Summary Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas, of a set of predominantly intrahepatic CCA cases, and propose a molecular classification scheme. We identified an IDH-mutant enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH-mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

Summary Background Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. Methods We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. Findings We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15–33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. Interpretation To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. Funding National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Transducer-like enhancer of split 1 (TLE1) is overexpressed in synovial sarcomas. We investigated TLE1 expression by immunohistochemical analysis in a well-characterized series of synovial sarcomas and other mesenchymal tumors most commonly considered in the differential diagnosis. Whole tissue sections of 212 tumors were evaluated: 73 synovial sarcomas (23 biphasic, 28 monophasic, 22 poorly differentiated), 47 malignant peripheral nerve sheath tumors (MPNSTs), 49 solitary fibrous tumors (SFTs), 20 fibrosarcomatous variants of dermatofibrosarcoma protuberans, and 23 Ewing sarcomas/primitive neuroectodermal tumors (PNETs). All monophasic and poorly differentiated SSs and Ewing sarcoma/PNETs were previously confirmed to harbor t(X;18) and EWSR1 gene rearrangements, respectively. In total, 60 (82%) of 73 synovial sarcomas were positive for TLE1, including 18 biphasic (78%), 22 monophasic (79%), and 20 poorly differentiated (91%) tumors. Of the other tumors, only 7 MPNSTs (15%) and 4 SFTs (8%) were positive for TLE1, most of which showed only weak staining. TLE1 is a sensitive and specific marker for synovial sarcoma and can be helpful to distinguish synovial sarcoma from histologic mimics, particularly if moderate or strong staining is observed. In this study, only a small subset of MPNSTs and SFTs showed limited staining for TLE1.

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