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Histologic classification of ampullary carcinomas as intestinal versus pancreatobiliary is rapidly becoming a part of management algorithms, with immunohistochemical classification schemes also being devised using this classification scheme as their basis. However, data on the reproducibility and prognostic relevance of this classification system are limited. In this study, five observers independently evaluated 232 resected ampullary carcinomas with invasive component >3 mm. Overall interobserver agreement was ‘fair’ (κ 0.39; P

Trends in gallbladder cancer incidence and mortality in populations across the Americas can provide insight into shifting epidemiologic patterns and the current and potential impact of preventative and curative programs. Estimates of gallbladder and extrahepatic bile duct cancer incidence and mortality for the year 2018 were extracted from International Agency for Research on Cancer (IARC) GLOBOCAN database for 185 countries. Recorded registry-based incidence from 13 countries was extracted from IARCs Cancer Incidence in Five Continents series and corresponding national deaths from the WHO mortality database. Among females, the highest estimated incidence for gallbladder and extrahepatic bile duct cancer in the Americas were found in Bolivia (21.0 per 100,000), Chile (11.7) and Peru (6.0). In the US, the highest incidence rates were observed among Hispanics (1.8). In the Chilean population, gallbladder cancer rates declined in both females and males between 1998 and 2012. Rates dropped slightly in Canada, Costa Rica, US Whites and Hispanics in Los Angeles. Gallbladder cancer mortality rates also decreased across the studied countries, although rising trends were observed in Colombia and Canada after 2010. Countries within Southern and Central America tended to have a higher proportion of unspecified biliary tract cancers. In public health terms, the decline in gallbladder cancer incidence and mortality rates is encouraging. However, the slight increase in mortality rates during recent years in Colombia and Canada warrant further attention. Higher proportions of unspecified biliary tract cancers (with correspondingly higher mortality rates) suggest more rigorous pathology procedures may be needed after surgery.

In the ampulla of Vater, carcinomas with “diffuse-infiltrative”/“signet ring cell” morphology, designated as “poorly cohesive carcinoma” (PCC) in the WHO classification, are very rare and poorly characterized. Nine cases with a classical PCC morphology constituting >50% of the tumor were identified. Mean age was 64.8 years (vs 64.6 in ampullary carcinomas [ACs]) and 6 were males, 3 females. The mean invasive tumor size was 2.5 cm (vs 1.9 in ACs). Other morphologic patterns displayed included cord-like infiltration (n=2), plasmacytoid cells (n=2), and microglandular component (n=4), including goblet cell adenocarcinoma-like foci. None of the cases were associated with dysplasia. By immunohistochemistry, the carcinomas did not show intestinal differentiation (CDX2 0/9, CK20 1/9, MUC2 3/9), MUC1 was positive in 4/9, MUC5AC was positive in 7/8. E-cadherin loss was noted in 4/9. All cases were advanced stage (6/9-pT3, 3/9-pT4) (vs 43% in ACs). Lymph node metastases were identified in 44% (vs 45% in AC). Six patients (67%) died of disease at a median of 25 months, 3 were alive at 13, 15, and 60 months. Overall median survival was significantly worse than that of intestinal-type ACs (26 vs 122 months, P = .006) and trended toward worse than pancreatobiliary type (26 vs 42 months, P = .1). In conclusion, PCCs constitute 2.45% of all ACs. These present as advanced tumors and express upper-gastrointestinal immunoprofile with frequent MUC5AC labeling, which may be helpful in identifying subtle infiltration in the surface mucosa since MUC5AC is not expressed in the ampullary mucosa. Patients have poor prognosis.

BACKGROUND: Intraductal oncocytic papillary neoplasm(IOPN) of the pancreas is a rare tumor. Recent molecular data indicate that it is distinct from other intraductal neoplasms; however, its clinicopathologic characteristics, especially the frequency/significance of an invasive carcinoma component, and biologic behavior remain to be fully defined. DESIGN: Clinicopathologic characteristics and survival of 24 IOPNs were analyzed. By definition, all tumors exhibited intraductal growth and oncocytic morphology. RESULTS: The female:male ratio was 1.7, mean age was 59. In 44% of the patients, the IOPN was discovered incidentally; however, the working diagnosis was “ductal adenocarcinoma” in 42%. Fourteen IOPNs occurred in the head of the pancreas. The median tumor size was 4.5 cm. The tumors often grew along adjacent benign ducts, mimicking invasion, but only 29% exhibited unequivocal invasive carcinoma, mostly in the form of microscopic foci(pT1a=4, pT1b=1, pT2=2) and only 6% had lymph node metastasis. Invasive carcinoma was predominantly composed of small tubular units lined by oncocytic cells, or individual oncocytic cells infiltrating the periductal stroma. Follow-up information was available for 18 patients(median=6.8 years). No patients died from the disease and the overall 10-year survival was 94%. Patients with invasive carcinoma trended towards a lower 5-year recurrence-free survival than those with non-invasive IOPNs(66% vs. 93%, p=0.066), but overall survival was not impacted by the presence of invasion(p=0.38). CONCLUSION: IOPN is a distinct tumor type in the pancreas. Despite its morphologic complexity and often extensive pagetoid spread to adjacent ducts, conventional invasive carcinoma is seen in only 29% and usually as microscopic foci. Thus, it is not surprising that IOPN exhibits indolent behavior even when invasion is present.

Epithelioid hemangioendothelioma (EHE) is an angiocentric tumor that, when arising in liver, is centered around hepatic/portal veins. However, EHE cells can also track along sinusoids, which is not well recognized or studied. We identified 18 cases of hepatic EHE and 6 nonhepatic EHEs. For all cases, we recorded EHE multifocality and maximum size. When tumor cells were identified apart from the main mass, we recorded their location, maximum distance from the main tumor, density per high-power field, and cytomorphology. Immunohistochemical staining for CAMTA1, ERG, and CAM5.2 was performed on all cases. Lesional cells were present apart from the main mass in 17 of 18 (94%) liver cases, always within sinusoids and occasionally (4/17, 24%) in central veins. They appeared intensely hyperchromatic with vaguely cerebriform nuclei and multinucleation in 6 (35%) of cases. CAMTA1 and ERG positivity was seen in all 17 cases. Two cases (12%) demonstrated focal CAM5.2 positivity. Sinusoidal EHE cells ranged from 0.1 to 0.8 cm away from the main tumor. There were no statistically significant associations between histologic findings and patient outcome. In the 6 nonhepatic cases, tumor cells did not extend beyond the main EHE. Lesional cells in hepatic EHE often extend beyond the main lesion into sinusoids, where they demonstrate an unusual, somewhat distinctive morphology. Care should be taken to identify such cells in limited biopsies; immunohistochemistry for CAMTA1, a specific and sensitive marker for EHE, can be confirmatory.

Objective: endoscopic resections are increasingly being used for superficial gastrointestinal lesions. However, application of these techniques in the duodenum remains challenging, due to the technical difficulties and high complication rates. This study projects a western tertiary center's experience in the endoscopic treatment and diagnostic workup of 19 cases of non-ampullary duodenal lesions. Material and method: specimens (12 endoscopic mucosal resections, 6 endoscopic submucosal dissections, and one endoscopic full-thickness resection) were processed following a strict protocol (photographed, mapped digitally and submitted totally) for histopathologic examination. Clinicopathologic characteristics, margin status and follow-up information were analyzed. Results: the mean age of the 16 patients was 52 years (range: 22-81). Mean lesion size was 1.4 cm (range: 0.3-3.6 cm) for all cases, 2 cm for endoscopic submucosal dissections and 1.1 cm for endoscopic mucosal resections. Mean number of blocks submitted was 4/case. Seven neuroendocrine tumors, 3 tubulovillous adenomas were diagnosed along with nine benign lesions. For endoscopic submucosal dissections, en-bloc and R0 resection rates were 100% (n=6/6) and 83% (n=5/6); for endoscopic mucosal resections, they were 92% (n=11/12) and 83% (n=10/12), respectively. Only one patient had procedure-related late perforation that was managed endoscopically. No mortality was encountered. Conclusion: duodenal endoscopic resections proved successful, safe and feasible methods in a tertiary center. The pathologist's role is to designate the accurate diagnosis, related histopathologic parameters and margin status. The gross protocol was found to be essential in evaluating specimen margins and orientation, as well as in size measurement. We recommend following a standardized approach including gross photography and digital mapping when handling these specimens, for both diagnostic and data collection purposes., NA

Undifferentiated carcinomas with osteoclastic giant cells of the pancreas (OGC) are rare tumors. The current impression in the literature is that they are highly aggressive tumors similar in prognosis to ductal adenocarcinomas. In this study, the clinicopathologic characteristics of 38 resected OGCs were investigated and contrasted with 725 resected pancreatic ductal adenocarcinomas without osteoclastic cells (PDCs). The frequency among systematically reviewed pancreatic cancers was 1.4%. OGCs showed a slight female predominance (62.9%, vs. 51.4% in PDCs). The mean age was 57.9 years (vs. 65.0). The mean size of invasive cancer was 5.3 cm (vs. 3.2). They were characterized by nodular, pushing-border growth, and 8 arose in tumoral intraepithelial neoplasms (4 in mucinous cystic neoplasms, 4 in intraductal papillary mucinous neoplasms type lesions), and 23 (61%) also showed prominent intraductal/intracystic growth. Twenty-nine (76%) had an invasive ductal/tubular adenocarcinoma component. Osteoid was seen in 12. Despite their larger size, perineural invasion and nodal metastasis were uncommon (31.6% and 22.6%, vs. 85.5% and 64.0%, respectively). Immunohistochemistry performed on 24 cases revealed that osteoclastic cells expressed the histiocytic marker CD68, and background spindle cells and pleomorphic/giant carcinoma cells often showed p53 and often lacked cytokeratin. Survival of OGCs was significantly better than that of PDCs (5 yr, 59.1% vs. 15.7%, respectively, P=0.0009). In conclusion, pancreatic OGCs present with larger tumor size and in slightly younger patients than PDC, 21% arise in mucinous cystic neoplasms/intraductal papillary mucinous neoplasms, and 61% show intraductal/intracystic polypoid growth. OGCs have a significantly better prognosis than is currently believed in the literature.

Our understanding about the family of acinar neoplasms of the pancreas has grown substantially over the past 25 years. The prototype is acinar cell carcinoma, an uncommon variant of pancreatic carcinoma that demonstrates production of pancreatic exocrine enzymes, verifiable using immunohistochemistry, and exhibits characteristic histologic features. Related neoplasms include mixed acinar carcinomas such as mixed acinar neuroendocrine carcinoma and mixed acinar ductal carcinoma. In the pediatric age group, pancreatoblastoma is also closely related. Cystic and extrapancreatic forms have been described. These neoplasms share molecular alterations that are distinct from the more common ductal and neuroendocrine neoplasms of the pancreas. Although there is a broad range of genetic findings, a number of potential therapeutic targets have emerged. This review explores the clinical and pathologic features of pancreatic acinar neoplasms along with their more common molecular phenotypes. The differential diagnosis with other pancreatic neoplasms is explored as well.

Background Standard adjuvant treatment for pancreatic adenocarcinoma (PDAC) is gemcitabine [Gem(CONKO-001: Gem vs. placebo DFS:13.4 vs. 6.7 mo; P

Objectives: Pancreatic acinar cell carcinoma (ACC) is a rare tumor that frequently metastasizes to the liver and may present a diagnostic challenge due to its morphologic similarity to hepatocellular carcinoma. We investigated α-fetoprotein (AFP), hepatocyte paraffin antigen 1 (HepPar 1), glypican 3, arginase 1, and albumin messenger RNA (mRNA) in situ hybridization (ISH) in pancreatic neoplasms with ACC differentiation to assess their diagnostic value. Methods: AFP, HepPar 1, glypican 3, and arginase 1 immunohistochemical staining was performed on 28 ACCs using a tissue microarray. Albumin mRNA ISH was performed on full-faced sections. Results: Fifteen tumors were positive for at least one marker. Glypican 3 was positive in seven of 28, AFP in five 28, and albumin mRNA ISH in five of 20. None expressed arginase 1. Conclusions: Hepatocellular differentiation markers, including albumin mRNA ISH, may be positive in ACC, but arginase 1 appears to be uniformly negative. Thus, its use may improve the accuracy in distinguishing these neoplasms from hepatocellular carcinoma. If ACC diagnosis is considered, acinar differentiation can be reliably demonstrated by trypsin/chymotrypsin.

Pancreatic carcinoma ranks among the most lethal of human cancers. Besides late detection, other factors contribute to its lethality, including a high degree of chemoresistance, invasion, and distant metastases. Currently, the mainstay of therapy involves resection of local disease in a minority of patients (Whipple procedure) and systemic gemcitabine. While systemic chemotherapy has some benefit, even with optimal treatment, the five year survival after diagnosis is dismal. Thus, treatment of pancreatic carcinoma remains a tremendous unmet need. The organometallic compound tris DBA palladium is a potent inhibitor of N-myristoyltransferase 1 (NMT1), an enzyme that catalyzes the transfer of myristate to protein substrates. This compound is highly effective in vivo against murine models of melanoma with both mutant and wild type b-RAF genotypes. Based upon the signaling similarities between melanoma and pancreatic carcinoma, we evaluated the efficacy of tris DBA palladium in vitro and in vivo against pancreatic carcinoma. We found that tris DBA palladium decreased proliferation and colony formation of pancreatic cancer cells in vitro. In an orthotopic mouse model, tris DBA palladium was highly active in inhibiting growth, ascites production, and distant metastases in vivo. Furthermore, tris DBA palladium impaired chemotaxis and inhibited cilia formation in Pan02 cells in a NMT1-dependent manner. We propose that NMT1 is a novel regulator of cilia formation and tris DBA palladium a novel inhibitor of cilia formation and metastasis in pancreatic cancer. Thus, further evaluation of tris DBA palladium for the treatment of pancreatic cancer is warranted.

The literature on "variants" and "malignant" counterparts of pancreatic serous cystic neoplasms (SCNs) is highly conflicted. Clinicopathologic characteristics of 193 SCNs were investigated, along with a critical literature review. For the macrocystic (oligocystic) variant, in this largest series, a demographic profile in contrast to current literature was elucidated, with 21% frequency, predominance in female individuals (4:1), body/tail location (1.7×), younger age of patients (mean age, 50 y), and frequent radiologic misdiagnosis as other megacystic neoplasms. Solid SCNs were rare (n=4, 2%) and often misinterpreted radiologically as neuroendocrine tumors. Available fine-needle aspiration in 11 cases was diagnostic in only 1. Radiologic impression was "malignancy" in 5%. Associated secondary tumors were detected in 13% of resections, mostly neuroendocrine. Secondary "infiltration" (direct adhesion/penetration) of spleen, stomach, colon, and/or adjacent nodes was seen in 6 (3%) fairly large SCNs (mean, 11 cm) with no distant metastasis. Three SCNs recurred locally, but completeness of original resection could not be verified. Our only hepatic SCN lacked a concurrent pancreatic tumor. Literature appraisal revealed that there are virtually no deaths that are directly attributable to dissemination/malignant behavior of SCNs, and most cases reported as "malignant" in fact would no longer fulfill the more recent World Health Organization criteria but instead would represent either (1) local adhesion/persistence of tumor, (2) cases with no histologic verification of malignancy, or (3) liver SCNs with benevolent behavior (likely representing multifocality, rather than true metastasis, especially considering there was no fatality related to this and no reported metastases to other remote sites). In conclusion, in contrast to the literature, the clinicopathologic characteristics of solid and macrocystic SCN variants are similar to their microcystic counterpart, although their radiologic diagnosis is challenging. Recurrence/secondary invasion of neighboring organs occurs rarely in larger SCNs but seems innocuous. An SCN should not be classified as "malignant" unless there is clear-cut evidence of histologic malignancy or documented distant metastasis.

Colorectal cancer has a distinct clinicopathologic presentation in younger patients. The aim of this paper was to evaluate the outcome of younger (age below 50 y) and older patients with stage IV (advanced) colorectal cancer in the modern era of combination chemotherapy.Cases of metastatic colorectal cancer reported in Surveillance, Epidemiology, and End Results registry (1973 to 2008) were reviewed. Demographics, tumor characteristics, and overall and cancer-specific survivals in patients below 50 and above 50 years of age were compared by Cox proportional hazard analyses. Joinpoint regression analysis was used to evaluate secular trends in 2-year survival.Younger patients had a greater proportion of negative clinicopathologic features (male sex, African American ethnicity, and signet ring or mucinous histology). In multivariate analysis, older age, male sex, African American ethnicity, right-sided tumors, and signet ring histology were associated with higher mortality risk. Younger patients had improved survival (hazard ratio 0.72; 95% confidence interval: 0.70-0.75) compared with older patients, whereas all patients experienced increased 2-year survival by joinpoint analysis beginning in 1999-2000.The results confirm decreased mortality from advanced colorectal cancer in the era of modern combination chemotherapy in younger and older patients. Younger age, non-right-sided tumors, and absence of signet ring histology significantly associate with better survival.

WOS: 000474496100006, PubMed: 31177317, Sarcomatoid carcinomas recently came into the spotlight through genetic profiling studies and also as a distinct model of epithelial-mesenchymal transition. The literature on sarcomatoid carcinomas of gallbladder is limited. In this study, 656 gallbladder carcinomas (GBC) were reviewed. Eleven (1.7%) with a sarcomatoid component were identified and analyzed in comparison with ordinary GBC (O-GBC). Patients included 9 females and 2 males (F/M = 4.5 vs. 3.9) with a mean age-at-diagnosis of 71 (vs. 64). The median tumor size was 4.6 cm (vs. 2.5; P = 0.01). Nine patients (84%) presented with advanced stage (pT3/4) tumor (vs. 48%). An adenocarcinoma component constituting 1-75% of the tumor was present in nine, and eight had surface dysplasia/CIS; either in situ or invasive carcinoma was present in all cases. An intracholecystic papillary-tubular neoplasm was identified in one. Seven showed pleomorphic-sarcomatoid pattern, and four showed subtle/bland elongated spindle cells. Three had an angiosarcomatoid pattern. Two had heterologous elements. One showed few osteoclast-like giant cells, only adjacent to osteoid. Immunohistochemically, vimentin, was positive in six of six; P53 expression was >60% in six of six, keratins in six of seven, and p63 in two of six. Actin, desmin, and S100 were negative. The median Ki67 index was 40%. In the follow-up, one died peri-operatively, eight died of disease within 3 to 8 months (vs. 26 months median survival for O-GBC), and two were alive at 9 and 15 months. The behavior overall was worse than ordinary adenocarcinomas in general but was not different when grade and stage were matched. In summary, sarcomatoid component is identified in < 2% of GBC. Unlike sarcomatoid carcinomas in the remainder of pancreatobiliary tract, these are seldom of the "osteoclastic" type and patients present with large/advanced stage tumors. Limited data suggests that these tumors are aggressive with rapid mortality unlike pancreatic osteoclastic ones which often have indolent behavior.

Context.—Literature on factors impacting bile duct brushings (BDBs) performance characteristics remain limited.Objective.—To capture the current state of daily practice with BDB sign-out.Design.—Two hundred fifty-three of 444 BDBs signed out by more than 7 cytopathologists, with histopathologic and/or clinical follow-up of at least 18 months, were examined.Results.—One hundred thirty-five of 253 BDBs (53%) had histologically confirmed malignancies, 22 (9%) had cancer-related deaths, and 96 (38%) were benign. Cytologic diagnoses in the 444 BDBs were nondiagnostic (11 [2.5%]), negative (284 [64%]), atypical (62 [13.9%]), suspicious (34 [7.7%]), and malignant (53 [11.9%]). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of malignancy detection were 35%, 100%, 100%, 58%, and 66%, respectively. When atypical, suspicious, and malignant (ASM) categories were combined, sensitivity increased (58%), specificity and PPV dropped (97%), and accuracy increased (73%). Carcinoma type (bile-duct versus pancreatic-ductal) had no effect on accuracy (P = .60) or diagnostic class (P = .84), nor did time of performance (first 7.5 versus latter 7.5 years, P = .13). Interestingly, ThinPrep + cell block (n = 41) had higher sensitivity (61%) and lower specificity (80%) than ThinPrep only (versus 51% and 100%, respectively). Sensitivity and specificity were higher (47% and 100%) in nonstented than stented specimens (59% and 97%). Relative risk of malignancy for “suspicious” (2.30) and “atypical” (2.28) categories was lower but not very different from that of “malignant” category (2.41).Conclusions.—Bile duct brushings had fairly low sensitivity but high specificity and PPV with no false positives. Sensitivity almost doubled and specificity dipped minimally when ASM categories were combined, highlighting the need for better classification criteria for atypical/suspicious cases. Higher specificity, PPV, NPV, and accuracy but lower sensitivity in stented BDBs suggest that they be called malignant only when evidence is overwhelmingly convincing.

Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by frequent cutaneous and nervous system abnormalities. Patients with NF1 also have an increased prevalence of multiple gastrointestinal and peripancreatic neoplasms – neuroendocrine tumors of the ampulla that express somatostatin are particularly characteristic of NF1. In this study, we characterize the genetic alterations of a clinically well-characterized cohort of six NF1-associated duodenal neuroendocrine tumors using whole exome sequencing. We identified inactivating somatic mutations in the NF1 gene in three of six tumors; the only other gene altered in more than one tumor was IFNB1. Copy number analysis revealed deletion/loss of heterozygosity of chromosome 22 in three of six patients. Analysis of germline variants revealed germline deleterious NF1 variants in four of six patients, as well as deleterious variants in other tumor suppressor genes in two of four patients with deleterious NF1 variants. Taken together, these data confirm the importance of somatic inactivation of the wild-type NF1 allele in the formation of NF1-associated duodenal neuroendocrine tumors and suggest that loss of chromosome 22 is important in at least a subset of cases. However, we did not identify any genes altered in the majority of NF1-associated duodenal neuroendocrine tumors that uniquely characterize the genomic landscape of this tumor. Still, the genetic alterations in these tumors are distinct from sporadic neuroendocrine tumors occurring at these sites, highlighting that unique genetic alterations drive syndromic tumors.

Background & Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts ( BRAF , CDKN2A , CTNNB1 , GNAS , KRAS , NRAS , PIK3CA , RNF43 , SMAD4 , TP53 , and VHL ); to identify loss of heterozygozity at CDKN2A , RNF43 , SMAD4 , TP53 , and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%−100% sensitivity and 92%−98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

BACKGROUND Cytologic findings of pancreatic oncocytic-type intraductal papillary mucinous neoplasms (IPMNs)/intraductal oncocytic papillary neoplasms (IOPNs) are largely unknown.

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists was convened on 15 January 2014 to review current evidence on the management of gallbladder carcinoma in order to establish practice guidelines. In summary, within high incidence areas, the assessment of routine gallbladder specimens should include the microscopic evaluation of a minimum of three sections and the cystic duct margin; specimens with dysplasia or proven cancer should be extensively sampled. Provided the patient is medically fit for surgery, data support the resection of all gallbladder polyps of >1.0 cm in diameter and those with imaging evidence of vascular stalks. The minimum staging evaluation of patients with suspected or proven gallbladder cancer includes contrasted cross-sectional imaging and diagnostic laparoscopy. Adequate lymphadenectomy includes assessment of any suspicious regional nodes, evaluation of the aortocaval nodal basin, and a goal recovery of at least six nodes. Patients with confirmed metastases to N2 nodal stations do not benefit from radical resection and should receive systemic and/or palliative treatments. Primary resection of patients with early T-stage (T1b–2) disease should include en bloc resection of adjacent liver parenchyma. Patients with T1b, T2 or T3 disease that is incidentally identified in a cholecystectomy specimen should undergo re-resection unless this is contraindicated by advanced disease or poor performance status. Re-resection should include complete portal lymphadenectomy and bile duct resection only when needed to achieve a negative margin (R0) resection. Patients with preoperatively staged T3 or T4 N1 disease should be considered for clinical trials of neoadjuvant chemotherapy. Following R0 resection of T2–4 disease in N1 gallbladder cancer, patients should be considered for adjuvant systemic chemotherapy and/or chemoradiotherapy.

In the past decade, there have been significant developments in the terminology, classification and understanding of the precursor neoplastic lesions of the gallbladder and bile ducts. Many analogies with their pancreatic counterparts have been identified. Multiple cell lineages (biliary, intestinal, foveolar, pyloric, and oncocytic) are recognized, with differential molecular/genetic fingerprints. Two distinct types have been characterized: (1) Non-tumour forming ("flat") type dysplasia, now also recognized under the heading of biliary intraepithelial neoplasia (BilIN). As in other organs, low-grade BilINs seem to be negligible. High-grade BilINs of the bile ducts seldom are encountered outside the setting of adenocarcinoma and thus also typically clinically irrelevant, perhaps except when they involve the margins. In the gallbladder, low-grade dysplasia is believed to be clinically inconsequential. Cases with gallbladder high-grade dysplasia (also known as "carcinoma in situ") also are often cured, although some may have recurrence/metastasis attributable to missed invasion or field-defect/field-effect emphasizing the crucial nature of total sampling. (2) Polypoid/papillary preinvasive neoplasms (tumoural intraepithelial neoplasia; TINs; i.e., adenoma–carcinoma sequence), for which, in the bile ducts, two distinct entities have been characterized, intraductal papillary neoplasms, and intraductal tubular/tubulopapillary neoplasms. In the gallbladder, all TINs have been proposed to be unified under the umbrella of intracholecystic papillary-tubular neoplasms. Non-invasive TINs are often curable if invasion is excluded definitively, although some exhibit recurrence/metastasis (due to missed invasion and/or field phenomenon). Invasive carcinomas arising in TINs appear to have less aggressive behaviour than ordinary invasive carcinomas. It is important to appreciate the clinicopathologic characteristics of these precursor lesions, both for management purposes and as invaluable models of carcinogenesis.

Background: Outcomes for ampullary adenocarcinomas are heterogeneous, and numerous methods of categorisation exist. A histomolecular phenotype based on histology, caudal-type homeodomain transcription factor 2 (CDX2) staining and Mucin 1 (MUC1) staining has recently been tested and validated in two cohorts. We attempt to validate this classification in a large patient population. Methods: Tissue samples from 163 patients with resected ampullary adenocarcinoma were classified based on histology and immunohistochemical expression of CDX2 and MUC1. A pancreaticobiliary histomolecular classification (PB) was defined as a sample with pancreaticobiliary histology, positive MUC1 and negative CDX2 expression. Results: There were 82 deaths; median follow-up of 32.4 months; and median overall survival of 87.7 (95% CI 42.9–109.5) months. PB comprised 28.2% of the cases. Factors associated with overall survival were histological subtype (P=0.0340); T1/2 vs T3/4 (P=0.001); perineural (P

The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having20 mitotic figures/10 high-power fields or a Ki67 index of20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki6720% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.

Clinicians may order Octreoscan or positron emission tomography (PET) scan for staging patients with neuroendocrine tumors (NETs). (111)In-Octreoscan (Octreoscan) identifies tumors by radiolabeled targeting of somatostatin receptors, while 18F-fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) measures differential tissue glucose transport. We assessed the sensitivity of both nuclear imaging modalities with pathologic correlation to define the best initial choice for NET staging after standard cross-sectional imaging.We identified all patients diagnosed with NETs of gastrointestinal or pancreatic origin who underwent nuclear imaging staging by Octreoscan and/or PET from 2000 to 2013. Imaging results were correlated with tumor differentiation and grade of pathology specimens.Imaging and pathology results were identified for 153 patients. Of these, 131 underwent Octreoscan, 43 underwent PET, and 21 patients had both performed. Overall sensitivity of Octreoscan and PET for NET detection was similar (77 vs. 72 %; p = not significant). For well-differentiated NETs, Octreoscan (n = 124) demonstrated sensitivity of 80 vs. 60 % (p = 0.28) for PET (n = 30). For poorly-differentiated NETs, Octreoscan (n = 7) proved significantly less sensitive than PET (n = 13) (57 vs. 100 %; p = 0.02). The sensitivity of Octreoscan versus PET varied similarly when analyzed by WHO tumor grade: Grade 1 (79 vs. 52 %; p = 0.16), Grade 2 (85 vs. 86 %; p = not significant), and Grade 3 (57 vs. 100 %; p = 0.02).Tumor differentiation can be used to guide selection of nuclear imaging modalities for staging gastrointestinal and pancreatic NETs. Octreoscan appears more sensitive than (18)FDG-PET for well-differentiated NETs, whereas (18)FDG-PET demonstrates superior sensitivity for poorly-differentiated NETs.

Purpose To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR ( P =.03), and low HIF-1α expression was significantly associated with isolated LR ( P =.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P =.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.

Summary The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin ( p120ctn )-mediated epithelial identity. Mono-allelic p120ctn loss accelerates Kras G12D -driven pancreatic cancer formation and liver metastasis. Importantly, one p120ctn allele is sufficient for E-CADHERIN-mediated cell adhesion. By contrast, cells with bi-allelic p120ctn loss demonstrate marked lung organotropism; however, rescue with p120ctn isoform 1A restores liver metastasis. In a p120ctn -independent PDAC model, mosaic loss of E-CADHERIN expression reveals selective pressure for E-CADHERIN-positive liver metastasis and E-CADHERIN-negative lung metastasis. Furthermore, human PDAC and liver metastases support the premise that liver metastases exhibit predominantly epithelial characteristics. RNA-seq demonstrates differential induction of pathways associated with metastasis and epithelial-to-mesenchymal transition in p120ctn -deficient versus p120ctn -wild-type cells. Taken together, P120CTN and E-CADHERIN mediated epithelial plasticity is an addition to the conceptual framework underlying metastatic organotropism in pancreatic cancer.

The literature is highly conflicting on hepatobiliary mucinous cystic neoplasms (MCNs), aka "hepatobiliary cystadenoma/cystadenocarcinoma," largely because ovarian stroma (OS) was not a requirement until WHO-2010 and is not widely applied even today. In this study, MCNs (with OS) accounted for 24 of 229 (11%) resected hepatic cysts in one institution. Eight of the 32 (25%) cysts that had been originally designated as hepatobiliary cystadenoma/cystadenocarcinoma at the time of diagnosis proved not to have an OS during this review and were thus re-classified as non-MCN. In total, 36 MCNs (with OS) were analyzed-24 from the institutional files and 12 consultation cases. All were women. Mean age was 51 (28 to 76 y). Mean size was 11 cm (5 to 23 cm). Most (91%) were intrahepatic and in the left lobe (72%). Preoperative imaging mentioned "neoplasm" in 14 (47%) and carcinoma was a differential in 6 (19%) but only 2 proved to have carcinoma. Microscopically, only 47% demonstrated diffuse OS (>75% of the cyst wall/lining); OS was often focal. The cyst lining was often composed of non-mucinous biliary epithelium, and this was predominant in 50% of the cases. Degenerative changes of variable amount were seen in most cases. In situ and invasive carcinoma was seen in only 2 cases (6%), both with small invasion (7 and 8 mm). Five cases had persistence/recurrence, 2 confirmed operatively (at 7 mo and 15 y). Of the 2 cases with carcinoma, one had "residual cyst or hematoma" by radiology at 4 months, and the other was without disease at 3 years. In conclusion, many cysts (25%) previously reported as hepatobiliary cystadenoma/cystadenocarcinoma are not MCNs. True MCNs are uncommon among resected hepatic cysts (11%), occur exclusively in females, are large, mostly intrahepatic and in the left lobe (72%). Invasive carcinomas are small and uncommon (6%) compared with their pancreatic counterpart (16%). Recurrences are not uncommon following incomplete excision.

Clinicopathologic characteristics of paraduodenal (groove) pancreatitis (PDP) remain to be fully unraveled. In this study, 47 PDPs with preoperative enhanced images available were subjected to detailed comparative analysis in conjunction with pathologic findings. PDP were predominantly in males (3:1) with a mean age of 50 years, and 60% had a preoperative diagnosis of cancer. Mean lesional size was 3.1 cm. Three distinct subtypes were identified by imaging. Solid-tumoral (type-1) with groove-predominant (type-1A, 36%) forming a distinct solid band between the duodenum and pancreas often with histologic microabscesses (69% vs. 33% in others), and pancreas-involving (type-1B, 19%) forming a pseudotumoral mass spanning into the head-groove area, always diagnosed preoperatively as "cancer," but often lacked parenchymal atrophy of the body (44% vs. 92%). Cyst-forming (type-2) had groove-predominant (type-2A, 15%), often accompanied by Brunner gland hyperplasia, and pancreas-predominant (type-2B, 15%) were in younger (mean: 44 y) females (57% vs. 18%) and had less alcohol/tobacco abuse (50/33% vs. 81/69%). Ill-defined (type-3; 15%) often had main pancreatic duct dilatation (mean: 5.6 vs. 2.8 mm). The capricious presentations of PDP could be attributed to variable effects of different mechanistic and precipitative etiopathogenetic factors such as disturbed accessory duct outflow (dilated Santorini duct, 87%), aggravated by alcohol (77%) with superimposed stasis in the main ampulla (previous cholecystectomy, 47%; choledocholithiasis, 9%), strictured Wirsung duct (68%), and some likely exacerbated by ischemia (hypertension [59%], tobacco abuse [64%], arteriosclerosis in the tissue [23%]). In conclusion, our study identified 3 distinct types of PDP and each may reflect different pathogenetic contributing factors.

BACKGROUND Postoperative pancreatic fistula (POPF) is a potentially debilitating complication following pancreatoduodenectomy (PD). There are limited data correlating pancreatic parenchymal histopathologic features specifically fat and fibrosis content with development of POPF after PD. METHODS Patients who underwent PD (January 2010-May 2015) with archived pathologic slides were included. Each pancreatic neck transection margin was histologically graded for fat and fibrosis, scored from 0 to 4, and grader was blinded to clinical outcomes. Main pancreatic duct diameter and duct wall thickness were microscopically measured. Patients were dichotomized into high and low categories with respect to pancreatic fat and fibrosis and primary outcome of POPF. RESULTS Of 301 patients, 24 developed POPF (8.0%). One hundred ten patients (36.5%) had low fat (score

Recently, immunohistochemistry-based classifications of ampullary carcinomas have been proposed (Ang and colleagues [PMID: 24832159]; Chang and colleagues [PMID: 23439753]). In this study, the prognostic value of Ang/Chang panel markers (CK20, MUC1, MUC2, CDX2) as well as other markers (CK7, MUC5AC, and MUC6) were tested on full-faced sections of 136 ampullary carcinoma resections with substantial (>5 mm) invasion. Immunohistochemistry was correlated with both histologic classification (intestinal [INT], pancreatobiliary [PB], or nontubular based on ≥3/5 observer agreement) and clinical outcome. No prognostic correlation was found with MUC1, CDX2, MUC2 or CK20 despite testing with different quantitative cutoffs. CK7 and CK20 were nonspecific. Ang classification had reasonable correlation with histologic subclassification of tubular cases as INT versus PB with high specificity but low sensitivity and ambiguous category was large (29%) and included also some classical cases. Prognostically, Ang classification approached but did not reach statistical significance, even when their large "ambiguous" group was eliminated and only tubular cases were analyzed (Ang-INT vs. Ang-PB; P=0.08). The Chang panel, in which the definition of the INT subcategory is not clearly defined, only marginally reached prognostic significance when tested as MUC1+/CDX2- versus MUC1-/CDX2+ and only by Wilcoxon test (P=0.0485) but 31% of the cases were "unclassifiable." The only individual marker that was found to have direct and strong correlation with the clinical outcome was MUC5AC (not used in the Ang or Chang panels), with statistically significant survival differences found with various cutoffs tested (for 20% cutoff, 5-y survival, 68% vs. 31%; P=0.0002). In addition, MUC5AC significantly stratified the histologically PB and INT cases (P=0.01 and 0.03, respectively), as well as Ang's ambiguous and Chang's unclassified cases (P=0.006 and 0.007, respectively). In conclusion, the widely used putative lineage markers, MUC1/MUC2/CK7/CK20/CDX2, do not seem to have direct/significant prognostic correlation either individually or in combination of Ang and Chang panels. Ang panel is helpful as an adjunct in determining the cell lineage with a few caveats. MUC5AC proves to be a significant independent prognosticator and should be incorporated into evaluation of ampullary carcinomas.

Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

Intraluminal mass-forming preinvasive neoplasms occurring within the gallbladder and the ampulla of Vater are highly analogous to pancreatic or biliary intraductal papillary and tubular neoplasms, as evidenced by their papillary and/or tubular growth, variable cell lineage, and spectrum of dysplastic change (adenoma-carcinoma sequence), often with significant overlap. A uniform terminology of intracholecystic papillary-tubular neoplasm (ICPN) and intra-ampullary papillary-tubular neoplasm (IAPN) has therefore been proposed for the systematic analysis of these neoplasms. ICPN and IAPN are biologically indolent; noninvasive examples show an excellent prognosis, whereas those with invasion exhibit a malignant but nevertheless significantly better prognosis than ordinary invasive carcinomas unaccompanied by ICPN or IAPN.

Pancreaticoduodenectomy (PD) specimens present a challenge for surgical pathologists because of the relative rarity of these specimens, combined with the anatomic complexity. Here, we describe our experience on the orientation, dissection, and sampling of PD specimens for a more practical and accurate evaluation of pancreatic, distal common bile duct (CBD), and ampullary tumors. For orientation of PDs, identification of the "trapezoid," created by the vascular bed at the center, the pancreatic neck margin on the left, and the uncinate margin on the right, is of outmost importance in finding all the pertinent margins of the specimen including the CBD, which is located at the upper right edge of this trapezoid. After orientation, all the margins can be sampled. We submit the uncinate margin entirely as a perpendicular inked margin because this adipose tissue-rich area often reveals subtle satellite carcinomas that are grossly invisible, and, with this approach, the number of R1 resections has doubled in our experience. Then, to ensure proper identification of all lymph nodes (LNs), we utilize the orange-peeling approach, in which the soft tissue surrounding the pancreatic head is shaved off in 7 arbitrarily defined regions, which also serve as shaved samples of the so-called "peripancreatic soft tissue" that defines pT3 in the current American Joint Committee on Cancer TNM. With this approach, our LN count increased from 6 to 14 and LN positivity rate from 50% to 73%. In addition, in 90% of pancreatic ductal adenocarcinomas there are grossly undetected microfoci of carcinoma. For determination of the primary site and the extent of the tumor, we believe bisectioning of the pancreatic head, instead of axial (transverse) slicing, is the most revealing approach. In addition, documentation of the findings in the duodenal surface of the ampulla is crucial for ampullary carcinomas and their recent site-specific categorization into 4 categories. Therefore, we probe both the CBD and the pancreatic duct from distal to the ampulla and cut the pancreatic head to the ampulla at a plane that goes through both ducts. Then, we sample the bisected pancreatic head depending on the findings of the case. For example, for proper staging of ampullary carcinomas, it is imperative to take the sections perpendicular to the duodenal serosa at the "groove" area, as ampullary carcinomas often extend to this region. Amputative (axial) sectioning of the ampulla, although good for documentation of the peri-Oddi spread of the intra-ampullary tumors, unfortunately disallows documentation of mucosal spread of the papilla of Vater tumors (those arising from the edge of the ampulla, where the ducts transition to duodenal mucosa and extending) into the neighboring duodenum. Axial sectioning also often fails to document tumor spread to the "groove" area. In conclusion, knowledge of the gross characteristics of the anatomic hallmarks is essential for proper dissection of PD specimens. The approach described above allows practical and accurate documentation and staging of pancreas, distal CBD, and ampullary cancers.

Objectives: To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation. Methods: Whole-exome sequencing of numerous benign and malignant pancreatic tumors, along with the plethora of highly sensitive molecular studies now available for analyzing these tumors, provide mounting evidence to support the long-held belief that cancer is essentially a genetic disease. These genetic discoveries have not only helped to confirm the age-old, morphology-based classifications of pancreatic neoplasia but have shed new light on their mechanisms. Many of these molecular discoveries are currently being used in preoperative diagnosis. Results: Mutations in KRAS , P16/CDKN2A , TP53 , and SMAD4/DPC4 are commonly seen in ductal neoplasia but not in nonductal tumors; ductal adenocarcinomas with SMAD4/DPC4 loss are associated with widespread metastasis and poor prognosis. GNAS and RNF43 mutations have been discovered in most intraductal pancreatic mucinous neoplasms, providing critical molecular fingerprints for their diagnosis. Mutation in DAXX/ATRX is only seen in pancreatic neuroendocrine tumors, making it a useful potential marker in distinguishing these tumors from mimics. Conclusions: When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

In the past decade, the clinico-pathologic characteristics of neuroendocrine tumors (NETs) in the pancreas have been further elucidated. Previously termed “islet cell tumors/carcinomas” or “endocrine neoplasms”, they are now called pancreatic NETs (PanNETs). They occur in relatively younger patients and may arise anywhere in the pancreas. Some are associated with von Hippel–Lindau, MEN1, and other syndromes. It is now widely recognized that, with the exception of tumorlets (minute incipient neoplasms) that occur in some syndromes like MEN1, all PanNETs are malignant, albeit low-grade, and although they have a protracted clinical course and overall 10-year survival of 60–70 %, even low-stage and low-grade examples may recur and/or metastasize on long-term follow-up. Per recent consensus guidelines adopted by both European and North American NET Societies (ENETS and NANETs) and WHO-2010, PanNETs are now graded and staged separately, unlike previous classification schemes that used a combination of grade, stage, and adjunct prognosticators in an attempt to define “benign behavior” or “malignant” categories. For staging, the ENETs proposal may be more applicable than CAP/AJCC, which is based on the staging of exocrine tumors. Current grading of PanNETs is based on mitotic activity and ki-67 index. Other promising prognosticators such as necrosis, CK19, c-kit, and others are still under investigation. It has also been recognized that PanNETs have a rather wide morphologic repertoire including oncocytic, pleomorphic, ductulo-insular, sclerosing, and lipid-rich variants. Most PanNETs are diagnosed by fine needle aspiration biopsy, in which single, monotonous plasmacytoid cells with fair amounts of cytoplasm and distinctive neuroendocrine chromatin are diagnostic. Molecular alterations of PanNETs are also very different than that of ductal or acinar tumors. Loss of expression of DAXX and ATRX proteins has been recently identified in 45 %. Along with these improvements, several controversies remain, including grading, value of current cutoff ranges, and the best methods for counting ki-67 index (manual count by computer-captured image may be the most practical for the time being). More important is the controversial use of the term “carcinoma”, which was previously employed in WHO-2004 only for invasive and metastatic cases but has now been made synonymous with grade 3 group of tumors. It is becoming clear that grade 3 group comprises two distinct categories: (1) differentiated but proliferatively more active tumors which typically have ki-67 indices in the 20–50 % range and (2) true poorly differentiated NE carcinomas as defined in the lung, with ki-67 typically >50 %. Further studies are needed to address these controversial aspects of PanNETs.

DNA methylation is a rational therapeutic target in pancreatic cancer. The activity of novel curcumin analogues EF31 and UBS109 as demethylating agents were investigated. MiaPaCa-2 and PANC-1 cells were treated with vehicle, curcumin, EF31 or UBS109. EF31 and UBS109 resulted in significantly higher inhibition of proliferation and cytosine methylation than curcumin. Demethylation was associated with re-expression of silenced p16, SPARC, and E-cadherin. EF31 and UBS109 inhibited HSP-90 and NF-κB leading to downregulation of DNA methyltransferase-1 (DNMT-1) expression. Transfection experiments confirmed this mechanism of action. Similar results were observed in vitro when subcutaneous tumors (MiaPaCa-2) were treated with EF31 and UBS109.

The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.

Our investigation suggests that MR imaging is accurate for identification of paraduodenal pancreatitis and for differentiation of this entity from ductal carcinoma of the pancreatic head.

KRAS codon 12 mutations are present in about 90% of ductal adenocarcinomas and in undifferentiated carcinomas of the pancreas. The role of KRAS copy number changes and resulting KRAS mutant allele-specific imbalance (MASI) in ductal adenocarcinoma (n=94), and its progression into undifferentiated carcinoma of the pancreas (n=25) was studied by direct sequencing and KRAS fluorescence in situ hybridization (FISH). Semi-quantitative evaluation of sequencing electropherograms showed KRAS MASI (ie, mutant allele peak higher than or equal to the wild-type allele peak) in 22 (18.4%) cases. KRAS FISH (performed on 45 cases) revealed a trend for more frequent KRAS amplification among cases with KRAS MASI (7/20, 35% vs 3/25, 12%, P=0.08). KRAS amplification by FISH was seen only in undifferentiated carcinomas (10/24, 42% vs 0/21 pancreatic ductal adenocarcinoma, 0%, P=0.0007). In 6 of 11 cases with both undifferentiated and well-differentiated components, transition to undifferentiated carcinoma was associated with an increase in KRAS copy number, due to amplification and/or chromosome 12 hyperploidy. Pancreatic carcinomas with KRAS MASI (compared to those without MASI) were predominantly undifferentiated (16/22, 73% vs 9/97, 9%, P