Anna Caterina Milanetto

Parenchyma-sparing pancreatectomies for benign or border-line tumors of the pancreas.

Standard pancreatic resections, such as pancreaticoduodenectomy, distal pancreatectomy, or total pancreatectomy, result in an important loss of normal pancreatic parenchyma and may cause impairment of exocrine and endocrine function. Whilst these procedures are mandatory for malignant tumors, they seem to be too extensive for benign or border-line tumors, especially in patients with a long life expectancy. In recent years, there has been a growing interest in parenchyma-sparing pancreatic surgery with the aim of achieving better functional results without compromising oncological radicality in patients with benign, border-line or low-grade malignant tumors. Several limited resections have been introduced for isolated or multiple pancreatic lesions, depending on the location of the tumor: central pancreatectomy, duodenum-preserving pancreatic head resection with or without segmental duodenectomy, inferior head resection, dorsal pancreatectomy, excavation of the pancreatic head, middle-preserving pancreatectomy, and other multiple segmental resections. All these procedures are technically feasible in experienced hands, with very low mortality, although with high morbidity rate when compared to standard procedures. Pancreatic endocrine and exocrine function is better preserved with good quality of life in most of the patients, and tumor recurrence is uncommon. Careful patient selection and expertise in pancreatic surgery are crucial to achieve the best results.

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.

Health-Related Quality of Life After Surgery for Small Intestinal Neuroendocrine Tumours

BackgroundOverall survival for patients with small intestinal neuroendocrine tumours (siNETs) is long, even with metastatic disease, making quality of life issues relevant. The impact of surgery on quality of life is not known. We investigated determinants of health-related quality of life in patients who had undergone surgery for a siNET.MethodsPatients operated for a siNET between 1998 and 2016 at Skåne University Hospital (Lund, Sweden), who were alive in February 2017, were sent two questionnaires constructed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30, EORTC QLQ-GINET21). Global quality of life, physical function, disease-related worries, diarrhoea and endocrine symptoms were evaluated with linear and logistic regression in relation to patient-, tumour- and treatment-related factors. Statistical analysis was performed using STATA 11®.ResultsOne hundred patients (84%) completed the questionnaires. Women had worse global quality of life (p = 0.019), more disease-related worries (p < 0.001) and endocrine symptoms (p = 0.017) than men. Older age was associated with more disease-related worries (p = 0.007), but fewer endocrine symptoms (p = 0.034). Non-symptomatic tumour versus symptomatic tumour (p = 0.002), and treatment with somatostatin analogues versus no treatment (p = 0.040) were associated with less diarrhoea. Small versus large bowel resection was associated with better global quality of life (p = 0.036) and physical function (p = 0.035).ConclusionsMale gender, younger age, treatment with somatostatin analogues, non-symptomatic tumour, and small intestinal surgery rather than large bowel surgery were associated with better quality of life.

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

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.

PET Scan in Cystic Tumors of the Pancreas

Characterization of the pancreatic cystic lesion with reliable, noninvasive methods is crucial to distinguish benign from malignant cystic tumors of the pancreas in order to plan treatment options or follow-up. Despite evaluation with sophisticated preoperative investigations, a correct pathologic diagnosis rate does not exceed 68 %, due to heterogeneous variety of lesions with different behaviors, resulting often in over- or undertreatment of these lesions.

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.

Pancreatic Metastasis from Carcinoid Midgut Tumor. A Case Report

Context Metastatic lesions to the pancreas are rare. We present a case of an ileal carcinoid tumor with a synchronous pancreatic metastasis. Case report A 68-year-old male patient was admitted to our clinic in 2008 for diarrhea and flushing. Urinary serotonin (2x upper reference limit), 5HIAA (5x upper reference limit) and chromogranin A (2.5x upper reference limit) were increased. An octreoscan scintigraphy showed a focal uptake in the pancreatic head and a slight uptake in the lower abdomen. An abdominal CT scan did not show any pancreatic lesions, but a slightly enlarged pancreatic duct in the body of the pancreas. We reviewed the CT scan imaging and we found a hypervascular ileal lesion, confirmed by small bowel barium study. The pancreatic lesion was confirmed by MRI and resulted slightly hypermetabolic with 18 FDG-PET (SUV of 2.15). In November 2008 the patient underwent a duodenum-preserving pancreatic head resection (DPPHR), a cholecystectomy, an ileal resection (about 80 cm) and ablation of small multiple peritoneal nodules. Histology showed multiple well differentiated (Ki67 <2%) ileal carcinoid tumors with lymph-node metastases and tiny peritoneal secondary lesions. The pancreatic lesion resulted to be a metastasis of the carcinoid with positive serotonin staining. The patient is still alive with diarrhea, biochemical evidence of disease and multiple pulmonary metastases 48 months after surgery. Conclusion Pancreas is an uncommon site of metastatic spread in midgut carcinoids and should be considered in case of pancreatic synchronous lesions. In the literature we found a single case report in the last 10 years.

An Intraductal Variant of Acinar Cell Carcinoma. Report of a Case

Context Pancreatic intraductal neoplasms in the past few years had increasing importance, as the incidence of these tumors (especially intraductal papillary mucinous neoplasms-IPMNs) has grown and their significance as precursors of invasive cancer is now better appreciated. Acinar cell carcinomas (ACCs) are typically solid tumors; however, a few cases of ACCs with intraductal growth pattern have been described in the literature. These kind of neoplasia can be easily mistaken for IPMNs. We report a case of an acinar cell carcinoma of the pancreatic head with a polipoid intraductal growth. Case report A 42-year-old woman was observed in our unit for recurrent epigastric pain. Blood exams showed a mild increase of serum lipase and amylase levels (141 and 116 U/L, respectively). Serum tumor markers were negative. An abdominal ultrasound showed an hypoechoic area in the pancreatic head, with a maximum diameter of 14.5 mm. The patient underwent also a CT scan which confirmed the pancreatic head mass and showed a dilated Wirsung duct. A 18 F-fluorodeoxyglucose positron emission tomography showed a pathological uptake of the tracer in an area of 2 cm, corresponding to the pancreatic head, with a maximum SUV of 7.5. In the suspicion of a degenerated IPMN, the patient underwent a pancreaticoduodenectomy. The post-operative course was uneventful. Histology showed an acinar cell carcinoma of the pancreatic head with a polypoid intraductal growth (T2 N0 M0). The tumor size was 2.0x2.5 cm, the mitotic index was 30x10 HPF. Immunohistochemistry studies found trypsin expression and no mucin was detected. Surgical margins were free. The patient underwent six course gemcitabine chemotherapy and is still alive 62 months after surgery without evidence of recurrence. Conclusion A few cases of ACCs with intraductal growth pattern have been described in the literature. The clinical significance of this variant is difficult to determine; however, it appears that metastasis at presentation is less common than typically seen in ACCs.