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Browsing by Author "Koshiol, Jill"

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Adenomyomas of the Gallbladder An Analysis of Frequency, Clinicopathologic Associations, and Relationship to Carcinoma of a Malformative Lesion
(2024) Dursun, Nevra; Memis, Bahar; Pehlivanoglu, Burcin; Taskin, Orhun Cig; Okcu, Oguzhan; Akkas, Gizem; Bagci, Pelin; Balci, Serdar; Saka, Burcu; Araya, Juan Carlos; Bellolio, Enrique; Roa, Juan Carlos; Jang, Kee-Taek; Losada, Hector; Maithel, Shishir K.; Sarmiento, Juan; Reid, Michelle D.; Jang, Jin-Young; Cheng, Jeanette D.; Basturk, Olca; Koshiol, Jill; Adsay, N. Volkan
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, flattype 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.
Association of Aflatoxin and Gallbladder Cancer
(2017) Koshiol, Jill; Gao, Yu-Tang; Dean, Michael; Egner, Patricia; Nepal, Chirag; Jones, Kristine; Wang, Bingsheng; Rashid, Asif; Luo, Wen; Ferreccio Readi, Catterina; Van Dyke, Alison; Malasky, Michael; Shen, Ming-Chang; Zhu, Bin; Andersen, Jesper B.; Hildesheim, Allan; Hsing, Ann W.; Groopman, John
Association of Aflatoxin with Gallbladder Cancer in Chile
(2015) Nogueira, Leticia; Foerster, Claudia; Groopman, John; Egner, Patricia; Koshiol, Jill; Ferreccio Readi Fresia Catterina
In Chile, gallbladder cancer is a leading cause of cancer death in women. Other than gallstones, gallbladder cancer etiology remains largely unclear. Exposure to aflatoxin, a liver carcinogen, is associated with bile duct epithelium proliferation in both animals and humans, and with gallbladder cancer in primates. Aflatoxin contamination has been identified in Chile, including in ají rojo (red chili peppers). Ají rojo is associated with gallbladder cancer; however, the association of aflatoxin with gallbladder cancer in humans has not been directly evaluated.
Association of inflammatory and other immune markers with gallbladder cancer: Results from two independent case-control studies
(2016) Koshiol, Jill; Castro, Felipe; Kemp, Troy J.; Gao, Yu-Tang; Carlos Roa, Juan; Wang, Bingsheng; Nogueira, Leticia; Carlos Araya, Juan; Shen, Ming-Chang; Rashid, Asif; Hsing, Ann W.; Hildesheim, Allan; Ferreccio, Catterina; Pfeiffer, Ruth M.; Pinto, Ligia A.
Most gallbladder cancer (GBC) cases arise in the context of gallstones, which cause inflammation, but few gallstone patients develop GBC. We explored inflammation/immune-related markers measured in bile and serum in GBC cases compared to gallstone patients to better understand how inflammatory patterns in these two conditions differ. We measured 65 immune-related markers in serum and bile from 41 GBC cases and 127 gallstone patients from Shanghai, China, and calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for GBC versus gallstones. We then focused on the markers that were significantly elevated in bile and serum to replicate the findings in serum from 35 GBC cases and 31 gallstone controls from Chile. Comparing the highest versus lowest quantile, 15 markers (23%) were elevated in both serum and bile from GBC versus gallstone patients in the Shanghai study (p <0.05). The strongest OR was for CXCL8 (interleukin-8) in serum (96.8, 95% CI: 11.9-790.2). Of these 15 markers, 6 were also significantly elevated in serum from Chile (CCL20, C -reactive protein, CXCL8, CXCL10, resistin, serum amyloid A). Pooled ORs from Shanghai and Chile for these 6 markers ranged from 7.2 (95% CI: 2.8-18.4) for CXCL10 to 58.2 (95% CI: 12.4-273.0) for CXCL8. GBC is associated with inflammation above and beyond that generated by gallstones alone. This local inflammatory process is reflected systemically. Future longitudinal studies are needed to identify the key players in cancer development, which may guide translational efforts to identify individuals at high risk of developing GBC. Published by Elsevier Ltd.
Distribution of dysplasia and cancer in the gallbladder : an analysis from a high cancer-risk population
(2018) Koshiol, Jill; Bellolio, Enrique; Vivallo, Carolina; Cook, María Paz; McGee, Emma E.; Losada, Héctor; Van Dyke, Alison L.; Van De Wyngard, Vanessa; Prado, Rodrigo; Villaseca, Miguel; Riquelme, Pía; Acevedo, Johanna; Olivo, Vanessa; Pettit, Karen; Hildesheim, Allan; Medina, Karie; Memis, Bahar; Adsay, Volkan; Ferreccio Readi, Catterina; Araya, Juan Carlos
Follicular Cholecystitis: Reappraisal of Incidence, Definition, and Clinicopathologic Associations in an Analysis of 2550 Cholecystectomies
(SAGE PUBLICATIONS INC, 2020) Saka, Burcu; Memis, Bahar; Seven, Ipek Erbarut; Pehlivanoglu, Burcin; Balci, Serdar; Bagci, Pelin; Reid, Michelle; Dursun, Nevra; Tapia Escalano, Oscar; Carlos Roa, Juan; Carlos Araya, Juan; Kong, So Yeon; Basturk, Olca; Koshiol, Jill; Adsay, N. Volkan
Context.
Gallbladder cancer
(2022) Roa, Juan C.; Garcia, Patricia; Kapoor, Vinay K.; Maithel, Shishir K.; Javle, Milind; Koshiol, Jill
Gallbladder cancer is the most common cancer of the biliary tract and often has a very poor prognosis. This Primer by Roa and colleagues summarizes the epidemiology, mechanisms, diagnosis and treatment of gallbladder cancer, and discusses patient quality of life and open research questions for this disease.
Gallbladder cancer mortality in Chile: Has the government program targeting young gallstone patients had an impact?
(2024) Cid, Vicente; Vargas, Claudio; Delgado, Iris; Apablaza, Mauricio; Shiels, Meredith S.; Hildesheim, Allan; Koshiol, Jill; Ferreccio, Catterina
Inflammatory profiles in Chilean Mapuche and non-Mapuche women with gallstones at risk of developing gallbladder cancer
(2021) Jackson, Sarah S.; Van De Wyngard, Vanessa; Pfeiffer, Ruth M.; Cook, Paz; Hildesheim, Allan; Pinto, Ligia A.; Jackson, Sharon H.; Choi, Kelvin; Verdugo, Ricardo A.; Cuevas, Mara; Yanez, Cristian; Tobar-Calfucoy, Eduardo; Retamales-Ortega, Rocio; Araya, Juan Carlos; Ferreccio, Catterina; Koshiol, Jill
Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P=0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P=0.03 and P<0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.
Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes
(2021) Nepal, Chirag; Zhu, Bin; O'Rourke, Colm J.; Bhatt, Deepak Kumar; Lee, Donghyuk; Song, Lei; Wang, Difei; Van Dyke, Alison L.; Choo-Wosoba, Hyoyoung; Liu, Zhiwei; Hildesheim, Allan; Goldstein, Alisa M.; Dean, Michael; LaFuente-Barquero, Juan; Lawrence, Scott; Mutreja, Karun; Olanich, Mary E.; Bermejo, Justo Lorenzo; Ferreccio, Catterina; Roa, Juan Carlos; Rashid, Asif; Hsing, Ann W.; Gao, Yu-Tang; Chanock, Stephen J.; Araya, Juan Carlos; Andersen, Jesper B.; Koshiol, Jill
Background & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival. Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases. Results: Exome analysis revealed TP53was themostmutated gene. The overallmutation ratewas low(median 0.82Mut/Mb). APOBECmediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in >-50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features. Conclusion: These data suggest that the tumour microenvironment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Lay summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Non-steroidal anti-inflammatory drug use and inflammatory markers associated with gallbladder dysplasia: A case-control analysis within a series of patients undergoing cholecystectomy
(2024) Rosa, Lorena; Cook, Paz; Pfeiffer, Ruth M.; Kemp, Troy J.; Hildesheim, Allan; Pehlivanoglu, Burcin; Adsay, Volkan; Bellolio, Enrique; Araya, Juan Carlos; Pinto, Ligia; Ferreccio, Catterina; Aguayo, Gloria; Vinuela, Eduardo; Koshiol, Jill
Inflammation has been associated with the development of gallbladder cancer (GBC). However, little is known about the associations of both, inflammation and the use of non-steroidal anti-inflammatory drugs (NSAIDs), with preneoplastic lesions. We analyzed the association of NSAIDs and gallbladder dysplasia in 82 patients with dysplasia and 1843 patients with gallstones among symptomatic patients from a high-risk population. We also analyzed associations for 33 circulating immune-related proteins in a subsample of all 68 dysplasia cases diagnosed at the time of sample selection and 136 gallstone controls. We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Biliary colic was reported among most cases (97.6%) and controls (83.9%). NSAID use was inversely associated with gallbladder dysplasia (OR: 0.48, 95%CI: 0.26-0.83). Comparing the highest versus lowest category of each immune-related protein, eight proteins were inversely associated with dysplasia with sex- and age-adjusted ORs ranging from 0.30 (95%CI: 0.12-0.77) for IL-33 to 0.76 (95%CI: 0.59-0.99) for MIP-1B. Of those, GRO remained associated with dysplasia (OR: 0.64, 95%CI: 0.45-0.91) and BCA-1 was borderline associated (OR: 0.74, 95%CI: 0.54-1.01) after adjusting the logistic regression model for sex, age, and NSAIDs. In conclusion, NSAID users were less likely to have gallbladder dysplasia, suggesting that NSAIDs might be beneficial for symptomatic gallstones patients. The inverse association between immune-related markers and dysplasia requires additional research, ideally in prospective studies with asymptomatic participants, to understand the role of the inflammatory response in the natural history of GBC and to address the biological effect of NSAIDs.
Salmonella enterica serovar Typhi and gallbladder cancer : a case control study and meta-analysis
(2016) Koshiol, Jill; Wozniak Banchero, Aniela; Cook, María Paz; Adaniel, Christina; Acevedo, Johanna; Azócar, Lorena; Roa Strauch, Juan Carlos Enrique; Miquel P., Juan Francisco; Ferreccio Readi, Catterina; Díaz, Alfonso; Molina, Héctor; Miranda, Carolina; Castillo, Claudia
Sex disparities in gallstone disease: insights from the MAUCO prospective population-based cohort study
(2024) Gatta, Danae Rodriguez; Huidobro, Laura; Petermann-Rocha, Fanny; Van de Wyngard, Vanessa; Godoy, Franco; Cid, Vicente; Garrido, Macarena; Cook, Paz; Roa, Juan Carlos; Vargas, Claudio; Araya, Juan Carlos; Cortes, Sandra; Cruz, Francisco; Koshiol, Jill; Arrese, Marco; Ferreccio, Catterina
Objective To investigate factors associated with the prevalence and incidence of gallstone disease (GSD) in women and men of the MAUCO population-based prospective cohort. Design 8948 MAUCO participants (aged 38-74 years) underwent abdominal ultrasound at baseline (2015-2019); 4385 received follow-up ultrasound at years 2 or 4. Factors associated with prevalent GSD were assessed using Poisson multiple regression and with incident GSD using Cox regression models. Results GSD prevalence was 40.4% in women (13.1% gallstones, 27.3% cholecystectomies) and 17.1% in men (8.9% gallstones, 8.2% cholecystectomies). In men, GSD prevalence rate ratio (PRR) by age in >64 years was 3.85 (95% CI 3.00 to 4.94), doubling that of women's PRR 1.78 (95% CI 1.57 to 2.01). In women, waist circumference and diabetes were stronger GSD factors; a higher number of children and worse metabolic and socioeconomic conditions were also highlighted. GSD men had higher cardiovascular disease and a family history of GSD and gallbladder cancer. 198 GSD cases developed during follow-up, with incidence increasing by 2% (95% CI 1.005% to 1.03%) per each centimetre above the ideal waist circumference, statistically significant only in women. In men, age was the strongest factor for incidence, followed by a family history of GSD and low high-density lipoprotein increased incidence risk. Conclusions GSD burden was high in this population; a third of women had their gallbladder removed, which may pose them at risk of other health problems. Abdominal obesity was the only preventable GSD risk factor, highlighting the need for effective public health policies promoting obesity reduction.
Statin use is not associated with inflammation among Chilean women of Mapuche and non-Mapuche ancestry with gallstones
(2024) Jackson, Sarah S.; Lex, Marina; Van De Wyngard, Vanessa; Cook, Paz; Hildesheim, Allan; Pinto, Ligia A.; Jackson, Sharon H.; Choi, Kelvin; Minas, Tsion Zewdu; Morales, Hector Fabio Losada; Araya, Juan Carlos; Ferreccio, Catterina; Koshiol, Jill; Pfeiffer, Ruth M.
Aim: Statins are associated with lower risk of gallstones due to anti-inflammatory effects. We assessed whether statins impact circulating inflammation among Chilean women with gallstones. Materials & methods: 200 Mapuche women were matched on statin use and age to 200 non-Mapuche women in the Chile Biliary Longitudinal Study. We analyzed 92 inflammatory biomarkers using multivariable-adjusted regression models, random forests and pathway analyses. Results: Statins were not significantly associated with any inflammation marker when women were analyzed jointly or stratified by ancestry. No significant associations were found through random forest methods and pathway analyses. Discussion: We did not find significant associations between statin use and inflammation markers in women with gallstones, suggesting that statins do not reduce inflammation once gallstones have formed.
Subtypes of Native American ancestry and leading causes of death: Mapuche ancestry-specific associations with gallbladder cancer risk in Chile
(2017) Bermejo, Justo Lorenzo; Boekstegers, Felix; González Silos, Rosa; Marcelain, Katherine; Báez Benavides, Pablo; Barahona Ponce, Carol; Müller, Bettina; Ferreccio Readi, Catterina; Koshiol, Jill; Fischer, Christine
T2 gallbladder cancer shows substantial survival variation between continents and this is not due to histopathologic criteria or pathologic sampling differences
(2021) DeSimone, Mia S.; Goodman, Michael; Pehlivanoglu, Burcin; Memis, Bahar; Balci, Serdar; Roa, Juan Carlos; Jang, Kee-Taek; Jang, Jin-Young; Hong, Seung-Mo; Lee, Kyoungbun; Kim, Haeryoung; Choi, Hye-Jeong; Muraki, Takashi; Araya, Juan Carlos; Bellolio, Enrique; Sarmiento, Juan M.; Maithel, Shishir K.; Losada, Hector F.; Basturk, Olca; Reid, Michelle D.; Koshiol, Jill; Adsay, Volkan
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.
The case for aflatoxins in the causal chain of gallbladder cancer
(2016) Foerster, Claudia; Koshiol, Jill; Guerrero, Ariel R.; Kogan, Marcelo J.; Ferreccio Readi, Catterina
The Chile Biliary Longitudinal Study: A Gallstone Cohort
(2021) Koshiol, Jill; Van de Wyngard, Vanessa; McGee, Emma E.; Cook, Paz; Pfeiffer, Ruth M.; Mardones, Noldy; Medina, Karie; Olivo, Vanessa; Pettit, Karen; Jackson, Sarah S.; Paredes, Fabio; Sanchez, Raul; Huidobro, Andrea; Villaseca, Miguel; Bellolio, Enrique; Losada, Hector; Carlos Roa, Juan; Hildesheim, Allan; Carlos Araya, Juan; Ferreccio, Catterina
Gallbladder cancer (GBC) is a highly fatal cancer that can be cured through cholecystectomy if identified early. The presence of gallstones is the primary risk factor for GBC, but few people with gallstones develop GBC. A key question is what drives the development of GBC among persons with gallstones. We initiated the Chile Biliary Longitudinal Study (Chile BiLS) to address this question. From 2016 to 2019, Chile BiLS enrolled 4,726 women aged 50-74 years with ultrasound-detected gallstones from southern-central Chile, accounting for an estimated 36% of eligible women with gallstones in the study area. The median age was 59 years; 25% of the women were Amerindian (Mapuche), 60% were obese, 25% had diabetes, and 6% had cardiovascular disease. Participants will be followed for gallbladder dysplasia or cancer for 6 years. As of April 30, 2020, over 91% of those eligible completed the year 2 follow-up visit. Data being collected include epidemiologic and sociodemographic information, anthropometric measurements, blood pressure, and tooth counts. Biosamples being taken include baseline plasma, buffy coat, red blood cells, serum, blood clot from serum, and PAXgene whole blood (PreAnalytiX GmbH, Hombrechtikon, Switzerland). Complete gallbladder sampling is conducted for most participants undergoing cholecystectomy. The Chile BiLS cohort study will increase our understanding of GBC etiology and could identify potential risk stratification and early detection strategies in high-risk areas.
The inflammatory inception of gallbladder cancer
(2016) Espinoza, Jaime A.; Bizama, Carolina; García Cañete, Patricia; Ferreccio Readi, Catterina; Javle, Milind; Miquel P., Juan Francisco; Koshiol, Jill; Roa Strauch, Juan Carlos Enrique
TPPP-BRD9 fusion-related gallbladder carcinomas are frequently associated with intracholecystic neoplasia, neuroendocrine carcinoma, and a distinctive small tubular-type adenocarcinoma commonly accompanied with a syringomatous pattern
(2024) Pehlivanoglu, Burcin; Araya, Juan Carlos; Lawrence, Scott; Roa, Juan Carlos; Balci, Serdar; Andersen, Jesper B.; Rashid, Asif; Hsing, Ann W.; Zhu, Bin; Gao, Yu-Tang; Koshiol, Jill; Adsay, Volkan
A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors' database. Among the 16 TPPPBRD9 fusion-positive GBC cases, most were females (F:M = 7:1) of Chinese ethnicity (12/16), whereas the remaining cases were from Chile. The histopathological examination showed the following findings: 1) Intracholecystic neoplasm (ICN) in 7/15 (47% vs. 7% 645 reference GBCs, p < 0.001), all with gastropancreatobiliary phenotype, often with clear cell change, and in the background of pyloric gland metaplasia and extensive high-grade dysplasia. 2) Neuroendocrine carcinoma (NEC) morphology: 3 cases (27% vs. 4.6% in the reference database, p = 0.001) showed a sheet-like and nested/trabecular growth pattern of monotonous cells with salt-and-pepper chromatin characteristic of NECs. Two were large cell type, one had prominent clear cell features, a rare finding in GBNECs; the other one had relatively bland, well-differentiated morphology, and the remaining case was small cell type. 3) Adenocarcinoma identified in 8 cases had a distinctive pattern characterized by widely separated small, round tubular units with relatively uniform nuclei in a fashion seen in mesonephric adenocarcinomas, including hobnail-like arrangement and apical snouts, reminiscent of tubular carcinomas of the breast in many areas. In some foci, the epithelium was attenuated, and glands were elongated, some with comma shapes, which along with the mucinous/necrotic intraluminal debris created a "syringoid" appearance. 4) Other occasional patterns included the cribriform, glomeruloid patterns, and metaplastic tubularspindle cell pattern accompanied by hemorrhage. In conclusion, TPPP-BRD9 fusion-positive GBCs often develop through intracholecystic neoplasms (adenoma-carcinoma sequence) of gastro-pancreatobiliary lineage, appear more prone to form NEC morphology and have a propensity to display clear cell change. Invasive adenocarcinomas arising in this setting often seem to display a distinctive appearance that we tentatively propose as the TPPP-BRD9 fusion-positive pattern of GBC.

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