Shih‐Yao Lin

Analytical validation of human epidermal growth factor receptor 2 immunohistochemistry by the use of the A0485 antibody versus the 4B5 antibody and breast versus gastric scoring guidelines in ovarian clear cell carcinoma

AimsThe aim of this study was to evaluate human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) in ovarian clear cell carcinoma (OCCC) by using two antibodies and two scoring guidelines in correlation with HER2 amplification and clinicopathological features.Methods and resultsA tissue microarray was constructed by use of a total of 71 OCCC cases for IHC (the A0485 antibody and the 4B5 antibody) and dual‐colour silver in‐situ hybridisation (DISH). Two pathologists independently scored the IHC according to the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) breast cancer guidelines (breast guidelines) and the 2016 ASCO/CAP gastro‐oesophageal adenocarcinoma guidelines (gastric guidelines). IHC concordances between A0485 and 4B5 were 87.3–93.0%. Three to 16 (4.2–22.5%) cases had an IHC score of 2+/3+ with frequent basolateral/lateral membranous staining. The 4B5 antibody yielded fewer IHC 2+ cases than the A0485 antibody (n = 2–6 versus n = 5–12). Five (7.0%) cases had HER2 amplification as determined with DISH. Cases with papillary‐predominant growth patterns were significantly more likely to have HER2 amplification (P = 0.0051). In predicting DISH results, IHC scored according to the gastric guidelines yielded 100%/100% sensitivity and 83.3–95.5%/98.2–100% specificity, and IHC scored according to the breast guidelines yielded 60–80%/33.3–66.7% sensitivity and 95.5–100%/100% specificity (including/excluding IHC 2+ cases). One case had intratumoral heterogeneity, with discordant results between primary and metastatic tumour specimens.ConclusionWe demonstrated HER2 amplification in 7% of OCCC cases, and the molecular change is significantly associated with papillary‐predominant growth patterns. In predicting HER2 amplification, a combination of 4B5 IHC and gastric guidelines provides the best sensitivity and fewer equivocal (IHC 2+) cases. Given the intratumoral heterogeneity, assessment of HER2 status on whole tissue sections and on both primary and metastatic tumour specimens is recommended.

Loss of Major Histocompatibility Complex Class I, CD8+ Tumor-infiltrating Lymphocytes, and PD-L1 Expression in Ovarian Clear Cell Carcinoma

Ovarian clear cell carcinoma (OCCC), a chemoresistant ovarian cancer, shows a modest response to anti–programmed death-1/programmed death ligand-1 (PD-1/PD-L1) therapies. The effects of anti-PD-1/PD-L1 therapies rely on cytotoxic T-cell response, which is triggered by antigen presentation mediated by major histocompatibility complex (MHC) class I. The loss of MHC class I with simultaneous PD-L1 expression has been noted in several cancer types; however, these findings and their prognostic value have rarely been evaluated in OCCC. We collected data from 76 patients with OCCC for clinicopathologic analysis. Loss of MHC class I expression was seen in 44.7% of the cases including 39.3% to 47.4% of the PD-L1+ cases and was associated with fewer CD8+ tumor-infiltrating lymphocytes (TILs). PD-L1 positivity was associated with a higher number of CD8+ TILs. Cox proportional hazard models showed that high (≥50/mm2) CD8+ TILs was associated with shorter disease-specific survival (hazard ratio [HR]=3.447, 95% confidence interval [CI]: 1.222-9.720, P=0.019) and overall survival (HR=3.053, 95% CI: 1.105-8.43, P=0.031). PD-L1 positivity using Combined Positive Score was associated with shorter progression-free survival (HR=3.246, 95% CI: 1.435-7.339, P=0.005), disease-specific survival (HR=4.124, 95% CI: 1.403-12.116, P=0.010), and overall survival (HR=4.489, 95% CI: 1.553-12.972, P=0.006). Loss of MHC class I may contribute to immune evasion and resistance to anti-PD-1/PD-L1 therapies in OCCC, and CD8+ TILs and PD-L1 positivity using Combined Positive Score may have a negative prognostic value.