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A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.

The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4–4.5, P = 5.4 × 10−4). Increased dendritic cells (OR = 3.4, CI = 1.9–6.3, P = 5.5 × 10−5) and neutrophils (OR = 10.5, CI = 2.7–44, P = 8.7 × 10−4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6–13, P = 4.9 × 10−3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10−3, CI = 5.3 × 10−5–0.031, P = 4.1 × 10−5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.

Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P 0.00001). Notably, AR-V7 was detected in 2 primary BC and 7 metastatic/recurrent BC patients with no prior endocrine therapy. We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.

Context.— Given the growing clinical significance of human papillomavirus status in oropharyngeal squamous cell carcinoma, the College of American Pathologists established a set of evidence-based recommendations for high-risk human papillomavirus testing for publication in a guideline. Objective.— To evaluate the impact of the recommendations on human papillomavirus ancillary test ordering habits by comparing compliance before and after the guideline was published. Design.— We retrospectively reviewed head and neck squamous cell carcinoma biopsy or resection specimens from outside institutions during a 2.5-year period around guideline publication to determine whether human papillomavirus testing was performed in accordance with the guideline. Results.— Human papillomavirus testing deviated from the guideline in 45 of 107 cases (42.1%) before and 93 of 258 cases (36.0%) after its publication (P = .29). This included 6 of 26 cases of oropharyngeal squamous cell carcinoma (23.1%) before and 5 of 55 cases (9.1%) after (P = .16), with 5 of 5 (100.0%) after due to not performing p16 immunohistochemistry. This also included 30 of 68 cases of nonoropharyngeal carcinoma (44.1%) before and 69 of 163 (42.3%) after the guideline was published (P = .88), with 29 of 30 (96.7%) before and 67 of 69 (97.1%) after due to unnecessary use of p16 immunohistochemistry. Nodal metastasis testing deviated in 9 of 13 cases (69.2%) before and 19 of 40 cases (47.5%) after (P = .21) with marked variability in testing, including 3 of 9 (33.3%) before and 8 of 19 (42.1%) after, for not confirming certain p16 immunohistochemistry–positive tumors with human papillomavirus–specific testing. Conclusions.— Pathologists continue to deviate from the testing guideline significantly in everyday practice. Further education and discussion about the appropriate handling of head and neck cancer specimens may be needed.

Objective To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs). Patients and Methods Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes. Results Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76). Conclusion Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy.

Cutaneous angiosarcoma presents clinically in numerous ways, and can be mistaken for a different clinical entity, particularly when arising at unusual anatomic locations such as the eyelid.A 57-year-old woman presented with a 1-year history of eyelid swelling. Concurrent imaging was also suggestive of an edematous process. Multiple superficial biopsies showed nonspecific dermal inflammation and interstitial edema. A diagnosis of Morbihan disease (chronic and idiopathic lymphedema of the eyelid) was rendered, and the patient was treated with compression and local therapy without clinical improvement. Three years after initial presentation, a diagnostic blepharoplasty was performed revealing a deep dermal vascular proliferation composed of anastomosing vascular channels with an atypical endothelial lining. A diagnosis of cutaneous angiosarcoma was ultimately made.This case illustrates a unique presentation of cutaneous angiosarcoma and the implications of different biopsy techniques in acquiring the correct diagnosis.

Background Deregulation of CDK4/6, cyclin D/P16 and retinoblastoma (Rb) are known aberrations in certain malignancies. There has been a recent interest in exploring the combination of letrozole and CDK4/6 inhibitors in recurrent ER+ ovarian cancers. Methods This study aimed to determine the frequency of expression of Rb1, P16 and ER in ovarian epithelial tumors by immunohistochemistry. Results Co-expression of all 3 markers studied was seen in 10 % of high grade serous carcinoma (HGSC) and low grade serous carcinoma (LGSC). Coordinate expression of Rb1+ and ER+ in HGSC and LGSC was seen in 67 % of grade 1/2 vs. 44 % of grade three tumors (p