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

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

Quantitating hepatic steatosis is important in many liver diseases and liver transplantation. Since steatosis estimation by pathologists has inherent intra- and inter-observer variability, we compared and contrasted computerized techniques with magnetic resonance imaging measurements, pathologist visual scoring, and clinical parameters. Computerized methods applied to whole slide images included a commercial positive pixel count algorithm and a custom algorithm programmed at our institution. For all liver samples (n=59), including pediatric, adult, frozen section, and permanent specimens, statistically significant correlations were observed between pathology, radiology, and each image analysis modality (r=0.75-0.97, p

Tumors of the ampulla-pancreatobiliary tract are encountered increasingly; however, their staging can be highly challenging due to lack of familiarity. In this review article, the various issues encountered in staging of these tumors at the pathologic level are evaluated and possible solutions for daily practice as well as potential improvements for future staging protocols are discussed. While N-stage parameters have now been well established (the number of lymph nodes required in pancreatoduodenectomies is 12), the T-staging has several issues: for the pancreas, the discovery of small cancers arising in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) necessitates the creation of substages of T1 (as T1a, b, and c); lack of proper definition of "peripancreatic soft tissue" and "common bile duct involvement" (as to which part is meant) makes T3 highly subjective. Increasing resectability of main vessels (portal vein) brings the need to redefine a "T" for such cases. For the ampulla, due to factors like anatomic complexity of the region and the under-appreciation of three-dimensional spread of the tumors in this area (in particular, the frequent extension into periduodenal soft tissues and duodenal serosa, which are not addressed in the current system and which require specific grossing approaches to document), the current T-staging lacks reproducibility and clinical relevance, and therefore, major revisions are needed. Recently proposed refined definition and site-specific subclassification of ampullary tumors highlight the areas for improvement. For the extrahepatic bile ducts, the staging schemes that use the depth of invasion may be more practical to circumvent the inconsistencies in the histologic layering of the ducts; better definition of terms like "periductal spread" is needed. For the gallbladder, since many gallbladder cancers are "unapparent" (found in clinically and grossly unsuspected cholecystectomies), establishing proper grossing protocols and adequate sampling are crucial. Since the gallbladder does not have the distinct layering of the other gastrointestinal organs, the definitions of Tis/T1a/T1b lack practicality, and therefore, "early gallbladder carcinoma" category proposed in high-risk regions may have to be recognized instead. Involvement of the Rokitansky-Aschoff sinuses should be a part of the evaluation and management of these early gallbladder cancers; for advanced cancers, documentation of hepatic versus serosal involvement is necessary. In summary, T-staging of ampulla-pancreatobiliary tract tumors has many challenges. Proper grossing and appreciation of histo-anatomic subtleties of this region are crucial in addressing these issues and achieving more applicable and clinically relevant staging systems in the future.

Stage remains the most important prognosticator of most cancers. In the era of personalized medicine, as the determination of individual characteristics of a given tumor becomes increasingly more important, stage is perhaps one of the best ways to individualize the management of a patient. In the United States, reporting of the American Joint Committee on Cancer/Union for International Cancer Control TNM stage of tumors has all but become a mandate, linked to accreditation of laboratories by College of American Pathologists (CAP), as well as the maintenance of cancer center designations of institutions awarded by the National Cancer Institute and the American College of Surgeons' Commission on Cancer. Providing the stage is now also being considered one of the main "quality indicators" and is linked to reimbursement by insurers. Following suit, many laboratory information system programs have also now integrated CAP synoptic protocols into their software. These regulatory requirements and increasingly widespread usage of staging protocols have also brought to light the imperfections of the current staging protocols. Some are due to the inherent nature of the staging process, which attempts to segregate a continuum (which cancers are) into distinct clusters, which is not always possible. Additionally, although some of the parameters used in staging are evidence-based, many are arbitrary or based on assumptions or logistic progression models. Moreover, some parameters such as the spread of a tumor beyond an organ may seem valid at the theoretic level but are difficult to use in daily practice, for example, for organs without a well-defined capsule. The most problematic issue, however, is the fact that the pathologists are now being asked to incorporate into "pathologic stage" the information that they are not savvy about or cannot verify themselves, such as serum prostate-specific antigen levels or vocal cord paralysis. This current issue of Seminars in Diagnostic Pathology deals with the pitfalls in pathologic staging of common and challenging cancers. In this series of articles written by experts who deal with pathologic staging on daily basis, the authors highlight the problematic aspects of staging in routine practice, discuss the ways these can be dealt with, and also provide a platform for future discussions and improvements in tumor staging.

Locoregional therapy (LRT) is used as a bridge to orthotopic liver transplant (OLT) for hepatocellular carcinoma (HCC) patients. Liver explants in OLT patients with HCC were studied regarding both tumor stage, histology, and immunohistochemical staining for cytokeratin (CK)7, CK19, P53, Ki-67, and vascular endothelial growth factor (VEGF). Patients receiving no LRT (control) (n=30) were compared with LRT treatment groups with conventional transarterial chemoembolization (cTACE) (n=25) or drug-eluting bead transarterial chemoembolization (DEB TACE) (n=17). Tumor stage and histology were similar between treatment and control groups. The mean percent necrosis was significantly higher for treatment groups versus the control group (p

BackgroundPreoperative imaging is often inadequate in excluding unresectable pancreatic cancer. Accordingly, many groups employ staging laparoscopy (SL), although none have evaluated SL after preoperative magnetic resonance imaging (MRI). We performed a retrospective, indirect cost-effectiveness analysis of SL after MRI for pancreatic head lesions.MethodsAll MRI scans administered for proximal pancreatic cancer between 2004 and 2008 were reviewed and the clinical course of each patient determined. We queried our billing database to render average total costs for all inpatients with proximal pancreatic cancer who underwent pancreaticoduodenectomy, palliative bypass or an endoscopic stenting procedure. We then performed an indirect evaluation of the cost of routine SL.ResultsThe average costs of hospitalization for patients undergoing pancreaticoduodenectomy, open palliative bypass and endoscopic palliation were: US$26122.43, US$21957.18 and US$11304.00, respectively. The calculated cost of SL without laparotomy was US$2966.25 or US$1538.61 prior to laparotomy. The calculated cost of treating unresectable disease by outpatient laparoscopy followed by endoscopy was US$5943.17. Routine SL would increase our costs by US$76967.46 (3.6%).ConclusionsStaging laparoscopy becomes cost-effective by diverting unresectable patients from operative to endoscopic palliation. Given the paucity of missed metastases on MRI, the yield of SL is marginal and its cost-effectiveness is poor. Future studies should address the utility of SL by both examining this issue prospectively and investigating the cost-effectiveness of endoscopic vs. surgical palliation in a manner that takes account of survival and quality of life data.

The pancreas is versatile in the diversity of disorders that it can exhibit. In this article, characteristics of disorders such as chronic, autoimmune, eosinophilic, hereditary, and infectious pancreatitis are described. With regard to autoimmune pancreatitis, the role of clinical evaluation, histologic examination, and IgG4 immunohistochemistry is discussed. The role of pancreatitis in the pathogenesis of diabetes is also mentioned. Some implications of pancreatitis are highlighted, including the neoplastic predisposition caused by inflammatory lesions of the pancreas. The goal of this article is to convey an appreciation of these disorders because their recognition can benefit patients tremendously, as inflammatory lesions of the pancreas can be mass-forming, giving rise to pseudotumors, and leading to surgical resection that may otherwise be unnecessary.

Loss of E-cadherin expression has been linked to the invasive phenotypes of a variety of neoplasms, including lobular breast cancer. The expression of E-cadherin in variants of urothelial carcinoma relative to usual-type urothelial carcinoma, maximum depth of invasion and angiolymphatic invasion has not been well characterized. A total of eight cases of micropapillary urothelial carcinoma, four cases of plasmacytoid urothelial carcinoma, two cases of urothelial carcinoma with signet ring cell differentiation and two cases of urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation, all obtained from cystectomy/cystoprostatectomy cases, were identified. In all nine cases of usual-type invasive and noninvasive high-grade urothelial carcinoma were also included in the study. Immunohistochemical staining of E-cadherin was performed in all cases. Pathological parameters including depth of invasion and presence of angiolymphatic invasion were documented. Maximum depth of invasion: In micropapillary urothelial carcinoma, extravesical extension was seen in three of eight cases; muscularis propria invasion in four of eight cases; and lamina propria invasion in one of eight cases. In plasmacytoid urothelial carcinoma, extravesical extension was observed in two of four cases, and muscularis propria invasion and lamina propria invasion in one of four cases each. In urothelial carcinoma with signet ring cell differentiation, extravesical extension and muscularis propria invasion was seen in one of two cases each. In urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation, muscularis propria invasion and lamina propria invasion was observed in one of two cases each. In usual-type high-grade urothelial carcinoma, extravesical extension was seen in six of nine cases and noninvasive in three of nine cases. In angiolymphatic invasion, micropapillary urothelial carcinoma was observed in eight of eight cases; plasmacytoid urothelial carcinoma in two of four cases; urothelial carcinoma with signet ring cell differentiation in one of two cases; and urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation in one of two cases. Usual-type high-grade urothelial carcinoma was seen in six of nine cases. E-cadherin expression: All eight cases of micropapillary urothelial carcinoma were positive for E-cadherin in the micropapillary component and adjacent usual-type urothelial carcinoma. The four cases of plasmacytoid urothelial carcinoma, two cases of urothelial carcinoma with signet ring cell differentiation and two cases of urothelial carcinoma with mixed plasmacytoid and signet ring cell differentiation were all negative for E-cadherin. All nine additional cases of usual-type high-grade urothelial carcinoma were diffusely positive for E-cadherin. E-cadherin is diffusely positive in usual-type urothelial carcinoma and micropapillary urothelial carcinoma, irrespective of pathological stage and angiolymphatic invasion. Loss of E-cadherin expression may be a marker of plasmacytoid and signet ring cell differentiation in urothelial carcinoma.

Acinar cell carcinoma of pancreatic type rarely occurs at extra-pancreatic sites. We report four primary liver tumors with features of pancreatic acinar cell carcinoma. The patients were two males and two females with a mean age of 65 years (range, 49-72 years). They had upper abdominal pain, weight loss and/or an incidentally discovered liver mass. None had evidence of a primary pancreatic tumor. Grossly, the tumors were large (mean size, 12 cm), well circumscribed and showed a lobulated cut surface. Histologically, they showed a predominantly microacinar pattern, with occasional trabecular, solid and microcystic areas. Cellular atypia and mitotic activity varied within the same tumor and from tumor to tumor. Immunohistochemically, the tumor cells were positive for cytokeratin 18 and at least one acinar cell marker (ie, trypsin, amylase or lipase), but were negative for cytokeratins 7, 19 and 20, HepPar-1, AFP, CD10, carcinoembryonic antigen, CD56, Islet-1 and CDX2. Two tumors stained focally for synaptophysin and chromogranin A. Adjacent liver parenchyma displayed no evidence of cirrhosis. During a mean follow-up of 22 months (range, 3-38 months) no metastases occurred, but one patient developed local recurrence. Our study demonstrates that acinar cell carcinoma of pancreatic type may also originate from the liver and can be readily distinguished from other primary liver neoplasms by its distinct histological and immunohistochemical features. Because our cases were observed within a rather short period, it is likely that this tumor type is so far underrecognized and has been mistaken as a variant of hepatocellular carcinoma, cholangiocarcinoma or any other liver tumor.

Similar to the other von Hippel-Lindau (VHL)-related tumors such as renal cell carcinomas and capillary hemangioblastomas, serous cystadenomas (SCAs) of the pancreas are also characterized by clear cells. Over the years, we have also noticed that the tumor epithelium shows a prominent capillary network.Eighteen cases of SCA were reviewed histologically, and immunohistochemical analysis was performed for CD31 and vascular endothelial growth factor (VEGF) as well as the molecules implicated in clear-cell tumorigenesis: GLUT-1, hypoxia-inducible factor-1 (HIF-1alpha), and carbonic anhydrase IX (CA IX).There was an extensively rich capillary network that appears almost intraepithelially in all cases of SCA, which was confirmed by CD31 stain that showed, on average, 26 capillaries per every 100 epithelial cells. VEGF expression was identified in 10/18 cases. Among the clear-cell tumorigenesis markers, CA IX was detected in all cases, GLUT-1 and HIF-1alpha in most cases.As in other VHL-related clear-cell tumors, there is a prominent capillary network immediately adjacent to the epithelium of SCA, confirming that the clear-cell- angiogenesis association is also valid for this tumor type. Molecules implicated in clear-cell tumorigenesis are also consistently expressed in SCA. This may have biologic and therapeutic implications, especially considering the rapidly evolving drugs against these pathways. More importantly, SCA may also serve as a model of clear-cell-associated angiogenesis and tumorigenesis, and the information gained from this tumor type may also be applicable to other clear-cell tumors.

Lymph node status is one of the most important predictors of survival in resectable pancreatic ductal adenocarcinoma; therefore, thorough lymph node evaluation is a critical assessment in pancreatoduodenectomy specimens. There is considerable variability in pancreatoduodenectomy specimens processed histologically. This study compares two approaches of lymph node dissection and evaluation (standard vs orange peeling) of pancreatoduodenectomy specimens. A different approach to dissection of pancreatoduodenectomy specimens was designed to optimize lymph node harvesting: All peripancreatic soft tissues were removed in an orange-peeling manner before further dissection of the pancreatic head. This approach was applied to 52 consecutive pancreatoduodenectomy specimens performed for ductal adenocarcinoma at two institutions. Specimen dissection was otherwise performed routinely. Overall number of lymph nodes harvested, number of positive lymph nodes, and their anatomic distribution were analyzed and compared with cases that had been dissected by the conventional approach. The mean number of lymph nodes identified by the orange-peeling approach was 14.1 (by institution, 13.8 and 14.4), as opposed to 6.1 (by institution, 7 and 5.3) in cases processed by conventional approach (P=0.0001). The number of lymph node-positive cases also increased substantially from 50% (by institution, 54 and 46%) in the conventional method to 73% (by institution, 88 and 58%) in the orange-peeling method (P=0.02). The orange-peeling method of lymph node harvest in pancreatoduodenectomy specimens for ductal adenocarcinoma enhances overall and positive lymph node yield and optimizes ductal adenocarcinoma staging. Therefore, lymph node harvest by the orange-peeling method should be performed routinely before specimen sectioning in assessment of pancreatoduodenectomy for ductal adenocarcinoma.

The expression of mucin (MUC2) in prostate cancer has not been well studied previously and may be of prognostic and pathobiologic significance. It is, however, well known that MUC2 expression in mucinous pancreatic and breast cancer represents an indolent pathway since these tumors have a significantly better outcome than their conventional counterparts. Twenty-five cases each of Gleason pattern 3 and 4 mucinous adenocarcinoma of the prostate defined by greater than 25% mucinous component and nonmucinous adenocarcinoma of the prostate were obtained from the surgical pathology files of the Johns Hopkins Hospital and Emory University Hospital. Immunohistochemical stains were performed for MUC2 on all 50 cases. Mean patient age was 60 years (range 44-72 years). MUC2 was expressed in all 25 cases (100%) of mucinous adenocarcinoma of the prostate, irrespective of the Gleason pattern. The nonmucinous component of these cases was negative for MUC2. In contrast, MUC2 expression was significantly lower in nonmucinous adenocarcinoma of the prostate, detected in only 6/25 cases as a focal finding, while 19/25 (76%) of nonmucinous adenocarcinoma of the prostate were completely negative for MUC2 (P

A variety of distinct entities may form solid masses in the pancreas and mimic cancer, in particular pancreatic ductal adenocarcinoma (DA), at the clinical, radiographic, gross and microscopic levels. Recognition of their key diagnostic features is important for the proper clinical management of patients, and in some instances, histological examination of the completely resected lesion may be required to exclude malignancy. By some estimates, up to 5% of pancreatectomies performed for a preoperative diagnosis of neoplasm will prove to contain a non-neoplastic lesion with ‘pseudotumour' formation on pathological examination. Chronic inflammatory lesions are the leading cause of this phenomenon, and among these, autoimmune and paraduodenal pancreatitides are most important. Noninflammatory lesions that may also mimic DA, mostly at the clinical level, include ampullary adenomyoma, lipomatous pseudohypertrophy, hamartoma and pseudolymphoma. This review presents the useful histological and immunophenotypic features for the distinction of DA from chronic pancreatitis, and discusses the incidence, types and differential diagnosis of the pseudotumours of the pancreas.

Premalignant lesions of the gallbladder and extrahepatic bile ducts have been poorly studied compared with their counterparts in the remainder of the gastrointestinal tract. Some of the problematic issues, such as the subjectivity of grading and determination of the relative risk of cancer, are challenging. Although the understanding of the biology of these lesions has improved in the past several years, there are still many issues that can only be addressed by close collaboration between gastroenterologists, radiologists, hepatobiliary surgeons, oncologists, and pathologists.

Cholangiocarcinoma of the intrahepatic and extrahepatic bile ducts develops through a multistep histopathologic sequence. Premalignant or non-invasive neoplastic lesions of bile ducts have been historically called biliary dysplasia or atypical biliary epithelium. To this date, no standard terminology or classification system has been offered for these lesions. In 2005, a conceptual framework and diagnostic criteria for biliary intraepithelial neoplasia (BilIN) were proposed using the livers of patients with hepatolithiasis. We report herein an international interobserver agreement study on the diagnosis of biliary non-invasive neoplastic lesions with the goal to obtain a consensus on the terminology and grading. Seventeen pathologists from the United States, Europe and Asia participated in this study. They shared a digital file containing histological pictures of 30 foci of non-invasive neoplastic lesions selected from the biliary system of patients suffering from primary sclerosing cholangitis, choledochal cyst or hepatolithiasis. In the criteria, we proposed in 2005, BilIN was classified into three categories based on the degree of atypia: BilIN-1, BilIN-2 and BilIN-3. In this study, consensus was reached for the terminology of BilIN and the three-grade classification system. Interobserver agreement on the diagnosis was moderate (kappa-value=0.45). On the basis of the suggestions and opinions obtained from the 17 participants, the original criteria for BilIN were revised. We now propose a new consensus classification of BilIN that may assist in allowing a more uniform terminology for the diagnosis of biliary non-invasive neoplastic lesions. This classification should help to advance clinical and research applications.

SummaryOncogenic Kras initiates pancreatic tumorigenesis, while subsequent genetic events shape the resultant disease. We show here that concomitant expression of KrasG12D and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms (MCNs), which culminate in invasive ductal adenocarcinomas. Disease evolves along a progression scheme analogous to, but distinct from, the classical PanIN-to-ductal adenocarcinoma sequence, and also portends a markedly different prognosis. Progression of MCNs is accompanied by LOH of Dpc4 and mutation of either p53 or p16. Thus, these distinct phenotypic routes to invasive adenocarcinoma nevertheless share the same overall mutational spectra. Our findings suggest that the sequence, as well as the context, in which these critical mutations are acquired helps determine the ensuing pathology.

Summary Aims Pancreatic endocrine tumours (PET) containing ductules are an uncommon histological variant. Considerable conjecture surrounds the origin and histogenesis of the ductules. Opinions range from the ductules being an inherent part of the tumour, to others who feel they are merely entrapped. A study of 21 cases of this variant was undertaken with particular attention paid to the distribution and morphology of the ductules, the presence of entrapped acinar tissue and the surrounding uninvolved pancreatic tissue. Methods and results Twenty-one cases were detailed occurring in either gender equally and with a wide age range (19-85 years). All cases, except one, were sporadic, the vast majority were located in the tail and were of small size (less than 2.0 cm). All cases were typified by stromal fibrosis, either diffuse (15) or in the form of septae (6). Embedded within the fibrous tissue were ductular structures, some of which were dilated and ectatic. The ductules were centrally located (5), at the periphery of the tumour (9) or diffusely scattered throughout the lesion (7). All cases showed ductulo-insular complexes. Insulin was demonstrated in 15 immunohistochemically. Conclusions It is likely that in some cases the ductules are entrapped as the tumour grows into surrounding normal pancreatic tissue and the ductular proliferation is a secondary phenomenon. In a proportion of cases, the ductules are likely to be a part of the tumour arising as part of focal chronic inflammation or as a result of the growth factor effects of insulin, in cases associated with insulin production. There is nothing to suggest that the ductules confer any special biological characteristics to the PET and are merely a histological nuance. However, some cases may have a dominant tubular component, which could present problems at frozen section where the association with fibrosis may invoke a mistaken diagnosis of pancreatic ductal adenocarcinoma or chronic pancreatitis.

DeltaNp63 (DNp63) has become widely used, in particular, for distinguishing invasive carcinomas from noninvasive ducts by highlighting the myoepithelial or basal cells in the breast and prostate, respectively. It is not known whether this marker may have any application in another exocrine organ, the pancreas. As the ductal and intraductal proliferations of this organ become better characterized, the need for markers to distinguish among these processes increases. We investigated immunohistochemical expression of DNP63 in 105 cases. A total of 25 cases were non-neoplastic pancreata, 25 were pancreatic intraepithelial neoplasia (PanIN) of various grades, and 50 were examples of pancreatic ductal adenocarcinoma. Sections of non-neoplastic pancreata included various types of non-neoplastic processes such as squamous/transitional metaplasia (five cases), which can be mistaken for high-grade PanINs, as well as various degrees of reactive ductal atypia and incidental microcysts with attenuated lining (five cases). No DNp63 expression was noted in normal pancreatic ducts. On the other hand, all five foci of squamous/transitional metaplasia were strongly and uniformly positive for this marker. DNp63 labeling was also noted in those incidental microcysts lined by attenuated cells, seen amidst normal pancreatic lobules. All PanINs were negative. Among invasive carcinomas, DNp63 expression was detected only in areas of squamous differentiation and was completely absent in ordinary ductal areas. Based on this observation, five additional cases of adenosquamous/squamous carcinoma was retrieved and stained, and the squamous components of all of these were also positive. In conclusion, (I) DNp63 is a reliable marker of squamous differentiation in the pancreas. It is valuable in distinguishing squamous/transitional metaplasia from PanINs, a distinction of importance for both researchers and diagnosticians. Among invasive carcinomas, it seems to be entirely specific for areas of squamous differentiation. (II) Those incidental microcysts seen in acinar lobules and lined by attenuated cells are also positive for DNp63, which suggests that they may be metaplastic in nature, and that they do not represent neoplastic cells. (III) Unlike the ducts of other exocrine organs, breast and prostate, there are no DNp63-expressing cells in the normal pancreatic ducts, and therefore, this marker cannot be used in distinguishing invasive carcinomas from the non-invasive ducts. (IV) No p63-expressing 'stem' cells are present in the pancreas.

Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood. In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms. We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors. Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (

In the pancreas, a variety of non-neoplastic conditions may form solid masses that may mimic cancer. Up to 5% of pancreatectomies performed with the preoperative clinical diagnosis of carcinoma will prove to be non-neoplastic by pathologic examination, although this figure is decreasing with improved diagnostic modalities. Chronic inflammatory lesions are the leading cause of this phenomenon ("pseudotumoral pancreatitis"), and among these, autoimmune and paraduodenal pancreatitides (discussed separately in this issue) are most important. In this article, we will focus on the noninflammatory lesions that may form tumor-like lesions of the pancreas. Adenomyomatous hyperplasia of ampulla of Vater is a subtle lesion that is difficult to define; larger examples (>5 mm) have been found to be the cause of obstructive jaundice. Accessory (heterotopic) spleen may form a well-defined nodule within the tail of the pancreas and is typically mistaken for endocrine neoplasm. Lipomatous hypertrophy is the replacement of pancreatic tissue with mature adipose tissue that occasionally leads to moderate to marked enlargement of the pancreas. Hamartomas are very rare if the entity is defined strictly. They are characterized by irregularly arranged mature pancreatic elements admixed with stromal tissue. A cellular, spindle-cell variant with c-kit (CD117) expression is recognized. Pseudolymphoma forms well-defined nodules composed of hyperplastic lymphoid tissue. Rarely, foreign-body deposits, granulomatous inflammations (such as sarcoidosis or tuberculosis), and congenital lesions may form tumoral lesions. In conclusion, it is important to recognize the types of conditions that form pseudotumors in the pancreas so that they can be distinguished from ductal adenocarcinomas, especially clinically, but also pathologically. Nonspecific terms such as "inflammatory pseudotumor" ought to be avoided, and every attempt should be made to classify a "pseudotumor" into a more specific diagnostic category discussed above.

Lymphoplasmacytic sclerosing pancreatitis (LPSP), also known as autoimmune pancreatitis or nonalcoholic, duct destructive chronic pancreatitis, has been increasingly recognized in the past decade as a histologically distinctive type of pancreatitis that affects middle-aged patients who lack the typical risk factors for chronic pancreatitis (alcohol abuse in particular). LPSP is sometimes associated with other autoimmune diseases or fibroinflammatory lesions, although in some patients, pancreatic and biliary involvement represent the only known disease process. Many patients present with pancreatic masses clinically and radiographically simulating pancreatic carcinoma, and associated bile duct strictures enhance the resemblance. Elevated serum IgG4 levels have been described in patients with LPSP and have been used to distinguish LPSP from pancreatic carcinoma preoperatively. Although there is some heterogeneity of pathologic findings, resected cases of LPSP typically demonstrate dense periductal lymphoplasmacytic inflammation, periductal and parenchymal fibrosis, and obliterative venulitis; neutrophilic infiltration of the ductal epithelium ("granulocytic epithelial lesions") may also occur. Large tumor-like masses of fibroinflammatory tissue ("reactive fibroinflammatory pseudotumors") may develop and extend beyond the pancreas. Following surgical resection, a few patients suffer recurrence of fibroinflammatory lesions in the pancreatobiliary tree, or they may develop other manifestations of autoimmune disease elsewhere in the body. However, the overall prognosis is excellent. Response to steroid therapy has been noted. Current studies are focusing on identifying additional preoperative diagnostic tests and on characterizing possible variants of LPSP. This review presents the defining clinical and pathologic features of LPSP and discusses the ongoing efforts to understand the pathogenesis of this disease.

Pancreatic colloid carcinoma, also known as mucinous non-cystic carcinoma or gelatinous carcinoma, is a carcinoma of ductal origin, characterized morphologically by well-circumscribed pools of mucin that contain detached floating epithelial elements. Its distinction from conventional ductal adenocarcinoma is important because beyond the morphological dissimilarities, there are molecular and biologic differences between colloid and ordinary ductal carcinoma of the pancreas. Clinically, patients with colloid carcinoma often present with abdominal/epigastric pain and diarrhoea. They usually have larger tumours than ordinary ductal adenocarcinoma at presentation. Often, an associated intraductal papillary mucinous neoplasm is found. Macroscopically, colloid carcinoma is frequently well demarcated and characterized by gelatinous appearance. Microscopic examination reveals well-delineated mucin pools that contain detached and scanty malignant epithelial cells. In contrast with the mixed carcinomas, which may focally exhibit a similar pattern, pure mucinous carcinomas (those in which most of the tumour is composed of colloid pattern) seem to have a more indolent course with longer survival rates than conventional adenocarcinoma. Even in the presence of lymph node metastases, the patients can sometimes attain prolonged survival. There are certain characteristics of colloid carcinoma that are being recognized increasingly as the potential reasons for its distinctive clinicopathologic attributes. One distinctive feature of colloid carcinoma cells is that they exhibit altered cell polarity in which the secretory activity of the cell is manifested at its stroma-facing surfaces. In addition, it seems that production of MUC2 type mucin, which is specific for colloid carcinoma or its precursors, might act as a barrier limiting the growth and spread of the tumor and partially explaining the indolent nature of these cancers. The frequent association of colloid carcinoma with intraductal papillary mucinous neoplasms and also the observation that they share a similar profile of MUC1 and MUC2 expression have suggested that these neoplasms may be characterized by a different carcinogenetic pathway than ordinary ductal adenocarcinoma, which is believed to originate from pancreatic intraepithelial neoplasia.

Lymphoepithelial cyst (LEC) of the pancreas is a rare lesion of undetermined pathogenesis that had been documented almost exclusively in males. The literature on this entity is limited to reports of single or small numbers of cases. Here is presented a clinicopathologic analysis of 12 patients with LEC, 4 of whom were female. The mean age of the patients was 56 years. Four patients presented with abdominal pain and nausea, but in two patients, the cysts were detected incidentally. Only one patient had a history of chronic pancreatitis, and another had a family member with pancreatic cancer. In one patient, a clinical diagnosis of pseudocyst was rendered, and the remaining patients were clinically thought to have cystic neoplasms. None of the patients had any identifiable immunosuppression, HIV positivity, autoimmune disorder (such as Sjogren syndrome) or lymphoma. Seven cysts were located in the head of the pancreas, and 5 were in the tail. The mean size was 4.8 cm (range, 1.2-17 cm). Five LECs were multilocular, three were unilocular; in others, the number of loculi was not recorded. All were "macrocystic" lesions. Two patients had two separate lesions, both in the tail of the pancreas. Histologically, all cases were characterized by cysts, some containing keratin, and lined by mature stratified squamous epithelium surrounded by dense lymphoid tissue, often with prominent follicles. In some areas, the lining epithelium had more cuboidal, flattened, or transitional appearance. Mucinous goblet-like cells were seen in one case. Acute inflammation was not seen. Four cases contained solid lymphoepithelial islands, a feature not previously described in LECs. No squamous metaplasia was identified in the uninvolved pancreatic tissue and no epithelial elements were identified in peripancreatic lymph nodes. In summary, LEC of the pancreas is a rare but distinctive lesion that may be seen in the tail of the organ where most cystic pancreatic neoplasms are encountered. In contrast to the impression from the literature, LECs may also develop in females and, therefore, should be considered in the clinical differential diagnosis of mucinous cystic neoplasms that affect a similar age group. LECs are not associated with the clinical syndromes that are seen with their analogues in the salivary glands.

DPC4 (MADH4, SMAD4) encodes a nuclear transcription factor shown to be genetically inactivated in over one-half of conventional infiltrating ductal adenocarcinomas of the pancreas. Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been suggested to be distinct neoplasms with a significantly less aggressive course than conventional ductal adenocarcinomas of the pancreas, but molecular comparisons of these tumor types have previously been impaired by technical difficulties. Recently, immunohistochemical labeling for the DPC4 gene product has been shown to be an extremely sensitive and specific marker for DPC4 gene alterations in pancreatic adenocarcinomas. Therefore, we analyzed the immunohistochemical expression of Dpc4 protein in 79 IPMNs using a previously characterized monoclonal antibody. Twenty-nine of the IPMNs also had an associated infiltrating adenocarcinoma available for analysis. The labeling patterns observed were compared to those we have previously reported for conventional ductal carcinomas. All 79 of the intraductal components of the IPMNs strongly expressed Dpc4 protein. In 77 of the 79 cases (97%), the labeling was diffusely positive, and in 2 of the 79 (3%) the labeling was focally positive. Dpc4 expression was seen in 28 (97%) of the associated 29 invasive cancers. The one infiltrating carcinoma that showed loss of Dpc4 expression was associated with an intraductal component which showed focal loss of Dpc4 expression. The strong and almost universal expression of Dpc4 in IPMNs contrasts sharply with the loss of Dpc4 expression seen in approximately 30% of in situ adenocarcinomas of the pancreas (so-called pancreatic intraepithelial neoplasms, grade 3; P < 0.001) and in 55% of pancreatic duct carcinomas (P < 0.0001). Differences in Dpc4 expression between IPMNs and ductal carcinomas suggest a fundamental genetic difference in tumorigenesis, which may relate to the significantly better clinical outcomes observed for IPMNs.

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

tion) OR time, estimated blood loss and transfusions, tumor size and histology, lymph node status, postoperative hematocrit and leukocyte count and postoperative NSAID use. We defined DGE as failure to tolerate a regular diet by postoperative day seven. Data was analyzed with alpha=0.05 using Fisher exact test for categorical variables and Mann-Whitney U test for continuous variables. RESULTS: A total of 114 patients with DGE were compared with 134 patients without DGE. Patients who suffered DGE were significantly more likely to have smaller tumors (p=0.015) and fewer positive lymph nodes (p=0.025), while patients without DGE were more likely to have received preoperative chemotherapy (p= 0.005) or preoperative radiation (p= 0.010). A possible explanation for these results is that patients with malignant disease have less normal functioning pancreatic parenchyma and are consequently less at risk for digestive symptoms resulting from pancreatic injury and inflammation. In addition, DGE was associated with an infection during hospitalization (p=0.008.) Hematocrit on the third postoperative day was significantly lower (p=0.019) for patients who experienced DGE , excluding patients who experienced post-operative bleeding. We hypothesize that DGE patients experienced more postoperative third space sequestration and bowel edema, resulting in greater hemodilution when sequestered fluid redistributed back into the vasculature. CONCLUSIONS: Contrary to our expectations, patients with smaller tumors and benign disease were more likely to experience DGE than patients with more advanced, malignant disease. As our ability to diagnose premalignant lesions improves, there will likely be more PD performed for benign disease, with a subsequent increase in the frequency of patients with DGE.

Background and Objective: The role of CT in follow up of hepatocellular carcinoma (HCC) after local ablative therapy have been demonstrated in many clinical experience, whereas the role of contrast enhanced ultrasonography (CEUS) is still under evaluation. The aim of this study is to evaluate the role of immediate CEUS in prediction 30-days CT follow up after single local ablative therapy with radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI). Methods:100 consecutive patients with HCC treated 2006 to 2007 were prospectively included into the study. All the patients were treated with single session of PEI or RFA. After each single percutaneous procedure CEUS was performed in order to identify residual disease (persistence of contrast enhanced pattern). Three different CEUS patters were identified: 1-isovascular-hypervascular pattern, 2-ipovascular pattern, 3-avascular pattern. After 30 days complete necrosis of HCC was evaluated with contrast-enhanced CT scan in all cases. Results: Patients included into the study were submitted to RFA (43 patients) or PEI (57 patients) for HCCs with a mean diameter of 2.7 cm (range 1.5-5 cm). After RFA, isovascular pattern was found in 2% (1/43) of patients resulting in incomplete necrosis at CT; ipovascular pattern was found in 12% (5/43) patients that resulted in incomplete necrosis in 3/5 (60%); in 86% (37/43) avascular pattern was found with complete necrosis at CT in 28/37(76%) cases. Among the PEI group, isovascular pattern was found in 5% (3/57) of patients case resulting incomplete necrosis in 1/3 (33%) case; ipovascular pattern was found in 44% (25/57) of patients that resulted CT incomplete necrosis in 17/ 25(68%) ; in 19% (11/57) of patients avascular pattern was found with complete necrosis at CT in 2/11(18%) cases. Sensitivity, specificity, positive and negative predictive values for complete necrosis at CT of the CEUS avascular pattern after RFA were 93%, 31%, 76% and 67%,respectively, while the positive predictive value after PEI treatments was 18%. Conclusions Immediate CEUS control after percutaneous treatment of HCC have high predictive value after RFA where the avascular pattern is highly related with complete necrosis at 30 day CT. On the contrary predictive value of immediate CEUS after PEI is limited