Publications by authors named "Volkan Adsay"

249 Publications

Dysplasia and carcinoma of the gallbladder: pathologic evaluation, sampling, differential diagnosis and clinical implications.

Histopathology 2021 Feb 25. Epub 2021 Feb 25.

Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.

Pathologic evaluation of gallbladder neoplasia remains a challenge. A significant proportion of cases presents as clinically and grossly inapparent lesions, and grossing protocols are not well established. Among epithelial alterations, pseudo-pyloric gland metaplasia is ubiquitous and of no apparent consequence, whereas goblet cell metaplasia and a foveolar change in surface cells require closer attention. Low-grade dysplasia is difficult to objectively define and appears to be clinically inconsequential by itself; however, extra sampling is required to exclude the possibility of accompanying more significant lesions. For high-grade dysplasia ("high-grade BilIN" a.k.a. "carcinoma in-situ"), a complete sampling is necessary to rule out invasion. Designating in-situ or minimally invasive carcinomas limited to muscularis or above as early gallbladder carcinoma (EGBC) helps alleviate the major geographic differences (West/East) in the criteria for "invasiveness" to assign a case to pTis or pT1. Total sampling is crucial in proper diagnosis of such cases. A subset of invasive GBCs (5-10%) arise from the intracholecystic neoplasm (ICN, "adenoma-carcinoma sequence") category. About 2/3rds of ICNs have invasive carcinoma. However, this propensity differ by subtype. True "pyloric gland adenomas" (> 1 cm) are uncommon and scarcely associated with invasive carcinoma. A distinct subtype of ICN composed of tubular, non-mucinous MUC6+ glands (intracholecystic tubular non-mucinous neoplasm-ICTN) forms a localized pedunculated polyp. Although, it is morphologically complex and high-grade, appears to be invasion resistant. Some of the invasive carcinoma types in the gallbladder have been better characterized recently, with adenosquamous, neuroendocrine, poorly cohesive and mucinous carcinomas often being more advanced and aggressive.
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http://dx.doi.org/10.1111/his.14360DOI Listing
February 2021

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

Am J Surg Pathol 2021 May;45(5):627-637

Departments of Pathology.

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.
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http://dx.doi.org/10.1097/PAS.0000000000001666DOI Listing
May 2021

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors.

Endocr Pathol 2021 Mar 18;32(1):169-191. Epub 2021 Jan 18.

Green Templeton College, University of Oxford and ENETS Centre of Excellence, Royal Free Hospital, London, UK.

Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
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http://dx.doi.org/10.1007/s12022-021-09662-5DOI Listing
March 2021

T2 gallbladder cancer shows substantial survival variation between continents and this is not due to histopathologic criteria or pathologic sampling differences.

Virchows Arch 2021 Jan 7. Epub 2021 Jan 7.

Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Davutpasa Cad No 4., Topkapi, Istanbul, Turkey.

Published data on survival of T2 gallbladder carcinoma (GBC) from different countries show a wide range of 5-year survival rates from 30-> 70%. Recently, studies have demonstrated substantial variation between countries in terms of their approach to sampling gallbladders, and furthermore, that pathologists from different continents apply highly variable criteria in determining stage of invasion in this organ. These findings raised the question of whether these variations in pathologic evaluation could account for the vastly different survival rates of T2 GBC reported in the literature. In this study, survival of 316 GBCs from three countries (Chile n = 137, South Korea n = 105, USA n = 74), all adequately sampled (with a minimum of five tumor sections examined) and histopathologically verified as pT2 (after consensus examination by expert pathologists from three continents), was analyzed. Chilean patients had a significantly worse prognosis based on 5-year all-cause mortality (HR: 1.89, 95% CI: 1.27-2.83, p = 0.002) and disease-specific mortality (HR: 2.41, 95% CI: 1.51-3.84, p < 0.001), compared to their South Korean counterparts, even when controlled for age and sex. Comparing the USA to South Korea, the survival differences in all-cause mortality (HR: 1.75, 95% CI: 1.12-2.75, p = 0.015) and disease-specific mortality (HR: 1.94, 95% CI: 1.14-3.31, p = 0.015) were also pronounced. The 3-year disease-specific survival rates in South Korea, the USA, and Chile were 75%, 65%, and 55%, respectively, the 5-year disease-specific survival rates were 60%, 50%, and 50%, respectively, and the overall 5-year survival rates were 55%, 45%, and 35%, respectively. In conclusion, the survival of true T2 GBC in properly classified cases is neither as good nor as bad as previously documented in the literature and shows notable geographic differences even in well-sampled cases with consensus histopathologic criteria. Future studies should focus on other potential reasons including biologic, etiopathogenetic, management-related, populational, or healthcare practice-related factors that may influence the survival differences of T2 GBC in different regions.
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http://dx.doi.org/10.1007/s00428-020-02968-5DOI Listing
January 2021

Pancreatobiliary Maljunction-Associated Gallbladder Cancer is as Common in the West, Shows Distinct Clinicopathologic Characteristics and Offers an Invaluable Model for Anatomy-Induced Reflux-Associated Physio-Chemical Carcinogenesis.

Ann Surg 2020 Nov 12. Epub 2020 Nov 12.

Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.

Objective: To determine the associations of pancreatobiliary maljunction (PBM) in the West.

Background: PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBC), attributed to reflux of pancreatic enzymes.

Methods: Radiologic images of 840 patients in the U.S. who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan.

Results: Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs. 6.5% in non-PBM GBCs; p = 0.01); were uncommonly associated with gallstones (14% vs. 58%; p < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs. 44%; p = 0.04); arose more often through adenoma-carcinoma sequence (31% vs. 12%; p = 0.02); and had a higher proportion of non-conventional carcinomas (21% vs. 7%; p = 0.03).

Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.
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http://dx.doi.org/10.1097/SLA.0000000000004482DOI Listing
November 2020

Acinar cell induced autolysis is a frequent occurrence in CytoLyt-fixed pancreatic fine needle aspiration specimens: An analysis of 157 cytology samples.

Cancer Cytopathol 2021 Apr 2;129(4):283-290. Epub 2020 Nov 2.

Department of Pathology, Emory University Hospital, Atlanta, Georgia.

Background: Although 10% formalin is a standard preservative in pancreatic FNAs, the effect of CytoLyt on pancreatic tissue preservation has not been systematically explored.

Methods: Smears and cell blocks from CytoLyt-fixed (CF-CBs) and formalin-fixed (FF-CBs) pancreatic FNAs were blindly reviewed without knowledge of the fixative used, and the presence of tissue/tumor autolysis was noted. Controls included FF-CBs from pancreatic FNAs, CF-CBs from nonpancreatic FNAs, and 4 pancreatic FNAs with matched CF-CBs and FF-CBs.

Results: We found that 62 of 85 (73%) pancreatic FNAs with CF-CBs showed significant autolysis, which was most pronounced in acinar cells and/or tumor cells with benign acinar cells in the background, compared with 2 of 46 (4%) FF-CBs (P < .0001) and 3 of 26 (12%) CF-CBs from nonpancreatic FNAs (73% vs 12%; P < .0001). Of the 4 pancreatic FNAs with matched CF-CBs and FF-CBs, all 4 CF-CBs showed marked autolysis versus none of the matched FF-CBs. Of the 23 (27%) pancreatic FNAs with CF-CBs that did not show autolysis, 10 had no acinar cells, and 7 had only minute tissue fragments on CB.

Conclusion: While CytoLyt is a useful fixative for nonpancreatic FNAs it is a suboptimal fixative for pancreatic FNAs and is associated with tissue/tumor autolysis in the majority of cases, influencing morphologic evaluation, and potentially immunocytochemical staining. Autolysis appears to be due to acinar enzymes whose effect is likely interrupted/inhibited by formalin fixation. Cytopathologists and cytotechnologists should be mindful of this pitfall and should avoid using CytoLyt as a fixative for pancreatic FNAs.
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http://dx.doi.org/10.1002/cncy.22378DOI Listing
April 2021

Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity.

Am J Surg Pathol 2020 12;44(12):1649-1657

Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.

Intracholecystic neoplasms (ICNs) (pyloric gland adenomas and intracholecystic papillary neoplasms, collectively also called intracholecystic papillary/tubular neoplasms) form multifocal, extensive proliferations on the gallbladder mucosa and have a high propensity for invasion (>50%). In this study, 19 examples of a poorly characterized phenomenon, mural papillary mucinous lesions that arise in adenomyomatous nodules and form localized ICNs, were analyzed. Two of these were identified in 1750 consecutive cholecystectomies reviewed specifically for this purpose, placing its incidence at 0.1%. Median age was 68 years. Unlike other gallbladder lesions, these were slightly more common in men (female/male=0.8), and 55% had documented cholelithiasis. All were characterized by a compact multilocular, demarcated, cystic lesion with papillary proliferations and mucinous epithelial lining. The lesions' architecture, distribution, location, and typical size were suggestive of evolution from an underlying adenomyomatous nodule. All had gastric/endocervical-like mucinous epithelium, but 5 also had a focal intestinal-like epithelium. Cytologic atypia was graded as 1 to 3 and defined as 1A: mucinous, without cytoarchitectural atypia (n=3), 1B: mild (n=7), 2: moderate (n=2), and 3: severe atypia (n=7, 3 of which also had invasive carcinoma, 16%). Background gallbladder mucosal involvement was absent in all but 2 cases, both of which had multifocal papillary mucosal nodules. In conclusion, these cases highlight a distinct clinicopathologic entity, that is, mural ICNs arising in adenomyomatous nodules, which, by essentially sparing the "main" mucosa, not displaying "field-effect/defect" phenomenon, and only rarely (16%) showing carcinomatous transformation, are analogous to pancreatic branch duct intraductal papillary mucinous neoplasms.
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http://dx.doi.org/10.1097/PAS.0000000000001603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658044PMC
December 2020

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Mod Pathol 2021 01 12;34(1):4-12. Epub 2020 Oct 12.

Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.
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http://dx.doi.org/10.1038/s41379-020-00683-9DOI Listing
January 2021

Löwenstein-Buschke: Clinicopathologic Analysis of 78 Cases of Large and Giant Condyloma Acuminata of the Anus.

Turk Patoloji Derg 2021 ;37(1):18-25

Department of Pathology, Koç University Hospital, ISTANBUL, TURKEY.

Objective: The nature and clinicopathologic associations of Löwenstein-Buschke disease are unclear.

Materials And Methods: 78 anal condylomatous lesions (≥2 cm) were analyzed. Cases were classified based on size as "medium-large"(2-5 cm, n=59), "large" (5-10 cm, n=13) and "giant" ( > 10 cm, n=6).

Results: Patients were predominantly males (male/female=70/8). The mean age was 38 years (range:20-66). Two distinct lining types were recognized: 1) Epidermal type, typically lacking overt koilocytotic change, with associated invasive carcinoma in 8%; 2) Mucosal type, often manifesting koilocytotic change, with associated invasive carcinoma in 21%. Three types of high-grade dysplasia were discerned: 1) Basaloid, 8/9 showing high-grade dysplasia/carcinoma in-situ but non-invasive lesions; 2) Keratinizing, innocuous-appearing, but 5/6 was associated with invasion; 3) Giant cell, showing scattered individual bizarre cells, with 3/5 showing invasive carcinoma. Overall, invasion was found in 14% of the cases. The bulbous, broad-based destructive pattern characterizing verrucous carcinomas of the upper aerodigestive tract was not observed. A statistically significant trend existed between the incidence of invasion and size: 8.5% for medium-large, 23% for large, and 50% for giant (p=0.02). There was no discernable trend in the depth of invasion relative to condyloma size.

Conclusions: Our findings suggest that Löwenstein-Buschke lesions are mega versions of conventional condyloma. Being verrucoid, large and minimally invasive, they can be conceptually regarded as a form of verrucous carcinoma, but they do not display the histologic characteristics of verrucous carcinoma defined in the aerodigestive tract. They exhibit two types of linings: the mucosal type that often shows koilocytotic changes, and the epidermal type that can be difficult to recognize in biopsies. These lesions may be associated with invasive carcinoma, albeit limited in amount.
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http://dx.doi.org/10.5146/tjpath.2020.01508DOI Listing
January 2021

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

PLoS One 2020 11;15(9):e0237979. Epub 2020 Sep 11.

Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485812PMC
October 2020

Molecular and Immunohistochemical Analysis of Mucinous Cystic Neoplasm of the Liver.

Am J Clin Pathol 2020 11;154(6):837-847

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.

Objectives: Mucinous cystic neoplasm of the liver is characterized by neoplastic mucinous and/or biliary epithelium surrounded by ovarian-type stroma. Immunohistochemical studies have shown that the ovarian-type stroma expresses estrogen receptor, suggesting potential hormonal responsiveness. The molecular biology of mucinous cystic neoplasm of the liver remains poorly studied.

Methods: Transcriptome sequencing and immunohistochemistry were performed on a series of mucinous cystic neoplasms.

Results: Mucinous cystic neoplasm of the liver exhibited significantly increased RNA expression of ovarian stromal markers WT1, PR, and ER2 and sex cord stromal markers SF-1, inhibin-α, and calretinin compared with nonneoplastic liver. Immunohistochemistry confirmed the RNA-level data. Evidence for sex hormone biosynthesis was identified by significant overexpression of multiple estrogen biosynthetic enzymes. Expression of 17β-hydroxysteroid dehydrogenase 1 was confirmed immunohistochemically. Pathway analysis also identified significant upregulation of the hedgehog and Wnt pathways and significant downregulation of T-helper 1 and T-helper 2 pathways.

Conclusions: Mucinous cystic neoplasm of the liver recapitulates ovarian stroma at the morphologic, DNA, RNA, and protein levels. These data support the concept that this tumor likely arises from ectopic primitive gonadal tissue and/or stromal cells with capacity to transdifferentiate to ovarian cortical cells.
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http://dx.doi.org/10.1093/ajcp/aqaa115DOI Listing
November 2020

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

Cancer 2020 Nov 28;126(21):4788-4799. Epub 2020 Aug 28.

Department of Pathology, Koç University School of Medicine, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1002/cncr.33135DOI Listing
November 2020

Genomic characterization of malignant progression in neoplastic pancreatic cysts.

Nat Commun 2020 08 14;11(1):4085. Epub 2020 Aug 14.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.
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http://dx.doi.org/10.1038/s41467-020-17917-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428044PMC
August 2020

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

Virchows Arch 2021 Mar 20;478(3):435-447. Epub 2020 Jul 20.

Department of Pathology, Koç University Hospital, Davutpasa Caddesi No:4, Topkapi, 34010, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1007/s00428-020-02877-7DOI Listing
March 2021

Pancreatic neuroendocrine neoplasms: current state and ongoing controversies on terminology, classification and prognostication.

J Gastrointest Oncol 2020 Jun;11(3):548-558

Department of Pathology, Koç University Hospital, Istanbul, Turkey.

Significant improvements have taken place in our understanding of classification neuroendocrine neoplasms of the pancreas in the past decade. These are now regarded in three entirely separate categories: (I) neuroendocrine tumors (PanNETs) are by definition well differentiated, the pancreatic counterpart of carcinoids; (II) neuroendocrine carcinomas, which are poorly differentiated (PDNEC), the pancreatic examples of small cell carcinomas or large cell neuroendocrine carcinomas; (III) other neoplasms that have neuroendocrine differentiation or a distinct neuroendocrine component. PanNETs are by far the most common. They are now regarded as malignancies (albeit often curable when low grade and low stage) with the exception of minute incidental proliferations (tumorlets, or dysplastic-like changes) seen in the setting of some syndromes like MEN. PanNETs are staged based on their size, and for small T1 tumors, watchful waiting is now being considered, although these tumors are also known to show about 10% metastatic rate and/or progression, creating concerns about this approach. PanNETs are graded into 3, based on the proliferative activity, mostly based on the Ki-67 index, and also partly mitotic activity, although the latter seldom if ever is the determinant of the final grade. Neuroendocrine neoplasms with well differentiated morphology but Ki-67 >20% are now regarded as PanNET Grade 3 (G3); they have been shown to have a prognosis significantly worse than lesser grade PanNETs but still incomparably better than frank PDNECs, the latter typically has Ki-67 >50% (often much higher) and require platinum-based chemotherapy. There are also cases that are ambiguous between PanNET-G3 and PDNEC, and very rarely transformation of the former to the latter appears to occur. For low grade (G1/G2) PanNETs, more refined criteria to further prognosticate this group are needed. Morphologic variants being recognized may bring new perspectives to this group.
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http://dx.doi.org/10.21037/jgo.2020.03.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340800PMC
June 2020

Morphologic Variants of Pancreatic Neuroendocrine Tumors: Clinicopathologic Analysis and Prognostic Stratification.

Endocr Pathol 2020 Sep;31(3):239-253

Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Davutpaşa Caddesi No: 4, Topkapı, 34010, Istanbul, Turkey.

Better prognostication/stratification of pancreatic neuroendocrine tumors (PanNETs) is needed. In this detailed morpheomic study of 163 resected PanNETs, 11 unusual variants, some of which were not previously recognized, and others scarcely documented in the literature, were identified, and their pathologic characteristics were further analyzed. By behavior and clinicopathologic associations, these variants could be grouped into three prognostically different categories. I. More aggressive (20%). Included in this group were the variants that in average showed higher grade and stage and adverse outcome including oncocytic, plasmacytoid, lipid-rich and previously unrecognized hepatoid variants, which often had a more diffuse/broad-band growth pattern, with some also displaying discohesiveness. They were characterized by abundant cytoplasm and often had prominent nucleoli (as seen in metabolically active cells), thus the provisional name "metabolic cell phenotype." Because of their diversion from classical neuroendocrine cytomorphology, these variants created challenges on original diagnostic workup, particularly hepatoid examples, which revealed Arginase 1/Hep Par-1 expression in 50%. II. Less aggressive (10%). These cases either showed signs of maturation, including nested growth, paraganglioid pattern (which was previously unrecognized), and organoid PanNETs such as "ductulo-insular" growth, or showed symplastic/degenerative changes, and despite their paradoxically disconcerting histology, were more benevolent in behavior. III. Undetermined. There were other variants including mammary tubulolobular-like, pseudoglandular, peliotic, and sclerotic PanNETs, which although diagnostically challenging, their biologic significance could not be determined because of rarity or heterogeneous characteristics. Prognostic associations: Features that were significantly different in the more aggressive group than the less aggressive group were median size (5.0 vs 1.6 cm, p < 0.001), percentage of pT3+T4 cases (72% vs 12%, p < 0.001), Ki67 index (5.3% vs 2.3%, p = 0.001), % G2 and G3 cases (77% vs 27%, p < 0.001), and rate of lymph node and distant metastasis (96% vs 27%, p < 0.001). In stepwise logistic regression model using the 3 established prognosticators of T stage, size, and grade along with morphology, only aggressive-morphology (metabolic cell phenotype) was found to be associated with metastatic behavior with an odds ratio of 5.9 with 95% confidence interval (C.I.) 1.688 to 22.945 and p value 0.007. In conclusion, PanNETs display various morphologic patterns that are not only challenging and important diagnostically but appear to have biologic significance. Tumors with more diffuse growth of cells with nucleoli and abundant cytoplasm and/or discohesion (oncocytic, hepatoid, lipid-rich, plasmacytoid PanNETs), provisionally termed "metabolic cell phenotype," show aggressive characteristics and are an independent determinant of adverse outcome and thus may require closer post-surgical follow-up, whereas variants with more degenerative or mature features (ductuloinsular, pleomorphic, paraganglioma-like) appear to be more benevolent despite their more atypical and worrisome morphology.
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http://dx.doi.org/10.1007/s12022-020-09628-zDOI Listing
September 2020

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

Int J Surg Pathol 2020 Dec 18;28(8):826-834. Epub 2020 May 18.

52979Koc University, Istanbul, Turkey.

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, = .77). When the 39 FC in nonneoplastic GBs contrasted with ordinary chronic cholecystitis, they were associated with older age (68 vs 49 years, < .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/ infection. Of 17 cases who had undergone gastric biopsy, 5 had chronic gastritis (2 with ). 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.
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http://dx.doi.org/10.1177/1066896920924079DOI Listing
December 2020

Guidelines on the histopathology of chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and the European Pancreatic Club.

Pancreatology 2020 Jun 29;20(4):586-593. Epub 2020 Apr 29.

Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK. Electronic address:

Background: Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP).

Methods: An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated.

Results: Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP.

Conclusions: Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.
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http://dx.doi.org/10.1016/j.pan.2020.04.009DOI Listing
June 2020

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications.

Gut 2021 Jan 29;70(1):148-156. Epub 2020 Apr 29.

ARC-Net Research Center and Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.

Objective: Recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC).

Design: PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project).

Results: Overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%-2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a / wild-type molecular background (p<0.01), with more common genes mutations. Data on survival are still unclear.

Conclusion: PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.
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http://dx.doi.org/10.1136/gutjnl-2020-320726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211065PMC
January 2021

Pathologic Evaluation of Large Colorectal Endoscopic Submucosal Dissections: An Analysis of 279 Cases With Emphasis on the Importance of Multidisciplinary Work and Establishing Examination Protocols.

Int J Surg Pathol 2020 Sep 29;28(6):600-608. Epub 2020 Apr 29.

Department of Pathology, Koç University Hospital, Istanbul, Turkey.

Endoscopic submucosal dissections (ESDs) allow removal of large gastrointestinal tumors and help patients avoid major oncologic surgery. In this study, the challenges and development of approaches toward successfully handling ESDs were analyzed in 279 colorectal specimens (114 rectal, 47 left, 118 right colonic; 90% adenoma with/without carcinoma). Each specimen was processed according to an established protocol including gross photography, mapping, and total submission for histopathologic examination. Mean lesion size was 4.2 cm (range: 0.5-22 cm; 28% ≥5 cm; 6% ≥10 cm). Invasive carcinoma was present in 38 cases (14%), which had a mean overall tumor size of 3.8 cm (range: 1.1-17.5 cm), and mean largest size of the invasive component was 0.93 cm (range: 0.04-3 cm). Fifteen cases were staged as pT1a (submucosal invasion of <1000 µm) and 13 cases as pT1b (submucosal invasion of ≥1000 µm). En-bloc and R0 resection rates were 99.3% and 90.6%, respectively. Various histopathologic challenges were encountered, which were carefully evaluated by dedicated pathologists with familiarity to the subtleties in handling and reporting these specimens. We recommend these specimens to be prepared in the endoscopy suite, submitted to the Pathology Department oriented, pinned, and placed into copious amount of fixative. Total sampling, gross photography, mapping, and proper fixation are crucial components in the histopathologic evaluation. Micromeasurement of invasion depth and substaging per European/Japanese guidelines as well as accurate measurement of the distance from the resection margins are highly recommended. In conclusion, ESD is an adequate method that can be successfully implemented in a tertiary care center to perform en-bloc and margin-free resections of clinically selected large colorectal superficial lesions.
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http://dx.doi.org/10.1177/1066896920918309DOI Listing
September 2020

Variant anatomy of the biliary system as a cause of pancreatic and peri-ampullary cancers.

HPB (Oxford) 2020 Dec 24;22(12):1675-1685. Epub 2020 Apr 24.

Department of Pathology, Koç University Hospital, Istanbul, Turkey; Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey. Electronic address:

Background: The cause of most pancreatic and periampullary cancers (PAC) is unknown. Recently, anatomic variations such as pancreatobiliary maljunction have been recognized as risk factors, similar to Barrett-related gastro-esophageal cancers.

Methods: Pre-operative MRI from 860 pancreatic/biliary resections, including 322 PACs, were evaluated for low-union (cystic duct joining the common hepatic duct inside of the pancreas or within 5 mm of the pancreatic border) RESULTS: Low-union, seen <10% of the population, was present in 44% of PACs (73% distal bile duct/cholangiocarcinoma, 42% pancreatic head, and 34% ampullary). It was significantly lower(11%) in conditions without connection to the ductal system (thus not exposed to the ductal/biliary tract contents), namely mucinous cystic neoplasms and intrahepatic cholangiocarcinomas(p < 0.0001). Intra-pancreatic type low-union was seen in 16% of PACs versus 2% of controls(p < 0.0001).

Discussion: This study establishes an association between low-union and PACs, and points to an anatomy-induced chemical/bilious carcinogenesis. This may explain why most pancreas cancers are in the head. It is possible that the same chemical milieu, caused by conditions other than low-union/insertion, may also play a role in the remaining half of PACs. This opens various treatment opportunities including milieu modifications (chemoprevention), focused screening of at-risk patients, and early detection with possible corrective actions.
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http://dx.doi.org/10.1016/j.hpb.2020.03.014DOI Listing
December 2020

Clinicopathologic and immunohistochemical characteristics of upper gastrointestinal leiomyomas harboring interstitial cells of Cajal: A potential mimicker of gastrointestinal stromal tumor.

Ann Diagn Pathol 2020 Apr 5;45:151476. Epub 2020 Feb 5.

Koç University Hospital, Department of Pathology, Turkey.

Objective: To analyze clinicopathologic characteristics of upper gastrointestinal leiomyomas and to determine the distribution and immunohistochemical features of interstitial cells of Cajal, in order to designate whether they can cause diagnostic challenges.

Materials And Methods: Twenty-four upper gastrointestinal leiomyomas (14 esophagus, 10 stomach) were retrieved. CD117, DOG-1 and muscle markers were performed. The staining was analyzed based on the distribution and percentage. Interstitial cells of Cajal were distinguished based on their positivity for both CD117 and DOG-1 immunohistochemistry, along with their morphological features.

Results: Mean age of patients was 49 years, M/F ratio was 2.4. Patients with gastric leiomyomas were significantly younger than those with esophageal leiomyomas (41.5 vs. 54.3, p = 0.012). Histologically, leiomyomas were similar to their endometrial counterpart. Immunohistochemically, all tumors had strong/diffuse positivity for muscle markers. CD117 highlighted mast cells in all cases. Three cases had prominently increased mast cells. Both CD117 and DOG-1 also highlighted interstitial cells of Cajal in 24/24 (100%) of cases. Interstitial cells of Cajal were distributed in variable proportions, from focal to homogenous. In one case, they constituted 50% of tumor cells. In 16 cases, the distribution was homogenous. Superficial leiomyomas (n = 3) had only focal CD117 and DOG-1 positivity.

Conclusion: Upper gastrointestinal leiomyomas harbor expression of CD117 and DOG-1 in entrapped/colonized interstitial cells of Cajal, which can cause a potential pitfall in the differential diagnosis, especially in cases that show prominent immunohistochemical positivity. Evaluation of the immunohistochemistry can be exceptionally challenging in small biopsy/cytology specimens. Careful histologic evaluation of the tumor as well as the recognition of interstitial cells of Cajal will help the pathologist render the accurate diagnosis.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151476DOI Listing
April 2020

Gallbladder and extrahepatic bile duct cancers in the Americas: Incidence and mortality patterns and trends.

Int J Cancer 2020 08 21;147(4):978-989. Epub 2020 Jan 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Trends in gallbladder cancer incidence and mortality in populations across the Americas can provide insight into shifting epidemiologic patterns and the current and potential impact of preventative and curative programs. Estimates of gallbladder and extrahepatic bile duct cancer incidence and mortality for the year 2018 were extracted from International Agency for Research on Cancer (IARC) GLOBOCAN database for 185 countries. Recorded registry-based incidence from 13 countries was extracted from IARCs Cancer Incidence in Five Continents series and corresponding national deaths from the WHO mortality database. Among females, the highest estimated incidence for gallbladder and extrahepatic bile duct cancer in the Americas were found in Bolivia (21.0 per 100,000), Chile (11.7) and Peru (6.0). In the US, the highest incidence rates were observed among Hispanics (1.8). In the Chilean population, gallbladder cancer rates declined in both females and males between 1998 and 2012. Rates dropped slightly in Canada, Costa Rica, US Whites and Hispanics in Los Angeles. Gallbladder cancer mortality rates also decreased across the studied countries, although rising trends were observed in Colombia and Canada after 2010. Countries within Southern and Central America tended to have a higher proportion of unspecified biliary tract cancers. In public health terms, the decline in gallbladder cancer incidence and mortality rates is encouraging. However, the slight increase in mortality rates during recent years in Colombia and Canada warrant further attention. Higher proportions of unspecified biliary tract cancers (with correspondingly higher mortality rates) suggest more rigorous pathology procedures may be needed after surgery.
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http://dx.doi.org/10.1002/ijc.32863DOI Listing
August 2020

Pathologic Evaluation of Endoscopically Resected Non-Ampullary Duodenal Lesions: A Single Center Experience.

Turk Patoloji Derg 2020 ;36(2):109-115

Departments of Pathology, Koç University Hospital, ISTANBUL, TURKEY.

Objective: Endoscopic resections are increasingly being used for superficial gastrointestinal lesions. However, application of these techniques in the duodenum remains challenging, due to the technical difficulties and high complication rates. This study projects a western tertiary center's experience in the endoscopic treatment and diagnostic workup of 19 cases of non-ampullary duodenal lesions.

Material And Method: Specimens (12 endoscopic mucosal resections, 6 endoscopic submucosal dissections, and one endoscopic full-thickness resection) were processed following a strict protocol (photographed, mapped digitally and submitted totally) for histopathologic examination. Clinicopathologic characteristics, margin status and follow-up information were analyzed.

Results: The mean age of the 16 patients was 52 years (range: 22-81). Mean lesion size was 1.4 cm (range: 0.3-3.6 cm) for all cases, 2 cm for endoscopic submucosal dissections and 1.1 cm for endoscopic mucosal resections. Mean number of blocks submitted was 4/case. Seven neuroendocrine tumors, 3 tubulovillous adenomas were diagnosed along with nine benign lesions. For endoscopic submucosal dissections, en-bloc and R0 resection rates were 100% (n=6/6) and 83% (n=5/6); for endoscopic mucosal resections, they were 92% (n=11/12) and 83% (n=10/12), respectively. Only one patient had procedure-related late perforation that was managed endoscopically. No mortality was encountered.

Conclusion: Duodenal endoscopic resections proved successful, safe and feasible methods in a tertiary center. The pathologist's role is to designate the accurate diagnosis, related histopathologic parameters and margin status. The gross protocol was found to be essential in evaluating specimen margins and orientation, as well as in size measurement. We recommend following a standardized approach including gross photography and digital mapping when handling these specimens, for both diagnostic and data collection purposes.
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http://dx.doi.org/10.5146/tjpath.2019.01474DOI Listing
March 2021

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

Am J Surg Pathol 2020 04;44(4):467-476

Department of Pathology, Koç University Hospital.

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.
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http://dx.doi.org/10.1097/PAS.0000000000001405DOI Listing
April 2020

Poorly Cohesive (Signet Ring Cell) Carcinoma of the Ampulla of Vater.

Int J Surg Pathol 2020 May 15;28(3):236-244. Epub 2019 Oct 15.

Koç University, Istanbul, Turkey.

In the ampulla of Vater, carcinomas with "diffuse-infiltrative"/"signet ring cell" morphology, designated as "poorly cohesive carcinoma" (PCC) in the WHO classification, are very rare and poorly characterized. Nine cases with a classical PCC morphology constituting >50% of the tumor were identified. Mean age was 64.8 years (vs 64.6 in ampullary carcinomas [ACs]) and 6 were males, 3 females. The mean invasive tumor size was 2.5 cm (vs 1.9 in ACs). Other morphologic patterns displayed included cord-like infiltration (n=2), plasmacytoid cells (n=2), and microglandular component (n=4), including goblet cell adenocarcinoma-like foci. None of the cases were associated with dysplasia. By immunohistochemistry, the carcinomas did not show intestinal differentiation (CDX2 0/9, CK20 1/9, MUC2 3/9), MUC1 was positive in 4/9, MUC5AC was positive in 7/8. E-cadherin loss was noted in 4/9. All cases were advanced stage (6/9-pT3, 3/9-pT4) (vs 43% in ACs). Lymph node metastases were identified in 44% (vs 45% in AC). Six patients (67%) died of disease at a median of 25 months, 3 were alive at 13, 15, and 60 months. Overall median survival was significantly worse than that of intestinal-type ACs (26 vs 122 months, = .006) and trended toward worse than pancreatobiliary type (26 vs 42 months, = .1). In conclusion, PCCs constitute 2.45% of all ACs. These present as advanced tumors and express upper-gastrointestinal immunoprofile with frequent MUC5AC labeling, which may be helpful in identifying subtle infiltration in the surface mucosa since MUC5AC is not expressed in the ampullary mucosa. Patients have poor prognosis.
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http://dx.doi.org/10.1177/1066896919880968DOI Listing
May 2020

Pancreatoblastoma: Cytologic and histologic analysis of 12 adult cases reveals helpful criteria in their diagnosis and distinction from common mimics.

Cancer Cytopathol 2019 Nov 3;127(11):708-719. Epub 2019 Oct 3.

Department of Pathology, Koç University Hospital, Istanbul, Turkey.

Background: Pancreatoblastoma (PBL) is a rare malignant pancreatic tumor seen predominantly in childhood, and its cytologic diagnosis remains challenging.

Methods: Twelve fine-needle-aspirations from 11 adults were analyzed.

Results: In total, 6 men and 5 women (median age, 45 years; age range, 32-60 years) had tumors measuring a median 5.6 cm (range, 2.5-12 cm) located in the pancreatic head (n = 7) or tail (n = 4), including 3 with familial adenomatous polyposis (FAP)/FAP-related syndromes and 4 with metastasis at diagnosis. The median follow-up was 39.8 months (range, 0.8-348 months), and 5 patients died of disease. The original cytology diagnoses were: PBL (n = 2), neuroendocrine neoplasm (n = 2), poorly differentiated neuroendocrine carcinoma (n = 2), well differentiated neuroendocrine tumor (n = 1), poorly differentiated carcinoma (n = 2), "positive for malignancy" (n = 1), acinar cell carcinoma (n = 1), and epithelioid neoplasm with endocrine and acinar differentiation versus PBL (n = 1). Universal cytopathologic findings included hypercellularity; 3-dimensional clusters; and single, monotonous, blast-like cells that were from 1.5 to 2.0 times the size of red blood cells with high nuclear-to-cytoplasmic ratio, fine chromatin, small, distinct nucleoli, and a resemblance to well differentiated neuroendocrine tumor and poorly differentiated neuroendocrine carcinoma. Branching pseudopapillae (n = 7) and grooved nuclei (n = 3) raised the differential diagnosis of solid-pseudopapillary neoplasm, but with more atypia. Uncommon features included pleomorphism (n = 4) and numerous mitoses (n = 1). Squamoid morules were seen on smears (n = 5) or cell blocks (n = 6) in 70% of patients and were characterized by epithelioid cells with elongated, streaming nuclei, fine chromatin, absent nucleoli, and positive nuclear β-catenin (n = 6 of 8). The median Ki-67 index was 21% (range, 2%-70%), and neuroendocrine marker expression was common (100%), but acinar markers were variable (63%).

Conclusions: A combination of cytologic findings in PBL, including a predominant population of primitive blast-like cells, subtle squamoid morules, frequent neuroendocrine and variable acinar phenotype, should facilitate accurate cytologic diagnosis and distinction from common mimics.
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http://dx.doi.org/10.1002/cncy.22187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484954PMC
November 2019

Response to: 'The efficacy and safety of endoscopic ultrasound-guided ablation of pancreatic cysts with alcohol and paclitaxel: a systematic review'.

Eur J Gastroenterol Hepatol 2019 11;31(11):1475

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA.

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http://dx.doi.org/10.1097/MEG.0000000000001489DOI Listing
November 2019

Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples.

Cancer Cytopathol 2019 Nov 13;127(11):691-699. Epub 2019 Sep 13.

Department of Pathology, Emory University Hospital, Atlanta, Georgia.

Background: Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs).

Methods: The pathology archives of 5 institutions were searched for BDBs with HCC involvement.

Results: A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5 years (range, 22-80 years). The median hepatic tumor size was 6.2 cm (range, 2.2-13.0 cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5 months.

Conclusions: HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.
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http://dx.doi.org/10.1002/cncy.22185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482131PMC
November 2019

Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity.

Mod Pathol 2020 03 5;33(3):456-467. Epub 2019 Aug 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of "sclerosing epithelioid mesenchymal neoplasm" of the pancreas.
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http://dx.doi.org/10.1038/s41379-019-0334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000300PMC
March 2020