Valbona Liço

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05–4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.

Lack of Association for Reported Endocrine Pancreatic Cancer Risk Loci in the PANDoRA Consortium

Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms for which very little is known about either environmental or genetic risk factors. Only a handful of association studies have been performed so far, suggesting a small number of risk loci. Methods: To replicate the best findings, we have selected 16 SNPs suggested in previous studies to be relevant in PNET etiogenesis. We genotyped the selected SNPs (rs16944, rs1052536, rs1059293, rs1136410, rs1143634, rs2069762, rs2236302, rs2387632, rs3212961, rs3734299, rs3803258, rs4962081, rs7234941, rs7243091, rs12957119, and rs1800629) in 344 PNET sporadic cases and 2,721 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium. Results: After correction for multiple testing, we did not observe any statistically significant association between the SNPs and PNET risk. We also used three online bioinformatic tools (HaploReg, RegulomeDB, and GTEx) to predict a possible functional role of the SNPs, but we did not observe any clear indication. Conclusions: None of the selected SNPs were convincingly associated with PNET risk in the PANDoRA consortium. Impact: We can exclude a major role of the selected polymorphisms in PNET etiology, and this highlights the need for replication of epidemiologic findings in independent populations, especially in rare diseases such as PNETs. Cancer Epidemiol Biomarkers Prev; 26(8); 1349–51. ©2017 AACR.

Primary Carcinoid Tumors of the Pancreas: Report of Eight Cases

Context Primary pancreatic carcinoid tumors (foregut) are very rare. A typical carcinoid syndrome with diarrhea and flushing may be present. The diagnosis is based on the high urinary 5-HIAA (5-hydroxyndole acetic acid) levels (or high serum serotonin levels) or the immunostaining of serotonin (5-HT) in the tumor cells. Objective We evaluated clinical presentation, endocrine tumor markers, histology, therapeutic approach and follow up. Methods From 1986 to 2011 in our department we observed 211 neuroendocrine (NE) pancreatic tumors and 8 of them (3.8%) were primary carcinoid tumors (5 males and 3 females; averaging 55.8 years, range: 38-69 years). Follow up was updated until December 2012. Results Among the eight patients enrolled, 3 were symptomatic. Seven had high serum 5-HT or high urinary 5-HIAA, and one was asymptomatic with immunostaining of 5-HT in tumor cells. Location: 6 body-tail. All were malignant tumors: 7 liver and 1 single nodal metastases. Markers: 4 high serum 5-HT (up to 176 µmol/L), 7 high urinary 5-HIAA (up to 522 µmol/L). Surgery: 1 left pancreatectomy, 7 biopsy. Histology: 7 NE tumor, 1 negative pancreatic biopsy (liver metastases). Other therapy: 3 treated with somatostatin analogues (SST-A) and chemotherapy (CT), 1 CT and radiometabolic therapy after hepatic artery embolization (HAE), 1 HAE and SST-A, 1 CT. Follow up: 6 dead for disease progression (mean survival 52 months), 2 alive (1 without disease 78 months after surgery; 1 asymptomatic with high 5-HIAA 33 months after SST-A and CT). Conclusion Most of primary pancreatic carcinoids are locally advanced tumors or have liver metastases at time of diagnosis, then patients are not amenable to surgery. Although most patients had high 5-HIAA urinary excretion, few patients had carcinoid syndrome. A long term survival may be achieved with multimodal approach, including chemotherapy, in foregut carcinoid tumors.

Mixed Exocrine-Endocrine Tumors of the Pancreas

Context Mixed exocrine-endocrine pancreatic tumors are extremely rare representing only 0.2% of all pancreatic tumors. They are characterized by the association of an exocrine (ductal or acinar) with an endocrine component with positive immunostaining for endocrine markers in >30% of the tumor cells. Mixed pancreatic carcinomas are usually large tumors, located in the head of the pancreas (60%), occurring mostly in middle aged patients. Objective To evaluate clinical presentation, surgical therapy, histological features, outcome and follow up of mixed exocrine/endocrine tumors observed in the last 10 years. Methods We reviewed the clinical records of 6 patients affected by mixed exocrine-endocrine tumors of the pancreas, admitted in our Unit from June 2002 to December 2011. Results Out of six patients enrolled in the study (3 females and 3 males averaging 67.5 years) 2 were asymptomatic, 3 had jaundice, and 1 had hypoglycemia. Five were in the head and 1 in the whole pancreas, with 2 cases of hepatic and peritoneal metastases. The size of the primary tumor ranged 1.4-10.0 cm. Three cases expressed exocrine serum tumor markers (CA 19-9, aFP, CEA, CA 125), and 1 neuroendocrine markers. We performed 2 pancreaticoduodenectomy, 1 bypass surgery for vascular involvement and 1 enucleation. Two cases had only pancreatic/hepatic percutaneous biopsy. Post-operative mortality was nihl and morbidity was 2/4:1 abdominal fluid collection and 1 asymptomatic pseudocyst. Histological features: 2 acinar cell carcinomas with neuroendocrine component, 2 ductal adenocarcinomas with neuroendocrine component, 2 neuroendocrine tumors with a ductal carcinoma component. Mean follow up was 28.8 months (range: 3-114 months; in 5/6 cases with at least 3 months of follow up). In 2/5 cases who had primary tumor resection DFS was 17 and 114 months. In 2/5 cases with peritoneal metastatic disease survival was 3 and 6 months. Conclusion The prognosis of pancreatic tumor with mixed exocrine/endocrine cells is strongly conditioned by the behavior of the exocrine component. In most cases the histological diagnosis is known only postoperatively and the therapeutic approach is not changed by the final diagnosis.

Microglandular Carcinoma of the Pancreas: A Case Report

Context Microadenocarcinoma (MA) of the pancreas is a rare kind of neoplasm. The term microadenocarcinoma was first proposed for a subtype of pancreatic carcinoma by Cubilla and Fitzgerald in 1975 based largely on the morphological features: small crowded microglandular structures, forming a cribriform pattern, sometimes solid sheets. The status of microadenocarcinoma as an independent tumor entity is still a matter of controversy. We present a case of microglandular carcinoma of the pancreatic head. Case report A 77-year-old man was observed in our department for dyspepsia and important loss of weight. He underwent an abdominal ultrasound which showed a pancreatic head mass of 5.0x5.5 cm. CA 19-9 was 46,300 U/L (reference range: 0-37 U/L). The patient underwent also a CT scan and MRI which confirmed the pancreatic head mass. A 18 F-fluorodeoxyglucose positron emission tomography showed a pathological uptake of the tracer in an area of 5 cm, corresponding to the pancreatic head, with a maximum SUV of 3.0. The patient underwent a pancreaticoduodenectomy with a Traverso-Longmire reconstruction. The postoperative course was uneventful. Histology revealed a microglandular carcinoma of the pancreatic head with ductal and acinar differentiation. The tumor size was 6.5x5.0 cm, the MIB1 was 70%. The immunohistochemical study showed positive staining of the neoplastic cells with CAM 5.2 antibodies and negative staining with a battery of neuroendocrine-related markers. The patient underwent chemotherapy with gemcitabine. He died of progression of disease 55 months after surgery. Conclusion MA is a rare pancreatic neoplasia. The main importance of recognizing this rare variant of pancreatic carcinoma lies in avoiding misdiagnosis with other primary and metastatic neuroendocrine neoplasms. Immunohistochemical studies will be of value in such cases for differential diagnosis.

Surgical Treatment of Pancreatic Insulinoma: 45 Years of Experience in a Single Center

Context Insulinoma is the most common endocrine tumor of the pancreas. Over 90% of insulinomas are benign, single and evenly distributed in head, body and tail of the pancreas. Depending on the location, they can be enucleated or may require partial pancreatectomy. Objective To evaluate histological features, type of surgery, early complications (within 30 days) and prognosis. Methods We reviewed clinical data of patients observed for organic hyperinsulinism from January 1966 to December 2010 in our Department (follow up to December 2011). Results From 1966 to 2010 we observed 102 patients with organic hyperinsulinism (60 females and 42 males averaging 49.5 years). We had 7 cases of hyperplasia/ nesidioblastosis, 7 multiple tumors and 7 malignant insulinomas. Localization: 32 pancreatic head, 8 neck, 21 body, 33 tail, 5 whole pancreas, 1 left ovary and 2 unknown. Surgery: 39 enucleations, 38 distal pancreatectomies, 6 central pancreatectomies, 3 DPPHR, 2 pancreaticoduodenectomies, 4 total/subtotal pancreatectomies, 3 other surgery. Perioperative mortality was 5% (3 acute pancreatitis, 1 stroke, 1 disseminated intravascular coagulation). Perioperative morbidity was 23% (3 acute pancreatitis, 13 pancreatic fistulas, 4 abdominal abscesses, 2 pseudocysts, 1 biliary leakage). In 5 cases a second operation was necessary. Excluding malignant cases, postoperative deaths and not operated cases, 86/88 patients were cured after surgery and we had 2 cases of persistent hypoglycemia (1 hyperplasia, 1 not found). After a mean follow up of 212 months (89 patients included), 64/89 are still alive and free of disease. Among the dead patients, 3/23 died of disease progression. Among 7 malignant cases, 2/7 with lymph node metastases had a survival of 167 and 388 months after resection of the primary tumor and nodes. The median survival of the 5/7 not resected was 12 months. Conclusion Surgical treatment of insulinomas can be challenging and in some cases is still associated to mortality (5%). A high rate of surgical success (98%) was obtained with 5% of reoperation.

Dermoid Cyst of the Pancreas: A Challenging Differential Diagnosis Among Benign Pancreatic Cysts

Context Dermoid cysts are congenital developmental abnormalities of germ cell origin arising from embryonic residues and they are usually benign, well-differentiated lesions. They are commonly found in the ovary, testes and retroperitoneum; the pancreas is extremely rare as a primary site. Case report A 68-year-old woman presented a cystic lesion (4 cm) of the pancreatic tail as an incidental finding at a MR scan performed for other reasons. A CT scan confirmed the tail lesion, which had a lamellar calcification on the posterior wall. A 18 FDG-PET was negative. Laboratory examination showed normal values, including CEA and CA 19-9. Because of the size of the lesion and the risk of malignancy, the patient underwent a spleen-preserving distal pancreatectomy. Histology showed a squamoid cyst (3 cm) of the pancreatic ducts. It was unilocular and had serous content and fibrous wall, with multilayered epithelium without cytological atypias (immunehistochemistry: CK7 positive and CK5 negative). The post-operative course was uneventful, but the patient was readmitted a few days after discharge for abdominal pain due to a peripancreatic fluid collection. She was treated with a percutaneous drainage and the catheter was removed after one month. She is still alive after 22 months of follow up. She is asymptomatic, with mild diabetes and a normal exocrine pancreatic function. The last CT scan and tumor markers were negative. Conclusion Less than 30 cases of dermoid cyst of the pancreas have been reported in the English literature. Most of patients were symptomatic by unspecific gastrointestinal discomfort. Imaging techniques failed the correct preoperative diagnosis, because the appearance may vary depending on the proportions of tissue components. They should be considered in the differential diagnosis of slow-growing benign pancreatic cysts. Despite the benign nature of dermoid cyst, oncologic resection is usually performed due to difficult preoperative diagnosis. No reliable predictive features were found to allow an organ- or parenchyma-preserving procedure. Surgery remains the treatment of choice to exclude malignancy.

Primary Clear Cell Carcinoma of Exocrine Pancreas: A Case Report

Context According to WHO classification, primary clear cell carcinoma of the pancreas is rare and it is classified as a “miscellaneous” carcinoma. There is not an adequate systematic overview of this entity and the few reports lack detailed morphological and immunocytochemical data. Case report A 65-year-old man presented in March 2009 with dyspepsia and a feeling of epigastric mass since two months, with an increase of serum amylase and lipase. The US showed a hypoechoic mass of the pancreatic head (3 cm), confirmed by the abdominal MR, which also detected a solid hepatic lesion, without encasement of the mesenteric vessels. At the 18 FDG-PET the lesion of the head of the pancreas had an increased tracer uptake (SUV max 9.2; SUV med 5.3) and CA 19-9 was 1,726 U/L. The patient underwent a palliative biliary and gastric bypass surgery and the histology of the hepatic lesion showed a metastasis of a clear cell adenocarcinoma. The post-operative course was uneventful. Then the patient received palliative radiotherapy and chemotherapy with gemcitabine and carboplatin. The patient died 23 months later of pancreatic cancer progression. Conclusion We presented a case of clear cell carcinoma of the pancreas with a single hepatic metastasis. Only few cases of clear cell carcinoma have been reported in the English literature. Clinical features and survival data were not significantly different from that of ductal adenocarcinoma.