Little is known of the natural history of thymic carcinoids in multiple endocrine neoplasia type 1 (MEN1). This is important because in 1993 they were identified as a frequent cause of death, yet only small retrospective studies and case reports exist. We report results of a prospective study of 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed over a mean of 8 yr with serial chest computed tomography, magnetic resonance imaging (MRI), chest x-ray, and, since 1994, octreoscans [somatostatin receptor scintigraphy (SRS)]. Seven patients (8%) developed thymic carcinoids. Patients with and without carcinoids did not differ in clinical, laboratory, or MEN1 tumor features, except for male gender and the presence of a gastric carcinoid. All thymic tumors were hormonally inactive. Four thymic carcinoids lacked 11q loss of heterozygosity, although it was found in three pancreatic endocrine tumors. Computed tomography and/or MRI were more sensitive than SRS or chest x-ray in detecting tumors initially or with recurrence. All patients underwent resection of the thymic carcinoid, and in all patients followed more than 1 yr, the tumor recurred. Bone metastases developed in two patients and were detected early only on MRI, not SRS. This study provides information on early thymic carcinoids and allows modifications of existing guidelines to be recommended for their diagnosis, surveillance, and treatment.
Multiple endocrine neoplasm type 1 (MEN1) is associated with parathyroid, pancreatic, and pituitary tumors. Although most patients present with hyperparathyroidism, the diagnosis can be difficult, because a significant proportion present with other endocrinopathies or may lack a family history, and other MEN1 manifestations may be mild. Recently, multiple cutaneous lesions (angiofibromas and collagenomas) were reported to be frequent in MEN1 patients, and it was proposed that their discovery suggested the diagnosis of MEN1. The purpose of this study was to prospectively assess the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status (48 with MEN1, 62 without MEN1), dermatological evaluation, and tumor imaging studies. Angiofibromas and collagenomas were more frequent in MEN1 patients (64% vs. 8% and 62% vs. 5%; P < 0.00001) and were multiple in 77-81% of the MEN1 patients. Lipomas occurred in 17%. The presence of these skin lesions did not correlate with age, disease duration, or other MEN1 features. Angiofibromas or collagenomas (single or multiple) had 50-65% sensitivity for MEN1 and 92-100% specificity. The combination criterion of multiple angiofibromas (more than three) and any collagenomas had the highest sensitivity (75%) and specificity (95%). This criterion has greater sensitivity than pituitary or adrenal disease and is comparable to hyperparathyroidism in some studies of patients with MEN1 with gastrinoma. This criterion should have sufficient sensitivity/specificity to be clinically useful.
Purpose: Recently, an increased incidence of some nonendocrine tumors are reported in patients with multiple endocrine neoplasia type 1 (MEN 1). There are rare reports of meningiomas and other central nervous system tumors in these patients, but it is unknown if they are more frequent or if allelic loss of the MEN1 gene is important in their pathogenesis. The aim of this study was to address these two latter questions.Experimental Design: Results from a prospective study of 74 MEN 1 patients with suspected/proven pancreatic endocrine tumors (PETs) were analyzed, as well as molecular studies performed on a resected meningioma. All patients had serial brain imaging studies (computed tomography, magnetic resonance imaging, and octreoscanning since 1994) and yearly studies evaluating MEN 1 involvement with a mean follow-up of 7.2 years. Results were compared with 185 patients with sporadic Zollinger-Ellison syndrome.Results: Six patients (8%) had meningiomas. Meningiomas were single and found late in the MEN 1 course (mean age ؍ 51 years). Magnetic resonance imaging/computed tomography were more sensitive than octreoscanning. Their diagnosis averaged 18 years after the onset of hyperparathyroidism, 10 -15 years after pituitary disease or PETs. Meningiomas were 11 times more frequent in patients with PETs with MEN 1 than without MEN 1 (P ؍ 0.017). No clinical, laboratory, or MEN 1 feature distinguished patients with meningiomas. Meningiomas were asymptomatic and 60% showed no growth. A resected meningioma showed loss of heterozygosity at 11q13 and 1p, including at p73 and ARHI/NOEY2 locus, but not at the neurofibromatosis 2 gene locus.Conclusions: These results show meningiomas are not an infrequent occurrence in MEN 1, and loss of the function of the MEN1 gene product plays a role in their pathogenesis in these patients.
Background: Chronic hypergastrinaemia causes gastric enterochromaffin cell proliferation and carcinoid tumours. The only reliable means to diagnose enterochromaffin cell changes/carcinoids is by biopsy. Aim: To assess whether serum histamine, chromogranin A or serotonin and urinary N‐methylimidazoleacetic acid or 5‐hydroxyindoleacetic acid correlate with advanced enterochromaffin cell changes or gastric carcinoids in patients with gastrinomas. Methods: Consecutive patients (n=145) had the above assays and endoscopy with gastric biopsies. Results: Lower N‐methylimidazoleacetic acid and chromogranin A levels (P < 0.0001) occurred in disease‐free patients. In patients with active disease, the fasting serum gastrin levels correlated (P < 0.0001) with both chromogranin A and N‐methylimidazoleacetic acid levels. Chromogranin A (P=0.005), but not N‐methylimidazoleacetic acid, serotonin, 5‐hydroxyindoleacetic acid or histamine levels, correlated with the enterochromaffin cell index. Carcinoids, but not advanced enterochromaffin cell changes only, were associated with higher chromogranin A and N‐methylimidazoleacetic acid levels. Conclusions: Serum chromogranin A levels and urinary N‐methylimidazoleacetic acid levels, but not serum histamine or serotonin or urinary 5‐hydroxyindoleacetic acid, correlate with the presence of gastric carcinoids. However, no assay identified patients with advanced enterochromaffin cell changes only with high sensitivity/specificity. Thus, N‐methylimidazoleacetic acid and chromogranin A levels are unable to identify patients with advanced changes in enterochromaffin cells and therefore neither can replace routine gastric biopsies.
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