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Context.— The nature and associations of gallbladder (GB) “adenomyoma” (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. Objective.— To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. Design.— Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. Results.— Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3–5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive (“adenomyomatosis”). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma was arising from AM (invasion was confined to AM, and dysplasia was predominantly in AM). Conclusions.— AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component; (ie, the name “adeno-myoma” is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

© 2021, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.The advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were

Purpose: To determine how often loss of ataxia-telangiectasia–mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance.Experimental Design: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival.Results: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27–5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response.Conclusions: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. Clin Cancer Res; 20(7); 1865–72. ©2014 AACR.

PDF file - 123KB, PCR and sequencing primer sequences.

PDF file - 981KB, Representative Immunohistochemistry for CHD7 Expression in Primary Tumor Tissue (S1). Network Analysis via MetaCore ExPlain Process Network Analysis for genes involved in CHK1, CDC25A, AURKB, PLK1, HUS1 pathway (S2). CHD7 Knockdown Causes Gemcitabine Sensitization (S3). Mice with Xenograft Tumors Showed No Significant Difference in Body Weight (S4). CHD7 Knockdown Effect on Cell Cycle (S5). Gemcitabine Does Not Significantly Change CHD7 Protein Levels in Cells (S6).

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XLS file - 675KB, Full Results of Primary Gemcitabine Sensitivity Screen (S1). Known DNA Damage Response Genes Identified as Hits in Gemcitabine Sensitivity Screen (S2). Dysregulation, Differential Expression, and Literature RNAi Cross-Reference for Known DDR Genes and Select Hits (S3). Selected Top 15% of Gemcitabine Sensitivity Genes Tested on Secondary Screen (S4).

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor outcomes with current therapies. Gemcitabine is the primary adjuvant drug used clinically, but its effectiveness is limited. In this study, our objective was to use a rationale-driven approach to identify novel biomarkers for outcome in patients with early-stage resected PDAC treated with adjuvant gemcitabine. Using a synthetic lethal screen in human PDAC cells, we identified 93 genes, including 55 genes linked to DNA damage responses (DDR), that demonstrated gemcitabine sensitization when silenced, including CHD7, which functions in chromatin remodeling. CHD7 depletion sensitized PDAC cells to gemcitabine and delayed their growth in tumor xenografts. Moreover, CHD7 silencing impaired ATR-dependent phosphorylation of CHK1 and increased DNA damage induced by gemcitabine. CHD7 was dysregulated, ranking above the 90th percentile in differential expression in a panel of PDAC clinical specimens, highlighting its potential as a biomarker. Immunohistochemical analysis of specimens from 59 patients with resected PDAC receiving adjuvant gemcitabine revealed that low CHD7 expression was associated with increased recurrence-free survival (RFS) and overall survival (OS), in univariate and multivariate analyses. Notably, CHD7 expression was not associated with RFS or OS for patients not receiving gemcitabine. Thus, low CHD7 expression was correlated selectively with gemcitabine sensitivity in this patient population. These results supported our rationale-driven strategy to exploit dysregulated DDR pathways in PDAC to identify genetic determinants of gemcitabine sensitivity, identifying CHD7 as a novel biomarker candidate to evaluate further for individualizing PDAC treatment. Cancer Res; 74(10); 2677–87. ©2014 AACR.

Purpose: Extreme obesity (EO) is one of the biggest public health problems in the world and has grown considerably over the years. The aim of the study is to examine the effect of Roux-en-Y gastric bypass (RYGB), whey protein (WP), and omega-3 polyunsaturated fatty acid (PUFA) supplementation applied to EO rats on weight loss, histopathological changes in internal organs and biochemical alterations. Materials and Methods: Wistar albino female rats (n = 28) were used in the study and randomly divided into four groups. All rats were made obese by adding high fructose corn syrup (HFCS) to their drinking water. After the EO, WP and omega-3 PUFA supplementation was given and RYGB process was applied. At the end of the study, glucose, total cholesterol, HDL, VLDL, AST, ALT and uric acid changes and liver, kidney and pancreatic tissues were evaluated histopathologically. Results: WP and omega-3 PUFA supplementation decreased body weight (p > 0.05). Omega-3 PUFA and RYGB caused a decrease in total cholesterol (p < 0.05), WP decreased HDL (p < 0.05), WP and omega-3 PUFA caused an increase in ALT (p < 0.05). WP has been shown to have greater curative effects in rat liver and kidney tissues. It has been determined that RYGB causes necrosis in the liver and HFCS causes inflammation in the kidney. Conclusion: In the study; the positive effects of WP, omega-3 PUFA and bariatric surgery on obesity and dyslipidemia have been demonstrated. With this result, it was determined that WP, omega-3 PUFA supplementation and bariatric surgery were not superior to each other. Graphical abstract: [Figure not available: see fulltext.]

© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.There are highly conflicting data on relative frequency (2–32%), prognosis, and management of pT1b-gallbladder carcinoma (GBC), with 5-year survival ranging from > 90% in East/Chile where cholecystectomy is regarded as curative, versus < 50% in the West, with radical operations post-cholecystectomy being recommended by guidelines. A total of 473 in situ and invasive extensively sampled GBCs from the USA (n = 225) and Chile (n = 248) were re-evaluated histopathologically per Western invasiveness criteria. 349 had invasive carcinoma, and only 24 were pT1. Seven cases previously staged as pT1b were re-classified as pT2. There were 19 cases (5% of all invasive GBCs) qualified as pT1b and most pT1b carcinomas were minute (< 1mm). One patient with extensive pTis at margins (but pT1b focus away from the margins) died of GBC at 27 months, two died of other causes, and the remainder were alive without disease (median follow-up 69.9 months; 5-year disease-specific survival, 92%). In conclusion, careful pathologic analysis of well-sampled cases reveals that only 5% of invasive GBCs are pT1b, with a 5-year disease-specific survival of > 90%, similar to findings in the East. This supports the inclusion of pT1b in the “early GBC” category, as is typically done in high-incidence regions. Pathologic mis-staging of pT2 as pT1 is not uncommon. Cases should not be classified as pT1b unless extensive, preferably total, sampling of the gallbladder to rule out a subtle pT2 is performed. Critical appraisal of the literature reveals that the Western guidelines are based on either SEER or mis-interpretation of stage IB cases as “pT1b.” Although the prognosis of pT1b-GBC is very good, additional surgery (radical cholecystectomy) may be indicated, and long-term surveillance of the biliary tract is warranted.

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight >= 1 cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10 cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as "hepatobiliary cystadenoma." II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11 cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (

Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary type carcinomas (3%) were found and analyzed. In addition to diagnostic medullary pattern, six showed focal mucinous, and 8 had focal abortive gland-like formations. They occurred in younger patients (57 vs 65 y; p=0.02), had larger invasion size (mean, 3.2 vs 1.9 cm; p=0.01), formed nodular polypoid or plaque-like tumors, often lacked pre-invasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5/11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, two were ampullary-duodenal origin, one had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of non-medullary ACs (47%), although this did not reach statistical significance (p=0.47). Programed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, three were positive by CPS; two by TPS. Overall, only one of 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, non-medullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike "medullary carcinomas" of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.

Aim The aim was to investigate theRASdiscordance between initial and recurrent metastasectomy specimens in metastatic colorectal cancer (mCRC) patients treated with chemotherapy (CT) plus biological agents in a first-line setting. Methods Patients who had been treated with CT plus bevacizumab or cetuximab or panitumumab followed by R0 resection for potentially resectable colorectal cancer liver metastases were scanned. Among these, patients who developed resectable new metastases after a disease-free interval longer than 6 months were included in the study. We compared theRASmutation status between the first biopsy and the second metastasectomy specimen. Results A total of 82 mCRC patients treated with CT plus biological agents in a first-line setting were included in the study. The first biopsy assessment showed wild-typeRAStumours in 39 (47.6%) patients and mutantRAStumours in 43 (52.4%) patients. The mean time for new operable liver metastasis after R0 resection was 15.5 months. In the second metastasectomy specimens, the numbers of wild-type and mutantRAStumours were 30 (36.6%) and 52 (63.4%), respectively. The comparison with the first biopsy specimens showedRASstatus conversions in 17 (20.7%) patients. Univariate comparison between patients with and withoutRASstatus conversion revealed that grade, pathological T stage, wild-typeRAStumour and longer biological agent use time in the first-line treatment were significant factors forRASconversion. Conclusion Our results suggest that re-biopsy is needed for an optimal second-line treatment decision in mCRC patients regardless of backbone biological agent, especially in patients with wild-typeRASmCRC. Interdisciplinary Oncology Association

We aimed to determine the prognostic role of whole tumor-associated inflammatory cells, especially eosinophils, and stromal histological characteristics in relation to other prognostic parameters in patients with colorectal carcinoma (CRC). A total of 122 patients who underwent an operation for CRC were included in this retrospective study. Conventional (tumor grade, TNM stage and venous invasion [VI]) and other histopathological (intratumoral/peritumoral budding [ITB/PTB], desmoplasia) tumor parameters were recorded and classified by density, as were the tumor-associated inflammatory parameters (intratumoral/peritumoral lymphocytes [ITL/PTL], eosinophils [IE/PTE], overall inflammation [ITI/PTI], Crohn-like inflammation [CLI]). Cancer-specific survival data were analyzed with respect to all tumor parameters. High ITB and PTB were significantly correlated with a higher rate of pT4, VI and desmoplasia (p < 0.05). An association of moderate ITL and extensive PTL with lesser likelihood of VI and metastasis; an association of extensive CLI with a significantly lower rate of metastasis and TNM stage IV; and minimal PTE with a significantly higher rate of pT4 stage, metastasis and ITB were detected (p < 0.05 for each). Our findings revealed that low score tumoral budding and an increase in tumor-related inflammation were associated with lesser likelihood of poor prognostic tumor parameters. Nonetheless, given the association of an increase in PTE with lesser likelihood of ITB, pT4, metastasis, and with non-significantly for better survival rates, our findings emphasize the potential role of peritumoral eosinophils as an additional prognostic parameter in CRC.

Background The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. Methods In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. Results MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. Conclusions In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.

Preinvasive tumor-forming gallbladder neoplasms that are composed of small, non-mucinous tubules with complex architecture remain a poorly characterized group. Here, we evaluated the clinicopathological characteristics of this entity. Twenty-eight examples were analyzed. Tumors were invariably pedunculated polyps with thin stalks, often presented as loosely attached intraluminal nodules, with cauliflower architecture (akin to cholesterol polyps) comprised of compact, back-to-back acinar-like, small tubular units with minimal/no cytoplasm showing variable complexity, creating a picture distinct from the other tubular type dysplasia in the gallbladder. Their limited stroma showed distinctive amorphous amyloid-like hyalinization (39%). While some had round nuclei with single prominent nucleoli, others exhibited slightly more elongated nuclei with washed out chromatin reminiscent of papillary thyroid carcinoma. Squamoid/meningothelial-like morules (71%) and subtle neuroendocrine cell clusters (39%) were frequent. The level of cytoarchitectural atypia qualified as high-grade dysplasia (HGD) in all cases, but none were invasive. The background mucosa showed no dysplasia, but cholesterolosis. The majority (n = 8/12) showed diffuse MUC6 expression and lacked MUC5AC expression. Based on these observations, 635 gallbladder carcinomas were re-analyzed for residual/adjacent lesions with entity-defining characteristics disclosed here, and none could be identified. Preinvasive tubular non-mucinous neoplasm of the gallbladder, which we propose to classify as intracholecystic tubular non-mucinous neoplasm, is a clinicopathologically discrete entity, which tends to occur in uninjured gallbladders and in association with cholesterol polyps. By being tubular, non-mucinous and MUC6-positive, it is akin to intraductal tubulopapillary neoplasms of pancreatobiliary tract, but it is also different in many other aspects. Although their cytoarchitectural complexity warrants an HGD/carcinoma classification, they do not show invasion and their distinct characteristics warrant their separate classification.

Objective: to determine the frequency of granulomatous inflammation within hepatocellular carcinoma (HCC) and its clinicopathologic associations. Material and method: fifty-eight HCCs (51 explants, 3 lobectomies, and 4 segmentectomies) were reviewed. Results: five (8.6%) cases (F/M=1/4, mean age: 63.6) were identified with granulomas.1/5 had history of neoadjuvant therapy. 4/5 patients presented with early stage (pT1/2). All were well-differentiated (Grade1-2/4). The mean number of tumor foci was 3.6, with a median size of 2.2 cm. All of them had advanced fibrosis. No difference was identified from cases without granulomas (n=53) in terms of prognosis and aforementioned parameters (p> 0.05). Granulomas were mainly concentrated in peripheral parts of the tumors. One case with nodule-in-nodule formation had granulomas lined along the border of the inner nodule. In 2 cases, granulomas were identified in steatohepatitic areas, while another had clear cell change. Only 1 had necrotizing granulomas, none with acid resistant bacilli. Two cases revealed concomitant granulomas in the adjacent liver parenchyma in addition to the tumor stroma. Except for one with a history of tuberculosis, none of the cases had a granulomatous disease.Conclusion: this is the largest case series of HCCs with granulomas by far. Our data revealed neither clinicopathologic and prognostic difference nor definite etiology related to granulomas. Yet, association with steatotic and clear tumor cells suggests the role of cytoplasmic content, while distribution of granulomas points to host immune response., NA

BackgroundDifferent perspectives exist regarding the clinicopathologic characteristics, biology and management of gallbladder polyps. Size is often used as the surrogate evidence of polyp behavior and size of ≥1cm is widely used as cholecystectomy indication. Most studies on this issue are based on the pathologic correlation of polyps clinically selected for resection, whereas, the data regarding the nature of polypoid lesions from pathology perspective -regardless of the cholecystectomy indication- is highly limited.MethodsIn this study, 4231 gallbladders -606 of which had gallbladder carcinoma- were reviewed carefully pathologically by the authors for polyps (defined as ≥2 mm). Separately, the cases that were diagnosed as "gallbladder polyps" in the surgical pathology databases were retrieved.Results643 polyps identified accordingly were re-evaluated histopathologically. Mean age of all patients was 55 years (range: 20-94); mean polyp size was 9 mm. Among these 643 polyps, 223 (34.6%) were neoplastic: I. Non-neoplastic polyps (n = 420; 65.4%) were smaller (mean: 4.1 mm), occurred in younger patients (mean: 52 years). This group consisted of fibromyoglandular polyps (n = 196) per the updated classification, cholesterol polyps (n = 166), polypoid pyloric gland metaplasia (n = 41) and inflammatory polyps (n = 17). II. Neoplastic polyps were larger (mean: 21 mm), detected in older patients (mean: 61 years) and consisted of intra-cholecystic neoplasms (WHO's "adenomas" and "intracholecystic papillary neoplasms", ≥1 cm; n = 120), their "incipient" version (ConclusionsApproximately a third of polypoid lesions in the cholecystectomies (regardless of the indication) prove to be neoplastic. The vast majority of (90%) of polyps ≥1 cm and virtually all of those ≥2 cm are neoplastic confirming the current impression that polyps ≥1 cm ought to be removed. However, this study also illustrates that 30% of the neoplastic polyps are

Objective: Cholecystectomy materials are frequently encountered in routine practice. The aim of this study was to determine the true frequency of gallbladder lesions, the diagnostic consistency, and standardization of reports after macroscopic sampling and microscopic evaluation based on previously defined criteria. Material and Method:14 institutions participated in the study within the Hepato-Pancreato-Biliary Pathology Study Group. Routinely examined cholecystectomies within the last year were included in the study in these institutions. Additional sampling was performed according to the indications and criteria. The number of blocks and samples taken in the first macroscopic examination and the number of blocks and samples taken in the additional sampling were determined and the rate of diagnostic contribution of the additional examination was determined. Results: A total of 5,244 cholecystectomy materials from 14 institutions were included in the study. Additional sampling was found to be necessary in 576 cases (10.98%) from all institutions. In the first macroscopic sampling, the mean of the numbers of samples was approximately 4 and the number of blocks was 2. The mean of the numbers of additional samples and blocks was approximately 8 and 4, respectively. The diagnosis was changed in 144 of the 576 new sampled cases while the remaining 432 stayed unaltered. Conclusion: In this study, it was observed that new sampling after the first microscopic examination of cholecystectomy materials contributed to the diagnosis. It was also shown that the necessity of having standard criteria for macroscopic and microscopic examination plays an important role in making the correct diagnosis.

Context. Follicular cholecystitis (FC) is a poorly characterized entity. Objective. To determine its frequency/clinicopathologic associations. Design. A total of 2550 cholecystectomy specimens were examined. Two hundred three of these were consecutive routine cholecystectomies submitted entirely for microscopic examination to determine the relative frequency of incidental pathologies in gallbladders (GBs). The remainder had representative sampling. Underlying conditions were nonobstructive pathologies (1270 nonspecific cholecystitis), obstructive (62 distal biliary tract tumors, 35 primary sclerosing cholangitis, and 31 autoimmune pancreatitis), and neoplastic (n = 949). FC was defined as 3 distinct lymphoid follicles (LFs)/centimeter. Results. In the GBs totally submitted for microscopic examination, the true frequency of FC was found to be 2.5% (5/203), and in the representatively sampled group, it was 1.9%, with similar frequencies in nonobstructive, obstructive, and neoplastic cases (2.3%, 3.1%, and 1.3%, respectively, P = .77). When the 39 FC in nonneoplastic GBs contrasted with ordinary chronic cholecystitis, they were associated with older age (68 vs 49 years, P < .0001), similar gallstone frequency (68 vs 81%), female/male ratio (2.7 vs 2.6), and wall thickness (4 mm for both). None had lymphoma/parasites/ Salmonella infection. Of 17 cases who had undergone gastric biopsy, 5 had chronic gastritis (2 with Helicobacter pylori). Microscopically, the LFs were the main inflammatory process often with minimal intervening inflammation. IgG4-positive plasma cell density was low (Conclusions. Follicular cholecystitis is seen in 2% of cholecystectomies, typically in significantly older patients, suggesting a deranged immune response. A third of the patients reveal biopsy-proven gastritis. FC does not seem to be associated with autoimmunity, lymphoma, or obstructive pathologies.

There is no systematic histopathologic analysis of non-neoplastic polyps in the gallbladder. In this study, in addition to a computer search for cases designated as "polyp," a systematic review of 2533 consecutive routinely sampled archival and 203 totally submitted prospective cholecystectomies were analyzed for >2 mm polyps (cut-off was based on radiologic sensitivity). A total of 447 non-neoplastic polyps were identified. The frequency was 3% in archival cases and 5% in totally submitted cases. Only 21 (5%) were >= 1 cm. The average age was 52 years, and the female to male ratio was 3.1. Two distinct categories were delineated: (1) injury-related polyps (n=273): (a) Fibro(myo)glandular polyps (n=214) were small (mean=0.4 cm), broad-based, often multiple (45%), almost always (98%) gallstone-associated, and were composed of a mixture of (myo)fibroblastic tissue/lobular glandular units with chronic cholecystitis. Dysplasia seen in 9% seemed to be secondary involvement. (b) Metaplastic pyloric glands forming polypoid collections (n=42). (c) Inflammatory-type polyps associated with acute/subacute injury (11 granulation tissue, 3 xanthogranulomatous, 3 lymphoid). (2) Cholesterol polyps (n=174) occurred in uninjured gallbladders, revealing a very thin stalk, edematous cores devoid of glands but with cholesterol-laden macrophages in 85%, and cholesterolosis in the uninvolved mucosa in 60%. Focal low-grade dysplasia was seen in 3%, always confined to the polyp, unaccompanied by carcinoma. In conclusion, non-neoplastic polyps are seen in 3% of cholecystectomies and are often small. Injury-related fibromyoglandular polyps are the most common. Cholesterol polyps have distinctive cauliflower architecture, often in a background of uninjured gallbladders with cholesterolosis and may lack the cholesterol-laden macrophages in the polyp itself. Although dysplastic changes can involve non-neoplastic polyps, they do not seem to be the cause of invasive carcinoma by themselves.

Alveolar echinococcosis is an infectious disease caused by Echinococcus multilocularis and it is frequently diagnosed as a space-occupying lesion in the liver. The growth pattern may be similar to that of a malignant tumour with extensive liver infiltration, spreading into neighbouring organs and forming metastasis-like masses in distant organs. Thus, it is one of the differential diagnoses of liver cancer. We report a case that presented as a klatskin tumour clinically and radiologically, but was revealed by pathologic and serologic work-up. Since the courses of these two diseases, a malignancy and an infectious disease, are far beyond comparison, echinococcosis should always be considered in differential diagnosis of obstructive jaundice, especially in the endemic regions. Alveolar Ekinokokkosis, Echinococcus multilocularis’in sebep olduğu bir enfeksiyon hastalığı olup, sıklıkla karaciğerde yer kaplayan lezyon ile kendini gösterir. Karaciğerdeki lokal infiltratif paterni yanısıra, çevre organlara yayılımı ve uzak organlarda metastazile karışan kitle oluşturması nedeniyle, malign bir tümörü taklit eder. Bu nedenle karaciğer kanserlerinin önemli bir ayırıcı tanısını oluşturur. Burada, klinik ve radyolojik olarak klatskin tümörünü düşündüren ancak patolojik ve serolojik çalışmalarla Alveoler Ekinokokkosis tanısı alan bir olgu sunulmuştur. Malign tümörlerin ve enfeksiyon hastalıklarının tedavi ve prognozlarının birbirinden çok farklı olması nedeniyle, özellikle Ekinokkozisin endemik olduğu bölgelerde, tıkanma sarılığının ayırıcı tanısında bu etken mutlaka akla gelmelidir.

Purpose: To evaluate and compare the diagnostic performance of non-enhanced computed tomography (NECT) and contrast-enhanced CT (CECT) attenuation indices in the assessment of hepatic steatosis by using biopsy as the reference standard. Materials and methods: This retrospective study was approved by our Institutional Review Board. 55 Potential donors who underwent both NECT and triphasic CECT and core liver biopsy, were included the study. Average attenuation measurements that were obtained from multiple regions in liver, spleen, and psoas muscle on both unenhanced and CECT were used for analysis. Hepatic attenuation measurements were analyzed with and without normalization with the spleen and psoas muscle. Linear regression and receiver operating characteristic (ROC) curve analysis were used to evaluate the statistical association between CT indices and steatosis at histology. Results: Linear regression analysis confirmed the strongest correlation between steatosis and normalized measurements of hepatic attenuation with splenic attenuations on hepatic venous phase of CECT scan (R 0.821; R2 0.674 and R 0.816; R2 0.665, respectively). The use of ROC curve analysis also demonstrated that normalized measurements of hepatic attenuation with splenic attenuations on hepatic venous phase of CECT showed high diagnostic performance regarding the qualitative distinction of steatosis (AUC values greater than 0.9). Conclusion: Attenuation measurements of liver normalized with spleen on hepatic venous phase may be useful in evaluating steatosis in donor candidates with moderate to severe steatosis who are unacceptable for liver donation. In this manner unnecessary liver biopsy may be avoided in those donor candidates.

Amaç: Yağlanma oranı, steatohepatit tanısında ve transplantasyon öncesi verici adayı karaciğer biyopsilerinde değerlendirilmesi gereken parametrelerdendir. Kantitatif/semikantitatif olarak değerlendirilen yağlanma yüzdeleri, gözlemci-içi ve gözlemciler arası farklılık göstermektedir. Bu farklılığı en aza indirgemek amaçlı, görüntü analizi yöntemleri geliştirilmektedir. Çalışmamızda, karaciğer yağlanmasını taklit eden sanal olarak oluşturulmuş dijitalize resimler, patologlar tarafından incelenmiştir. Sonuçların bilgisayarca hesaplanan değerler ile uyum oranları ve klinik yönetimi etkileyecek değerlendirme farklılıklarına neden olup olmadığı araştırılmıştır. Yöntem: ’Kameram’ programı ile hazırlanmış, pembe zeminde, yağlanmayı temsil eden, alan ölçüleri bilinen beyaz dairesel boşluklar içeren 9 resim, İstanbul Hepatopankreatobiliyer patoloji çalışma grubu ile paylaşıldı. Katılımcılardan her resim için yağlanma yüzdesi belirtmeleri istendi. Sonuçlar, bilgisayar tarafından hesaplanan değerler ile kıyaslandı. Bulgular: Çalışmaya 19 patolog katıldı. Onbeşi resimlerin tamamında ya da çoğunda bilgisayarın hesapladığı değerlere göre yüksek yağlanma yüzdesi belirtti. Sadece 1 katılımcı, bilgisayar ile aynı değerleri bildirdi. Bilgisayar değerleri ile patologların değerleri arasında %40’a kadar yüksek, %20’ye kadar düşük değişkenlik mevcuttu. Resimlerin verici adayı karaciğerini temsil ettiği düşünüldüğünde, 11 patolog 1 olguda, 4 patolog 2 olguda, 1 patolog 3 olguda klinik yönetimi etkileyebilecek değerlendirme yaparken, 3 patolog tüm olgularda klinik yönetimi etkilemeyecek değerlendirme yaptı. Resimlerin steatohepatit değerlendirmesini temsil ettiği düşünüldüğünde, sadece 2 resim tüm patologlar tarafından bilgisayar ile aynı şekilde skorlandı ve resimlerin 5’inde en az 2 patologun bilgisayar değerlerine göre yüksek skor verdiği görüldü. Patologlar arası uyum steatohepatit ve verici karaciğerini değerlendirmede orta-iyi düzeydeydi (sırasıyla kappa değerleri: 0.51 ve 0.63) Sonuç: Çalışmamızda, karaciğer yağlanma oranlarının patologlar tarafından genel olarak yüksek değerlendirildiği gözlenmektedir. Steatohepatit sınıflamasında ve greft yönetimi açısından kliniği farklı etkileyen kararlar verilebileceği düşünülmüştür. Patoloji rutinine her geçen gün daha fazla dahil olan bilgisayar destekli otomatize programların, patologlar arası değerlendirme farklılıkları ve klinik yansımaları nedeniyle, karaciğer yağlanma oranlarının doğru tespitinde de yeri olabileceği görülmektedir. Objective: The rate of steatosis is the parameter that should be assessed in steatohepatitis and donor liver biopsies before transplantation. The percentage of steatosis, evaluated as quantitative / semiquantitative, differs between observers and intra-observers. Various image analysis methods have been developed in order to reduce this difference. In our study, pathologists examined virtually created digitized images mimicking liver fat. The results’ accuracy rates and differences in assessment, that would impact clinical management, were investigated. Methods: Nine pictures with white circles on a pink background, simulating steatosis, were prepared with the ‘Kameram’ program. The steatosis area was calculated by computer. These pictures were shared with the Istanbul Hepatopancreatobiliary pathology study group. Participants were asked to specify the percentage of steatosis for each image. The results were compared to computer values. Results: Nineteen pathologists participated in the evaluation. Fifteen of the pathologists indicated higher steatosis percentage than the computirised calculated values, either in all pictures or most of the pictures. Only 1 participant reported the same values with the computer. Difference between computer values and pathologists' values ranged from as high as 40% to as low as 20%. When the images were thought to represent the donor liver, only 3 pathologists succeeded in proper clinical management in all cases, while 11 of the pathologists had misdiagnosed clinical management in 1 case, 4 pathologists in 2 cases, 1 pathologist in 3 cases. When it was thought that the pictures represented the steatohepatitis evaluation, all pathologists correctly scored only 2 pictures and at least 2 pathologists gave high scores in 5 of the pictures. Inter-pathologist agreement was moderate to good with assessing steatohepatitis and donor liver (kappa values, respectively: 0.51 and 0.63). Conclusion: In our study, it is observed that pathologists generally evaluate the steatosis rate higher than real calculated values. This can affect the clinic, in both steatohepatitis scoring classification and graft management differently. Computer-aided automated programs, which are increasingly used in routine pathology to overcome the differences in pathologist evaluations and clinical manifestations, also can have a role in the detection of liver steatosis ratio.

Amaç: Yağlanma oranı, steatohepatit tanısında ve transplantasyon öncesiverici adayı karaciğer biyopsilerinde değerlendirilmesi gerekenparametrelerdendir. Kantitatif/semikantitatif olarak değerlendirilen yağlanmayüzdeleri, gözlemci-içi ve gözlemciler arası farklılık göstermektedir. Bu farklılığıen aza indirgemek amaçlı, görüntü analizi yöntemleri geliştirilmektedir.Çalışmamızda, karaciğer yağlanmasını taklit eden sanal olarak oluşturulmuşdijitalize resimler, patologlar tarafından incelenmiştir. Sonuçların bilgisayarcahesaplanan değerler ile uyum oranları ve klinik yönetimi etkileyecekdeğerlendirme farklılıklarına neden olup olmadığı araştırılmıştır.Yöntem: ’Kameram’ programı ile hazırlanmış, pembe zeminde, yağlanmayıtemsil eden, alan ölçüleri bilinen beyaz dairesel boşluklar içeren 9 resim,İstanbul Hepatopankreatobiliyer patoloji çalışma grubu ile paylaşıldı.Katılımcılardan her resim için yağlanma yüzdesi belirtmeleri istendi. Sonuçlar,bilgisayar tarafından hesaplanan değerler ile kıyaslandı.Bulgular: Çalışmaya 19 patolog katıldı. Onbeşi resimlerin tamamında ya daçoğunda bilgisayarın hesapladığı değerlere göre yüksek yağlanma yüzdesibelirtti. Sadece 1 katılımcı, bilgisayar ile aynı değerleri bildirdi. Bilgisayardeğerleri ile patologların değerleri arasında %40’a kadar yüksek, %20’ye kadardüşük değişkenlik mevcuttu. Resimlerin verici adayı karaciğerini temsil ettiğidüşünüldüğünde, 11 patolog 1 olguda, 4 patolog 2 olguda, 1 patolog 3 olgudaklinik yönetimi etkileyebilecek değerlendirme yaparken, 3 patolog tümolgularda klinik yönetimi etkilemeyecek değerlendirme yaptı. Resimlerinsteatohepatit değerlendirmesini temsil ettiği düşünüldüğünde, sadece 2 resimtüm patologlar tarafından bilgisayar ile aynı şekilde skorlandı ve resimlerin5’inde en az 2 patologun bilgisayar değerlerine göre yüksek skor verdiğigörüldü. Patologlar arası uyum steatohepatit ve verici karaciğerinideğerlendirmede orta-iyi düzeydeydi (sırasıyla kappa değerleri: 0.51 ve 0.63)Sonuç: Çalışmamızda, karaciğer yağlanma oranlarının patologlar tarafındangenel olarak yüksek değerlendirildiği gözlenmektedir. Steatohepatitsınıflamasında ve greft yönetimi açısından kliniği farklı etkileyen kararlarverilebileceği düşünülmüştür. Patoloji rutinine her geçen gün daha fazla dahilolan bilgisayar destekli otomatize programların, patologlar arasıdeğerlendirme farklılıkları ve klinik yansımaları nedeniyle, karaciğer yağlanmaoranlarının doğru tespitinde de yeri olabileceği görülmektedir.

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

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.

WOS: 000404313200010 PubMed ID: 28554753 Objective: To investigate the immunohistochemical expressions of HIF-1 alpha, CA9 and CXCR4 in resected human CRC specimens in relation to clinicopathologic and prognostic variables. Methods: A total of 186 patients (mean(SD) age: 56.7(12.6) years, 54.0% were males) with colorectal adenocarcinoma were included in this retrospective study. Resection specimens of the primary tumor were reviewed to confirm the diagnoses and the stage of the disease. Data on age, gender, tumor characteristics (localization, size, macroscopic growth pattern, histologic type, grade, angiolymphatic invasion, TNM stage), applied treatments and clinical outcome (overall survival, local recurrence and distant metastasis) were obtained from the hospital records. Immunohistochemical analysis of tissue specimens was performed to determine HIF-1 alpha, CA9 and CXCR4 expressions. Results: Overall, 94.0% of cases showed HIF-1 alpha immunoreactivity, 89% showed CXCR4 immunoreactivity, and 15.6% showed CA9 immunoreactivity, while weak expression of immunohistochemical markers was noted in 51.1%, 93.0% and 50.5% of cases, respectively. HIF-l alpha expression was higher among males than in females (median (min-max) final score of 6 (0-9) vs. 3 (0-9), p = 0.013). CA9 expressed at higher levels in ulcerovegetative and depressed tumors than in polypoid ones [0(0-9) vs. 0(0-6), p = 0.039]. CXCR4 expression was significantly higher in tumors < 5 cm than >= 5 cm [6(0-9) vs. 3(0-9), p = 0.028] and in grade 1-2 than grade 3 tumors [4(0-9) vs. 3(0-9), p = 0.030]. No significant difference was noted in survival with respect to strength of HIF-1 alpha, CA9 and CXCR4 immunoreactivity. Conclusion: In conclusion, our findings revealed weak-to-moderate HIF-l alpha and CXCR4 immunoreactivity in majority of resection samples, and weak CA9 immunoreactivity in majority of CA9 positive cases. Other than gender (HIF-1 alpha), macroscopic growth pattern (CA9) and tumor size and histologic grade (for CXCR4), none of the clinicopathologic and prognostic factors investigated were associated with expression of immunohistochemical markers and level of immunoreactivity had no impact on survival.

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

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

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

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

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

Background Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC).

WOS: 000394069800004 PubMed ID: 27666767 Signet ring cell carcinoma is an extremely rare type of gallbladder carcinoma: In the gastrointestinal system, carcinomas with single-cell or cord-like infiltration, previously called "diffuse-infiltrative" type or "signet ring cell," are now designated as "poorly cohesive cell" (PCC) type (regardless of with/without signet ring cells) in the World Health Organization 2010 classification. Six hundred twenty-eight primary invasive gallbladder carcinomas were reviewed for the PCC pattern. Twenty-four cases in which classical PCC pattern constituted greater than 50% of the tumor were included in the study. The mean age was 63 (range, 44-84) years. A strong female predominance was present (female/male ratio, 6.3 versus 3.9 for all gallbladder carcinomas). Most cases (79%) had advanced carcinoma (pT3+) in comparison with 51% of usual carcinomas (P < .01). All cases (100%) showed at least focal signet ring morphology (intracytoplasmic mucin), and this was predominant in 50%. Twelve cases (50%) demonstrated a focal invasive glandular component of the usual type. Overlying focal high-grade dysplasia was identified in 11 (46%). Due to block loss, immunohistochemistry could be performed in only 5 cases and revealed a profile similar to upper gastrointestinal carcinomas CK7++/CK20-+/CDX2+-/p53+. E-cadherin was decreased in the PCC component of all cases. The clinical course appeared to be more aggressive than ordinary gallbladder. carcinomas, with median survival of 3.3 months versus 11.8 months, which did not reach statistical significance (P = .06 by log-rank test). In conclusion, PCC carcinoma originating in the gallbladder should be kept in mind for the differential diagnosis of disseminated poorly differentiated carcinomas in the abdomen.

Literature on non-ampullary–duodenal carcinomas is limited. We analyzed 47 resected non-ampullary–duodenal carcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type and only 19% pure intestinal. Immunohistochemistry (n=38) revealed commonness of ‘gastro-pancreatobiliary markers’ (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas ‘intestinal markers’ were relatively less common (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each); previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform, one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common in ampullary–duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth. Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-border infiltration). When compared with ampullary (n=355) and pancreatic ductal (n=227) carcinomas, non-ampullary–duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm (vs 1.9, and 3.3) and 59% nodal metastasis (vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar to that of ampullary–duodenal carcinomas (59 and 52%; P=0.78), but was significantly better than the ampullary ductal (41 and 29%, P

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.

Background Ampullary adenocarcinoma is a rare gastrointestinal cancer associated with diverse outcomes due to clinical and pathological heterogeneity. Standardized methods to better prognosticate and inform therapeutic selection for ampullary adenocarcinoma are needed. This study explored the novel use and potential prognostic utility of a 92-gene cancer classifier in ampullary adenocarcinomas. Methods In this prospectively-defined, blinded study of ampullary adenocarcinoma [N =54; stage T3 or higher (57 %); Grade III (44 %); Node positive (55 %)], the performance of a 92-gene classifier was examined to predict the ampullary subtype that was derived from histomorphological examination of resected ampullary samples. Outcome data for relapse-free survival (RFS) and overall survival (OS) were plotted to compare the prognostic utility of histological subtyping, histomolecular phenotyping, and the 92-gene classifier. Multivariate analysis was used to determine clinicopathological variables that were independently associated with overall survival. Results The 92-gene classifier demonstrated sensitivities and specificities of 85 % [95 % CI, 66–94] and 68 % [95 % CI, 48–84] and 64 % [95 % CI, 46–79] and 88 % [95 % CI, 70–98] for the pancreaticobiliary and intestinal histological subtypes, respectively. For the 92-gene classifier, improved outcomes were observed for the intestine versus the pancreaticobiliary prediction (median OS 108.1 v 36.4 months; HR, 2.17; 95 % CI, 0.98 to 4.79; P = 0.05). Similar results were seen for ampullary adenocarcinoma stratification by histological subtype (P = 0.04) and histomolecular phenotype (P = 0.02). Within poorly differentiated ampullary adenocarcinomas only the 92-gene classifier demonstrated statistically significant differences in RFS and OS (P