Multiple Leiomyomas of the Esophagus, Lung, and Uterus in Multiple Endocrine Neoplasia Type 1

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by multiple parathyroid, pancreatic, duodenal, and pituitary neuroendocrine tumors. Nonendocrine mesenchymal tumors, such as lipomas, collagenomas, and angiofibromas have also been reported. MEN1-associated neuroendocrine and some mesenchymal tumors have documented MEN1 gene alterations on chromosome 11q13. To test whether the MEN1 gene is involved in the pathogenesis of multiple smooth muscle tumors, we examined the 11q13 loss of heterozygosity (LOH) and clonality patterns in 15 leiomyomata of the esophagus, lung, and uterus from five patients with MEN1. Forty sporadic uterine leiomyomata were also studied for 11q13 LOH. LOH analysis was performed using four polymorphic DNA markers at the MEN1 gene locus; D11S480, PYGM, D11S449, and INT-2. The gene for multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant tumor syndrome, has been mapped to chromosome 11q13 1 and recently identified. 2 The MEN1 gene is thought to act as a tumor suppressor based on the presence of inherited inactivating mutations in the constitutional DNA of affected family members accompanied by the loss of the wild-type allele in associated tumors. 2-4 Somatic inactivation of the MEN1 gene has been also documented in a subset of sporadic counterpart parathyroid, enteropancreatic, and pulmonary endocrine tumors, and mesenchymal tumors. 5 MEN1 patients typically present first with primary hyperparathyroidism resulting from multiple parathyroid tumors caused by MEN1 gene alterations. 6 Neuroendocrine tumors of the pancreas, duodenum, anterior pituitary gland, stomach, and lung are other tumors that are an integral part of MEN1. 7,8 Nonendocrine mesenchymal tumors, such as lipomas, angiofibromas, and collagenomas, have also been shown to be associated with MEN1 and MEN1 gene alterations. 8 -10 Leiomyomata have been occasionally documented in MEN1 patients, 8,[11][12][13][14] and loss of heterozygosity (LOH) at the MEN1 locus was recently shown in two esophageal leiomyomata from one MEN1 patient. 15 MEN1 gene inactivation in lung or uterine leiomyomata, however, has not been studied. To test whether MEN1 gene alterations are involved in the development of multiple smooth muscle tumors in MEN1 patients, we analyzed 15 leiomyomata from five patients with documented MEN1 germline mutations for LOH at the MEN1 gene locus. To assess whether MEN1 gene alterations are present in sporadic smooth muscle tumors, we analyzed 40 sporadic uterine leiomyomata for MEN1 gene deletion for comparison. Furthermore, to evaluate whether MEN1-associated leiomyomata arise as independent clonal events at different anatomical sites within an organ, the patterns of 11q13 LOH in different tumors from individual patients

Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype–phenotype correlation

“…The aetiology of these and other tumours outside the classical MEN1 tumour spectrum (Table 4) noted in our study is not known. However, others had shown by loss of heterozygosity studies that leiomyomas of the oesophagus and uterus, meningioma and lipoma may be part of MEN1 syndrome (8,9,39). It is also of note that medullary thyroid carcinoma (Table 4, patient 11-6) is a typical finding in patients with MEN2 and its occurrence in our patient with MEN1 is probably coincidence.…”

“…Adrenal lesions are seen in 5-40% (1, 2, 6, 7) and neuroendocrine tumours of the gastrointestinal tract, bronchus or thymus in 4-9% of patients (1,2,6). Leiomyoma of various sites and angiofibroma, collagenoma and lipoma of the skin are also seen in association with MEN1 (8,9).…”

Smooth muscle tumors of soft tissue and non-uterine viscera: biology and prognosis

“…In addition, these MEN-1 patients can have multiple cutaneous fibromas (somewhat reminiscent but distinctive from usual dermatofibromas). 67 Histologically, GI leiomyomas are composed randomly oriented or fascicularly organized eosinophilic smooth muscle cells. These often contain …”

Multiple endocrine neoplasia type 1 (MEN1): Not only inherited endocrine tumors

“…66,67 GENETIC ASPECTS OF MEN1 SYNDROME Chromosomal location of the MEN1 gene and model for the related tumorigenesis Combined studies of both linkage in MEN1 kindreds, 68 and microdeletion analysis in tumors 68 -70 demonstrated that the MEN1 trait was closely linked to PYGM gene, encoding for muscle phosphorylase, at chromosome 11q13. The proposed model for tumorigenesis in familial MEN1 is, according to Knudson's "two hits" hypothesis, 71 a mutated MEN1 copy is inherited at the germline level from the affected parent (first hit), whereas the wild-type copy, inherited from the healthy parent, is lost at the somatic level (second hit), resulting in a tumor.…”