Tubulocystic carcinoma of the kidney (TC-RCC) is a rare renal tumor with unique gross and microscopic features unlike other types of renal cell carcinoma (RCC). Several recent studies recommend that it should be classified as a distinct RCC subtype. In this study, we provide pathologic and cytogenetic evidence supporting that TC-RCC is closely related to papillary RCC (PRCC). This study included 20 cases of renal tumors that partially or exclusively comprised a TC-RCC component. Pathologic examination documented the gross and microscopic features of TC-RCC, including multicentricity and the presence of concomitant PRCC and papillary adenoma. Formalin-fixed, paraffin-embedded sections from 12 TC-RCC and 20 PRCC were subjected to a multicolor fluorescence in situ hybridization assay containing probes for chromosomes 7, 17, and Y. One hundred nuclei were examined to enumerate the copy numbers of chromosomes in each tumor and its corresponding normal kidney tissue. A tumor with a percentage of cells harboring a chromosomal change +3 SD of normal tissue was considered to harbor that chromosomal change, and a tumor with a percentage of cells with null Y chromosome count (loss of Y chromosome) mean+3SD of normal tissue was considered to harbor Y chromosome loss. Four of the 20 TC-RCCs were multicentric. Ten had associated PRCC or papillary adenoma within the same kidney as the TC-RCC. In 4 cases, the tubulocystic and papillary components were admixed together within the same lesion. The tumor cells lining both the tubulocystic and papillary components had similar cytologic features. Ten of 12 TC-RCCs had a chromosome 7 gain, 8 of 12 cases had a chromosome 17 gain, and 8 of 9 cases had a loss of Y chromosome. Six of 9 cases with all 3 chromosomes studied had a gain of chromosomes 7 and 17 and a loss of Y chromosome. Our study shows that TC-RCCs and PRCCs are closely related entities. With its distinctive gross and microscopic features, TC-RCC may be considered a unique "morphologic entity." However, before it is accepted as a distinct renal cell carcinoma subtype, further studies are needed to document a characteristic molecular signature associated with this tumor. © 2009 by Lippincott Williams & Wilkins.