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Importance: National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear., Objective: To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC., Design, Setting, and Participants: This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021., Interventions: Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours)., Main Outcomes and Measures: Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection., Results: Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively., Conclusions and Relevance: This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting., Trial Registration: ClinicalTrials.gov Identifier: NCT02839343.

Context.—: Pancreatic adenocarcinoma is the third leading cause of cancer death in the United States. Surgery remains the mainstay of treatment, and frozen section analysis is used to confirm diagnosis and determine resectability and margin status., Objective.—: To evaluate use and accuracy of frozen section and how diagnosis impacts surgical procedure., Design.—: We reviewed patients with planned pancreatic resections between January 2014 and March 2019 with at least 1 frozen section. Pathology reports including frozen sections, preoperative cytology, and operative notes were reviewed. Frozen sections were categorized by margin, primary pancreatic diagnosis, metastasis, or vascular resectability. The deferral and error rates and surgeons' response were noted., Results.—: We identified 898 planned pancreatic resections and 221 frozen sections that were performed on 152 cases for 102 margins, 94 metastatic lesions, 20 primary diagnoses, and 5 to confirm vascular resectability. The diagnosis was deferred to permanent sections in 13 of 152 cases (8.6%) on 16 of 221 frozen sections (7.2%): 6 for metastasis, 8 for margins, and 2 for primary diagnosis. Discrepancies/errors were identified in 4 of 152 cases (2.6%) and 4 of 221 frozen sections (1.8%). Surgeons' responses were different than expected in 8 of 221 frozen sections (3.6%), but their actions were explained by other intraoperative findings in 6 of 8., Conclusions.—: Frozen section remains an important diagnostic tool used primarily for evaluation of margins and metastasis during pancreatectomy. In most cases, a definitive diagnosis is rendered, with occasional deferrals and few errors. Intraoperative findings explain most cases where surgeons act differently than expected based on frozen section diagnosis.

Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with an overall five-year survival rate of 9%, and few patients are candidates for pancreatectomy at presentation. The role of neoadjuvant therapy (NAT) is evolving, especially for high-risk potentially resectable tumors. Owing to the increasing number of NAT resection specimens, we aim to characterize the histologic changes associated with NAT and to compare two tumor regression grading schemes. One hundred eighteen resections for PDAC were selected from the cases between 2011 and 2018, 59 not treated and 59 treated with NAT. All H&E stained tumor slides were reviewed for histologic changes and graded using the four-tier modified Ryan score (recommended by College of American Pathologists) and the three-tier MD Anderson (MDA) score. The histologic changes evaluated included blue/grey fibrosis, islet cell hyperplasia, dystrophic calcification, amyloid deposition, cholesterol clefts, nerve hypertrophy, elastotic stromal/vascular change, abscess formation, and eosinophilic tumor cell changes. There were statistically significant differences for dystrophic calcification, eosinophilic tumor cell changes, elastotic stromal/vascular change, islet cell hyperplasia, and nerve hypertrophy between the two groups, with these features seen more frequently in NAT cases. Blue/grey stromal fibrosis was present in all cases regardless of NAT, except few complete regression cases and one treated case with intraneural invasion only. Blue/grey fibrosis is a useful histologic visual clue to suggest the possibility of adjacent tumor in the majority of PDAC cases regardless of NAT. By Kaplan-Meier analysis, neither grading scheme correlated with overall survival in our cohort. However, the MDA score was significantly correlated with both time to primary tumor recurrence (p = 0.002) and time to distant recurrence (p = 0.04), whereas the modified Ryan score was not., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)-modified FOLFIRINOX (mFOLF) vs nanoparticle albumin-bound paclitaxel plus gemcitabine (nab-P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan-Meier method and log-rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy-two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab-P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab-P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis-free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab-P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186-0.987) and abnormal postoperative CA 19-9 (hazard ratio, 2.47; 95% CI, 1.06-5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab-P/G., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone., Background: Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient's metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies., Methods: The first patient's tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured., Results: Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce., Conclusions: The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic hormone.

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 having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. 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 Ki67>20% 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.

Objective: The presence of an enhancer element, RD (RD), in the prominent INK4-ARF locus provides a novel en bloc mechanism to simultaneously regulate the transcription of p15, p14ARF, and p16 genes. However, knowledge about RD alterations and its potential contributions to cancer progression remains limited. In this study, we aimed to evaluate the incidence of RD alterations in pancreatic tumors., Methods: DNAs from 14 gastrinomas and 6 nonfunctioning pancreatic neuroendocrine tumors were subjected to quantitative real-time polymerase chain reaction-based assays to determine deletions in p15, p14ARF, and p16 (both exons 1 and 2)., Results: RD was frequently deleted in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors with an incidence of 30% (6/20 samples). In comparison, the incidences of deletions of p15 (exon 1), p14ARF (exon 1β), and p16 (exon 1α) are 10% (2/20 samples), 10% (2/20 samples), and 45% (9/20 samples), respectively. Whereas some RD deletion events arose from deletions of the entire INK4-ARF locus, RD deletions in some specimens seemed to be independent of genetic alterations in any of the p15, p14ARF, and p16 genes., Conclusions: Our results strongly support that the deletion of RD may represent a novel mechanism to simultaneously downregulate p15, p14ARF, and p16, thus contributing to the development of human pancreatic cancers.

Background: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited., Design: A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed., Results: The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively., Conclusions: Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

Background: Cancers of the bile duct and the pancreas are virtually indistinguishable using conventional histopathological and clinical characteristics. We sought to use microRNA (miR) profiling to differentiate these two cancers., Methods: RNA was harvested from the tumors of patients undergoing curative resection for cholangiocarcinoma or pancreatic adenocarcinoma and compared with adjacent normal bile duct or pancreas, respectively. There were 31 pairs of cholangiocarcinoma with matched tumor and adjacent bile duct and nine pairs of pancreatic cancer with matched tumor and adjacent uninvolved pancreas that had sufficient quantity of RNA that were included in the final analysis. Differential microRNA expression profiles were determined using the nCounter System from nanoString Technologies (Seattle, WA,USA)., Results: A total of 41 differentially expressed miRs were identified in cholangiocarcinoma (25 overexpressed, 16 underexpressed) and 52 differentially expressed miRs were found in pancreatic adenocarcinoma (30 overexpressed, 22 underexpressed) relative to adjacent normal tissue. Of these two profiles, 15 miRs were commonly dysregulated between tumor types. Also, eight miRs were similarly overexpressed or underexpressed in cholangiocarcinoma and pancreatic adenocarcinoma, whereas the other seven miRs had inverse expression levels., Conclusions: Cholangiocarcinoma has a distinct miR profile from pancreatic adenocarcinoma. Discrimination between these two tumor types may be possible with as few as seven miRs.

Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n = 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, α-smooth muscle actin (α-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF) ] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n = 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target., (©2013 AACR.)

Background: Osteopontin (OPN) is a secreted protein of the extracellular matrix. It has been used as a marker for tumor aggressiveness and correlated with clinical outcomes in several solid tumors, such as liver, lung, and breast. We determined the OPN expression and its influence on survival in patients with resected pancreatic adenocarcinoma., Methods: Tissue microarrays were constructed from 245 resected pancreatic adenocarcinomas. Immunohistochemical staining for OPN was undertaken and compared to normal pancreas (n = 12). OPN expression was then correlated with patient demographics, tumor size, grade, node, and margin status. Survival curves were created by the Kaplan-Meier method and compared by log rank analysis., Results: In total, 181 (74 %) of pancreatic adenocarcinoma tissues expressed OPN compared to 7 (58 %) of normal controls (p = 0.004). Expression was observed predominantly in the cytoplasm of the tumor cells. The median and 2 year overall survival was longer when OPN was expressed (17.1 vs. 11.6 months, and 38 vs. 24 %, respectively, p = 0.04). Multivariate analysis showed OPN expression and T stage to be independent predictors of overall survival, while other histopathologic factors such as tumor grade, tumor size, and nodal status were not., Conclusions: These results suggest that the presence of OPN expression in pancreatic adenocarcinoma may have a protective effect independent of tumor stage. This emphasizes the importance of the interaction between pancreatic cancer cells and their stromal elements.

DOG1, a transmembrane calcium-regulated chloride channel protein, is a sensitive and specific marker for gastrointestinal stromal tumors compared with other spindle cell and epithelioid neoplasms. Overexpression has also been described in a variety of both benign and malignant epithelial neoplasms. Recently, DOG1 immunoreactivity has been reported in pancreatic solid pseudopapillary tumors (SPT), suggesting a role as a marker for SPT. Utilizing immunohistochemistry, we evaluated DOG1 expression in pancreatic neoplasms to determine the prevalence of staining and establish diagnostic utility. Multiple tissue microarrays (TMA) were created from cores of formalin-fixed paraffin-embedded blocks containing pancreatic adenocarcinomas (n=112), neuroendocrine tumors (n=99), serous cystadenomas (n=28), and SPT (n=14) as well as normal pancreas (n=12). Immunoreactivity for DOG1 (clone K9) was assessed for intensity (1 to 3+), percentage of tumor positivity and location. Of the 99 cases of neuroendocrine tumors, only 2 (2%) were focally positive. Patchy staining was identified in 8 cases (7%) of adenocarcinoma of 1 to 2+ intensity, involving 15% to 80% of the tumor cells and primarily seen in a membranous and luminal distribution. In contrast to a previous report, no DOG1 positivity was observed in SPT, evaluated by both TMA and full sections. The TMAs of serous cystadenomas and normal pancreas were negative for DOG1. Rarely, pancreatic islets displayed granular, cytoplasmic staining. DOG1 antibody clone K9 is not a useful marker for SPT or other primary pancreatic neoplasms. Additional studies may be helpful to evaluate differences between clones of DOG1.

Hematologic malignancies often involve the pancreas, causing potential diagnostic pitfalls and, rarely, potentially avoidable surgical resection. We review the spectrum of hematologic malignancies involving the pancreas and describe features useful in preoperative distinction from adenocarcinoma. Archived clinical, pathologic, and radiologic data (1965 to present) for hematologic malignancies involving the pancreas were reviewed and compared with the data for 157 surgically resected pancreatic adenocarcinomas. Of 42 cases, 27 (64%) were clinically "suspicious" for hematologic malignancies. Of the remaining 15 cases, 4 patients underwent resection for presumed pancreatic adenocarcinoma. Isolated pancreatic masses proved most difficult to identify clinically. Significant factors in distinguishing hematologic malignancies from adenocarcinoma included history of hematologic malignancy, young age, large tumor size, low CA19-9 level, B symptoms, and lack of jaundice or diabetes mellitus. Various hematologic malignancies involve the pancreas, most commonly diffuse large B-cell lymphoma. Pancreatic masses are usually correctly identified clinically. Preoperative and operative sampling is strongly recommended when hematologic malignancies cannot be excluded.

Introduction: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase critical to cell growth and proliferation through its effects on protein translation. Activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway has been described in various tumor types. Earlier studies have demonstrated loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function in some pancreatic ductal adenocarcinomas (PDAs). We performed immunohistochemistry for PTEN and p-RPS6 (major downstream mTOR effector) in a group of PDAs. An assessment of chronic pancreatitis (CP) and normal pancreas (NL) was performed in parallel., Materials and Methods: Tissue microarrays were constructed from 49 PDA, 27 CP, and 12 NL. Cases were scored as follows: PTEN (intact: ≥ 5% staining and lost: < 5%) and p-RPS6 (0, 1+: modest intensity in ≥ 5% of cells and 2+: strong intensity ≥ 5% of cells)., Results: Forty-one percent of PDAs demonstrated loss of PTEN, and 75% demonstrated p-RPS6 immunoreactivity (1+ in 22 and 2+ in 3). PTEN was uniformly intact in NL and CP. Although p-RPS6 immunoreactivity was only noted in 1 NL control (8%), 1+ positivity was observed in 62% of CP., Conclusions: mTOR pathway activation, as evidenced by p-RPS6 immunoreactivity, is frequent in PDA. p-RPS6 expression was also frequent in CP, highlighting the importance of this pathway in both neoplastic and inflammatory processes. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR represents a logical target for directed biologic therapy.

Background: Loss of expression of fragile gene products, Fhit and Wwox, occurs in many cancer types, with loss exhibited early in the neoplastic process in some. Wwox has been understudied in pancreatobiliary cancers, especially in relation to other involved tumor suppressors. We have assessed the status of the Fhit and Wwox proteins encoded by DNA damage susceptible chromosome fragile sites encompassed by FHIT and WWOX tumor suppressor genes., Methods: Pancreatic, gallbladder and ampullary cancers, normal pancreas, chronic pancreatitis, and benign gallbladder specimens were stained for expression of Fhit, Fhit effector protein Fdxr, Wwox, and other tumor suppressors by immunohistochemistry, and comparisons were made between benign and malignant tissue. Correlations of expression among proteins and clinicopathologic features were sought using Spearman's rank order. Survival curves were created using the Kaplan-Meier method and compared by log-rank analysis. Predictors of survival were determined using multivariate Cox proportional hazards analysis., Results: Fhit and Wwox were ubiquitously expressed in benign samples and significantly and coordinately reduced in pancreatic, gallbladder, and ampullary cancers. In pancreatic cancers, Fdxr expression was positively correlated with Fhit and Wwox expression. Neither Fhit nor Wwox expression correlated with expression of other tumor suppressors or with clinicopathologic characteristics measured., Conclusion: Loss of Fhit and Wwox expression does not predict tumor progression or patient survival, suggesting that loss of expression of genes at the exquisitely replication stress sensitive chromosome fragile regions is an early event in the pathogenesis of cancers of the gallbladder, pancreas, and ampulla.

The diagnosis of serous microcystic adenoma (SMA) is usually straightforward. For small biopsies and/or unusual variants, the differential diagnosis includes other pancreatic or metastatic neoplasms showing cystic or clear cell features. We evaluated immunostains for potential use in the diagnosis of SMA. Cases of SMA were identified from archival files. Tissue cores (2 per block) were arrayed to create a microarray of cores measuring 2mm each. Additionally, microarrays previously constructed from 56 pancreatic adenocarcinomas (PACs) and 64 pancreatic endocrine tumors (PENs) were studied. The microarrays were stained with calponin, chromogranin, CD10, alpha-inhibin, and monoclonal neuron-specific enolase (m-NSE). Subsequently, some were stained with MUC6, melan-A, D2-40, h-caldesmon, smooth muscle actin, and smooth muscle myosin. For SMAs, staining was seen with calponin (85.2%), alpha-inhibin (96.2%), and m-NSE (96.2%). Focal weak staining was seen with MUC6 (65%). All SMAs were negative with chromogranin, CD10, melan-A, D2-40, h-caldesmon, smooth muscle actin, and smooth muscle myosin. In contrast, calponin was negative in all PACs and PENs. Staining for alpha-inhibin was absent in PACs and present in 4.1% of PENs; whereas immunoreactivity for m-NSE was present in 26.8% of PACs and 73.7% of PENs. Chromogranin staining was present in 9.1% of PACs and 100% of PENs. An immunohistochemical profile of staining with calponin, alpha-inhibin, and m-NSE and absent staining with chromogranin supports the diagnosis of SMA, and distinguishes SMA from PAC and PEN. Calponin and alpha-inhibin are the most useful positive markers for SMA, and are negative in most entities in the differential diagnosis.

Purpose: We sought to examine the synergistic antipancreatic cancer effect by simultaneously targeting hypoxic cancer cells with heat-shock protein 90 (HSP90) inhibitor and blockade of energy production., Experimental Design: The anticancer effects of an HSP90 inhibitor (geldanamycin) in pancreatic cells were investigated in hypoxia and normoxia. A hexokinase II inhibitor, 3-broma-pyruvate (3BrPA), was evaluated for selective glycolysis inhibition in hypoxia as a sensitizer of HSP90 inhibitor against pancreatic cancer. The HSP90 client protein degradation was monitored by Western blot. The synergistic antitumor effect of geldanamycin and 3BrPA was evaluated in a xenograft pancreatic cancer model and monitored by a noninvasive dynamic contrast-enhanced magnetic resonance imaging., Results: Hypoxia enhanced HIF-1alpha expression by 11-fold in pancreatic cancer cells, and HSP90 inhibitor exhibited a seven- to eightfold higher anticancer effect in hypoxia compared with normoxia via HSP90 client protein degradation. 3BrPA selectively inhibited glycolysis and sensitized geldanamycin against pancreatic cancer cells by 17- to 400-fold through HSP90 client protein degradation. The synergistic anticancer effect of reduced doses of geldanamycin and 3-BrPA was confirmed in xenograft models in vivo by more than 75% tumor growth inhibition., Conclusions: The combination of HSP90 inhibitors and glycolysis inhibitors provides preferential inhibition of cancer cells in hypoxia through HSP90 client protein degradation and selective glycolysis inhibition. This may provide a new therapeutic regimen to battle chemotherapy-resistant pancreatic cancers, by enhancing the synergistic therapeutic efficacy and reducing dose-limiting toxicity.

Aim: To report the clinicopathological features of patients with serous cystadenomas of the pancreas., Methods: Thirty-three cases of serous cystadenoma diagnosed between 1977 and 2006 were retrieved from the files of the Ohio State University Medical Center. Clinical data and microscopic slides were reviewed., Results: The patients included 27 women and 6 men with an age range of 38-83 (mean 64.3) years. The clinical presentation included 13 patients with abdominal pain and 8 patients with abdominal mass; 9 tumors were found incidentally. Abdominal CT scans in 25 patients were interpreted as suspicious for carcinoma in 8 (32%), suspicious for serous cystadenoma in 8, neoplasm not otherwise specified in 8, and suspicious for a pseudocyst in 1. Only 7 patients underwent a preoperative biopsy, and 5 of these were diagnosed as having a serous cystadenoma. All but 2 of the patients underwent surgical resection of the tumor. The serous cystadenomas varied in size from 1.0 to up to 13 cm in maximum dimension, and all but one had a multicystic appearance. Of the 33 serous cystadenomas, 20 (61%) were located in the pancreatic tail, 4 (12%) in the pancreatic body, 4 in the pancreatic body and tail, and 5 (15%) in the head of the pancreas. Follow-up in 17 patients (median 3 years, range from 1 month to 11 years) showed no recurrence of serous cystadenomas. One patient had von Hippel-Lindau syndrome, 4 patients had diabetes mellitus, 3 patients had metastatic cancer, and 2 patients had ovarian tumors., Conclusions: Serous cystadenoma is an uncommon neoplasm that can be confused with malignancy both clinically and radiologically; a correct diagnosis is important in order to provide an accurate prognosis., (Copyright 2008 S. Karger AG, Basel.)

Introduction: In an attempt to identify better prognostic factors, and the genetic basis of pancreatic endocrine tumors (PETs), we evaluated immunohistochemical reactivity for c-erb B2 (Her-2/neu), bcl-2, and p53., Methods and Materials: Two pathologists reviewed hematoxylin and eosin slides and immunohistochemical stains from 28 cases, 27 tumors and 1 nesidioblastosis. Using WHO criteria for malignancy (presence of local or lymphovascular invasion and/or metastases), cases were divided into malignant (20 cases) and benign or uncertain (8 cases). Nuclear staining in >1% of cells was considered positive for p53 and bcl-2, whereas membranous staining was considered positive for c-erb B2 (Her-2/neu)., Results: All cases were nonimmunoreactive with anti-c-erb B2 (Her-2/neu), but focal granular or diffuse cytoplasmic staining was seen in occasional neoplasms. One malignant PET showed reactivity with anti-p53, whereas all others were negative. bcl-2 reactivity was identified in 15/28 cases: 9/20 malignant PETs and 6/8 others were positive., Conclusions: c-erb B2 (Her-2/neu) and p53 are not useful prognostic factors in PET. c-erb B2 (Her-2/neu) staining must be carefully evaluated to avoid the misinterpretation of artifactual/background staining. bcl-2 is occasionally expressed in PET, but the significance of this finding is still to be determined.

Many patients with pancreatic carcinoma have stent placement for biliary obstruction before resection. Stent-associated atypia, found in common bile duct (CBD) margins at the time of resection, may be confused with malignancy. We evaluated histologic and immunohistochemical changes in CBD margins from resection specimens for pancreatic carcinoma. Histologic findings in CBDs, including ulcer and inflammation; epithelial metaplasia, atypia, and gland complexity; and increased wall thickness, nerve entrapment, and smooth muscle content, were compared in 30 stented and 31 nonstented CBD margins from pancreaticoduodenectomies for carcinoma and 13 normal CBDs from autopsy material. The proliferation index was calculated for stented and nonstented CBDs after Ki-67 immunohistochemical staining. Immunostaining for Ki-67, p53, and c-erbB-2 was performed in stented CBDs and corresponding carcinomas. All the histologic changes occurred more frequently in stented and nonstented CBD margins from carcinoma patients than in normal CBDs. Stented CBDs had significantly increased epithelial changes and Ki-67 proliferation rate as compared with nonstented CBDs. The stented CBDs had significantly less p53 and c-erbB-2 expression as compared with corresponding pancreatic carcinomas. Caution should be applied when interpreting atypia in CBD margins from patients with a history of CBD stenting. Changes found in stented CBDs are characteristic, and in most cases can be distinguished from malignancy. In difficult cases, immunohistochemistry may be useful.

In this case report, we describe an accessory spleen that presented as a mass in the tail of the pancreas and mimicked a neoplasm. Intrapancreatic accessory spleen have a relatively high prevalence and can be mistaken for tumors. We present a case of intrapancreatic accessory spleen in a 40-year-old man, which was discovered incidentally during a workup for an aortic dissection. Computerized axial tomography and magnetic resonance imaging scans demonstrated a hypervascular mass in the tail of the pancreas. The clinical and radiological differential diagnosis included pancreatic mucinous cystic neoplasm, pancreatic endocrine neoplasm, solid pseudopapillary tumor, ductal adenocarcinoma, and metastasis. After a distal pancreatectomy was completed, microscopic examination revealed heterotopic splenic tissue.

Context: While global microRNA (miRNA) expression patterns of many embryologic, physiologic, and oncogenic processes have been described, description of the role of miRNAs in ductal adenocarcinoma of the pancreas is lacking., Objective: To define the expression pattern of miRNAs in pancreatic cancer and compare it with those of normal pancreas and chronic pancreatitis., Design and Setting: Specimens were obtained at a National Cancer Institute-designated comprehensive cancer center from patients with ductal adenocarcinoma of the pancreas (n = 65) or chronic pancreatitis (n = 42) (January 2000-December 2005). All patients underwent curative pancreatectomy; those with pancreatic cancer were chemotherapy-naive. RNA harvested from resected pancreatic cancers and matched benign adjacent pancreatic tissue as well as from chronic pancreatitis specimens was hybridized to miRNA microarrays., Main Outcome Measures: Identification of differentially expressed miRNAs that could differentiate pancreatic cancer from normal pancreas, chronic pancreatitis, or both, as well as a pattern of miRNA expression predictive of long-term (>24 months) survival. Significance of Analysis of Microarrays and Prediction of Analysis of Microarrays were undertaken to identify miRNAs predictive of tissue type and prognosis. P values were calculated by t test, adjusted for multiple testing. Kaplan-Meier survival curves were constructed using mean miRNA expression (high vs low) as threshold and compared by log-rank analysis., Results: Twenty-one miRNAs with increased expression and 4 with decreased expression were identified that correctly differentiated pancreatic cancer from benign pancreatic tissue in 90% of samples by cross validation. Fifteen overexpressed and 8 underexpressed miRNAs differentiated pancreatic cancer from chronic pancreatitis with 93% accuracy. A subgroup of 6 miRNAs was able to distinguish long-term survivors with node-positive disease from those dying within 24 months. Finally, high expression of miR-196a-2 was found to predict poor survival (median, 14.3 months [95% confidence interval, 12.4-16.2] vs 26.5 months [95% confidence interval, 23.4-29.6]; P = .009)., Conclusions: Pancreatic cancer may have a distinct miRNA expression pattern that may differentiate it from normal pancreas and chronic pancreatitis. miRNA expression patterns may be able to distinguish between long- and short-term survivors, but these findings need to be validated in other study populations.

Context: Immunohistochemical stains have been used for the distinction of pancreatic adenocarcinoma from chronic pancreatitis., Objective: To determine if a double stain for MUC/p53 improved specificity and sensitivity for distinction of pancreatic adenocarcinoma from chronic pancreatitis by comparing maspin, mucin 4 (MUC4), p53, Smad4, and the double stain MUC4/p53., Design: Seventy-four pancreatic adenocarcinomas and 19 chronic pancreatitis cases were retrieved from archival files. Tissue cores were arrayed to create a tissue microarray of 2-mm cores. Sections were stained with antibodies against maspin, MUC4, p53, and Smad4. Additionally, a 2-color, double stain for MUC4 and p53 was developed and evaluated. Five percent or greater staining in either of the cores was considered positive. Intensity (0, 1, 2) and extent (%) of tumor cells staining was also determined., Results: The sensitivity for distinction of pancreatic adenocarcinoma from chronic pancreatitis with maspin, MUC4, p53, and Smad4 was 90%, 77%, 60%, and 63%, respectively; the specificity was 67%, 78%, 88%, and 88%, respectively. When MUC4 and p53 were combined in a double stain, and positive staining for either considered a positive result, the sensitivity increased to 96% but specificity was 73%. When immunoreactivity for both antibodies was necessary for a positive result, sensitivity fell to 39% but specificity was 100%. No correlation was found between intensity or extent of staining with any of the individual stains and tumor differentiation., Conclusion: The double immunohistochemical stain for MUC4/p53 can be a useful diagnostic tool in conjunction with the hematoxylin-eosin-stained section for pancreatic adenocarcinoma, particularly when limited tumor is available for multiple stains.

Background: Cystic neoplasms of the pancreas are less common than solid tumors, and portend a better prognosis. They can be divided into serous and mucinous subtypes, with the former behaving less aggressively and generally considered benign. Of the serous neoplasms, serous microcystic adenoma is the most common. An extremely rare solid variant of serous microcystic adenoma lacking secretory capability has been described. Herein, we present the fourth described case of this solid variant and review the literature., Case Presentation: We present a case of a 62 year-old man with a history of abdominal pain, who on CT scan was found to have a solid mass at the junction of the head and body of the pancreas. The patient was offered resection for diagnosis and treatment, and subsequently underwent distal pancreatectomy and splenectomy. Based on gross pathology, histology and immunohistochemistry, the mass was determined to be a solid serous microcystic adenoma., Conclusion: Solid serous microcystic adenoma shows similar histologic and immunohistologic features to its classic cystic counterpart, but lacks any secretory functionality. It appears to behave in a benign manner, and as such, surgical resection is curative for patients with this tumor. Furthermore, until more cases of solid SMA are identified to further elucidate its natural history and improve the reliability of preoperative diagnosis, surgical resection of this solid pancreatic tumor should be considered standard therapy in order to exclude malignancy.

Maspin, a member of the serpin family of serine protease inhibitors, has been shown to limit invasion and metastases in breast and prostate carcinomas. Maspin gene expression is up-regulated in pancreatic cancer, but not in normal pancreatic tissue. Maspin expression has been documented using immunohistochemical studies in pancreatic adenocarcinoma and high-grade intraductal dysplasia. We studied pancreatic ductal adenocarcinomas and chronic pancreatitis utilizing tissue microarray technology to determine the utility of maspin in differentiating these lesions. Immunohistochemistry was performed on tissue microarrays made from 72 cases of pancreatic ductal adenocarcinoma and 24 cases of chronic pancreatitis. Carcinomas were graded as well, moderately, or poorly differentiated using the WHO criteria. The primary antibody used was monoclonal antimaspin antibody (clone G167-70, 1:800, PharMingen, San Diego, CA). Nuclear and/or cytoplasmic staining for maspin was qualitatively scored from 1 + to 3 + based on intensity. Cases were considered positive if one or more cores demonstrated staining. Cases of chronic pancreatitis showed focal, weak (1 + to 2 +) staining within occasional benign ductal epithelial cells in 29% of cases (7/24). Diffuse and intense (3 +) staining was present in ducts with squamous metaplasia (3 cases). The majority of ducts showed no staining. Ductal adenocarcinomas showed diffuse staining in 91% (66/72) of cases with generally more intense staining than cases of chronic pancreatitis. Maspin may be helpful in differentiating ductal adenocarcinoma from chronic pancreatitis, once squamous metaplasia is ruled out.

microRNAs are functional, 22 nt, noncoding RNAs that negatively regulate gene expression. Disturbance of microRNA expression may play a role in the initiation and progression of certain diseases. A microRNA expression signature has been identified that is associated with pancreatic cancer. This has been accomplished with the application of real-time PCR profiling of over 200 microRNA precursors on specimens of human pancreatic adenocarcinoma, paired benign tissue, normal pancreas, chronic pancreatitis and nine pancreatic cancer cell lines. Hierarchical clustering was able to distinguish tumor from normal pancreas, pancreatitis and cell lines. The PAM algorithm correctly classified 28 of 28 tumors, 6 of 6 normal pancreas and 11 of 15 adjacent benign tissues. One hundred microRNA precursors were aberrantly expressed in pancreatic cancer or desmoplasia (p < 0.01), including microRNAs previously reported as differentially expressed in other human cancers (miR-155, miR-21, miR-221 and miR-222) as well as those not previously reported in cancer (miR-376a and miR-301). Most of the top aberrantly expressed miRNAs displayed increased expression in the tumor. Expression of the active, mature microRNA was validated using a real-time PCR assay to quantify the mature microRNA and Northern blotting. Reverse transcription in situ PCR showed that three of the top differentially expressed miRNAs (miR-221, -376a and -301) were localized to tumor cells and not to stroma or normal acini or ducts. Aberrant microRNA expression may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma., (Copyright 2006 Wiley-Liss, Inc.)

We reviewed our experience with pancreatectomy for neuroendocrine tumors (NE) to determine outcomes after R0/R1 or R2 resection and compare them to patients in whom resection was not attempted. Data were reviewed for all patients presenting with NE tumors of the pancreas between 1990 and 2005. Kaplan-Meier survival curves were compared by log-rank analysis. Multivariate analysis was completed using Cox proportional hazards to identify risk factors for poor survival after resection. Of 120 patients, 65 (54%) had functional tumors. Resection was undertaken in 83: distal pancreatectomy in 41, pancreaticoduodenectomy in 27, enucleation in 14, and central pancreatectomy in 1. Survival was significantly longer after resection (91 months versus 24, P<0.001). R0/R1 resection was accomplished in 64 (77%) and resulted in lower perioperative mortality (2% versus 21%, P<0.01) and longer survival (112 months versus 24, P<0.001) compared to R2 resection. Survival after R2 resection was no better than after no resection. Factors predictive of decreased survival were moderate/poor differentiation, R2 resection, and high-risk features. Long-term survival is possible following complete resection for NE tumors of the pancreas. However, cytoreduction resulting in incomplete tumor removal carries significant perioperative mortality without long-term survival benefit and should be discouraged.

Endocrine tumors of the pancreas represent 1% to 2% of all pancreatic neoplasms. The tumors tend to have an indolent behavior, and long-term survival is common. There is no gender or age predilection. Patients can present with symptoms due to hormonal excess or a local mass effect or be asymptomatic. The tumors tend to be solid and well circumscribed. Typical microscopic findings include an organoid pattern of growth, with cells containing scant to moderate amounts of cytoplasm, and nuclei with dispersed chromatin and inconspicuous nucleoli. The morphologic spectrum of these tumors can be variable, and the differential diagnosis includes chronic pancreatitis with neuroendocrine hyperplasia, ductal adenocarcinoma, solid pseudopapillary tumor, acinar cell carcinoma, and pancreatoblastoma. The classification of these tumors remains controversial, and prognosis is difficult to predict, but important features include metastasis and invasion of adjacent structures. Resection remains the mainstay of surgical treatment. It is important to be aware that unusual morphologic variants of pancreatic endocrine tumors are common, and immunohistochemical stains can help avoid misdiagnosis.

We report a carcinosarcoma of the pancreas in a 67-year-old woman who presented with nausea, vomiting, and painless jaundice. A work-up demonstrated a well-circumscribed mass in the head of the pancreas. After pylorus-preserving pancreaticoduodenectomy, the tumor was found to be grossly yellow, and it compressed the common bile duct and pancreatic duct. Histological examination of the neoplasm showed a 4.0 x 4.0 x 3.0-cm mucinous cystadenocarcinoma with invasive poorly differentiated carcinoma, well-differentiated squamous cell carcinoma, and sarcomatous stroma invading into the duodenum. There was no evidence of nodal metastasis (pT3N0M0). Immunohistochemical studies showed that the epithelial cells stained positive for cytokeratin 7, cytokeratin AE1/3, cytokeratin monoclonal antibody 5.2, epithelial membrane antigen, M-carcinoembryonic antigen, and low-molecular-weight kininogen, and the sarcomatous component was immunoreactive with vimentin. The patient had an uneventful recovery, but died 4 months later of rapidly progressive metastatic disease to the liver and peritoneum. To the best of our knowledge, this is the second case of carcinosarcoma with invasive epithelial and sarcomatous areas in the background of a mucinous cystic neoplasm of the pancreas.

Background: The effect of overexpression of epidermal growth factor receptor (EGFR) in pancreatic carcinoma is not clear. Utilizing tissue microarrays, we evaluated EGFR expression in pancreatic cancer to determine the association of EGFR expression with histopathologic characteristics and patient outcome., Methods: 71 cases of pancreatic adenocarcinoma and 18 cases of chronic pancreatitis were retrieved from archival files. Tissue cores from donor blocks were arrayed to create a tissue microarray. Sections were stained with EGFR and the intensity of membranous staining and percentage of tumor cells showing immunoreactivity were determined. At least 1% membranous staining and 1+ intensity were considered positive., Results: EGFR was present in 49 of 71 (69%) cases of pancreatic adenocarcinoma and 7 of 18 (39%) cases of chronic pancreatitis (p = 0.03). There was no statistically significant correlation between intensity or extent of EGFR expression and tumor grade, size, or lymph node status. While median survival was nearly twice as long when EGFR was expressed (15.2 vs. 8.3 months), this did not reach statistical significance., Conclusions: EGFR is overexpressed in pancreatic cancers independent of histopathologic characteristics and does not predict survival. Immunohistochemical analysis of EGFR staining may help in identifying candidates for EGFR inhibitor therapy.

Lymphoplasmacytic sclerosing pancreatitis is a rare entity that has been described under many different names and constitutes a diagnostic challenge as it may simulate a neoplastic process. Herein, we report a case of a 61-year-old woman who presented to our institution complaining of left flank pain and was found to have normal levels of amylase and lipase. An abdominal magnetic resonance image showed thickening of the pancreatic tail and compression of the pancreatic duct. The radiographic differential included both chronic pancreatitis and a neoplastic process. She underwent an exploratory laparotomy, during which a pancreatectomy and splenectomy were performed. Grossly, the pancreas contained a yellowish white, firm homogeneous mass measuring 6.5 x 3.3 x 2.9 cm involving the entire pancreatic tail and hilum of the spleen. Histologically, pancreatic sections showed extensive fibrosis admixed with an inflammatory infiltrate. This infiltrate was composed mainly of lymphocytes with multiple germinal centers, as well as plasma cells and eosinophils that surrounded pancreatic ducts and extended into the peripancreatic adipose tissue. No malignancy was identified, and the process was diagnosed as lymphoplasmacytic sclerosing pancreatitis.

Context: Splenic rupture secondary to solid malignancy is an infrequent complication that usually occurs late in the progression of a previously diagnosed cancer. In rare instances, splenic rupture precipitates the discovery of an unsuspected pancreatic carcinoma. We report 2 cases of adenocarcinoma of the pancreas in which the patients presented with splenic rupture., Objectives: To review the clinicopathologic features of splenic rupture due to pancreatic carcinoma and to increase awareness of malignancy as a possible etiology for atraumatic splenic rupture., Design: We reviewed the clinical and pathologic data from 2 patients. A literature search was conducted to identify previous reports of splenic rupture associated with pancreatic cancer. We summarized the characteristics of the earlier cases and compared them with those of our patients., Results: We found only 4 previous reports of splenic rupture preceding the diagnosis of pancreatic cancer. In 3 of these cases, the pancreatic carcinoma grossly invaded the spleen at the time of resection. In contrast, malignancy was not suspected as the etiology of the rupture in our patients until histologic examination of the resected spleen revealed carcinoma., Conclusion: Splenic rupture is an unusual presentation of cancer of the pancreas, and to our knowledge only 4 cases have been reported previously in the literature. Although an underlying malignancy is relatively rare, spleens resected for atraumatic rupture should be carefully examined for possible neoplastic etiologies.

Microvascular density (MVD), a marker for tumor angiogenesis, has been demonstrated to have prognostic significance in various malignancies. Previous studies have demonstrated that MVD is an independent prognostic factor in pancreatic adenocarcinoma and that longer survival is associated with hypovascular tumors. The prognostic importance of MVD in pancreatic neuroendocrine tumor (NET) has not been documented. We evaluated MVD in pancreatic NET and correlated it with clinicopathologic features and patient outcome to determine whether MVD is a useful prognostic indicator for these patients. Twenty-five pancreatic NETs from our archival files resected between 1981 and 2000 were identified. The mean MVD was determined for each tumor from the 3 most vascularized 200 x fields. Clinical follow-up ranged from 1 to 19 years, with a mean of 4.9 years. At last follow-up, 6 patients were dead of disease, 10 patients were alive without disease, 4 patients were alive with disease, and 5 patients were alive with disease status unknown. Mean MVD ranged from 43 to 527 microvessels per 200 x field. MVD did not correlate with tumor size, the examined histologic parameters, or patient outcome. MVD in pancreatic NET does not correlate with the clinicohistologic features evaluated in this study or with the patient outcome and is not a useful prognostic indicator in these patients. These results suggest that factors other than the simple number of microvessels are important in determining pancreatic NET behavior. However, most tumors were highly vascular, and additional studies may be helpful to clarify further the role of vascularity and assess the utility of antiangiogenic agents in the treatment of pancreatic NET.

Intrapancreatic schwannoma is a rare neoplasm. We report a case of a 46-year-old man with a cystic schwannoma in the head of the pancreas. This tumor, based on clinical manifestations and radiologic features, was initially suspected to be a cystic mucinous tumor of the pancreas or a pseudocyst. Histologically, the tumor was a typical schwannoma with cyst formation caused by degenerative changes. Immunostaining showed the tumor cells to be strongly and diffusely positive for S-100 protein, vimentin, and CD56, and negative for cytokeratin AE1/AE3, desmin, smooth muscle myosin specific, CD34, and CD117, which support the diagnosis of schwannoma. Cystic schwannoma is a rare neoplasm occurring in the pancreas and should be considered in the differential diagnoses for patients presenting with pancreatic cystic lesions.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Immunohistochemistry with different cytokeratin subsets has been successfully used in the differential diagnosis of various human epithelial neoplasms. Cytokeratin 5/6 antibody, which recently became commercially available, has been found useful in the diagnosis of mesothelioma. Studies have reported only infrequent staining in adenocarcinomas. We investigated the pattern of immunoreactivity for cytokeratin 5/6 in hepatobiliary and pancreatic tumors to determine its diagnostic utility in the morphologic evaluation of these neoplasms. Formalin-fixed. paraffin-embedded tissue sections from 10 hepatocellular carcinomas, seven hepatocellular adenomas, 10 cholangiocarcinomas, 10 pancreatic ductal adenocarcinomas, and 13 pancreatic neuroendocrine carcinomas were immunostained with anticytokeratin 5/6 after heat-induced antigen retrieval utilizing a modified avidin-biotin complex technique. Positive and negative controls stained appropriately. Two pathologists evaluated the slides. Strong but focal cytoplasmic immunoreactivity was observed in five of 10 pancreatic ductal adenocarcinomas and two of 10 cholangiocarcinomas. No immunoreactivity was identified in any cases of hepatocellular carcinoma (0/10), hepatocellular adenoma (0/7), or pancreatic neuroendocrine carcinoma (0/13). Additionally, occasional cytokeratin 5/6 immunoreactive benign ductal epithelial cells were seen in the background in some cases. Fifty percent of pancreatic ductal adenocarcinomas and 20% of cholangiocarcinomas are positive with anti-cytokeratin 5/6 immunostaining. For the evaluation of poorly differentiated neoplasms in the liver, immunoreactivity with cytokeratin 5/6 may help to exclude the possibility of hepatocellular carcinoma. Cytokeratin 5/6 may be helpful as a component in the panel of immunostains to differentiate between poorly differentiated neoplasms.