Our recent study of early-onset unclassified eosinophilic
renal cell carcinoma (RCC) demonstrated that two third of cases could be reclassified by performing a limited number of immunohistochemistry stains. Following the same approach, we aimed to investigate what proportion of adult unclassified RCC could be reclassified. We identified 79 cases. The mean age at presentation was 58 years (range, 29 to 84 y).
Tumors were grouped based on their predominant morphologic features as oncocytic (n=23); papillary (n=22); clear cell (n=22); mucinous tubular and spindle cell (MTSC; n=5); rhabdoid (n=4); or lacking a dominant pattern (n=3). By reviewing the morphologic features and performing ancillary studies, we were able to reclassify 10 cases (13%). Four cases were positive for CK20 and showed morphologic features consistent with eosinophilic solid and cystic RCC. Four cases were reclassified as MTSC based on VSTM2A expression by
RNA in situ hybridization. One case was negative for SDHB and reclassified as
succinate dehydrogenase-deficient RCC. None of the cases showed loss of expression of
fumarate hydratase. One case was diffusely positive for CK7 and negative for CD117 and reclassified as a low-grade oncocytic
tumor. Four cases were positive for both
cathepsin-K and TFE3 by immunohistochemistry, although fluorescence in situ hybridization failed to identify rearrangement in either TFE3 or TFEB genes. Of the
tumors that remained unclassified, those with oncocytic features were less likely to be a high grade (odds ratio [OR]=0.22, P=0.013) or advanced stage (OR=0.19, P=0.039) and were more common in women (OR=3.4, P=0.05) compared with those without oncocytic features.
Tumors with rhabdoid morphology were associated with advanced stage (relative risk=3.6, P=0.009), while
tumors with clear cell or papillary features had a wide range of grades and stages at presentation. In summary, the most frequent reclassified entity is eosinophilic solid and cystic RCC. Investigation of expression of
succinate dehydrogenase or
fumarate hydratase in individuals older than 35 years with unclassifiable
tumors is low yield in the absence of specific morphologic features. A subset of MTSC without well-developed morphologic features can be reclassified by using
RNA-ISH for VSTM2A. Recognition of more-recently described RCC subtypes allows for their distinction from the unclassified subtype and improves the prognostic information provided.