Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression

Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1α, HIF-2α and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm−2, respectively, P<0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1α expression. Poorly differentiated carcinomas were associated with nuclear HIF-1α and membranous CA9 expression. Low MVD (P=0.0001) and membranous CA9 expression (P=0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours

Les tumeurs kystiques du pancréas

Les lésions kystiques du pancréas regroupent les pseudo-kystes, les tumeurs kystiques et les kystes vrais du pancréas. Les pseudo-kystes représentent à eux-seuls près de 90%des lésions kystiques du pancréas. Les cystadénomes séreux et mucineux, les cystadénocarcinomes et les tumeurs intra-canalaires papillaires et mucineuses du pancréas représentent la majorité des tumeurs kystiques du pancréas. Les autres lésions kystiques (tumeurs kystiques et papillaires, tumeurs endocrines kystiques, kystes congénitaux du pancréas uniques ou multiples…) sont encore plus rares. Le diagnostic pré-opératoire des lésions kystiques conditionne l’attitude thérapeutique. En effet, certaines d’entre elles sont potentiellement malignes (cystadénomes mucineux, cystadénocarcinomes, tumeur intra-canalaire papillaire et mucineuse, tumeur kystique et papillaire, tumeur endocrine kystique) et doivent être réséquées chirurgicalement alors que d’autres (pseudo-kystes, et cystadénomes séreux) sont bénignes ou pratiquement toujours bénignes. Le contexte clinique peut orienter vers un type de lésion. Ainsi, le diagnostic de pseudokyste doit être évoqué en priorité chez un malade atteint de pancréatite chronique; à l’opposé, le diagnostic de cystadénome pancréatique doit être envisagé d’emblée en présence d’une lésion kystique peu ou pas symptomatique chez une femme d’âge moyen n’ayant pas d’antécédent de pancréatite. Le diagnostic pré-opératoire du type de lésion est correctement effectué trois fois sur quatre avec les techniques d’imageries (échographie, scanner, CPRE, écho-endoscopie). En revanche, lorsque l’on est en présence d’une lésion macrokystique unique du pancréas, il est souvent impossible de trancher entre un pseudo-kyste, un cystadénome mucineux ou un cystadénome séreux macro-kystique. La ponction et le recueil de liquide kystique au mieux effectués par voie écho-endoscopiquement guidée permettent alors de réaliser une étude cytologique et une analyse du taux des enzymes pancréatiques et des marqueurs tumoraux (ACE, CA 19-9, CA 72-4, mucines) qui sont susceptibles d’apporter des informations complémentaires à celles de l’imagerie pour le diagnostic de la lésion kystique étudiée

Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.

Objective Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. Methods Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. Results Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. Conclusions Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour

Mutational screening of the cationic trypsinogen gene in a large cohort of subjects with idiopathic chronic pancreatitis

Several missense mutations, including R122H, N29I, K23R, A16V and D22G, in the cationic trypsinogen gene (PRSS1), have been associated with certain forms of hereditary pancreatitis (HP). Their occurrence in the idiopathic chronic pancreatitis (ICP) and whether novel mutations could be identified in PRSS1 remain to be further evaluated. These were addressed by the mutational screening of the entire coding sequence and the intronic/exonic boundaries of the PRSS1 gene in 221 ICP subjects, using a previously established denaturing gradient gel electrophoresis technique. Among the known PRSS1 mutations, only the R122H was detected in a single subject and the A16V in two subjects in the cohort, strengthening that HP-associated PRSS1 mutations are rare in ICP. Additional missense mutations, including P36R, E79K, G83E, K92N and V123M, were identified once separately. By analogy with the known PRSS1 mutations, predisposition to pancreatitis by some of them, particularly the V123M autolysis cleavage site mutation, is suspected. Functional analysis is expected to clarify their possible medical consequences