Abstract
Clear cell morphology is an uncommon finding in human tumors and reflects the distinctive appearance of the cytoplasm under standard histopathologic examination. Granular cell morphology appears to be a closely related phenomenon and reflects an abundant eosinophilic cytoplasm. Accumulating evidence suggests a central role for the MITF/TFE family of transcription factors in diverse clear cell and granular cell neoplasms. A principal function of these transcription factors concerns cytoplasmic organellar biogenesis: TFEB is the master regulator of lysosome biogenesis while MITF controls the biogenesis of lysosome-related organelles known as melanosomes, which are responsible for melanin pigment production. This article reviews the role of MITF/TFE pathway activation in a variety of benign and malignant tumors, with an emphasis on the diverse oncogenic mechanisms that activate this pathway and the resulting altered cell biology that contributes to the distinctive histomorphologic features.