We explored pancreatic neuroendocrine tumors (PanNETs) associated with tuberous sclerosis complex (TSC) to determine their incidence in the TSC population; define their clinical, radiological, and pathological characteristics; and investigate their association with underlying genotypes. Retrospectively reviewed abdominal imaging of 219 patients with TSC, evaluating the incidence, size, and architecture of pancreatic lesions. Pathology records at Massachusetts General Hospital (MGH) were reviewed for all PanNET diagnoses in patients with TSC. Literature was reviewed for TSC-related PanNET cases. Nine patients with TSC were found to have a pancreatic lesion(s) on abdominal imaging and six patients have been diagnosed with a PanNET by pathology at MGH. Twelve cases of TSC-associated PanNETs have been reported in the literature. Of these 18 PanNET cases, one third were cystic, and the average age at resection was 26 years. Germline TSC2 mutations were found in all patients for whom genetic data were available (n = 3). We did not identify pancreatic angiomyolipomas in this series. Our results suggest that PanNETs are the most common pancreatic lesion in patients with TSC. Focal pancreatic mass lesions, solid or cystic, in patients with TSC should be considered possible PanNETs, and resection of the lesion may be clinically indicated. Conflict of interestNothing to declare. Pancreatic neuroendocrine tumors (PanNETs) are rare, representing 1-2% of all pancreatic cancer, with an annual incidence of 2.2 in 1,000,000 individuals (1). Although they carry a much better prognosis than pancreatic adenocarcinoma, survival rates remain 64% at 5 years and 44% at 10 years (2). The current standard of care for PanNETs is surgical resection. PanNETs can occur sporadically or in the setting of an autosomal dominant genetic syndrome, principally, multiple endocrine neoplasia type 1 (MEN1) but also von Hippel Lindau, neurofibromatosis type 1, and tuberous sclerosis complex (TSC) (3-6). To date, the connection between PanNETs and TSC has not been formally investigated beyond several single case reports (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). In this study, we examine a large series of TSC patients to define the clinical characteristics of TSC-associated PanNETs. AMTSC is an autosomal dominant genetic disorder, characterized by the development of hamartomas, benign tumors, and rarely, malignant tumors in multiple organs including the brain, heart, eyes, kidney, skin, and lungs. The underlying genetic abnormality is a germline mutation in TSC1 and TSC2 tumor suppressor genes, resulting in loss of the respective encoded proteins hamartin or tuberin and activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, 558

Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis. A retrospective review of the clinical records and radiological images of 205 patients with tuberous sclerosis complex (TSC) was performed to evaluate the prevalence and progression of hepatic lesions; examine the association of hepatic phenotype with genotype, age, and gender; and investigate the relationships between hepatic, renal, and pulmonary involvement. Hepatic angiomyolipomas (AML), cysts, and other benign lesions were identified in 30% of the cohort, and some lesions grew significantly over time. However, no patient had clinical symptoms or complications from hepatic lesions. TSC2 patients exhibited a higher frequency of AML compared to TSC1 patients (p = 0.037), and patients with no mutation identified exhibited a higher frequency of cysts compared to TSC2 patients (p = 0.023). Age was positively correlated with frequency of hepatic involvement (p < 0.001), whereas hepatic phenotype was independent of gender. Presence of hepatic AML was associated with presence of renal AML (p = 0.001). These findings confirm a high rate of asymptomatic hepatic lesions in TSC and further characterize the TSC phenotype.