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The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4 patients were alive with regional, lymph node, and liver metastases, and 2 patients were alive with no evidence of disease. The tumor described here is an aggressive form of neuroectodermal tumor that should be separated from other primitive epithelioid and spindle cell tumors of the gastrointestinal tract. The distinctive ultrastructural features and absence of melanocytic differentiation serve to separate them from soft tissue clear cell sarcomas involving the gastrointestinal tract. The designation "malignant gastrointestinal neuroectodermal tumor" is proposed for this tumor type.

Most solid pancreatic tumors are invasive ductal adenocarcinoma (PDAC). Because PDAC is the most common tumor, it has become synonymous with the term "Pancreas Cancer." However, other malignant neoplasms occur in the pancreas (acinar, neuroendocrine and colloid carcinomas, and metastases) all with different outcomes. Because these tumors are often combined with PDAC in research databases, it causes misleading variability in the analysis of pancreatic cancers. We examine the histopathology of a variety of pancreatic cancers.

Tumor expression of excision cross-complementing gene-1 (ERCC1), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2), is associated with the efficacy of platinum and gemcitabine chemotherapy. The authors of this report recently demonstrated that high ERCC1 and RRM2 expression levels are independent negative prognostic markers for survival in early stage pancreas cancer. The differential expression and prognostic value of these biomarkers in biliary tract malignancy (BTM) is unknown.In total, 63 patients who had tissue available for analysis were selected from a prospective database of all patients (n = 104) who underwent resection of BTM (intrahepatic, hilar, or distal cholangiocarcinoma; gallbladder carcinoma) between January 2000 and December 2008. Immunohistochemistry for ERCC1, hENT1, RRM1, and RRM2 expression was performed. Staining was scored by a single pathologist who was blinded to patient outcomes.The median patient age was 67 years. The median overall survival (OS) was 16.2 months, and the median follow-up was 32.7 months. Only 3 BTMs (4.8%) had high ERCC1 expression, and 92.1% and 81% of BTMs exhibited high hENT1 and RRM1 expression, respectively. RRM2 expression varied, and 32% of tumors demonstrated high RRM2 expression. ERCC1 and RRM1 were not associated with OS. High RRM2 expression was associated with a trend toward improved OS (30.8 months vs 16.2 months; P = .06), and high hENT1 expression was associated with improved OS (17.7 months vs 9.5 months; P = .04).Most BTMs exhibited low ERCC1 expression and high hENT1 and RRM1 expression, whereas RRM2 expression levels varied. High expression of hENT1 was associated with improved OS. These findings may have implications for the selection of chemotherapy agents (gemcitabine vs platinum) and the stratification of patients in chemotherapy trials that assess outcome.

Acinar cell carcinoma (ACC) of the pancreas is a very rare tumor that has various morphologic features, which may give rise to diagnostic difficulties. Because of its rarity, many clinicopathologic characteristics remain to be further elucidated, and prognostic factors are yet to be well established. With the aim of better characterizing this carcinoma and searching for prognostic indicators, we collected 62 ACCs and investigated the following parameters: site, size, local infiltration, node and distant metastases, architectural pattern, nuclear atypia, presence of necrosis, lymphovascular and perineural invasion, proliferation, BCL10, trypsin, carboxyl ester lipase, amylase, lipase, PDX1, cytokeratin 19 (CK19), CK7, p53, and β-catenin expression. Twelve cases showing >30% of endocrine cells were reclassified as mixed acinar-neuroendocrine carcinomas, whereas 1 tumor was reclassified as a mixed ductal-acinar carcinoma and was excluded from the statistical prognostic evaluations. BCL10 and trypsin were the most reliable immunohistochemical markers, whereas amylase and lipase were not. Surgery was statistically correlated with a better prognosis (P=0.0008). Among resected tumors there was no difference in survival between ACCs and mixed acinar-neuroendocrine carcinomas, and factors that significantly correlated with poor prognosis were size >6.5 cm (P=0.004), lymph node (P=0.0039) and distant (P=0.008) metastases, and UICC stage (P=0.009). Stage was the only independent prognostic factor at multivariable analysis, and the best prognostic discrimination was observed on grouping together stages I and II and grouping together stages III and IV, suggesting a simplification of the UICC staging for such cancers. In addition, vascular and perineural invasion and CK19 and p53 expression showed a trend for poor prognosis, not reaching statistical significance.

The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated newguidelines. Since the levelsof evidence forallitemsaddressed in these guidelinesarelow,being4or5, we still have to designate them “consensus”, rather than “evidence-based”, guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required. Copyright 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

We report a case of an 8-year-old boy who initially presented with a painful subungual mass that was diagnosed as a "glomus tumor" largely based on the clinical presenta tion. Local excision was performed, and the patient remained tumor free for 17 years, after which he experienced three local recurrences and massive pleural metastases within the next 2 years. The tumor was poorly differentiated with small round cells and increased mitotic activity on light microscopy. The precise nature of the tumor was difficult to characterize and was unraveled primarily by immunoperoxidase studies, particularly the diffuse strong positivity of HBA-71 (MIC 2) antibody, also called pe ripheral neuroectodermal tumor-Ewing's sarcoma antigen, which is reported to be fairly specific for these tumors, and the expression of neural markers Leu-7 (HNK-1 ) and neuron-specific enolase. In addition, ultrastructural examination revealed imma ture cell junctions, cell processes, and abundant pools of intracytoplasmic glycogen. Metastatic pleural tumor recurred very rapidly after excision, but showed a dramatic, although short-lasting, response to chemotherapy with cisplatin and etoposide. The thumb is an uncommon location for peripheral neuroectodermal tumor-Ewing's sar coma, and a 17-year, disease-free interval is most unusual for a malignant tumor of this nature. We discuss this case with respect to its unique clinical behavior and in the context of the differential diagnosis of small, round cell neoplasms. Int J Surg Pathol 2(2):147-156, 1994

Most pathology analyses and measurements are prevalently carried out by trained reviewers in both clinical and research settings. Therefore, the resulting outputs are inexorably biased by interpreters and degraded with poor reproducibility. In this paper, we propose a computerized image analysis paradigm enabling quantitative characterizations of steatosis areas in microscopy images of pediatric liver biopsies. With the same set of patients, we also acquired the lipid measurements from magnetic resonance imaging data analysis for correlation investigation. Our preliminary results suggest a high correlation between the steatosis areas quantized with microscopy images and the lipid percentages calculated from radiology imaging data. Additionally, we compared the performance of the proposed analysis method with those of three certified pathologists and a popular commercial algorithm. The results suggest the superiority of our method to both human reviewers and the commercial method in terms of the steatosis-lipid correlation strength. This demonstrates that the developed method is promising for generating quantitative and reliable analysis results to better support further liver disease study.

To measure diagnostic performance in the detection of hepatocellular carcinoma (HCC) by using the most recent technology and multiphase gadolinium-enhanced magnetic resonance (MR) imaging and to compare with earlier results at the same institution.This retrospective study was institutional review board approved and HIPAA compliant. Informed consent was obtained. Between January 2008 and April 2010, 101 patients underwent liver transplantation and pretransplantation abdominal MR imaging within 90 days. Prospective image interpretations from the clinical record were reviewed for documentation of HCC, including size, number, and location. Liver explant histologic examination provided the reference standard for lesion analysis and was performed in axial gross slices in conjunction with the MR imaging report for direct comparison. Tumors were categorized according to size (≥ 2 cm or2 cm), and MR imaging detection sensitivity, specificity, predictive values, and accuracy were calculated according to category. The Fisher exact test was used to compare results from this study against prior reported results.Thirty-five (34.7%) of 101 patients had HCC at explant analysis. Patient-based analysis of all lesions showed a sensitivity and specificity of 97.1% (34 of 35) and 100% (66 of 66), respectively. For lesions 2 cm or larger, MR imaging had a sensitivity and specificity of 100% (23 of 23) and 100% (78 of 78), respectively. For lesions smaller than 2 cm, MR imaging had a sensitivity and specificity of 82.6% (19 of 23) and 100% (78 of 78), respectively. Lesion-based sensitivity for all tumors was 91.4% (53 of 58) in the current study, compared with 77.8% in 2007 (P = .07). For lesions smaller than 2 cm, the sensitivity was 87.5% (28 of 32) in the current study, compared with 55.6% previously (P = .02).MR imaging remains a highly accurate diagnostic method for the preoperative evaluation of HCC, and detection of small (2 cm) tumors has been significantly improved compared with that of earlier studies.

The interaction between tumor cells and inflammatory cells has an important role in cancer initiation and progression; however, this interaction has not been systematically investigated in pancreatic neoplasia. In this study, the presence of tumor-infiltrating neutrophils within and/or adjacent to neoplastic cells was investigated in pancreatic neoplasms. Areas with >10 tumor-infiltrating neutrophils/100 epithelial cells were arbitrarily classified as positive. Those with 11–15 tumor-infiltrating neutrophils were considered ‘borderline’ while those with >15 tumor-infiltrating neutrophils were considered ‘significant’. Among 363 invasive ductal carcinomas, 15 showed significant tumor-infiltrating neutrophils (8 were micropapillary carcinomas and 7 were undifferentiated carcinomas). Of 19 mucinous cystic neoplasms with a carcinomatous high-grade papillary component, 11 showed significant tumor-infiltrating neutrophils (mean, 25; range, 14–63 tumor-infiltrating neutrophils). Among intraductal papillary mucinous neoplasms, significant tumor-infiltrating neutrophils were identified in 4/16 pancreatobiliary type, but were uncommon in other types (1/11 oncocytic and 1/23 intestinal types had borderline tumor-infiltrating neutrophils, and 0/10 gastric type had tumor-infiltrating neutrophils). Non-carcinomatous (low-grade and non-papillary) components of these neoplasms did not have tumor-infiltrating neutrophils. Tumor-infiltrating neutrophils were not striking in neuroendocrine tumors (40), serous cystadenomas (18), acinar cell carcinomas (9) or solid-pseudopapillary neoplasms (8). In conclusion, significant tumor-infiltrating neutrophils are uncommon in pancreatic ductal adenocarcinoma, and when they occur it is typically in the micropapillary and undifferentiated types with a known poor prognosis. Among pre-invasive neoplasia, tumor-infiltrating neutrophils show a predilection for papillary in-situ carcinomas of mucinous cystic neoplasms, or less commonly, pancreatobiliary-type intraductal papillary mucinous neoplasms (both of which express cell surface-associated mucin 1 (MUC1)). MUC1 expression by these tumors may have biologic implications, considering its recently established relationship with inflammatory cells in carcinogenesis, and the differential expression of mucins in pancreatic neoplasia. Larger studies are needed to investigate the association between tumor-infiltrating neutrophils and pancreatic neoplasms and their role in their clinical behavior.

The information in the literature on squamous cell and adenosquamous carcinomas of the gallbladder is highly limited. In this study, 606 resected invasive gallbladder carcinoma cases were analyzed. Squamous differentiation was identified in 41 cases (7%). Those without any identifiable glandular-type invasive component were classified as pure squamous cell carcinomas (8 cases) and those with the squamous component constituting 25-99% of the tumors were classified as adenosquamous carcinomas (26 cases) and included into the analysis. The remaining 7 that had

Context.—Recently we have observed distinctive acidophilic intranuclear inclusions in cases of usual intraductal hyperplasia of the breast. Similar inclusions were described almost 20 years ago in cases of mammary hyperplasia. These correlated ultrastructurally with so-called helioid inclusions. However, there since has been little discussion of these inclusions in the literature. Objective.—To examine the incidence and specificity of these inclusions in proliferative lesions of the breast. Design.—Forty cases of usual intraductal hyperplasia, 15 cases of atypical ductal hyperplasia, and 34 cases of low-grade ductal carcinoma in situ were examined for the presence of acidophilic intranuclear inclusions. Results.—Acidophilic intranuclear inclusions were present in 50% of cases of usual intraductal hyperplasia (20 of 40) but were not identified in any cases of atypical ductal hyperplasia (0 of 15) or low-grade ductal carcinoma in situ (0 of 34). Conclusions.—Acidophilic intranuclear inclusions appear to be a common, specific feature found in usual intraductal hyperplasia and may be helpful in distinguishing it from atypical ductal hyperplasia and low-grade ductal carcinoma in situ in some cases. Elucidating the nature of these inclusions may provide insight into the pathogenesis of usual intraductal hyperplasia.

Ducts of Luschka are a developmental abnormality found within the gallbladder fossa in up to 10% of cholecystectomy specimens. They are most often encountered by surgeons when injured during laparoscopic or open cholecystectomy, leading to bile leakage and subsequent peritonitis. Histologically, they are typically composed of lobular aggregates of small ductules lined by bland, cuboidal-to-columnar biliary-type epithelium, associated with centrally located, larger ductules surrounded by concentric fibrosis. We have identified 6 cases of florid Luschka duct proliferation in which the ductules demonstrated irregular growth pattern, loss of characteristic concentric fibrosis, and epithelial atypia that strongly suggested the diagnosis of invasive pancreatobiliary adenocarcinoma or metastatic adenocarcinoma involving the gallbladder serosa. Two of the cases were initially diagnosed as invasive adenocarcinoma, whereas the other 4 were sent for consultation to rule out adenocarcinoma. All cases were associated with marked acute and chronic cholecystitis with mucosal ulceration, cholelithiasis, and thickening of the gallbladder wall. The ducts of Luschka were located within the rim of adherent liver in all 6 cases and the gallbladder serosa in 5 cases. Limited follow-up information was available for all patients with no documentation of progressive disease. Awareness and proper recognition of the anatomic location and histologic features are imperative in distinguishing florid ducts of Luschka from both non-neoplastic conditions and most importantly adenocarcinoma.

Over half of all gallbladder carcinoma (GBC) is discovered incidentally after cholecystectomy for benign disease. There are scant data comparing presentation and outcome for patients with incidental versus suspected GBC. The goal of this study is to determine the clinical differences between these two entities.Patients with GBC were identified retrospectively from records at academic healthcare institutions in Temuco, Chile; Atlanta, GA; and Rochester, MN between 1984 and 2008. Overall survival was compared for patients with and without preoperative suspicion using Kaplan-Meier curves and a multivariate Cox proportional hazards model.Of 571 patients, 128 (22.4%) had preoperative suspicion of malignancy, and 443 (77.6 %) were discovered incidentally. Incidental tumors were of lower stage, better differentiated, and with lower rates of metastases. Median survival for incidentally discovered GBC was 32.3 versus 5.8 months for suspected GBC (p0.0001). In a Cox proportional hazards model controlling for operation extent, T stage, differentiation, and other factors, preoperative suspicion remains a strong risk factor (odds ratio, 2.0; confidence interval, 1.5-2.9; p0.0001).Tumor characteristics differed significantly between patients with incidentally discovered versus preoperatively suspected GBC. Incidental GBC has a significantly better median survival.

GLUT-1 has been found to have an important role in the upregulation of various cellular pathways and implicated in neoplastic transformation correlating with biological behavior in malignancies. However, literature regarding the significance of GLUT-1 expression in pancreatic neoplasia has been limited and controversial.Immunohistochemical expression of GLUT-1 was tested in a variety of pancreatic neoplasia including ductal adenocarcinomas (DAs), pancreatic intraepithelial neoplasms (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and serous cystadenomas.There was a progressive increase in the expression of GLUT-1 from low- to higher-grade dysplastic lesions: All higher-grade PanINs/IPMNs (the ones with moderate/high-grade dysplasia) revealed noticeable GLUT-1 expression. Among the 94 DAs analyzed, there were minimal/moderate expression in 46 and significant expression in 24 DAs. However, all 4 clear-cell variants of DAs revealed significant GLUT-1 immunolabeling, as did areas of clear-cell change seen in other DAs. Moreover, all 12 serous cystadenomas expressed significant GLUT-1. GLUT-1 expression was also directly correlated with DA histological grade (P = 0.016) and tumor size (P = 0.03).GLUT-1 may give rise to the distinctive clear-cell appearance of these tumors by inducing the accumulation of glycogen in the cytoplasm. Additionally, because GLUT-1 expression was related to histological grade and tumor size of DA, further studies are warranted to investigate the association of GLUT-1 with prognosis and tumor progression.

Sclerosing epithelioid fibrosarcoma (SEF) is a distinctive variant of fibrosarcoma characterized by epithelioid tumor cells arranged in nests, cords, or sheets embedded within a sclerotic collagenous matrix. It is a relatively newly described malignant fibroblastic tumor, with only fewer than 100 cases reported in English literature. Most cases are located in the lower extremities and limb girdles. Here, we present a case of SEF of the pancreas in a 67-year-old white man and provide a review of literature to date, with emphasis on the differential diagnosis. To our knowledge, this is the first reported case of SEF involving the pancreas.

In order to appreciate the molecular pathology of carcinomas occurring in the extrahepatic bile ducts (EBD), it is important to understand the epidemiology and risk factors for these cancers. A chapter on cholangiocarcinoma with focus on intrahepatic biliary neoplasms is included independently in this textbook ( Chap. 59).

Gallbladder cancer (GBC) is an uncommon disease in most developed countries, with the exception of some geographical areas. The highest gallbladder cancer incidence rates have been reported in women from North India (21.5/100,000), Chile (18.1/100,000), Pakistan (13.8/100,000), and Ecuador (12.9/100,000). High incidences have also been found in Korea and Japan and some central and eastern European countries such as Poland, the Czech Republic, and Slovakia [1, 2]. GBC is up to three times higher among women than men in most countries and up to six times in select populations [1, 3].

Pancreatic ductal adenocarcinoma (PDCA) is characterized by well-defined tubular units in the vast majority of the cases; however, variations in this theme do occur. It is important to recognize the morphologic spectrum of PDCA to avoid misdiagnosis especially in small specimens and also in metastatic foci. Here, we document a morphologic variant of PDCA that is characterized by a distinctive pattern of infiltrating cribriform nests in a distinctive “microcystic” or “secretory” pattern. Twenty-four cases of PDCA have been identified in a review of 505 cases diagnosed with PDCA. Histologically, this pattern was characterized by infiltrating nests of tumor cells with large vacuoles and “signet-ring” like appearance imparting a cribriform growth pattern. The vacuoles were one to five cells in size, often merging to form multilocular spaces separated by a thin rim of cell membrane. Many of these spaces contained CA19.9 positive granular secretory material. The nuclei were often pushed to the periphery and compressed in a pattern resembling adipocytes, although the nuclei were often densely hyperchromatic and displayed significant atypia. Especially in biopsies from the peripancreatic fat and peritoneum, these neoplastic cells had been misdiagnosed as degenerating adipocytes, and in the lymph nodes, they had been misinterpreted as lipogranulomas. Clinical findings of the patients were similar to that of conventional PDCA, except higher incidence of history of smoking (83% vs. 60%; p = 0.034). In conclusion, vacuolated cell adenocarcinoma is a distinct morphologic variant of PDCA, and the presence of this peculiar pattern in a metastatic site, although not specific, should raise the suspicion of a PDCA.

The aim of this study was to examine differences in presentation and outcome in pancreaticoduodenectomy for benign and malignant processes. Pancreaticoduodenectomies performed for pancreatic adenocarcinoma or chronic pancreatitis from 2000 to 2008 were identified from a prospectively maintained database and compared. Pancreaticoduodenectomy revealed adenocarcinoma in 220 patients and benign chronic pancreatitis in 40 patients. Patients with adenocarcinoma were older (64 +/- 10.6 years and 47.6 +/- 10.8 years, respectively, P0.001) and more likely to demonstrate jaundice (92 and 13%, respectively, P0.001), weight loss (76 and 58%, respectively, P = 0.01), and discrete masses (72 and 55%, respectively, P = 0.03). By contrast, chronic pancreatitis presented with increased pain (98 and 49%, respectively, P0.001) and nausea (68 and 32%, respectively, P0.001). Patients with pancreatitis experienced reduced blood loss (227 +/- 156 and 571 +/- 626 mL, respectively, P = 0.05) and transfusion (10 and 42%, respectively, P0.001). Postoperatively, the groups were similar in risk of fistula, gastroparesis, overall morbidity, and mortality. Infection rates were higher in adenocarcinoma (42 and 20%, respectively, P = 0.01). Forty-nine patients underwent pancreaticoduodenectomy for presumptive chronic pancreatitis, of which nine had adenocarcinoma; logistic regression identified increasing age and jaundice as predictors of malignancy. Compared with patients with adenocarcinoma, those who undergo pancreaticoduodenectomy for chronic pancreatitis are less likely to require preoperative biliary drainage and perioperative transfusion. Infectious complication risk is higher in patients with adenocarcinoma. Increased age and jaundice should raise suspicion of cancer in patients with chronic pancreatitis undergoing evaluation for surgical treatment.

Merkel cell carcinoma (MCC) or primary cutaneous neuroendocrine carcinoma is a malignant tumor considered to demonstrate differentiation towards Merkel cells that are present at the base of the epidermis or around the apical end of some hair follicles and are thought to play an yet uncertain role in sensory transduction. Here we present the case of a 54-year-old female with a basal cell carcinoma (BCC) of the skin with neuroendocrine features (positivity for chromogranin) that has evolved during multiple recurrences and radiotherapy into a high-grade neuroendocrine carcinoma with morphologic and immunohistochemical features of MCC (trabecular and nesting arrangement, positivity for chromogranin, cytokeratin 20, neuron specific enolase, and also neurosecretory granules on electron microscopy). The progression from a chromogranin positive basal cell carcinoma of the skin, to a high grade neuroendocrine carcinoma demonstrates the potential for cross differentiation among skin tumors.

Owing to the challenges in obtaining pancreatic biopsies, pancreatic resection for presumed malignancy is often performed without histological confirmation. As a result, benign lesions are sometimes surgically removed. One such condition, which is poorly defined in the literature, is referred to as lipomatous pseudohypertrophy (LPH) of the pancreas.Five cases of LPH were analyzed.Four patients underwent surgical resection, 3 of which were diagnosed preoperatively by radiology as having ductal adenocarcinoma. The fourth case was correctly interpreted by magnetic resonance imaging as LPH, but the patient underwent resection because of the intractable pain due to pancreatitis. The fifth patient has been placed on watchful waiting.Two tumors were in the pancreatic head, one in the tail, one in the uncinate process, and one demonstrated diffuse involvement. Microscopically, they were characterized as having normal lipocytes without lipoblasts or inflammation. Within the adipose tissue, scattered microscopic foci of pancreatic parenchyma could be seen.Lipomatous pseudohypertrophy of the pancreas is a distinct entity characterized by localized/diffuse replacement of pancreatic parenchyma with mature adipose tissue. It forms a pseudotumor that may be difficult to distinguish clinically from pancreatic adenocarcinoma. This entity should be considered when evaluating patients with a new diagnosis of a hypodense pancreatic neoplasm on imaging.

Appendiceal carcinomas are classified into three distinct histopathological disease entities: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), or peritoneal mucinous carcinomatosis with intermediate or discorant features (PMCA I/D). The treatment of appendiceal tumors should be based on accurate histopathological classification, per previously reported case series. The objective of this study was to evaluate the clinicopathologic presentation and outcome of patients with appendiceal tumors treated at our institution over a 15-year period. We identified patients with appendiceal tumors diagnosed or treated at our institution from January 1989 through May 2004. Chart review for age, gender, signs and symptoms at diagnosis, and treatment was performed. Review of the pathologic specimens was performed and tumors were classified as DPAM, PMCA I/D, or PMCA. Forty patients were identified (median age 52.5 years; males 38%). The number of patients with DPAM, PMCA I/D, and PMCA was 15 (38%), 6 (15%), and 18 (46%), respectively. Peritoneal involvement was seen in 11 (73%) of patients with DPAM, 5 (83%) of PMCA I/D, and 11 (61%) of PMCA. The median survival for patients with DPAM, PMCA I/D, and PMCA was 7.7 years (90% CI: 2.9--upper limit not estimable), 1.2 years (90% CI: 0.9-1.6), and 0.7 years (90% CI: 0.4-1.5), respectively. The difference in survival across the three groups was statistically significant. Three distinct histopathological disease entities exist in appendiceal tumors. The prognosis and management of these tumors should be based on the extent of disease and pathologic diagnosis.

Background Associations between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDAC) are well established; however, the impact of DM on perioperative morbidity and mortality after PDAC resection is unclear. Study Design A prospectively maintained database review identified all patients undergoing PDAC resection between January 1, 2000, and December 31, 2008. Diagnosis of DM was established by history and biochemical profile. Records were reviewed for comorbidities, operative variables, and histologic parameters. Postoperative morbidity and mortality were assessed for diabetic and nondiabetic patients using standardized definitions. Results Of 251 PDAC cases, 116 (46%) patients had preoperative DM. Pancreaticoduodenectomy was performed in 220 (87.6%), left pancreatectomy in 29 (11.6%), and total pancreatectomy in 2 (0.8%). The major complication rate was 25.5%, with 60-day mortality of 3.6%. Delayed gastric emptying (DGE) occurred in 40.1% of patients. Pancreatic fistulas developed in 17 (6.8%) patients; 11 of them were clinically significant (grades B/C). DM patients had a higher likelihood of developing fistulas (DM 10.3%, non-DM 3.7%, p=0.04). When controlled for age, comorbidities, body mass index, preoperative albumin level, operation type, operative time, and pancreatic quality, DM maintained an independent association with fistula formation (odds ratio 4.3, 95% CI 1.18 to 15.8, p=0.027). Acute kidney injury was more frequent in the DM group (DM 23.3%, non-DM 12.6%, p=0.03). DM and non-DM patients had similar frequency of DGE, wound infections, intra-abdominal abscesses, and cardiovascular and pulmonary complications, as well as length of stay and mortality. Conclusions Comorbid DM does not influence perioperative outcomes dramatically after pancreatectomy for ductal adenocarcinoma. The role of PDAC-associated DM as a risk factor for postresection pancreatic fistula should be further explored. Evaluation of glycemic control and outcomes after PDAC resection may be useful.

Ampullary adenocarcinoma (AmpCA) carries a better overall survival (OS) rate than other periampullary cancers. We examined clinicopathologic features in AmpCA for impact on OS. Records of patients undergoing pancreaticoduodenectomy from 2000 to 2007 for AmpCA were reviewed and histological specimens were reanalyzed. Of 302 patients undergoing pancreaticoduodenectomy for malignancy, 45 (14.9%) had AmpCA. Mean age was 61.3 +/- 12.2 years, mean tumor size was 2.6 +/- 1.3 cm, 57 per cent wereor = T3 tumors, 42 per cent were N1 stage, 13 (49%) had perineural invasion (PNI), and 29 (64%) had lymphovascular invasion (LVI). Thirteen were intestinal (29%), 14 were pancreaticobiliary (31%), and 18 were mixed (40%). Median OS was 42 months (range 4-80 mos). On log rank testing,or = T3 (24 vs 65 mos, P0.01), N1 (25 vs 61 mos, P0.01), poor differentiation (24 vs 44 mos, P = 0.01), pancreaticobiliary subtype (23 vs 44 mos, P = 0.01), and PNI (23 vs 44 mos, P0.01) were significant for worse survival. By multivariate analysis, N1 disease (hazard ratio [HR] 4.50, 95% confidence interval [CI] 1.16-17.40) and PNI (HR 4.62, CI 1.11-19.21) maintained associations with worse survival, whereas histological subtype did not. N1 disease and presence of PNI demonstrated independent associations with worse survival. Given high percentage of mixed histology, PNI may be more informative than the subtype in predicting outcome for patients with AmpCA.

Tumors of the urinary bladder may have a variety of histological patterns. Tumors with either glandular or villous features, such as villous adenomas, in situ adenocarcinomas, invasive adenocarcinomas, and variants of urothelial carcinoma such as micropapillary carcinomas have been described. However, urothelial carcinomas with both villous and glandular features have not been well characterized. We identified 14 cases of urothelial carcinoma with villoglandular differentiation. These cases were defined as having villoglandular features if they contained superficial finger-like processes lined by epithelium having true glandular lumina. Mean patient age at presentation was 70 years (range: 46–84 years) with a male predominance (5:1). A total of 3 cases (21%) were non-invasive, five cases (36%) had lamina propria invasion, five cases (36%) had muscularis propria invasion and one case (7%) had extravesicular extension. A concurrent high-grade papillary urothelial carcinoma component was identified in 11 cases (79%), micropapillary component in 5 (36%) cases, in-situ urothelial carcinoma component in 3 cases (21%), plasmacytoid component in 3 cases (21%), invasive adenocarcinoma in 2 cases, sarcomatoid carcinoma component in one case (14%), and small-cell carcinoma component in 1 case (7%). Cystitis cystica et glandularis was present in 3 cases (21%). Angiolymphatic invasion was identified in 3 cases (21%). Histologically, the villoglandular components were composed of finger-like processes lined by glands intimately admixed with high-grade urothelial carcinoma. Many of the glands had cribriform features lined by non-mucin producing cuboidal to columnar cells. Urothelial carcinoma with villoglandular differentiation are high-grade tumors typically seen in elderly males, characterized by superficial filliform processes lined by glands intimately admixed with high-grade urothelial carcinoma (in situ or invasive) and other aggressive variants of urothelial carcinoma. These relatively rare tumors should be recognized as a variant of urothelial carcinoma.

The recent sequencing of the pancreatic cancer genome provides unprecedented insight into the fundamental nature of this deadly malignancy. Although much work still needs to be done, a molecular classification of neoplasms of the pancreas is emerging. Molecular genetics have been used to identify unique clinical subtypes of pancreatic cancer, to guide the clinical diagnosis of pancreatic tumors, and to identify targeted therapies for select pancreatic neoplasms. This review examines the emerging molecular classification of neoplasms of the pancreas. This classification does not ignore previous histology-based classification systems but instead embraces them, creating an integrated histological-molecular classification.

Context.—Distinguishing chronic pancreatitis from pancreatic ductal adenocarcinoma (PDAC) is a well-known challenge, at both the clinical and the morphologic level.Objective.—To focus on the histopathologic findings that are diagnostic or suggestive of PDAC.Data Sources.—Findings that are specific to PDAC are the presence of duct structures in perineural and vascular spaces and (“naked”) ducts in fatty tissue. However, these findings are only observed in specimens containing extrapancreatic tissue. The features that are suggestive of PDAC in specimens from the pancreas include haphazard distribution of ductlike structures (ie, loss of a lobular pattern), markedly irregular ductal contours, ruptured ducts, nuclear enlargement, pleomorphism and hyperchromatism, and mitotic figures. Immunohistologic markers that are helpful are carcinoembryonic antigen, MUC1, p53, and Ki-67/ MIB1.Conclusions.—There are a few features that are diagnostic and a number that are suggestive of PDAC. Therefore, a combination of several features may be required to clearly distinguish chronic pancreatitis from invasive PDAC.

OBJECTIVES: Detection of neoplastic changes using optical spectroscopy has been an active area of research in recent times. Raman spectroscopy is a vibrational spectroscopic technique that can be used to diagnose various tumors with high sensitivity and specificity. We evaluated the ability of Raman spectroscopy to differentiate normal pancreatic tissue from malignant tumors in a mouse model. METHODS: We collected 920 spectra, 475 from 31 normal pancreatic tissue and 445 from 29 tumor nodules using a 785-nm near-infrared laser excitation. Discriminant function analysis was used for classification of normal and tumor samples. RESULTS: Using principal component analysis, we were able to highlight subtle chemical differences in normal and malignant tissue. Using histopathology as the gold standard, Raman analysis gave sensitivities between 91% and 96% and specificities between 88% and 96%. CONCLUSIONS: Raman spectroscopy along with discriminant function analysis is a useful method to detect cancerous changes in the pancreas. Pancreatic tumors were characterized by increased collagen content and decreased DNA, RNA, and lipids components compared with normal pancreatic tissue.

Classification of pancreatic neoplasia is based on their cellular lineage, i.e which histologic cell type of the pancreas they recapitulate, which is in essence the main determinant of their clinicopathologic and biologic characteristics. Virtually every cell type that exists in the pancreas has been described to have one or more neoplastic counterparts. Cellular components of the pancreas can be regarded under six categories ( 1 ) (Fig. 1.1 ): (1) acinar and (2) ductal, which together constitute the exocrine component of the organ responsible for the production of digestive enzymes (trypsin, chymotrypsin, lipases, and others) and their transportation to the duodenum, respectively; (3) islets of Langerhans, the endocrine component, which is responsible for the production of hormones involved in regulation of glucose and other metabolic activities; (4) ambiguous cells, such as centroacinar cells, which are less well characterized; (5) supportive elements, which encompass fibrous tissue, vessels, nerves, and other connective tissue elements; and (6) “potential” cells, such as stem cells, the existence of which is evidenced based on in vitro studies, but their representatives in normal human pancreata have not yet been clearly identified in histologic sections ( 2 ). In the ensuing text, an overview of the clinicopathologic characteristics of pancreatic neoplasia is discussed based on their lineage. Emphasis is given to those that are more common and not covered in the other chapters of this book.

Background & Aims Extensive evidence suggests that Akt signaling plays an important role in β-cell mass and function, although its function in the regulation of the different pancreatic fates has not been adequately investigated. The goal of these studies was to assess the role of Akt signaling in the pancreatic differentiation programs. Methods For these experiments, we have generated a double reporter mouse model that provides activation of Akt signaling in a cell type–specific manner. This mouse model conditionally overexpresses a constitutively active form of Akt upon Cre-mediated recombination. Activation of Akt signaling in pancreatic progenitors and acinar and β-cells was achieved by crossing this animal model to specific Cre-lines. Results We showed that overexpression of a constitutively active Akt in pancreatic and duodenal homeobox 1 (Pdx1) progenitors induced expansion of ductal structures expressing progenitor markers. This expansion resulted in part from increased proliferation of the ductal epithelium. Lineage-tracing experiments in mice with activation of Akt signaling in mature acinar and β-cells suggested that acinar-to-ductal and β-cell–to-acinar/ductal transdifferentiation also contributed to the expansion of the ductal compartment. In addition to the changes in cell plasticity, these studies demonstrated that chronic activation of Akt signaling in Pdx1 progenitors induced the development of premalignant lesions and malignant transformation in old mice. Conclusions The current work unravels some of the molecular mechanisms of cellular plasticity and reprogramming, and demonstrates for the first time that activation of Akt signaling regulates the fate of differentiated pancreatic cells in vivo.

Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-κB (NF-κB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-κB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-κB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA–transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-κB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis. [Cancer Res 2007;67(23):11377–85]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of

In contrast with solid tumors, most of which are invasive ductal adenocarcinoma with dismal prognosis, cystic lesions of the pancreas are often either benign or low-grade indolent neoplasia. Those that are mucinous, namely, intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), constitute the most important category, not only because they are the most common, but more importantly because they have well-established malignant potential, representing an adenomacarcinoma sequence. While many are innocuous adenomas--in particular, those that are small and less complex, and in the case of IPMN, those that are branch-duct type are more commonly benign, some harbor or progress into in situ or invasive carcinomas. For this reason, pancreatic cysts with mucinous differentiation ought to be evaluated carefully, preferably by experts familiar with subtle evidences of malignancy in these tumors. In the past few years, the definition of IPMNs and MCNs has become more refined. The presence of ovarian-type stroma has now almost become a requirement for the diagnosis of MCN, and when defined as such, MCN is seen almost exclusively in women of perimenopausal age group as thick-walled multilocular cystic mass in the tail of the pancreas in contrast with IPMN which afflicts an elder population, both genders in almost equal numbers, and occur predominantly in the head of the organ. While mucinous lesions have well-established pre-malignant properties, most of the entities that fall into the nonmucinous true cyst category such as serous tumors, lymphoepithelial cysts, congenital cysts, and squamoid cyst of ducts have virtually no malignant potential. In contrast, the rare cystic tumors that occur as a result of degenerative/necrotic changes in otherwise solid neoplasia such as the rare cystic ductal adenocarcinomas, cystic endocrine neoplasia, and most importantly, solid-pseudopapillary tumor (SPT) in which cystic change is so common that it used to be incorporated into its name ("solid-cystic," "papillary-cystic") are malignant neoplasia, albeit variable degrees of aggressiveness. SPT holds a distinctive place among pancreatic neoplasia because of its highly peculiar characteristics, undetermined cell lineage, occurrence almost exclusively in young females, association with beta-catenin pathway, and also by being a very low-grade curable malignancy. In conclusion, cystic lesions in the pancreas constitute a biologically and pathologically diverse category most (but not all) of which are either benign or treatable diseases; however, a substantial subset, especially mucinous ones, has malignant potential that requires careful analysis.

Although cystic tumors of the pancreas are relatively rare, they constitute an increasingly important category. Advances in imaging and interventional techniques and the sharp drop in the mortality rate of pancreatic surgery have rendered pancreatic biopsies and resections commonplace specimens. Consequently, in the past two decades, the nature of many cystic tumors in this organ has been better characterized. The names of some existing entities were revised; for example, what was known as papillary-cystic tumor is now regarded as solid-pseudopapillary tumor. New entities, in particular, intraductal papillary mucinous neoplasm and its variants, such as oncocytic and intestinal subtypes were recognized. The importance of clinical and pathologic correlation in the evaluation of these lesions was appreciated, in particular, with regards to the multifocality of these lesions, their association with invasive carcinomas, and thus their 'preinvasive' nature. Consensus criteria for the distinction of these from the ordinary precursors of adenocarcinoma, the pancreatic intraepithelial neoplasia, were established. The definition of mucinous cystic neoplasms was refined; ovarian-like stroma has now become almost a requirement for the diagnosis of mucinous cystic neoplasia, and defined as such, the propensity of these tumors to occur in perimenopausal women became even more striking. The validity and clinical value of classifying the pancreatic cysts of mucinous type as adenoma, borderline, CIS and invasive have been established. Related to this, the importance of thorough sampling in accurate classification of these mucinous lesions was recognized. Greater accessibility of the pancreas afforded by improved invasive as well as noninvasive modalities has also increased the detection of otherwise clinically silent cystic tumors, which has led to the recognition of more innocuous entities such as acinar cell cystadenoma and squamoid cyst of pancreatic ducts. As the significance of the cystic lesions emerged, cystic forms of otherwise typically solid tumors were also better characterized. Thus, significant developments have taken place in the classification and our understanding of pancreatic cystic tumors in the past few years, and experience with these lesions is likely to grow exponentially in the coming years.

This report describes an unusual pancreatic tumor in a 3-year-old boy. He presented with abdominal pain secondary to pancreatitis and was found to have a complex, multicystic lesion within the head of the pancreas. He subsequently underwent a pancreatoduodenectomy. Grossly, the mass was 3 cm, multicystic, and well demarcated. Histologically, there were numerous variably sized, dilated ducts lined by tall columnar mucinous cells surrounded by a stroma that exhibited foci of cellular condensations resembling primitive pancreatic mesenchyme. Acinar and endocrine cells were often seen budding into the ducts forming “ductulo-insular bodies.” As a result of its superficial resemblance to Stocker type 2 cystic adenomatoid malformation of the lung, we are proposing the name “multicystic adenomatoid hamartoma” for this lesion.

The recognition and differential diagnosis of pancreatic intraductal neoplasms (IN) have gained importance in the past few years, as the incidence of these tumors (especially intraductal papillary mucinous neoplasms-IPMNs) have risen to >10% of pancreatic resections, and their significance as precursors of invasive cancer is better appreciated. Acinar cell carcinomas (ACCs) are typically solid tumors; however, we have recently encountered 7 ACCs with either intraductal growth and/or a papillary/papillocystic pattern that could be mistaken for IN. The clinicopathologic features of these cases were studied. Four patients were male and 3 female, with a mean age of 59 and mean tumor size of 4.9 cm (as compared with 10 cm in conventional ACCs). Only 1 patient had metastasis at the time of diagnosis (as opposed to 50% in usual ACCs). In 5 cases, the tumors had nodular growth of sheet-forming acinar cells, some of which were within ducts, as evidenced by the polypoid nature of the process, partial ductal lining, and presence of small tributary ducts in the walls. In 3 cases, the tumor had papillary and/or papillocystic growth, at least focally. All cases had cystic areas. No mucin was identified. All expressed trypsin. Markers of ductal differentiation were either absent or focal. A minor endocrine component was present in 3. The main histologic findings that distinguished these tumors from IPMNs were the more sheetlike nature of the nodules (rather than villous or arborizing papillae), cuboidal cells, overall basophilia of the cytoplasm, prominent nucleoli, apical granules, intraluminal crystals or pale, acidophilic secretions (enzymatic condensations), and lack of mucin. In conclusion, some ACCs show intraductal growth or exhibit papillary patterns, which can mimic IN, especially IPMNs. In such cases, attention to morphologic details described above, and immunohistochemistry are helpful. The clinical significance of this variant is difficult to determine; however, it appears that the tumors are relatively small and metastasis at presentation is less common than typically seen in ACCs (1/7 vs. 50%).