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Background The aim of this study was to investigate the genotype-phenotype relationship of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 treated at our institution. Methods We conducted a retrospective chart review of all patients with multiple endocrine neoplasia type 1 treated at our center from January 1993 to December 2015. Presence of a pancreatic neuroendocrine tumor was determined based on imaging performed at any time from presentation to conclusion of follow-up. Results We reviewed 188 patients. The most common site of multiple endocrine neoplasia type 1 mutation was in exon 2 (34/188; 18%). Of 188 patients, 125 had a pancreatic neuroendocrine tumor (61%). Among all patients, 30 of 34 (88%) with an exon 2 mutation had a pancreatic neuroendocrine tumor compared with 95 of 154 (62%) with a mutation in exons 3–10 (P = .002). In the age group of 20 to 40 years, 8 of 9 patients with an exon 2 mutation had a pancreatic neuroendocrine tumor, compared with 24 of 52 patients (46%) with a mutation in exons 3–10 (P = .028). Patients with an exon 2 mutation had a greater frequency of pancreatic neuroendocrine tumor distant metastasis (53% vs 23%, P = .049). Conclusion Young patients with multiple endocrine neoplasia type 1 and an exon 2 mutation appear to have a 2-fold greater risk for developing a pancreatic neuroendocrine tumor, and patients with an exon 2 mutation may be at greater risk for developing distant metastasis. Consideration should be given to more intensive screening and more liberal application of primary operative intervention in this potentially high-risk group.

Background The cyclin-dependent-kinase inhibitor/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in medullary thyroid carcinoma patients. We evaluated CDKN2C loss in a prospective clinical environment using a novel Clinical Laboratory Improvement Amendments–certified assay to confirm its association with aggressive disease and to interrogate response to targeted therapy. Methods Patients with advanced sporadic medullary thyroid carcinoma underwent tumor genotyping for the purpose of management of targeted therapy and prognostication. Results Of patients with informative CDKN2C assay results, 30 (51.8%) were haploinsufficient/1N and 28 (48.3%) were 2N. Forty patients (69.0%) had a somatic RET mutation, and 36.9% had alterations of both genes. Thirty patients (51.7%) were treated with systemic therapy. Presence of genetic alterations in CDKN2C or RET did not predict treatment response. Patients with 1N CDKN2C loss had significantly shorter time-to-distant-metastasis than patients with normal copy number (P = .03). Conclusion This is the first evaluation in the clinical setting of CDKN2C haploinsufficiency in sporadic medullary thyroid carcinoma. Although a larger cohort and longer follow-up will be required, loss seems to be associated with more aggressive disease and may indicate patients that might receive benefit from treatment with a CDK inhibitor.

Background Radiation-associated fusion oncogenes play a direct role in papillary thyroid cancer development and pathogenic fusions have recently been reported in medullary thyroid cancer. To date, no studies have evaluated oncogenic events in medullary thyroid cancer in a radiation-exposed population. Methods Somatic and germline alterations, including RET fusions, were evaluated in paired medullary thyroid cancer tumor and normal samples from the Chernobyl Tissue Bank, a heavily screened population affected by the Chernobyl disaster. Results Tissue was available for 49 individuals. The median age of diagnosis was 26 years (range 9 to 43 years); 16 were radiation-exposed at a median age of 6 (range 2 days to 17 years). A total of 21 patients harbored germline RET mutations (codons 634[13], 918[5], 790[1], 609[1], and 620[1]); 4 had family history. Sporadic medullary thyroid cancer was identified in 27 patients (RET[18], KRAS[1], RET+KRAS[1], TP53[1], wild type [6]), with 1 RET fusion (1/49;2%). The age at operation for patients with hereditary medullary thyroid cancer was not different than sporadic medullary thyroid cancer (23.5 vs 28 years, P = .063). In sporadic medullary thyroid cancer, radiation was not associated with a difference in age at operation, tumor size, or tumor stage (P > .05). Conclusion In a heavily screened cohort, genetic analysis revealed germline RET mutations in previously unrecognized probands and a remarkable number of sporadic medullary thyroid cancer cases with a young age at presentation.

Background Controversy exists regarding the role and extent of operation for patients with multiple endocrine neoplasia type 1 (MEN1) and hypergastrinemia. Methods An institutional MEN1 database was reviewed to identify patients with evidence of hypergastrinemia. The relationship of extent of resection to achievement of eugastrinemia was evaluated. Results Operation was performed in 20 patients with MEN1 and hypergastrinemia with a median follow-up of 71 months. Duodenal gastrinomas were identified in 85% of patients who underwent duodenal evaluation. Nodal metastases were identified in 80%. Patients who underwent anatomic regional lymph node dissection (RLND) had a median of 16 nodes removed, vs 1 in patients who did not undergo a formal regional lymphadenectomy. Eugastrinemia was achieved in 12 patients (60%), and 8 (40%) had persistent hypergastrinemia. Compared with patients with persistent hypergastrinemia, patients rendered eugastrinemic more often underwent duodenal evaluation (11/12 vs 2/8; P = .01) and RLND (11/12 vs 3/8; P = .03); there was no relationship between pancreatic resection and achievement of eugastrinemia (P = .32). Conclusion For patients with MEN1-associated hypergastrinemia selected for operative treatment, a strategy including duodenal evaluation and anatomic regional lymphadenectomy is associated with long-term eugastrinemia. In contrast, the extent of pancreatic resection should be dictated by the extent and distribution of pancreatic neuroendocrine neoplasms, rather than by the presence of hypergastrinemia.

In this issue of Surgery, Bugalho and colleagues from Portugal, present their experience with RET testing of patients with sporadic and familial medullary thyroid carcinoma (MTC). Although their targeted approach to RET testing for patients in whom the mutation status is unknown (presumed sporadic MTC) is not often practiced in this country (where sequencing of exons 10, 11, and 13 to 16 is commonly performed), their paper serves to emphasize the importance of ordering RET gene testing on all patients with MTC. At present, knowledge of the RET mutation status and disease extent is required to determine the correct operation for any patient with MTC. Therefore, all surgeons caring for patients with presumed sporadic or inherited MTC need to know how to obtain genetic testing of the RET proto-oncogene. Inherited MTC can occur as part of multiple endocrine neoplasia type 2 (MEN 2) syndrome. MEN 2 is an autosomal dominant inherited cancer syndrome with 3 main subtypes: MEN 2A, MEN 2B, and familial MTC (FMTC). These clinical subtypes differ from each other in the spectrum of endocrine involvement and the biologic behavior of MTC. MEN 2A is clinically defined by the presence of MTC and either pheochromocytoma or hyperparathyroidism (or both) in a single individual, or the presence of 2 or more tumor types in multiple relatives of a single family. MEN 2B is characterized by MTC and pheochromocytoma, without hyper

Background: Most patients from typical multiple endocrine neoplasia type 1 (MEN 1) kindreds harbor mutations in the MEN-1 gene, MEN1 . We hypothesized that some patients with atypical endocrine neoplasia would also have mutations in MEN1 . Methods: DNA sequencing analysis of mutations in the coding region of MEN1 was performed with genomic DNA obtained from peripheral blood lymphocytes in a total of 21 patients who had: typical MEN 1 (n = 8), clinical features suggestive of MEN 1 but without a family history of endocrinopathy (n = 7), and atypical endocrine neoplasia and a family history of endocrinopathy suggestive of MEN 1 (n = 6). Results: All 8 patients with typical MEN 1 had mutations in MEN1 . None of the 7 patients with features of MEN 1 , but without a family history of endocrinopathy, had a MEN1 mutation. In contrast, 4 of 6 patients with atypical endocrine neoplasia that included components of MEN 1 and a family history of endocrinopathy had mutations in MEN1 , including 2 patients with pheochromocytoma. Conclusions: Genomic mutations in MEN1 may frequently be identified in patients with atypical endocrine neoplasia, especially in the setting of a family history of endocrinopathy. Atypical presentations of MEN 1 may include pheochromocytoma. (Surgery 1999; 126: 1097-104.)