Clinical and pathological characteristics of cancer of unknown primary with renal profile using gene expression profiling (GEP)–based cancer classification.

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e16627 Background: Cancers of unknown primary (CUP) are rare and heterogeneous tumors with clinically unidentifiable origin at time of diagnosis, accounting for approximately 1-3% of all malignant neoplasms. CUP with Renal Profile (CUP-RP) appears to be a clinically distinct subset, based on immunophenotyping, specifically PAX8 staining. Precision in diagnosis is critical, as cytotoxic chemotherapy options for CUP do not overlap with tyrosine kinase inhibitors or checkpoint inhibitors used for renal cell carcinoma. Gene expression-based cancer classification in patients with CUP offers an objective molecular assessment in the search for CUP origin and further categorization. Methods: We retrospectively evaluated 300 patients with CUP composed of cases classified as renal profile (N=100, clear cell or papillary) or controls (N=200, non-renal cases) using the 92-gene assay (CancerTYPE ID), a validated classifier for predicting tissue of origin, between January 2018 and December 2022. Clinicopathologic data including immunohistochemistry (IHC) and molecular profiling (NeoTYPE) results were collected using pathology specimens and reports. Results: At baseline, median age at diagnosis was 69 years (range 31-89). Most patients were male (63%). For CUP-RP patients, pathology was reported as poorly differentiated in 47% of tumors. Tumors were described as adenocarcinoma in 27%, carcinoma in 63%, and malignant neoplasm in 10%. Median number of IHC stains performed was 11 (range 0-33). PAX8 staining was found to be strongly or focally positive in 88%. PAX8 was not tested in 36% of cases. Compared to non-renal profile CUP, CUP-RP patients were more likely to have bone biopsies (28% vs 16.5%, OR 1.97, p=0.02). CUP-RP were much less likely to have high-TMB (2% vs 28.2%, OR 0.07, p=.001). CUP-RP had a lower proportion of TP53 mutations (18.8% vs 81.2%, OR 0.028, p<0.0001) and KRAS mutations (13.3% vs 86.7%, OR 0.045, p<0.0001). Detailed IHC from 30 CUP-RP cases is shown in the table. CA IX was tested in 2/30 (6.7%) of cases. Conclusions: In this cohort of CUP with a molecular classification of renal cell carcinoma, we found a wide range in diagnostic work-up. The 92-gene assay can serve as an adjunct to IHC, to improve diagnostic accuracy for CUP. Critical immune stains necessary in diagnosis are performed infrequently. While PAX8 was often positive in CUP-RP, it was omitted in over 1/3 of cases. CUP-RP cases had lower TMB and less often mutations in TP53 and KRAS. Gene expression profiling presents an opportunity to complement standard pathology in the workup of this subset of CUP to guide treatment selection and improve clinical outcomes. [Table: see text]