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Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ≥1 or a TPS score of ≥1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ≥10 or a TPS score of ≥10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas.

The purpose of this study was to develop and analytically and functionally validate a new human papillomavirus (HPV) in-situhybridization (ISH) assay and to determine whether the use of this assay combined with hemotoxylin and eosin (H&E) staining could potentially improve the diagnostic accuracy of interpreting cervical intraepithelial neoplasia (CIN) in human cervical tissue specimens. An automated HPV ISH assay was developed using probes that targeted the broad spectrum of HPV genotypes most commonly associated with CIN. In an exploratory study, tissue sections (n=118) were stained with H&E alone and H&E with HPV ISH and evaluated by 6 general surgical pathologists. Results were compared with diagnoses established by expert pathologists on H&E alone. The change in specificity (diagnosis of no-CIN) and sensitivity (diagnosis of CIN) using H&E plus HPV versus H&E alone was determined. The HPV ISH assay detected 21 HPV genotypes and demonstrated no cross-reactivity to Epstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV)-1, HSV-2, or human placental DNA. The assay detected HPV in a range of 1 to 600 copies on CaSki, HeLa, and SiHa xenografts. Use of this assay with H&E staining improved the average diagnostic specificity of the surgical pathologists from 68.5 to 89.9 (P<0.001), with fewer false-positive CIN 1 results (122 vs. 39). The diagnostic sensitivity was similar for assessments made with H&E alone and those made with HPV plus H&E (93.1 vs. 93.6). In conclusion, a new automated broad-spectrum HPV ISH assay combined with H&E-stained slides contributed to better ascertainment of CIN than H&E staining alone.