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Background: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). Design: An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. Results: (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤0.5, >0.5-≤1, >1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intrabiliary/cholecystic). Conclusions: These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low‐grade malignant neoplasms that metastasise to the liver or peritoneum in 10–15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterisation of metastatic disease has been conducted to date. We performed whole‐exome sequencing and copy‐number variation (CNV) analysis of 10 primary SPN and comparative sequencing of five matched primary/metastatic tumour specimens by high‐coverage targeted sequencing of 409 genes. In addition to CTNNB1‐activating mutations, we found inactivating mutations of epigenetic regulators (KDM6A, TET1, BAP1) associated with metastatic disease. Most of these alterations were shared between primary and metastatic lesions, suggesting that they occurred before dissemination. Differently from mutations, the majority of CNVs were not shared among lesions from the same patients and affected genes involved in metabolic and pro‐proliferative pathways. Immunostaining of 27 SPNs showed that loss or reduction of KDM6A and BAP1 expression was significantly enriched in metastatic SPNs. Consistent with an increased transcriptional response to hypoxia in pancreatic adenocarcinomas bearing KDM6A inactivation, we showed that mutation or reduced KDM6A expression in SPNs is associated with increased expression of the HIF1α‐regulated protein GLUT1 at both primary and metastatic sites. Our results suggest that BAP1 and KDM6A function is a barrier to the development of metastasis in a subset of SPNs, which might open novel avenues for the treatment of this disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Italian Group of Gastrointestinal Pathologists has named a committee to develop recommendations concerning the surgical pathology report for pancreatic cancer. The committee, formed by individuals with special expertise, wrote the recommendations, which were reviewed and approved by council of the Group. The recommendations are divided into several areas including an informative gross description, gross specimen handling, histopathologic diagnosis, immunohistochemistry, molecular findings, and a checklist. The purpose of these recommendations is to provide a fully informative report for the clinician.

Progesterone receptors (PgR) have been immunocytochemically localized in the nuclei of several (40% to 75%) endocrine cells of the human pancreas and in a more variable number of neoplastic cells of 7 of 18 endocrine pancreatic tumors. Conversely the exocrine epithelial cells of the pancreas did not exhibit any PgR immunoreactivity in normal as well as in different pathologic conditions, including pancreatic adenocarcinomas. Estrogen receptors were not detected in any of the pancreatic samples investigated. Double immunocytochemical experiments have documented that PgR immunoreactivity in normal Langerhans islets is a consistent feature of most (75%) glucagon-producing A cells, of approximately 5% to 20% of insulin-producing B cells, and of a variable percentage of pancreatic polypeptide (PP)-producing cells, ranging from 5% to 70%. These figures were not affected by the sex, age, or underlying disease of the patients. The reported findings corroborate previous clinical and experimental evidence indicating that sex steroid hormones may have some regulatory effects on the functional activity of the endocrine pancreas.

During our DNA fingerprinting studies of paired normal and pancreatic cancer tissues using arbitrarily primed PCR, we noticed a band showing an apparent homozygous deletion in a pancreatic cancer cell line and a decreased intensity in a number of primary cancers. That band was assigned to chromosome 7. Such information led us to analyze chromosome 7 loss of heterozygosity (LOH) in a panel of 12 cryostat-enriched primary pancreatic cancers and 2 pancreatic cancer cell lines, despite the reportedly low frequency of chromosome 7 LOH in xenograft-enriched pancreatic cancers. Seventeen PCR-amplified CA-microsatellite polymorphic sites were analyzed. One of the two cell lines and eight common-type cancers (including all five poorly differentiated and three of five moderately differentiated cancers) showed chromosome 7q LOH, whereas the two uncommon types of ductal cancer (one adenosquamous and one mucinous noncystic) scored negative. Our data suggest that chromosome 7q LOH is a frequent event (80%) in cryostat-enrichable common pancreatic ductal carcinomas, that is, those primarily of high cellularity. The chromosome 7q smallest common deleted region described by our cases was between 7q31.1 and 7q32.

We examined 2 normal pancreata, 21 primary pancreatic ductal cancers, and 19 pancreatic cancer cell lines for Fhit expression and FHIT gene status. The normal pancreas expressed Fhit protein in the cytoplasm of ductular cells, whereas interlobular and larger ducts, acini, and insulae of Langerhans were negative. Fhit protein was detected by immunoblot assay in 11 pancreatic cancer cell lines; of the 8 cell lines lacking Fhit protein, 7 lacked FHIT mRNA and 1 showed an abnormally sized transcript. DNA from five of these eight cell lines showed homozygous loss of FHIT exon 5. In 8 of the 21 primary cancers, Fhit expression was detected by immunohistochemistry. Reverse transcription-PCR analysis of 6 of the 13 cases lacking Fhit showed normal-sized FHIT product in 3 cases and a mixture of normal and abnormal products in the other 3. Sequencing showed that abnormal bands were missing variable numbers of exons. Loss of microsatellite DNA markers internal to the FHIT gene was observed in 10 of 13 primary cancers lacking Fhit protein (homozygous in two cases) and in only 1 of the 8 cancers expressing Fhit protein. In nine primary cancers, four expressing and five lacking Fhit protein, it was possible to obtain pure cancer DNA by microdissection. Three of the five microdissected cases lacking Fhit protein exhibited homozygous deletion of FHIT exon 5. In conclusion, the lack of Fhit protein in pancreatic cancers correlated with absence or alteration of FHIT mRNA and was often associated with FHIT gene anomalies.

Background & Aims The risk of malignancy is uncertain for intraductal papillary mucinous neoplasms (IPMNs) with main pancreatic duct (MPD) of 5-9 mm. No study has correlated MPD size and malignancy considering the anatomic site of the gland (head versus body-tail). Our aim was to analyze the significance of MPD in pancreatic head/body-tail as a predictor of malignancy in main-duct/mixed IPMNs. Methods Retrospective analysis of resected patients between 2009-2018 was performed. Malignancy was defined as high-grade dysplasia and invasive carcinoma. MPD diameter was measured with magnetic resonance imaging. Receiver operating characteristic curve (ROC) analysis was utilized to identify optimal MPD cut-off for malignancy. Independent predictors of malignancy were searched. Results Malignancy was detected in 74% of 312 identified patients. 213 patients (68.3%) had IPMNs of the pancreatic head and 99 (31.7%) of the body-tail. ROC analysis identified 9 and 7 mm as the optimal MPD cut-offs for malignancy in IPMNs of head and body-tail of the pancreas, respectively. Multivariate analysis confirmed that MPD ≥9 mm (pancreatic head) and ≥7 mm (body-tail) were independent predictors of malignancy along with macroscopic solid components, positive cytology and elevated CA 19-9. The risk of malignancy was low for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) unless high-risk stigmata or multiple worrisome features were present. Conclusions Different thresholds of MPD dilation are associated with malignancy in IPMNs of the head and body-tail of the pancreas. The risk of malignancy for IPMNs with MPD ≤8 mm (pancreatic head) or ≤6 mm (pancreatic body-tail) lacking high-risk stigmata or multiple worrisome features is low.

Background There is an increased interest in venous vascular resection associated with pancreatic resection for pancreatic ductal adenocarcinoma as an upfront procedure or after neoadjuvant treatment. The aim of this study was to evaluate the impact of venous vascular resection for pancreatic ductal adenocarcinoma on postoperative and long-term outcomes. Methods The study is a retrospective analysis of patients who underwent pancreatectomy for pancreatic head pancreatic ductal adenocarcinoma with and without venous vascular resection between January 2010 and April 2018. The impact of venous vascular resection on postoperative and pathologic data was analyzed. Univariate and multivariate analyses of predictors of disease-free and disease-specific survival were analyzed for the entire cohort. A propensity-score matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity. Results Four hundred and eighty-one patients were included, and 126 (26%) underwent a venous vascular resection. Patients undergoing venous vascular resection had higher morbidity (64% vs 54%; P = .026) with no differences in 90-day postoperative mortality (3.1 vs 2.8%; P = .5). Venous vascular resections were also significantly associated with R1 resections (52% vs 37%; P = .002) and perineural invasion (87% vs 77%; P = .017). Five-year disease-free survival in patients with and without venous vascular resection were 7% and 20% (P = .018), respectively. Independent predictors of worse disease-free survival included venous vascular resection, positive lymph node status, and perineural invasion. Independent predictors of worse disease-specific survival were perineural invasion and positive nodal status, while adjuvant treatment was a protective factor. Five-year disease-specific survival in patients with and without venous vascular resection were 19% and 35% (P = .42). Conclusion Pancreatectomy with venous vascular resection can be accomplished safely. Venous vascular resections are associated with poor prognostic factors and with a worse clinical outcome, being a significant predictor of cancer recurrence.

Summary Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.

Background Intraductal papillary mucinous neoplasms (IPMN) have been reported to be associated with concurrent, distinct pancreatic ductal adenocarcinoma (con-PDAC) in about 8% (range, 4–10%) of resected branch duct (BD) lesions. In addition, other pancreatic and ampullary tumors are occasionally diagnosed with IPMN in patients undergoing pancreatic surgery. The objective of this study is to describe the prevalence, clinicopathologic characteristics and prognosis of IPMN with concurrent pancreatic and ampullary neoplasms, especially con-PDAC. Methods The combined databases of pancreatic resections from the Massachusetts General Hospital and the Negrar Hospital, Italy, were analyzed for patients who had been diagnosed with IPMN and concurrent pancreatic or ampullary neoplasms. Results 2762 patients underwent pancreatic surgery from January 2000 to December 2012. Sixteen percent (n = 441) had pathologically confirmed IPMN and 11% of these (n = 50) had a different distinct synchronous pancreatic neoplasm. The majority of these, 62%, were con-PDAC, followed by neuroendocrine neoplasms (10%) and ampullary carcinoma (10%). Less frequently, mucinous (6%) as well as serous cystic neoplasms (6%), adenosquamous carcinoma (4%) and distal bile duct cancer (2%) were diagnosed. Among all patients with synchronous neoplasms, 66% harbored BD-IPMN, 28% combined IPMN and 6% main duct IPMN. Abdominal pain and/or jaundice were the leading symptoms in half of patients. Conclusion IPMN, mainly BD-IPMN, are associated with con-PDAC in about 7% of patients and account for 62% of all concurrent pancreatic/ampullary neoplasms. Other synchronous neoplasms may be found sporadically with IPMN without a suspected association.

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell’s C statistics, and Royston’s explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Limited data are available for pancreatic neuroendocrine carcinomas (NEC) defined by 2010 World Health Organization (WHO) criteria (mitotic count20 mitoses/10 high-power fields and/or a Ki67 index of20%), because most studies encompass heterogeneous cohorts of extrapulmonary/gastrointestinal NEC. Our aim was to evaluate the clinicopathologic characteristics, treatment, and prognosis of patients with pancreatic NEC defined by the 2010 WHO criteria.We conducted a retrospective analysis of 59 patients with a histologic diagnosis of NEC between 1990 and 2012. All cases were re-reviewed and classified according to the WHO 2010 classification and the WHO 2000 criteria.All patients had stage III pancreatic NEC (n = 34; 58%) or IV pancreatic NEC (n = 25; 43%). Overall, 49 (83%) had poorly differentiated (PD) and 10 (17%) had a well-differentiated (WD) morphology. Fifteen patients (26%) were operated with curative intent (R0/R1), and 8 (14%) were R2 resections. Median disease-specific survival (DSS) for the entire cohort was 14 months. Median DSS did not differ between patient not undergoing resection and those undergoing R2 resection (10 vs 12 months; P.46), but DSS was greater for patients who underwent R0/R1 resection compared with those with no resection/R2 resection (35 vs 11 months; P.005). WD morphologic NEC had a greater survival than PD ones (43 vs 12 months; P = .004). Performance status, R2 resection/no resection, PD morphologic NEC, and no medical treatment were independent predictors of poor survival.Pancreatic NEC constitute a heterogeneous group of tumors. Although NEC is an aggressive disease, curative resection in localized disease is associated with improved survival. Morphologic WD pancreatic NEC represents a subgroup with what seems to be a markedly improved survival. Within the NEC category, tumor treatment should be individualized considering tumor morphology as well as the other 2010 WHO criteria.

Neuroendocrine carcinomas (NEC) of the pancreas are defined by a mitotic count > 20 mitoses/10 high power fields and/or Ki67 index > 20%, and included all the tumors previously classified as poorly differentiated endocrine carcinomas. These latter are aggressive malignancies with a high propensity for distant metastases and poor prognosis, and they can be further divided into small- and large-cell subtypes. However in the NEC category are included also neuroendocrine tumors with a well differentiated morphology but ki67 index > 20%. This category is associated with better prognosis and does not significantly respond to cisplatin-based chemotherapy, which represents the gold standard therapeutic approach for poorly differentiated NEC. In this review, the differences between well differentiated and poorly differentiated NEC are discussed considering both pathology, imaging features, treatment and prognostic implications. Diagnostic and therapeutic flowcharts are proposed. The need for a revision of current classification system is stressed being well differentiated NEC a more indolent disease compared to poorly differentiated tumors.

Poorly differentiated, resectable pancreatic ductal adenocarcinoma is associated with early recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocarcinoma according to histologic grading.A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma between 1990 and 2008 were analyzed via the use of different histologic grading.Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients. Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%, respectively. Only the presence of symptoms was a significant clinical predictor of G3 status (P = .035). G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2, and G3 neoplasms (P.0001). Median disease-free survival was 63, 14, and 9 months for G1, G2, and G3 pancreatic ductal adenocarcinoma (P.0001). Adjuvant therapy improved disease-specific survival in G2 (P.04) and G3 (P.0001) pancreatic ductal adenocarcinoma, with a greater survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116).G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3 PDAC can be considered as possible targets for neoadjuvant treatment.

Cystic dystrophy of heterotopic pancreas, groove pancreatitis, pancreatic hamartoma of the duodenum, paraduodenal wall cyst, and myoadenomatosis are all terms grouped together, from a pathological viewpoint, as definitions of paraduodenal pancreatitis (PP). The objective of the present study was to investigate the clinical characteristics, therapeutic strategies, and results in 58 patients undergoing pancreatic resection for PP. From January 1990 to December 2006 data were prospectively collected on 58 patients who were diagnosed with PP who then underwent pancreaticoduodenectomy. In this patient cohort the median age was 44.7 years; only 4 patients were women, and only 3 had non-drinker and/or non smoker habits. The overall morbidity was 18.9%, and the median hospitalization was 11 days. There were no postoperative deaths. In a median follow-up of 96.3 months, all patients noted a decrease in the pain associated with PP; 35 patients (76%) had complete disappearance of pain, whereas occasional relapsing pain occurred in the remaining 11 (24%). Patients with PP have clinical characteristics similar to those of chronic pancreatitis. The diagnostic imaging modalities of choice are ultrasonographic endoscopy and magnetic resonance cholangiopancreaticography. Based on our surgical experience, pancreaticoduodenectomy seems to be a reasonable choice of treatment in patients with PP.

Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers.Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct.MCNs were seen mostly in women (95\%) and in the distal pancreas (97\%); 25\% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9\% presented with acute pancreatitis. One hundred eighteen patients (72\%) had adenoma, 17 (10.5\%) borderline tumors, 9 (5.5\%) in situ carcinoma, and 19 (12\%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter > or =60 mm (P = 0.0001). All neoplasms with cancer were either > or =40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49\%. Median follow-up was 57 months (range, 4-233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100\%, and for those with invasive cancer, 57\%.This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5\%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (< or =4 cm/no nodules), nonradical resections are appropriate.

To evaluate if contrast-enhanced ultrasonography (CEUS) improves the depiction of tumoral margins of pancreatic adenocarcinoma in relation to tumor enhancement, using pathology as criterion standard.Two hundred forty-one patients affected by pancreatic ductal adenocarcinoma were investigated at CEUS with a second-generation contrast medium of sulfur-hexafluoride microbubbles. Sixty-seven (27.8%) of 241 tumors were resected. By consensus, 2 radiologists reviewed the CEUS examination results of the 67 tumors judging the enhancement as low (hypovascular lesions, hypoechoic tothe adjacent parenchyma) or high (iso- or hypervascular lesions, iso- or hyperechoic to the adjacent parenchyma). The resected tumors were evaluated at pathology for the presence of positive neoplastic (R+) or negative neoplastic (R-) resected margins.Of the 67 resected tumors, 35 (52.3%) were R-, whereas 32 (47.7%) were R+. Moreover, at CEUS, of the 67 resected tumors, 43 (64.1%) were hypovascular with low enhancement and 24 (35.8%) were iso-hypervascular with high enhancement. In the R- group, 27 (77.1%) of 35 tumors were hypovascular. In the R+ group, 16 (50%) of 32 lesions were hypovascular.At CEUS the depiction of tumoral margins of pancreatic adenocarcinoma is more accurate in low enhancement than in high enhancement. The pattern of enhancement of pancreatic adenocarcinoma influences the depiction of tumoral margins at CEUS.

Pancreatic mucinous cystic tumors (MCT) are proliferations of mucin-producing epithelia supported by an ovarian-like stroma. They are classified into adenomas (MCA), borderline (MCB) and noninvasive or invasive carcinomas (MCC). The molecular mechanisms underlying their clinical behavior are poorly understood, partly due to the lack of cellular models. We report the establishment of MCC1, the first cell line from a pancreatic MCT, deriving from the highly dysplastic cell component of a noninvasive MCC. MCC1 has mutations in codon 12 of K-RAS (GGT>GAT), codon 58 of P16 (CGA>TGA) and codon 132 of P53 (AAG>AGG). The FHIT and DPC4 genes are unaltered. Immunohistochemistry shows abnormal expression of MUC1 and p53, loss of p16 and retention of Fhit and Dpc4 in both the cell line and the highly dysplastic cells of the primary lesion. The morphological and molecular features of MCC1 and its corresponding primary tumor are consistent with a model for non-invasive MCC, where K-RAS, P16, P53 and MUC1 alterations are pre-invasive changes associated with progression of malignancy of MCT from adenoma to carcinoma. MCC1 is sensitive to 5-fluorouracil, representing the first assessment of drug sensitivity for MCC. Finally, MCC1 is a suitable model for preclinical studies, as it grows in immunodeficient mice.

To determine the genetic differences/similarities in ampulla of Vater cancers (AVC) with respect to other pancreatic tumor types. We analyzed eight cases of primary AVC by genome-wide allelotyping on DNA obtained from frozen tissue. A total of 372 microsatellite loci were used for each case, for a total of 2,976 microsatellites analyzed. Of the 2,159 informative markers, 400 were allelic losses and 1,759 markers were retained for an average fractional allelic loss of 0.19. Seven cases showed LOH on at least two markers on chromosomal arm 11p, while six cases showed allelic losses on 11q. The high frequency of LOH on chromosome 11 was also confirmed by analysis of an additional 17 paraffin-embedded AVC. Frequent LOH (50% or greater) was also found on chromosome arms 5q, 6q, 9p, 13, 16p, 17p, and 18p. It can be inferred that the targets of inactivation on chromosomes 5q, 9p, and 17p appear to be APC, p16, and p53, respectively, while the critical target(s) of inactivation at the other frequently lost loci remain to be characterized. The resulting allelotype reveals that distinctive chromosomal alterations are present in these neoplasms, indicating that it is a tumor entity distinct from pancreatic adenocarcinoma.

We have investigated the status of sex chromosomes in 40 pancreatic endocrine tumors (PETs) using 2 complementary techniques: microsatellite and interphase FISH analysis. Twenty-five tumors were from female and 15 from male patients and included 31 nonfunctioning and 9 functioning PET (6 insulinomas, 2 glucagonomas and 1 VIPoma). Microsatellite and FISH analysis showed concordant results in all cases. PETs from females showed frequent loss of chromosome X (40%) whereas PETs from males showed relatively frequent loss of chromosome Y (36%) but never loss of the X chromosome. Statistical analysis showed significant association of sex chromosome loss with metastases (Spearman correlation test, r = 0.5, p < 0.001), local invasion (r = 0.33, p < 0.05) and high proliferation rate measured as Ki-67 index with a 5% cut-off (r = 0.42, p < 0.02). The analysis also showed that local invasion and metastases were highly correlated (r = 0.86). Multivariate survival analysis was therefore carried out including local invasion and loss of sex chromosomes. The presence of local invasion increased the risk of death almost 9 times whereas sex chromosome loss was an independent variable associated with a shorter survival period and an increased risk of death of approximately 4-fold. © 2002 Wiley-Liss, Inc.

Loss of immunohistochemical expression of Dpc4 occurs in about 50% of pancreatic ductal cancers and its loss correlates with DPC4/Smad4 gene inactivation. Dpc4 expression was also lost in 6 of 16 (37%) ampulla of Vater cancers (AVCs) previously analyzed. Furthermore, chromosomal losses involving 18q, where DPC4 is located, have been observed in 34% of AVCs and are associated with decreased survival. To evaluate the possibility that expression of Dpc4 may be correlated with survival, we analyzed 89 AVCs for inactivation of DPC4 by immunohistochemical staining. Thirty-seven cases showed no expression of Dpc4 (41%). Multivariate survival analysis was performed including age, sex, tumor size, histological subtype (intestinal or pancreatobiliary), grade of differentiation, T-stage, lymph-node metastases and Dpc4 status. T-stage and histological subtype were selected as independent prognostic factors, while Dpc4 immunostaining was not significantly associated with any clinicopathological variable, including histological subtype. Although Dpc4 expression is of no clinical relevance, its involvement in AVC gives additional weight to the hypothesis that, among all pancreatic exocrine and endocrine tumors, only AVC and common ductal adenocarcinomas have similar molecular fingerprints. Moreover, comparison of the frequencies of allelic loss on chromosomal arm 18q and the loss of Dpc4 expression (34% and 41%, respectively) is highly suggestive that DPC4 is the major target of these losses.

Mucinous cystadenoma (MCA) is a rare pancreatic primitive tumor that occurs predominantly among middle-aged women. It often arises from the pancreatic body tail as a large unilocular or multilocular cyst. Mucinous cystadenoma is thought to be a premalignant lesion. 1 , 2 Imaging characterization is fundamental for correct treatment of cystic pancreatic lesions. Contrast-enhanced ultrasonography (CEUS) with second-generation contrast media can improve the characterization of MCA thanks to the dynamic observation of the contrast-enhanced phases. We describe a case of CEUS diagnosis of unilocular MCA of the pancreatic tail.

Objective. The purpose of this series is to describe the value of contrast-enhanced ultrasonography (CEUS) in the characterization of small pseudopapillary tumors (SPTs) of the pancreas. Methods. Two cases of SPTs found on conventional ultrasonography, both located at the pancreatic body, were studied with spiral computed tomography, magnetic resonance imaging, and CEUS. A final diagnosis was obtained with histologic analysis after distal pancreatectomy. Immunohistochemical analysis of the tumors with the CD34 antigen was performed. Results. At CEUS, the 2 SPTs had a slight peripheral rim enhancement in the early dynamic phases. The presence of this enhancement pattern at CEUS, not clear at spiral computed tomography or at magnetic resonance imaging, suggested the diagnosis of SPTs with a peripheral pseudocapsule deriving from the compression of the pancreatic parenchyma. The presence of a perilesional pseudocapsule was proved at immunohistochemical analysis of the tumors with the CD34 antigen. Conclusions. Contrast-enhanced ultrasonography can improve the characterization of SPTs by showing the typical rim enhancement of these pancreatic tumors.