Review
Solid tumors associated with multiple endocrine neoplasias

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Abstract

We present an update on molecular and clinical genetics of solid tumors associated with the various multiple endocrine neoplasias (MEN) syndromes. MEN type 1 (MEN1) describes the association of pituitary, parathyroid, and pancreatic islet cell tumors with a variety of many other lesions. MEN type 2 (MEN2) conditions represent at least four different syndromes that associate pheochromocytoma with medullary thyroid carcinoma, hyperparathyroidism, and a number of other manifestations. Other pheochromocytoma-associated syndromes include von Hippel–Lindau disease; neurofibromatosis 1; the recently defined paraganglioma syndromes type 1, 3, and 4; Carney–Stratakis syndrome; and the Carney triad. Carney–Stratakis syndrome is characterized by the association of paragangliomas and familial gastrointestinal stromal tumors. In the Carney triad, patients can manifest gastrointestinal stromal tumors, lung chondroma, paraganglioma, adrenal adenoma and pheochromocytoma, esophageal leiomyoma, and other conditions. The Carney complex is yet another form of MEN that is characterized by skin tumors and pigmented lesions, myxomas, schwannomas, and various endocrine neoplasias.

Introduction

The first case of multiple endocrine neoplasia (MEN) was described in 1903 by Jacob Erdheim [1]. Erdheim reported a patient with acromegaly due to pituitary adenoma and tumors of the parathyroid glands [1]. In 1953, Underdahl et al. [2] reported eight patients with tumors of three endocrine glands: pituitary, parathyroid, and pancreatic islets of Langerhans. In 1962, the first association between thyroid carcinoma and pheochromocytoma was reported [1]. After these initial reports, Steiner et al. [3] proposed the term endocrine multiple neoplasia to describe the associations of endocrine tumors and defined two types of MEN: Wermer syndrome or MEN1 (familial pituitary, parathyroid, and pancreatic islet cell tumors), and Sipple syndrome or MEN2 (familial pheochromocytoma, medullary thyroid carcinoma, and hyperparathyroidism). In 1973, two distinct phenotypes for MEN2 were described: patients with hyperparathyroidism and a normal appearance (MEN2A); and patients without hyperparathyroidism but with mucosal neuromas and Marfanoid characteristics (MEN2B) [4].

In addition, two other syndromes (von Hippel–Lindau and neurofibromatosis type 1) were soon found to be associated with the development of pheochromocytoma [5], [6]. Pheochromocytoma was first associated with von Hippel–Lindau (VHL) disease 50 years after the initial description of the condition [7]. Neurofibromatosis type 1 (NF1) or von Recklinghausen disease [8], [9] is also listed among the classic pheochromocytoma-associated syndromes [10], as are VHL disease [11]; the recently defined paraganglioma syndromes type 1 [12], 3 [13], and 4 [14]; Carney–Stratakis syndrome [15]; and the Carney triad [16].

Finally, the complex of “spotty skin pigmentation, myxomas, endocrine tumors, and schwannomas,” a disorder that is now known as the Carney complex (CNC), was described in 1985 [17], [18], [19]. Isolated patients with some components of CNC had been previously diagnosed as NAME (nevi, atrial myxomas, and ephelides) and LAMB (lentigines, atrial myxoma, and blue nevi) [20], [21].

Section snippets

MEN1

Patients with MEN1 may present with any combination of more than 20 endocrine and nonendocrine lesions (Table 1) [22]. MEN1 is diagnosed by the association of at least two of the three main MEN1-related endocrine tumors (parathyroid adenomas, enteropancreatic endocrine tumors, pituitary tumor). Familial MEN1 is characterized by at least one MEN1 case associated with one or more first-degree relatives with at least one of those main endocrine tumors. The larger MEN1 families frequently show a

MEN2 syndromes

MEN2 is characterized by medullary thyroid carcinoma (MTC), with or without pheochromocytoma and hyperparathyroidism [22]. MEN2A consists on the association of MTC (90%), pheochromocytoma (50%), and HPT (20–30%). Variants of MEN2 include familial MTC, MEN2A, or familial MTC with Hirschsprung disease and MEN2A with cutaneous lichen amyloidosis. MEN2B is characterized by clinically aggressive MTC, pheochromocytoma, a Marfanoid habitus, and mucosal and intestinal ganglioneuromatosis. MEN2B is not

Isolated MTC

MTC is a calcitonin-producing tumor originated from the parafollicular or C cells of the thyroid gland and represents 5–10% of all thyroid cancers. Most of the cases are sporadic (75%), but the prevalence of familial MTC is high (25%) (Table 2) [36]. The clinical behavior of MTC correlates with the type of MEN2 syndrome and with the mutated RET codon. Calcitonin levels constitute the most important tumor marker for the diagnosis and follow-up of MTC; high calcitonin levels indicate persistent

Genetic syndromes associated with pheochromocytoma

Pheochromocytomas and paragangliomas are catecholamine-secreting tumors of neural crest origin arising from the adrenal medulla or extra-adrenal paraganglial sympathetic nervous system. Hereditary etiologies of pheochromocytoma include: MEN2A and MEN2B caused by RET mutations [10]; VHL disease caused by VHL gene mutations [11]; mutations of the NF1 gene, responsible for neurofibromatosis [40]; and familial paraganglioma syndromes caused by mutations in subunits B, C, or D of the succinate

Concluding remarks: new genes to be identified

The MEN syndromes recognized to date are familial disorders with autosomal-dominant inheritance. Genetic screening for the known germ line mutations associated with MENs has important implications for genetic counseling, treatment, and follow-up. RET mutations should be investigated in all apparent sporadic MTC. VHL, RET, SDHD, and SDHB mutations should also be screened in nonfamilial cases of pheochromocytomas and paragangliomas. However, new genetic defects are to be identified in the future:

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