Purpose: Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified?If so, what is their underlying pathogenetic basis and do they possess clinical significance? Experimental Design: We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs. Results: The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P < 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P < 0.017).Conclusions: This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.

It has been suggested that microadenomatosis of the endocrine pancreas is a hallmark of the multiple endocrine neoplasia type 1 syndrome (MEN1). This study attempts to elucidate the relationship between pancreatic microadenomatosis and the MEN1 and von Hippel-Lindau (VHL) syndromes. Pancreatic tissue specimens from 37 patients (with either microadenomatosis or the MEN1 syndrome) were analyzed using immunohistochemistry, confocal laser scanning microscopy, and morphometric methods. The MEN1 and the VHL status were assessed on the basis of clinical criteria (all patients) and PCR-based mutational analysis (15 and 5 patients, respectively). Pancreatic microadenomatosis was found in 35 of 37 patients, 28 of whom fulfilled the clinicopathologic criteria and 13 the genetic criteria for MEN1, whereas none of the patients had evidence of a VHL syndrome. Microadenomas were present in 26 of the 28 MEN1 patients, and all these tumors were consistently multihormonal. Five of the 9 patients with microadenomatosis and no clinical evidence for MEN1 or VHL also lacked mutations for the respective genes. Five of these 9 patients suffered from hyperinsulinism and revealed multiple insulin-positive tumors. The other patients were nonsymptomatic and showed multiple glucagon-expressing neoplasms. In microadenomatosis patients with and without the MEN1 syndrome, a subset of morphologically normal-appearing islets showed increased endocrine cell proliferation. In conclusion, endocrine multihormonal microadenomatosis of the pancreas is a feature of MEN1. In addition, a monohormonal type of pancreatic microadenomatosis was identified that consisted of either insulinomas or glucagon-producing tumors and was not associated with MEN1 or VHL.

The 2004 WHO classification with 4 risk groups is very reliable for predicting both disease-free survival and the time span until tumor-specific death. CK19 staining is a potential additional prognostic marker independent from the WHO criteria for pancreatic endocrine tumors.

Approximately 5-10% of neuroendocrine tumors (NETs) of the gastroenteropancreatic system (GEP) have a hereditary background. The known inherited syndromes include multiple endocrine neoplasia type 1, neurofibromatosis type 1, von Hippel-Lindau disease, and the tuberous sclerosis complex. This review discusses for each of these syndromes the: (1) involved genes and specific types of mutations, (2) disease prevalence and penetrance, (3) affected neuroendocrine tissues and related clinical syndromes, (4) special morphological features of NETs and their putative precursor lesions. In addition, GEP-NETs clustering in individual families or associated with other malignancies without known genetic background are discussed.

Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.

We analyzed pancreatic endocrine tumors (PETs) from 200 patients for the incidence of multihormonality and entrapped islets and correlated the results with clinicopathological features. Our series included 86 cases (43%) of functioning PET and 114 cases (57%) of nonfunctioning PET. Classified according to the WHO classification, there were 32 well-differentiated benign PETs, 85 well-differentiated PETs with uncertain behavior, and 83 well-differentiated malignant PETs. All tumors were immunostained for pancreatic hormones (insulin, glucagon, somatostatin, and pancreatic polypeptide) and for additional hormones such as gastrin, vasoactive intestinal polypeptide, calcitonin, seratonin, and adrenocorticotropic hormone. Multihormonality was found in 34% of all PETs and it was a frequent finding in the tumors of the uncertain behavior (38.8%) group. Islet entrapment was found in 57 tumors (28.5%) and was significantly more frequent in PETs with uncertain and malignant behavior than benign ones (p=0.01). In 57 cases, we also investigated whether ductule entrapment accompanied islet entrapment. Of these 57 tumors, 45 (79%) tumors had accompanying ductule entrapment. Ductule entrapment did not show significant correlation with malignancy and was a more frequent finding in nonfunctioning tumors. We conclude that the incidence of multihormonality in PETs is not as high as suggested previously and islet entrapping may reflect aggressive tumor growth and may be a complementary criterion for predicting the biological behavior of PETs.

In neonates, persistent hyperinsulinemic hypoglycemia (PHH) is associated with nesidioblastosis. In adults, PHH is usually caused by solitary benign insulinomas. We report on an adult patient who suffered from insulin-dependent diabetes mellitus, and subsequently developed PHH caused by diffuse nesidioblastosis. Mutations of the MEN1 and Mody (2/3) genes were ruled out. Preoperative diagnostic procedures, the histopathological criteria and the surgical treatment options of adult nesidioblastosis are discussed. So far only one similar case of adult nesidioblastosis subsequent to diabetes mellitus II has been reported in the literature. In case of conversion of diabetes into hyperinsulinemic hypoglycemia syndrome, nesidioblastosis in addition to insulinoma should be considered.

Neuroendokrine Tumoren des gastroenteropankreatischen Systems (GEP-NET) sind charakterisiert durch die Expression neuroendokriner Marker sowie die Synthese, Speicherung und Sekretion von Peptidhormonen und/ oder biogenen Aminen. Es handelt sich um mehr als 50 unterschiedliche Tumorentitäten mit klinisch sehr unterschiedlichem Verlauf. Sie können sporadisch oder familiär auftreten. Die hohe biologische und klinische Vielfalt äußert sich in unterschiedlichen genetischen Profilen auf DNA- und mRNA-Ebene, welche wie folgt zusammengefasst werden können: 1. NET unterscheiden sich genetisch von den häufigen nichtneuroendokrinen Karzinomen des Verdauungstraktes. 2. Die klinisch-pathologische Heterogenität der GEP-NET spiegelt sich auch auf genetischer Ebene wider. 3. Bei pankreatischen NET finden sich deutliche genetische Unterschiede zwischen Insulinomen und anderen Entitäten. 4. Die Tumorprogression geht bei pankreatischen NET mit einer Zunahme von genetischen Veränderungen einher. 5. Pankreatische NET unterscheiden sich genetisch von gastrointestinalen NET. 6. Sporadische GEP-NET unterscheiden sich genetisch von hereditären (familiären) GEP-NET.