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  • 1
    Online Resource
    Online Resource
    Unraveling Neuroendocrine Gallbladder Cancer: Comprehensive Clinicopathologic and Molecular Characterization
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  JCO Precision Oncology , No. 5 ( 2021-11), p. 473-484
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 5 ( 2021-11), p. 473-484
    Abstract: Neuroendocrine carcinomas and mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (NE GBC) are rare and highly aggressive entities. The cell of origin of NE GBC has been a matter of controversy. Here, we performed a comparative histopathologic and molecular analysis of NE GBC cases and, if present, associated precancerous lesions. PATIENTS AND METHODS We selected cases diagnosed between 2000 and 2019 in the Netherlands. Precursors and carcinomas were immunohistochemically compared and analyzed for mutations, gene amplifications, microsatellite instability, and tumor mutational burden using an next-generation sequencing panel containing 523 cancer-related genes. In addition, presence of fusion genes was analyzed using a panel of 55 genes. RESULTS Sixty percent of neuroendocrine cases (6/10) presented with a precursor lesion, either intracholecystic papillary neoplasm (n = 3) or biliary intraepithelial neoplasia (n = 3). Immunohistochemically, neuroendocrine components were different from the epithelial precursor lesions. Molecular profiling, however, revealed TP53 mutations shared between different components in five of six cases, indicating a clonal relation. Furthermore, 40% of cases (4/10) harbored at least one potentially actionable alteration. This included (likely) pathogenic mutations in RAD54L, ATM, and BRCA2; amplifications of ERBB2 and MDM2; and a gene fusion involving FGFR3-TACC3. All cases were microsatellite-stable and had a tumor mutational burden of 〈 10 mutations/Mb. CONCLUSION Our data provide insight into the development of NE GBC and suggest a common origin of precancerous epithelial lesions and invasive neuroendocrine components, favoring the hypothesis of lineage transformation. Moreover, nearly half of the NE GBCs carried at least one potentially actionable molecular alteration, highlighting the importance of molecular testing in this highly lethal cancer.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.20.00487
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Comprehensive clinicopathological and genomic profiling of gallbladder cancer reveals actionable targets in half of patients
    Springer Science and Business Media LLC ; 2022
    In:  npj Precision Oncology Vol. 6, No. 1 ( 2022-11-05)
    Details
    In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2022-11-05)
    Abstract: Gallbladder cancer (GBC) is a rare, highly aggressive malignancy with a 5-year survival rate of 5–10% in advanced cases, highlighting the need for more effective therapies. The aim of this study was to identify potentially actionable therapeutic targets for GBC. Specimens and clinicopathological data of 642 GBC patients, diagnosed between 2000 and 2019 were collected using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry. All cases were histologically reviewed and a subset was subjected to a comprehensive next generation sequencing panel. We assessed mutations and gene amplifications in a panel of 54 actionable genes, tumor-mutational burden (TMB), and microsatellite instability (MSI). Additionally, the entire cohort was screened for HER2, PD-L1, pan-TRK, and p53 expression with immunohistochemistry. Histopathological subtypes comprised biliary-type adenocarcinoma (AC, 69.6%), intestinal-type AC (20.1%) and other subtypes (10.3%). The median total TMB was 5.5 mutations/Mb (range: 0–161.1) and 17.7% of evaluable cases had a TMB of 〉 10 mutations/Mb. MSI was observed in two cases. Apart from mutations in TP53 (64%), tumors were molecularly highly heterogeneous. Half of the tumors (50%) carried at least one molecular alteration that is targetable in other tumor types, including alterations in CDKN2A (6.0% biallelically inactivated), ERBB2 (9.3%) and PIK3CA (10%). Immunohistochemistry results correlated well with NGS results for HER2 and p53: Pearson r  = 0.82 and 0.83, respectively. As half of GBC patients carry at least one potentially actionable molecular alteration, molecular testing may open the way to explore targeted therapy options for GBC patients.
    Type of Medium: Online Resource
    ISSN: 2397-768X
    URL: Article
    DOI: 10.1038/s41698-022-00327-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2891458-2
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  • 3
    Online Resource
    Online Resource
    Colorectal metastasis to the gallbladder mimicking a primary gallbladder malignancy: histopathological and molecular characteristics
    Wiley ; 2019
    In:  Histopathology Vol. 75, No. 3 ( 2019-09), p. 394-404
    Details
    In: Histopathology, Wiley, Vol. 75, No. 3 ( 2019-09), p. 394-404
    Abstract: Outcomes of colorectal cancer (CRC) treatment and survival have steadily improved during the past decades, accompanied by an increased risk of developing second primary tumours and metastatic tumours at unusual sites. Metastatic CRC can show mucosal colonisation, thereby mimicking a second primary tumour. This potential confusion could lead to incorrect diagnosis and consequently inadequate treatment of the patient. The aim of this study was to differentiate between metastatic CRC and a second primary (gallbladder cancer, GBC) using a combination of standard histopathology and molecular techniques. Methods and results Ten consecutive patients with both CRC and GBC were identified in our region using the Dutch National Pathology Archive (PALGA). Two patients served as negative controls. Histology of GBC was reviewed by nine pathologists. A combination of immunohistochemistry, microsatellite analysis, genomewide DNA copy number analysis and targeted somatic mutation analysis was used to aid in differential diagnosis. In two patients, CRC and GBC were clonally related, as confirmed by somatic mutation analysis. For one case, this was confirmed by genomewide DNA copy number analysis. However, in both cases, pathologists initially considered the GBC as a second primary tumour. Conclusions Metastatic CRC displaying mucosal colonisation is often misinterpreted as a second primary tumour. A combination of traditional histopathology and molecular techniques improves this interpretation, and lowers the risk of inadequate treatment.
    Type of Medium: Online Resource
    ISSN: 0309-0167 , 1365-2559
    URL: Issue
    URL: Article
    DOI: 10.1111/his.v75.3
    DOI: 10.1111/his.13892
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2006447-0
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