Clear Cell Stromal Tumor of the Lung: Clinicopathologic, Immunohistochemical, and Molecular Characterization of Eight Cases

Abstract

Clear cell stromal tumor is a recently described mesenchymal neoplasm of the lung, characterized by spindle cells with variably clear-to-pale eosinophilic cytoplasm and prominent vascularity, as well as a recurrent YAP1::TFE3 gene fusion in most cases. Diagnosis can be challenging given its rarity and the lack of supportive immunohistochemical (IHC) markers aside from TFE3. To date, less than 20 cases have been reported, and data on clinical behavior are also limited. Although most appear to be benign, aggressive behavior has been reported rarely. In this study, we present the largest multiinstitutional series of clear cell stromal tumor to date, comprising a total of 8 cases and including 6 previously unpublished cases. We investigate its clinicopathologic and genomic features, while also assessing the diagnostic use of IHC for YAP1 C-terminus. Five patients were men and 3 were women. The median age was 59 years (range: 35-84 years). In all cases, a TFE3 rearrangement was demonstrated by either fluorescence in situ hybridization or DNA/RNA sequencing. In 7 tumors, the YAP1::TFE3 fusion was identified by sequencing. We demonstrate that the combination of YAP1 C-terminus loss and TFE3 overexpression using IHC reliably predicts an underlying YAP1::TFE3 fusion in these neoplasms and may be more sensitive than TFE3 fluorescence in situ hybridization. Although the median follow-up time for our study was short (18 months, available in 7 cases), all cases pursued a benign clinical course, with no recurrences or metastases. Our study provides further characterization of this novel entity, supporting its wider recognition.