hyperplasia, where C cells often completely encircle and displace the follicular epithelium centrally. Nodular hyperplasia is characterized by the complete obliteration... 

Le Bodic M-F, Heyman M-F, Lecomete M, et al. Immuno histochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia type I. Am J Surg Pathol. 1996 20 1378-1384. 

About 5% to 10% of GI neuroendocrine tumors are associated with a hereditary disease. The inherited syndromes and their associated genes include multiple endocrine neoplasia type I MENl gene), neurofibromatosis type 1 NFl gene), von Hippel-Lindau disease VHL gene), and the tuberous sclerosis complex TSCl or TSC2 gene).406... 

Pancreatic endocrine neoplasms (PENs) are the majority of the endocrine neoplasms in the pancreas.Most PENs are sporadic. However, these tumors also constitute one of the major components of the multiple endocrine neoplasia I (MENl) syndrome or may arise in patients with vHL syndrome. Those that are associated with increased serum levels of hormones and lead to corresponding symptoms are referred to as functional and are named according to which hormone they secrete (e.g., insulinoma—42% of all functional variants, gastrinoma—24%, glucagonoma—14%,... 

The ampulla is also included in the gastrinoma triangle Endocrine tumors associated with Zollinger-Ellison syndrome and multiple endocrine neoplasia-1 (MEN-1) are often localized in this region and may be microscopic, and thus difficult to identify preopera-tively and grossly. 

Komminoth P. Review multiple endocrine neoplasia type 1, sporadic neuroendocrine tumors, and MENIN. Diagn Mol Pathol. 1999 8 107-112. 

Shan L, Nakamura Y, Nakamura M, et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest. 1998 78 471-475. 

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