Abstract
INTRODUCTION
The anti-PD-1 monoclonal antibody nivolumab, used in metastatic melanoma, renal carcinoma, and advanced non-small cell lung cancer, may be used off-label in some PD-L1 positivite tumors. We report the first use (to our knowledge) of nivolumab in metastatic carcinoma of unknown primary with hepatoid features, with subsequent loss of PD-L1 expression on the tumor. CASE PRESENTATION: A 62-year old man complained of worsening back and right thigh pain. X-rays revealed an L3 compression fracture, which was managed non-operatively. He developed worsening right hip pain. Imaging revealed a right iliac mass, associated pathologic fracture, and multiple osteoblastic and osteolytic metastases.
RESULTS
Iliac mass biopsy showed cords and nests of malignant epithelial cells with abundant eosinophilic cytoplasm, irregular nuclear contours, and prominent nucleoli. HepPar, Cam5.2, and PAX-8 (focal) immunohistochemical stains were positive, suggesting hepatic carcinoma. PD-L1 positivity was high (> 25% but < 50%). Genomic sequencing showed NF2, MLL2, and SETD2 mutations. Workup showed no hepatic involvement, so stage IV hepatoid carcinoma of unknown primary was diagnosed. TREATMENT: Several bony lesions were radiated. Nivolumab (240 mg every 2 weeks) and denosumab (monthly) were started. PROGRESSION: Seven months later he developed left ptosis and proptosis from a sellar/left cavernous sinus mass. Histology was similar to the previous iliac biopsy, but with more aggressive features (mitoses, atypical nuclei). Cam5.2 and synaptophysin immunohistochemical stains were positive; PD-L1 expression was <1%. Genomic sequencing showed PTEN, ERRFI1, CREBBP, EP300, LRP1B, MSH2, RB1 and P53 mutations, and increased mutational burden status (intermediate from low). DISCUSSION: PD-L1 expression may vary over time. Tumors can express PD-L1 constitutively or in response to IFNg from infiltrating lymphocytes. PD-L1 expression may decrease after IFNg levels decrease. Complete loss of PD-L1 has not, to our knowledge, been reported. CONCLUSION Loss of PD-L1 expression may represent a means by which tumors resist immunotherapy.