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Introduction. Intraductal papillary mucinous neoplasm (IPMN) is the most common cystic precancerous lesion of pancreatic cancer (PDA). IPMNs can progress from low to high-grade dysplasia, to invasive PDAC, but exact data regarding cancer risks are limited. PDAC is the fourth leading cause of cancer death . The overall 5-year survival is 6%, but survival of patients with early stage PDAC is significantly better. AIM We used an approach coupling high resolution cytogenetic analysis (Affymetrix Oncoscan FFPE Array) with a clinically-oriented bioinformatic interpretation of data to understand what are the most relevant pathways altered in precursor lesions. Materials and methods High resolution cytogenetic analysis was performed in 20 formalin fixed paraffin embedded samples of IPMNs by Oncoscan FFPE assay. Genomic data were analyzed for copy number gains and losses, loss of heterozygosity and for a panel of recurrent somatic mutations. Results were validated by qPCR and FISH analysis. Results Twenty samples, including 14 mixed-type IPMNs (70%), 4 branch-duct IPMNs (20%) and 2 main-duct IPMNs (10%), were collected. We identified micro-invasive carcinoma (< 1 mm) and invasive carcinoma in 25% and in 10% of IPMNs respectively. By our high resolution cytogenetic analysis we observed that 8 IPMNs (40%) presented a nearly normal karyotype (< 4 copy number alterations), while 12 IPMNs (60%) showed a complex karyotype (> 10 alterations). In the latter subgroup were detected specific copy number gains of TERC and c-MYC oncogenes. Interestingly we noticed that TERC and c-MYC overexpression, present in 92% and 45% of complex karyotype samples respectively, were only observed in high-grade IPMNs, suggesting a possible role in a progression to malignancy. Oncoscan data were confirmed by Real Time and FISH analysis. Conclusions Those results suggest a role of TERC and c-MYC overexpression as a possible biomarkers in the early identification of patients with complex karyotype IPMNs in order to better stratification of cystic lesions that could require surgery

Context The role of lymph node ratio (LNR) has been recognized as a prognostic factor in several malignancies. Objectives To evaluate the role of LNR in patients affected by pancreatic neuroendocrine tumors (pNETs). Methods Data regarding 45 patients were extracted from a dedicate database containing 92 patients undergone surgical exploration for pNETs. Patients who underwent palliative operation or enucleoresection or without Ki-67 determination were excluded. Sex, age, presence of symptoms, hormonal status, site of tumor, presence of MEN1, surgical procedure, R status, TNM-ENETS stage, WHO 2010 classification, Ki-67, and LNR were studied as possible factors influencing disease free survival (DFS) with univariate and multivariate analyses. Results Mean age of patients was 60±13 years. There were 22 (51.2%) female and 21 (48.8%) male. Symptoms were present in 27 (62.8%) patients. 34 (79.1%) patients had non-functioning pNETs and more frequently the tumor was located in the body (46.5%). Five (11.6%) patients were affected by MEN1. R0 resection was carried out in 38 (88.4%) cases. There were 17 (39.5%) pNETs G1, 24 (55.8%) pNETs G2 and 2 (4.7%) pancreatic neuroendocrine carcinomas (pNECs) G3. Mean Ki-67 was 6±10%. According to TNM-ENETS stage there were 17 (39.5%), 2 (4.7%), 17 (39.5%), and 7 (16.3%) patients in stage I, II, III, and IV, respectively. LNR was 0 in 26 (60.5%) patients, between 0 and 0.2 in 8 (18.6%) patients, and >0.2 in 9 (20.9%) patients. Mean DFS was 48±56 months. Multivariate analysis found that TNM-ENETS stage (HR 5.0; P=0.036) and Ki-67 (HR 1.2; P=0.016) were significantly related to DFS. There were no differences between patients with LNR=0 and LNR between 0 and 0.2 (HR 5.9; P=0.172) while patients with LNR between 0 and 0.2 had better DFS respect to those with LNR >0.2 (HR=0.2; P=0.01). A new cut off for LNR of 0.07 was obtained by ROC curve (AUC 0.771; P=0.008). Considering the new cut off, the multivariate analysis showed that LNR Conclusion LNR can be considered an important prognostic factor predicting DFS in patients affected by pNETs., JOP. Journal of the Pancreas, Vol 13, N° 5S (2012): September (Suppl.) - p. 548-650

Context Intraductal papillary mucinous neoplasms (IPMN) of the pancreas represent an evolving pancreatic disease. Case report A 68-year-old asymptomatic woman, mild smoker, with clinical history of gallstones, arterial hypertension and surgical treatment for breast carcinoma, was admitted to our surgical unit in January 2012. An ultrasound examination, performed as a follow-up for gallstones, showed a cystic lesion of the pancreatic head. Laboratory tests revealed an increase of pancreatic amylases (114 U/L; reference range: 8-52 U/L) and lipases (89 U/L; reference range: 8-78 U/L), while tumor markers were within reference range. A contrast-enhanced CT scan showed the presence of a 22 mm diameter, multilocular, cystic lesion of the pancreatic head, with contrast-enhanced mural nodules. An endoscopic ultrasonography confirmed the lesion, the mural nodules and showed no dilatation of the main pancreatic duct (MPD); a fine needle aspiration (FNA) revealed an increase of CEA (416.6 ng/mL; reference range: 0-192 ng/mL) in the cystic fluid and cytological analysis showed mild to high grade dysplasia. The CEA levels were suggestive of a mucinous cystic neoplasm, while the presence of mural nodules suggested a malignant type II IPMN. Thus, a pancreaticoduodenectomy was performed. The postoperative course was uneventful and the patient was discharged in postoperative day 18th. The pathological specimen macroscopically showed a solid 14 mm diameter microcystic lesion with endoluminal micropapillae. Microscopically, the lesion was characterized by a carcinoma with tubulo-papillary pattern of growth, atypical cube-shaped cells without cytoplasmatic mucin and intralesional necrotic foci. Moreover, in the pathological specimen, clusters of IPMN gastric-subtype, with low to moderate dysplasia, were detected. These findings suggested the diagnosis of a well differentiated tubulo-papillary carcinoma associated to a mild dysplasia type II IPMN. All lymph nodes were negative. The patient is well and alive at 6 months from surgery. Conclusion To our knowledge, in literature only ten cases of ITPN were reported and its peculiar characteristic seems to be a more aggressive natural history., JOP. Journal of the Pancreas, Vol 13, N° 5S (2012): September (Suppl.) - p. 548-650

Context Groove pancreatitis is a chronic inflammation of ectopic pancreatic tissue within the duodenal C-loop and the head of the pancreas. Case report A 56-year-old man affected by Crohn’s disease was admitted to our Surgical Unit in 2010 for epigastric pain associated with jaundice, weight loss and vomiting. He was not an alcohol drinker. Laboratory tests revealed abnormal levels of total bilirubin (25.6 mg/dL), amylase and lipase (108 and 293 UI/L, respectively) and CA 19-9 (2,435 IU/mL). An US and a CT scan showed dilatation of common bile duct, a 30 mm iso-hypodense area in the head of pancreas involving the duodenal wall and a dilatation of the main pancreatic duct (6 mm). A FNAB revealed the presence of a poorly differentiated adenocarcinoma. Finally, a 18F-FDG PET-CT scan showed an hyperfixation (SUVmax=4.3) of the pancreatic lesion. Thus, the patient underwent a pylorus-preserving pancreaticoduodenectomy. The postoperative course was regular, with discharge in postoperative day 14th. Macroscopically, the pathological specimen showed a 50 mm multicystic paraduodenal mass and a solid 30 mm pancreatic nodule. Microscopically, the first lesion was consistent with a pancreatic hamartoma of the duodenal wall, with morphologic aspects of “groove pancreatitis”, while the solid nodule was a poorly differentiated pancreatic adenocarcinoma. Moreover, the adjacent pancreatic parenchyma was affected by a diffuse lymphoplasmacytic and eosinophilic autoimmune pancreatitis with epithelial granulocytic lesions. Five lymph nodes were metastatic (n=22), while resection margins were free. Patient is well and alive at 2 years from surgery. Conclusion A recent literature review of 348 patients with groove pancreatitis showed the association either with chronic pancreatitis (62.5%) and ductal adenocarcinoma (0.3%), separately. Our case is peculiar because the groove pancreatitis is associated with both pancreatic adenocarcinoma and autoimmune pancreatitis. Furthermore, there is no evidence that these pathologic entities could be connected each other., JOP. Journal of the Pancreas, Vol 13, N° 5S (2012): September (Suppl.) - p. 548-650

Context Inflammatory myofibroblastic tumors (IMTs), although originally described in the pulmonary system, are being reported in different anatomical locations. Case report A 55-year-old, asymptomatic man with clinical history of arterial hypertension and past smoking behavior, was admitted to our Surgical Unit in March 2012. A previous CT scan, performed for benign prostatic hyperplasia, revealed a 30 mm diameter mass in the pancreatic tail. Laboratory tests were within normal range. A further contrast-enhanced CT scan confirmed the presence of a nodular hypodense lesion with calcifications in the pancreatic tail, with no involvement of the spleen. A CWRM showed no communication with the main pancreatic duct. Finally, a 18F-FDG PET-CT scan showed no areas of pathological hyperfixation. The patient underwent a laparoscopic distal pancreatectomy. During the surgical procedure, due to the infiltration of transverse mesocolon and retroperitoneal fat, an en-block resection of pancreatic body-tail, spleen and splenic flexure of the colon was performed. The postoperative course was uneventful and the patient was discharged in postoperative day 9th. Macroscopically, the pathological examination showed a whitish, solitary, calcific, irregular shaped nodule. Microscopically, the lesion was characterized by myofibroblastic spindle cells mixed with diffuse inflammation made up of lymphocytes, plasmacells and eosinophils. Moreover, a myxoid struma together with a rich vascular growth was detected. These findings were consistent with a fasciitis-like variant of IMT. The patient is well and alive at 3 months from surgery. Conclusion To our knowledge, only 26 case of pancreatic IMT are reported in literature. They were mostly discovered incidentally and surgically treated, as in our case. This management seems to be correct because IMT is described as a neoplasm of intermediate biological behavior, with tendency for local recurrence instead of distant metastasizing., JOP. Journal of the Pancreas, Vol 13, N° 5S (2012): September (Suppl.) - p. 548-650

Context Mucinous cystic neoplasms (MCN) of the pancreas concern usually female patients and are characterized by an ovarian-type stroma. Case report A 65-year-old man was admitted to our Institute for the incidental finding, at ultrasonography, of a cystic mass of the body-tail of the pancreas. Laboratory tests, including tumor markers (CEA and CA 19-9), were within normal range. A CT scan confirmed the mass, hypodense, unilocular, 45 mm in diameter, regular shaped and without neither contrast enhancement nor signs of infiltration of adjacent structures. A CWRM showed a well-shaped pancreatic gland with a 49 mm in diameter fluid mass of the body, without septa or endoluminal solid nodules, without a clear communication with the main pancreatic duct. Contrast enhanced-US confirmed a strict connection with the splenic vessels, without infiltration, and revealed the absence of contrast-enhancement as well as the presence of communication with the pancreatic duct. These features suggested an IPMN branch duct type larger than 3 cm. The patient underwent a subtotal pancreatectomy with spleen resection. Pathological examination showed a cystic lesion measuring 40 mm in diameter, with unilocular pattern, smooth and white inner walls, containing viscous whitish mucin and without communication with the main pancreatic duct. Microscopically, the lesion showed two components: a mucinous epithelial layer and a low-grade dysplasia ovarian-type stroma. Tumor cells displayed diffuse positivity for estrogen, progesteron and calretinin. Lymph-nodes (n=6) were negative and surgical margins were tumor-free. A final diagnosis of MCN was performed. Postoperative course was complicated by a pancreatic fistula, grade B, treated with a CT-guided abdominal drainage. The patient was discharged in postoperative day 14 with a minimal residual drainage output and he is alive, disease-free at 6 months after surgery. Conclusion Only 9 cases of MCN have been reported in male patients in literature. Thus, the occurrence of MCN in male patients is very rare and its possible pathogenesis could be referred to embryological abnormalities., JOP. Journal of the Pancreas, Vol 13, N° 5S (2012): September (Suppl.) - p. 548-650

// Sandra Durante 1, * , Silvia Vecchiarelli 2, * , Annalisa Astolfi 1 , Elisa Grassi 2 , Riccardo Casadei 3 , Donatella Santini 4 , Riccardo Panzacchi 4 , Claudio Ricci 3 , Salvatore Serravalle 5 , Giuseppe Tarantino 1 , Mirella Falconi 6 , Gabriella Teti 6 , Valentina Indio 1 , Andrea Pession 5 , Francesco Minni 3 , Guido Biasco 1, 2 , Mariacristina Di Marco 2 1 Giorgio Prodi Cancer Research Centre, University of Bologna, Bologna, Italy 2 Department of Experimental, Diagnostic and Specialty Medicine University of Bologna, Sant’Orsola-Malpighi Hospital, Bologna, Italy 3 Department of Medical and Surgical Sciences, University of Bologna, Sant’Orsola-Malpighi Hospital, Bologna, Italy 4 Pathology Unit, Sant'Orsola-Malpighi Hospital, Bologna, Italy 5 Department of Medical and Surgical Sciences, “Lalla Seragnoli” Hematology-Oncology Unit, University of Bologna, Bologna, Italy 6 DIBINEM—Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy * These authors contributed equally to this work Correspondence to: Annalisa Astolfi, email: annalisa.astolfi@unibo.it Keywords: PDA, IPMN, chromosome 3, NGS, PIK3CA Received: April 11, 2016 Accepted: August 10, 2016 Published: August 22, 2016 ABSTRACT Background: Intraductal papillary mucinous neoplasm (IPMN) is the most common cystic preneoplastic lesion of pancreatic cancer. We used an approach coupling high resolution cytogenetic analysis (Affymetrix Oncoscan FFPE Array) with clinically-oriented bioinformatic interpretation of data to understand the most relevant alterations of precursor lesions at different stages to identify new diagnostic markers. Results: We identified multiple copy number alterations, particularly in lesions with severe dysplasia, with 7 IPMN with low-intermediate dysplasia carrying a nearly normal karyotype and 13 IPMN with complex Karyotype (> 4 alterations), showing high grade dysplasia. A specific gain of chromosome arm 3q was found in IPMN with complex Karyotype (92%). This gain of 3q is particularly interesting for the presence of oncogenes such as PIK3CA, GATA2 and TERC that are part of pathways that deregulate cell growth and promote disease progression. Quantitative PCR and FISH analysis confirmed the data . Further demonstration of the overexpression of the PIK3CA gene supports the identification of this alteration as a possible biomarker in the early identification of patients with IPMN at higher risk for disease progression. Materials and methods: High resolution cytogenetic analysis was performed in 20 formalin fixed paraffin embedded samples of IPMN by Oncoscan FFPE assay. Results were validated by qPCR and FISH analysis. Conclusions: The identification of these markers at an early stage of disease onset could help to identify patients at risk for cancer progression and new candidates for a more specific targeted therapy.

Borderline ovarian tumors are rare low malignant potential neoplasms characterized by the absence of stromal invasion, whose main prognostic factors are stage and type of peritoneal implants. The latter are defined as invasive when cell proliferation invades the underlying tissue (peritoneal surface, omentum and intestinal wall), or noninvasive. It is still unknown if these implants are metastatic spread from the primary ovarian mass or a neoplastic transformation de novo of the peritoneal surface. Mitochondrial DNA sequencing was performed to assess clonality in eight patients presenting both borderline ovarian tumors and implants. In 37.5% of the cases, the same mitochondrial DNA mutation was present in both borderline ovarian tumors and the peritoneal implant, being this evidence that implants may arise as a consequence of a spread from a single ovarian site. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0614-y) contains supplementary material, which is available to authorized users.