Performance of CT in the locoregional staging of colon cancer: detailed radiology-pathology correlation with special emphasis on tumor deposits, extramural venous invasion and T staging.

PURPOSE: To investigate the performance of computed tomography (CT) in the local staging of colon cancer in different segments, with emphasis on parameters that have been found to be significant for rectal cancer, namely, extramural venous invasion (EMVI) and tumor deposits (TDs). METHODS: CT and pathology data from 137 patients were independently reviewed by radiology and pathology teams. The performance of CT in categorizing a given patient into good, versus poor prognostic groups was assessed for each segment, as well as the presence of lymph nodes (LNs), TDs and EMVIs. Discordant cases were re-evaluated to determine potential sources of error. Elastic stain was applied for EMVI discordance. RESULTS: The T staging accuracy was 80.2%. For T stage stratification, CT performed slightly better in the left colon, and the lowest accuracy was in the transverse colon. Under-staging was more common (in 12.4%), and most of the mis-staged cases were in sigmoid colon. According to the first comprehensive correlative analysis, the sensitivity, specificity, and accuracy of CT for detecting TDs were found to be 57.9%, 92.4%, 87.6%, respectively. These figures were 44.7%, 72.7%, and 63.5% for LN, and 58.5%, 82.1% and 73% for EMVI. The detection rate was better for multifocal EMVI. The detection rate was also comparable (although substantially underestimated) for LNs, with the half of the LNs missed by CT being < 5 mm. Four patients that were classified as TD by CT, disclosed to be LNs by pathology. Correlative analysis led to refinement of the pathology criteria, with subsequent modifications of the initial reports in 13 (9.5%) patients. CONCLUSION: Overall, CT performed well in the evaluation of colon cancer, as did TD and EMVI. It is advisable to include these parameters in CT-based staging. Radiologists should be aware of the pitfalls that occur more commonly in different segments.

Adenomyomas of the Gallbladder: An Analysis of Frequency, Clinicopathologic Associations, and Relationship to Carcinoma of a Malformative Lesion.

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 arose 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.

Eosinophilic Cholecystitis and Eosinophils in Gallbladder Injuries: A Clinicopathological Analysis of 1050 Cholecystectomies.

"Eosinophilic cholecystitis" has been an elusive concept. Around 1050 consecutive cholecystectomies with chronic (CC, n = 895), subacute (SAC, n = 100), and acute cholecystitis (AC, n = 55) were reviewed for eosinophilic infiltration. Eosinophilic hot spots (>40 eosinophils/HPF) were seen in 63% of SAC and 35% of AC (vs. 6% of CC, p < 0.001). Eosinophils were mostly encountered in areas of wall thickening, revealing edema with early collagenization and young tissue-culture-type fibroblasts. However, in ten chronic cholecystitis patients (<1%), prominent eosinophilia with eosinophil-rich foci (>100 eosinophils/HPF) was noted. These ten cases, classified as "eosinophilic cholecystitis", were analyzed further: The patients were relatively young (mean age = 43 years), with a 9:1 female:male ratio. None had blood eosinophilia/eosinophilia syndromes. Although one had ulcerative colitis, others did not have any autoimmune diseases. The mean gallbladder wall thickness was 3.5 mm (vs. 4.2 mm in ordinary CC). In conclusion, eosinophils are a part of especially subacute injuries in the gallbladder. They are typically condensed in the areas of healing and appear to signify a distinctive state of injury in which there are erosions leading to slow/sustained exposure of the mural tissues to the bile contents that induce chemical injury/recruit eosinophils. Eosinophilic cholecystitis is a very uncommon occurrence and appears to be an exaggerated response in allergic patients who are prone to recruit eosinophils in reaction to injury.

Effects of Whey Protein, Omega-3 Fatty Acid and Roux-En-Y Gastric Bypass on Body Weight, Biochemical Parameters and Organ Functions in an Obese Rat Model: Experimental Research.

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.

Reappraisal of T1b gallbladder cancer (GBC): clinicopathologic analysis of 473 in situ and invasive GBCs and critical review of the literature highlights its rarity, and that it has a very good prognosis.

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.

Medullary carcinoma of the ampulla has distinct clinicopathologic characteristics including common association with microsatellite instability and PD-L1 expression.

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 the diagnostic medullary pattern, 6 showed focal mucinous and 8 had focal abortive gland-like formations. They occurred in younger patients (57 versus 65 y; P = .02), had larger invasion size (mean, 3.2 versus 1.9 cm; P = .01), formed nodular polypoid or plaque-like tumors, and often lacked preinvasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5 of 11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, 2 were ampullary-duodenal origin, 1 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 nonmedullary ACs (47%), although this did not reach statistical significance (P = .47). Programmed 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, 3 were positive by CPS; 2 by TPS. Overall, only 1 of the 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, nonmedullary 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.

Hepatic Cysts: Reappraisal of the Classification, Terminology, Differential Diagnosis, and Clinicopathologic Characteristics in 258 Cases.

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 (<3 cm); choledochal cyst (5%), foregut cyst (2%). V. Miscellaneous (4%). In conclusion, hepatic cysts occur predominantly in women (3/1), are mostly (90%) non-neoplastic, and seldom (<2%) malignant. Cystic bile duct hamartomas and their relative not otherwise specified-type benign biliary cysts are frequently multifocal and often misdiagnosed as "cystadenoma/carcinoma." Defined by OTS, MCNs (the true "hepatobiliary cystadenoma/carcinoma") are solitary, constitute only 10.5% of hepatic cysts, and have a significantly different profile than the impression in the literature in that essentially all are perimenopausal females, and rarely associated with carcinoma (7%). Since MCNs can only be diagnosed by demonstration of OTS through complete microscopic examination, it is advisable to avoid the term "cystadenoma/cystadenocarcinoma" solely based on radiologic examination, and the following simplified terminology would be preferable in preoperative evaluation to avoid conflicts with the final pathologic diagnosis: (1) noncomplex (favor benign), (2) complex (in 3 subsets, as favor benign, cannot rule out malignancy, or favor malignancy), (3) malignant features.

Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading.

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 <=2 cm. Three tumor slides representative of the spectrum (least, medium, and most) of invasiveness at the advancing edge of the tumor were selected, and then each slide was scored as follows. Well-demarcated/encapsulated, 1 point; Mildly irregular borders and/or minimal infiltration into adjacent tissue, 2 points; Infiltrative edges with several clusters beyond the main tumor but still relatively close, and/or satellite demarcated nodules, 3 points; No demarcation, several cellular clusters away from the tumor, 4 points; Exuberantly infiltrative pattern, scirrhous growth, dissecting the normal parenchymal elements, 5 points. The sum of the rankings on the three slides was obtained. Cases with scores of 3-6 were defined as "non/minimally infiltrative" (NI; n = 77), 7-9 as "moderately infiltrative" (MI; n = 68), and 10-15 as "highly infiltrative" (HI; n = 36). In addition to showing a statistically significant correlation with all the established signs of aggressiveness (grade, size, T-stage), this grading system was found to be the most significant predictor of adverse outcomes (metastasis, progression, and death) on multivariate analysis, more strongly than T-stage, while Ki-67 index did not stand the multivariate test. As importantly, cases <=2 cm were also stratified by this grading system rendering it applicable also to this group that is currently placed in "watchful waiting" protocols. In conclusion, the proposed grading system has a strong, independent prognostic value and therefore should be considered for integration into routine pathology practice after being evaluated in validation studies with larger series.

Hepatocellular Carcinomas with Granulomatous Inflammation In Tumor Stroma: Clinicopathologic Characteristics.

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.

Evaluation and Pathologic Classification of Choledochal Cysts: Clinicopathologic Analysis of 84 Cases From the West.

Choledochal cyst (CC) is believed to be a mostly Asian disorder. As a clinically defined entity, its pathologic correlates are poorly characterized. Eighty-four resected CCs from the West were reanalyzed. After applying established Japanese criteria, 9/66 with available imaging were disqualified and 10/39 with preoperative cyst typing had to be recategorized. None had been diagnosed with, or evaluated for, pancreatobiliary maljunction, but on retrospective analysis of radiologic images, 12/66 were found to have pancreatobiliary maljunction. The clinical findings were: F/M=5.7; mean age, 48; most (77%) presented with abdominal pain; mean size, 2.9 cm; choledocholithiasis 11%. Gross/histologic examination revealed 3 distinct pathology-based categories: (I) Cystic dilatation of native ducts (81%). (II) Double bile duct (13%), almost all of which were found in women (10/11); all were diagnosed by pathologic examination, and not preoperative diagnosis. (III) Gastrointestinal (GI) duplication type (6%). Microscopic findings of the entire cohort included mucosal-predominant lymphoplasmacytic inflammation (50%), follicular cholangitis (7%), mucosal hyperplasia (43%; 13% with papillae), intestinal metaplasia (10%), BilIN-like hyperplasia (17%), erosion/ulceration (13%), and severe dysplasia-mimicking atypia including "detachment atypia" and micropapillary degeneration (11%). Carcinomatous changes were seen in 14 cases (17%) (high-grade dysplasia/carcinoma in situ in 7, intraductal papillary neoplasm 1, and invasive carcinoma 6); and 13/14 of these occurred in pathologic category I, all with cyst size >1 cm. In conclusion, diagnostic imaging guidelines used in Asia are not routinely used (but should be adopted) in the West. Pathologically, cases designated as CC are classifiable in 3 groups: category 1 (dilated native duct type), more prone to carcinomatous change; category 2, double-duct phenomenon (all but 1 being female in this study); and category 3, GI-type duplication. Overall, 17% of CCs show carcinomatous change (50% of them invasive). CC specimens should be carefully examined with this classification and submitted entirely for assessment of at-risk mucosa and cancerous transformation.

The conversion of RAS status in metastatic colorectal cancer patients after first-line biological agent treatment.

AIM: The aim was to investigate the RAS discordance 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 the RAS mutation 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-type RAS tumours in 39 (47.6%) patients and mutant RAS tumours 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 mutant RAS tumours were 30 (36.6%) and 52 (63.4%), respectively. The comparison with the first biopsy specimens showed RAS status conversions in 17 (20.7%) patients. Univariate comparison between patients with and without RAS status conversion revealed that grade, pathological T stage, wild-type RAS tumour and longer biological agent use time in the first-line treatment were significant factors for RAS conversion. 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-type RAS mCRC.

Intracholecystic tubular non-mucinous neoplasm (ICTN) of the gallbladder: a clinicopathologically distinct, invasion-resistant entity.

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.

The potential prognostic role of peritumoral eosinophils within whole tumor-associated inflammatory cells and stromal histological characteristics in colorectal cancer.

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.

Gallbladder polyps: Correlation of size and clinicopathologic characteristics based on updated definitions.

BACKGROUND: Different 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. METHODS: In 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. RESULTS: 643 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 (<1 cm) (n = 44), polypoid invasive carcinomas (n = 26) and non-neoplastic polyps with incidental dysplastic changes (n = 33). In terms of size cut-off correlations, overall, only 27% of polyps were ≥1 cm, 90% of which were neoplastic. All (except for one) ≥2 cm were neoplastic. However, 14% of polyps <1 cm were also neoplastic. Positive predictive value of ≥1 cm cut-off -which is widely used for cholecystectomy indication-, was 94.3% and negative predictive value was 85%. CONCLUSIONS: Approximately 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 <1 cm and therefore small polyps should also be closely watched, especially in older patients.

Should be Remembered in the Differential Diagnosis of Klatskin Tumour: Alveolar Echinococcosis

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.

Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated.

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.

The Contribution of Additional Sampling in Cholecystectomy Materials: A Multicenter Prospective Study.

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.

Follicular Cholecystitis: Reappraisal of Incidence, Definition, and Clinicopathologic Associations in an Analysis of 2550 Cholecystectomies.

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 (<10/high-power field) in 21/24(87.5%) cases. 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.

Non-neoplastic Polyps of the Gallbladder: A Clinicopathologic Analysis of 447 Cases.

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.

The effect of fibrin glue in preventing staple-line leak after sleeve gastrectomy. An experimental study in rats.

PURPOSE: To evaluate the effect of fibrin glue on staple-line leak after sleeve gastrectomy. METHODS: Fourteen adult wistar rats 300 gr were randomized into two groups: Control group (n=7) and study group (n=7). All the rats underwent sleeve gastrectomy using lineer stapler. In the study group, fibrin glue was used to reinforce the staple-line. The rats were sacrificed 7 days after surgery. The stomach was resected, submerged in saline and exposed to excess pressure to obtain a burst pressure value. The gastric staple line was evaluated histopathologically according to the Ehrlich Hunt scale. The results of the two groups were compared. RESULTS: The mean Ehrlich-Hunt scores for inflammation, fibroblastic activity and neo-angiogenesis were similar between the groups (p>0.05). Collagen deposition was significantly higher in study group (3.42±0.53) when compared with control group (2.57±0.78) (p=0.035). The mean burst pressure was 137.8±8.5 mmHg for control group and 135.0±8.1 mmHg for study group (p=0.536). CONCLUSION: Reinforcement of the staple-line with fibrin glue has no effect on the burst pressure after sleeve gastrectomy. More studies are needed to evaluate the precautions against leak after sleeve gastrectomy.