Diagnostic challenges in pathologic staging of renal cell carcinoma following systemic immunotherapy

Immune checkpoint inhibitors (ICIs) are increasingly used prior to surgical resection of clear cell renal cell carcinoma (RCC) and can produce varied histologic response patterns, including complete tumor regression. Response to treatment can mimic or obscure residual tumor, leading to diagnostic pitfalls that are not well characterized in the RCC literature.

A retrospective search was performed to identify cases of clear cell RCC treated with preoperative ICIs at our institution. Pathology reports and slides were reviewed by a fellowship-trained genitourinary pathologist. Clinicopathologic, radiographic, gross, and microscopic features were assessed, including treatment-related histologic changes.

A total of 13 clear cell RCC cases treated with ICI before nephrectomy were identified. Three cases demonstrated no residual carcinoma (ypT0). Histologic features after ICI therapy included fibrosis, myxoid change, and histiocytes, often hemosiderin laden. Foamy histiocytes often mimicked clear cell RCC tumor cells, including 9 cases classified as "moderate" or "difficult" to distinguish and necessitating immunohistochemistry in 5 cases. Resected lymph nodes (n = 8) showed similar features of treatment effect. One lymph node resection demonstrated extensive well-formed granulomas mimicking sarcoidosis.

Recognition of the varied histologic features seen after ICI treatment is critical for accurate pathologic staging. Consensus guidelines for gross and microscopic examination in this setting have not yet been determined but should consider the specific pathologic changes associated with ICI therapy.