Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma are rare aggressive neoplasms of putative distal nephron origin. First described in 1949, case reports and review articles constitute a major source of information on collecting duct carcinoma, whereas Davis and colleagues and the pediatric tumor registry have contributed the seminal works on renal medullary carcinoma. Here we present a detailed study of collecting duct carcinoma (n=39) and renal medullary carcinoma (n=13), characterizing these rare neoplasms and analyzing their interrelationship. Both collecting duct carcinoma and renal medullary carcinoma exhibited significant similarities, such as predilection for the right kidney, tumor mass with an epicenter in the renal medulla, and a mean size of 7 cm. Overall, both tumors exhibited a poorly differentiated adenocarcinoma histology with desmoplastic stromal response (100%), inflammatory infiltrate (100%), frequent perinephric extension (collecting duct carcinoma: 97%; renal medullary carcinoma: 83%), lymphovascular invasion (100%), intraluminal mucin (collecting duct carcinoma: 42%; renal medullary carcinoma: 73%), high nuclear grade (97%), overlapping immunoreactivity for Ulex europaeus agglutinin 1 (collecting duct carcinoma: 75%; renal medullary carcinoma:55%), CK7 (collecting duct carcinoma: 44%; renal medullary carcinoma: 71%), and high-molecular weight cytokeratin (collecting duct carcinoma: 26%; renal medullary carcinoma: 29%), and nonimmunoreactivity for Ksp-cadherin. Histologically, collecting duct carcinoma frequently had tubular, tubulopapillary, or irregular glandular architecture, whereas renal medullary carcinoma commonly demonstrated islands of anastomosing tubules and cords forming irregular microcystic spaces. Multiple metastases to the lymph nodes, lung, bone, and liver were observed in both categories at presentation (collecting duct carcinoma: 17%; renal medullary carcinoma: 36%). Only patients with organ-confined small tumors were disease free beyond the median survival time. Differential clinical features between collecting duct carcinoma and renal medullary carcinoma included proclivity for younger male individuals of African ancestry with hemoglobin abnormalities and a shorter median survival of 17 weeks (vs. 44 wk for collecting duct carcinoma) for renal medullary carcinoma. The markedly overlapping clinical features, histology, immunophenotype, metastasis patterns, and uniformly aggressive outcome in collecting duct and renal medullary carcinomas suggest that renal medullary carcinoma is a distinctive clinicopathologic subtype within the entity of collecting duct carcinoma. The extremely poor prognosis and ongoing clinical trials with specific therapeutic protocols argue for their accurate distinction from other renal cell carcinoma subtypes.

Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH⁻/2SC⁺ or FH^±/2SC⁺ with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor–like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion–like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.

The common histopathologic subtypes of renal epithelial neoplasms include conventional, or clear cell, renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, and renal oncocytoma. These subtypes differ clinically and pathologically, making accurate classification important. However, this differential diagnosis can be challenging because of overlapping morphology, suggesting a potential utility for ancillary immunohistochemical markers. We used cDNA microarrays to identify candidate markers for distinguishing renal tumor subtypes. In this report we validated differential expression of three candidate markers, beta defensin-1, parvalbumin, and vimentin, and evaluated the use of this immunohistochemical panel as a potential diagnostic tool. Consistent with our cDNA microarray data, chromophobe RCCs and oncocytomas exhibited similar expression profiles: 8 of 8 examples of each subtype were immunohistochemically positive for beta defensin-1 and parvalbumin and negative for vimentin (sensitivity 100%, specificity 100%); 4 of 7 papillary RCCs were positive for beta defensin-1, parvalbumin, and vimentin (sensitivity 57%, specificity 97%); and 22 of 23 conventional RCCs were negative for beta defensin-1, parvalbumin, or both markers (sensitivity 96%, specificity 96%) as well as positive for vimentin (sensitivity 83%). The immunohistochemical panel distinguished renal tumor subtypes with greater specificity than any marker used alone. This work demonstrates that a useful panel of immunohistochemical markers can be derived from differential gene expression profiles determined using cDNA microarrays.

Gleason score, which has a high interobserver variability, is used to classify prostate cancer. The most recent consensus valued the tertiary Gleason pattern and recommended its use in the final score of needle biopsies (modified Gleason score). This pattern is considered to be of high prognostic value in surgical specimens. This study emphasized the evaluation of the modified score agreement in needle biopsies and in surgical specimen, as well as the interobserver variability of this score. Three pathologists evaluated the slides of needle biopsies and surgical specimens of 110 patients, reporting primary, secondary and tertiary Gleason patterns and after that, traditional and modified Gleason scores were calculated. Kappa test (K) assessed the interobserver agreement and the agreement between the traditional and modified scores of the biopsy and of the surgical specimen. Interobserver agreement in the biopsy was K = 0.36 and K = 0.35, and in the surgical specimen it was K = 0.46 and K = 0.36, for the traditional and modified scores, respectively. The tertiary Gleason grade was found in 8%, 0% and 2% of the biopsies and in 8%, 0% and 13% of the surgical specimens, according to observers 1, 2 and 3, respectively. When evaluating the agreement of the traditional and modified Gleason scores in needle biopsy with both scores of the surgical specimen, a similar agreement was found through Kappa. Contrary to what was expected, the modified Gleason score was not superior in the agreement between the biopsy score and the specimen, or in interobserver reproducibility, in this study.