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It has been estimated that familial aggregation and genetic susceptibility play a role in as many as 10% of patients with pancreatic cancer (PC). The quantified prospective risk of PC among first-degree relatives of PC patients has not been investigated. Families enrolled in the National Familial Pancreas Tumor Registry (NFPTR) prior to September 1, 1998 were followed to estimate the risk and incidence of PC among first-degree relatives of patients with PC. Analyses were performed separately on kindreds with at least two first-degree relatives with PC (familial pancreatic carcinoma (PC); n = 150) at the time the kindred was enrolled in the NFPTR and on kindreds without a pair of affected first-degree relatives (sporadic PC; n = 191). A subanalysis was performed on familial PC kindreds containing three or more affected members at the time of enrollment in the NFPTR (n = 52). Risk was estimated by comparing observed new cases of PC during the observation period with expected numbers based on the United States population-based Surveillance, Epidemiology and End Results program data. Incidence was estimated using person-years risk analyses. During the observational period, six incident PCs developed in the first-degree relatives: two in the sporadic PC kindreds, and four in the familial PC kindreds. The PC risk in the sporadic PC kindreds was not significantly greater than expected [observed/expected = 6.5 (95% CI = 0.78-23.3)] with an incidence rate of 24.5/10(5)/ year. There was a significantly increased 18-fold risk (95% CI = 4.74-44.5) of PC among first-degree relatives in familial PC kindreds, with an incidence of 76.0/10(5)/year. In the subset of familial PC kindreds with three or more affected family members at the time of enrollment, there was a 57-fold (95% CI = 12.4-175) increased risk of PC and an incidence of 301.4/10(5)/year compared with the Surveillance, Epidemiology and End Result age-adjusted incidence of PC in the U.S. (8.8/10(5)/year). When stratified by age, the risk was largely confined to relatives over the age of 60. This study is the first analysis of incident PC occurring in familial PC kindreds. The risk and incidence of PC is exceptionally high among at-risk first-degree relatives in familial PC kindreds in which at least three first-degree relatives have already been diagnosed with PC. Familial PC kindreds are a reasonable high-risk group for PC screening and chemoprevention research

SMAD4 (also called Dpc4) is a tumor suppressor in the TGF-beta signaling pathway that is genetically inactivated in approximately 55% of all pancreatic adenocarcinomas. We investigated whether prognosis after surgical resection for invasive pancreatic adenocarcinoma is influenced by SMAD4 status. Using immunohistochemistry, we characterized the SMAD4 protein status of 249 pancreatic adenocarcinomas resected from patients who underwent pancreaticoduodenectomy (Whipple resection) at The Johns Hopkins Hospital, Baltimore, MD, between 1990 and 1997. The SMAD4 gene status of 56 of 249 (22%) pancreatic carcinomas was also determined. A multivariate Cox proportional hazards model assessed the relative risk of mortality associated with SMAD4 status, adjusting for known prognostic variables. Patients with pancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival (unadjusted median survival was 19.2 months as compared with 14.7 months in patients with pancreatic cancers lacking SMAD4 protein expression; P = 0.03). This SMAD4 survival benefit persisted after adjustment for prognostic factors including tumor size, margins, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy. The relative hazard of mortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 (95% confidence interval, 1.01-1.83; P = 0.04). Patients undergoing Whipple resection for pancreatic adenocarcinoma survive longer if their cancers express SMAD4

Medullary carcinomas of the pancreas are a recently described, histologically distinct subset of poorly differentiated adenocarcinomas that may have a unique pathogenesis and clinical course. To further evaluate these neoplasms, we studied genetic, pathological, and clinical features of 13 newly identified medullary carcinomas of the pancreas. Nine (69%) of these had wild-type K-ras genes, and one had microsatellite instability (MSI). This MSI medullary carcinoma, along with three previously reported MSI medullary carcinomas, were examined immunohistochemically for Mlh1 and Msh2 expression, and all four expressed Msh2 but did not express Mlh1. In contrast, all of the medullary carcinomas without MSI expressed both Msh2 and Mlh1. Remarkably, the MSI medullary carcinoma of the pancreas in the present series arose in a patient with a synchronous but histologically distinct cecal carcinoma that also had MSI and did not express Mlh1. The synchronous occurrence of two MSI carcinomas suggests an inherited basis for the development of these carcinomas. Indeed, the medullary phenotype, irrespective of MSI, was highly associated with a family history of cancer in first-degree relatives (P < 0.001). Finally, one medullary carcinoma with lymphoepithelioma-like features contained Epstein-Barr virus-encoded RNA-1 by in situ hybridization. Therefore, because of medullary carcinoma's special genetic, immunohistochemical, and clinical features, recognition of the medullary variant of pancreatic adenocarcinoma is important. Only by classifying medullary carcinoma as special subset of adenocarcinoma can we hope to further elucidate its unique pathogenesis

For many years anecdotal case reports have suggested that pancreatic cancer aggregates in some families. Two recent advances have established that this is in fact the case. First, large registries, such as the National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins, have identified a number of families in which multiple family members have been diagnosed with pancreatic cancer. As a result, the patterns of inheritance of pancreatic cancer can now be studied on a scale not possible before. Second, advances in molecular genetic techniques make it possible to test members of these families for germline mutations in known candidate cancer causing genes. As a result, some of the genetic alterations responsible for the familial aggregation of pancreatic cancer have been identified in some families. The NFPTR has enrolled 362 families in which at least one family member has been diagnosed with pancreatic cancer. These include 151 families in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Analysis of these families has revealed that even second-degree relatives of patients from these families are at increased risk of developing pancreatic cancer. In addition, a number of kindreds which exhibit aggregation of cancer have been tested for germline mutations in known cancer causing genes. Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in p16 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS). Pancreatic cancer aggregates in some families, and relatives of patients with pancreatic cancer have an increased risk of developing pancreatic cancer themselves. The genetic basis for the familial aggregation of pancreatic cancer has been shown to be germline mutations in known cancer causing genes in some of these families

An understanding of incipient pancreatic neoplasia is an essential foundation for the future development of effective screening tests for pancreatic cancer. Only when we understand early pancreatic neoplasms will we be able to detect tumors that are curable with surgical resection. Two approaches have helped define incipient pancreatic neoplasia. First, the histologic examination of pancreata has helped identify the most common histologic lesions in pancreatic tissues adjacent to infiltrating carcinomas. The assumption is that some of these lesions represent the precursors to the infiltrating cancers. Second, advances in molecular genetics now make it possible to define the genetic alterations present in small lesions. The demonstration that a suspected precursor lesion and an infiltrating pancreatic carcinoma share the same genetic alterations would help establish that the lesion is indeed a precursor to infiltrating pancreatic carcinoma. A spectrum of intraductal proliferations in the pancreas has been found associated with infiltrating adenocarcinoma of the pancreas. These lesions, called "duct lesions," have even been identified in pancreata years before patients develop infiltrating carcinoma. Molecular genetic analysis of these lesions has revealed that they frequently harbor many of the same alterations present in infiltrating carcinoma of the pancreas. These alterations include activation of K-ras and inactivation of p16, p53 and, rarely BRCA2. From these morphologic and molecular observations, we can now develop a progression model for the development of infiltrating carcinoma of the pancreas. Infiltrating carcinomas of the pancreas may arise from pancreatic duct lesions, and the progression of duct lesions to infiltrating cancer is associated with the accumulation of generalized and specific genetic alterations

Pancreatic adenocarcinoma develops from histologically identifiable intraductal lesions that undergo a series of architectural, cytological, and genetic changes. Limited genetic evidence recently suggested that the p16 gene plays a role in the progression of these "duct lesions." Duct lesions were identified in pancreata from 33 pancreaticoduodenectomies performed for infiltrating adenocarcinoma. All of these infiltrating adenocarcinomas were previously shown to contain alterations in the p16 gene or its promoter. Monoclonal and polyclonal anti-p16 antibodies were used for histological immunodetection. One hundred twenty-six duct lesions were identified. Nine (30%) of 30 flat, 4 (27%) of 15 papillary, 37 (55%) of 67 papillary with atypia, and 10 (71%) of 14 carcinoma in situ duct lesions showed loss of p16 expression. These included 30% of the flat lesions versus 53% of the nonflat lesions and 29% of the nonatypical lesions versus 58% of the atypical lesions. For both comparisons, the differences were statistically significant (P = 0.036 and P = 0.003, respectively). Loss of p16 expression occurs more frequently, but not exclusively, in higher-grade duct lesions. These data support the hypothesis that pancreatic duct lesions are neoplastic and that they represent the precursors of infiltrating adenocarcinoma. Immunohistochemical detection of p16 provides a new technology to study the genetic alterations in and stages of progression of large numbers of morphologically defined pancreatic duct lesions

The clinical and pathological features of carcinomas of the pancreas with DNA replication errors (RER+) have not been characterized. Eighty-two xenografted carcinomas of the pancreas were screened for DNA replication errors using polymerase chain reaction amplification of microsatellite markers. Cases with microsatellite instability in at least two markers of a minimum of five tested were considered RER+. RER status was correlated with histological appearance, karyotype of the carcinomas when available, K-ras mutational status, and patient outcome. Three (3.7%) of the eighty-two carcinomas were RER+. In contrast to typical gland-forming adenocarcinomas of the pancreas, all three RER+ carcinomas were poorly differentiated and had expanding borders and a prominent syncytial growth pattern. Neither a Crohn's-like lymphoid infiltrate nor extracellular mucin production were prominent. Ductal adenocarcinomas of the pancreas typically contain a mutant K-ras gene, yet all three RER+ carcinomas had wild-type K-ras. One of the three RER+ carcinomas was karyotyped and showed a near diploid pattern. All three of the RER+ tumors were removed via Whipple resection. One of the three patients is free of disease 16 months after pancreaticoduodenectomy, one is alive and free of tumor at 52 months but developed two colon carcinomas during this period, and the third died of pancreatic cancer at 4 months. None of the three patients had a family history of colorectal carcinoma. A review of the K-ras wild-type carcinomas in a previously characterized series of pancreatic carcinomas with known K-ras mutational status identified two additional cancers with poor differentiation, a syncytial growth pattern, and pushing borders. Both of the cancers were diploid and both patients were longterm survivors (over 5 years). The inclusion of such patients in previous prognostic studies of pancreas cancer may explain the failure of histological grade to be a predictor of prognosis. These data suggest that DNA replication errors occur in a small percentage of resected carcinomas of the pancreas and that wild-type K-ras gene status and a medullary phenotype characterized by poor differentiation, and expanding pattern of invasion, and syncytial growth should suggest the possibility of DNA replication errors in carcinomas of the pancreas

Molecular genetic alterations are known to be important in human carcinoma, but the structural basis of these changes is largely unknown. To examine the basis of these changes, we compared the karyotypic chromosomal abnormalities of primary pancreatic adenocarcinomas with the molecular changes identified in these same cancers. In 14 cancers with abnormal karyotypes, 65% (123 of 188) of the chromosomal arms with molecular loss of heterozygosity (LOH) were associated with karyotypic structural anomalies. Karyotypic changes accounting for these molecular allelic losses included 83 chromosome losses, 18 partial deletions, nine isochromosomes, eight additions, and five translocations. Eight bomozygous deletions were also identified by molecular analyses. Of the three homozygous deletions identified at 9p21, the only karyotypic change was a single case in which one entire copy of chromosome 9 was deleted. Of the four homozygous deletions identified at 18q21.1, one showed a loss of both copies of chromosome 18, two showed a loss of one copy of chromosome 18, and the fourth had two structurally normal copies of chromosome 18. One homozygous deletion was identified at 13q12.3, and the karyotype revealed the loss of one entire copy of chromosome 13. The second copy of chromosome 13 in this carcinoma was structurally normal. These results indicate that chromosomal structural anomalies can account for two-thirds of the LOH in pancreatic adenocarcinomas and that most homozygous deletions are likely to be interstitial chromosomal deletions that are below the detection limit of conventional karyotypic analyses. Some of the molecular deletions detected as LOH on chromosomes with karyotypically normal structure can be explained by chromosomal loss with reduplication of the remaining chromosome.

Objective: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. Summary Background Data: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. Methods: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). Results: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. Conclusion: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.