Chromophobe renal cell carcinoma - a rare kidney cancer with limited therapy options: a narrative review

Chromophobe renal cell carcinoma (chRCC) is a rare subtype of renal cell carcinoma (RCC) and is the most common form of non-clear cell renal cell carcinoma in young women. Compared to clear cell renal cell carcinoma (ccRCC), chRCC usually has an excellent prognosis, indicating the need for a reliable differential diagnosis, especially to distinguish it from eosinophilic variants of ccRCC. Another important differential diagnosis is renal oncocytoma (RO), which remains a major challenge even for experienced pathologists. The treatment of RO typically involves active surveillance, with surgical resection indicated if there is significant tumor growth. In contrast, for chRCC, the approach depends on tumor size, with either partial or radical nephrectomy being required. This review therefore summarizes key unique features and recent findings on this tumor, aiming to ensure a reliable differential diagnosis, thereby facilitating appropriate treatment selection and prognosis assessment. The histology of chRCC, including both for the classic and the eosinophilic subtype, is characterized by the appearance of raisinoid cell nuclei with perinuclear halos on microscopic imaging. In rare cases, signs of sarcomatoid, glandular and/or anaplastic dedifferentiation can also be observed, which significantly worsens the prognosis. The immunohistochemical marker phospho-S6 can be used to detect these changes. In addition to other routinely used markers such as C-Kit, CK7, EpCAM, CAIX and Claudin 7, we recommend the use of progesterone receptors as markers, as many chRCC express them and are thus progesterone-sensitive. This progesterone sensitivity could indicate that chRCC, similar to breast cancer, may represent a contraindication for the use of hormonal contraceptives. In addition to immunohistochemistry, molecular features of chRCC such as genetic, epigenetic, transcriptomic and proteomic alterations can be considered in the differential diagnosis. In this review, we therefore outline the most important established alterations in this context. In the treatment of metastatic chRCC, checkpoint inhibitors and tyrosine kinase inhibitors have demonstrated efficacy and may represent a promising new approach for managing dedifferentiated, aggressive or metastatic chRCC. This review aims to present recent therapeutic advances and provide innovative approaches for future clinical treatment decisions.