Clear cell papillary renal cell carcinoma: a clinicopathological study emphasizing ultrastructural features and cytogenetic heterogeneity

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognized renal neoplasm, which was initially described in end-stage renal disease (ESRD), but some cases have been reported in otherwise normal kidneys. We report a series of 11 CCPRCC (age range, 33-72 years; male-to-female ratio, 8:3). Follow-up was available for 8 patients. No patients developed local recurrence, distant or lymph-node metastasis, or cancer death. Histologically, all tumors exhibit morphologic features typical of CCPRCC including a mixture of cystic and papillary components, covered by small to medium-sized cuboidal cells with abundant clear cytoplasm. All 11 cases exhibited moderate to strong positivity for CK7, CA9, Vim, and HIF-1α, coupled with negative reactions for CD10, P504S, and RCC. We did not find any VHL gene mutations in all 11 cases. Losses of chromosomes 3 (monoploid chromosome 3) was detected in 3 cases. Ultrastructurally, the tumor cells composed of numerous glycogens with scanty cell organelles, reminiscent of clear cell renal cell carcinoma (CCRCC). In conclusion, the coexpression of CA9 and HIF-1α in the absence of VHL gene abnormalities in CCPRCC suggests activation of the HIF pathway by mechanisms independent of VHL gene mutation. Losses of chromosomes 3 (monosomies chromosome 3) was detected in 3 cases suggesting that at least some of these lesions have demonstrated abnormalities of chromosomes 3. Ultrastructurally, CCPRCC composed of numerous glycogens with scanty cell organelles, reminiscent of CCRCC suggesting the close pathogenesis relationship of CCPRCC with CCRCC.     

Clear cell papillary renal cell carcinoma with angiomyomatous stroma: a histological,immunohistochemical, and fluorescence in situ hybridization study

Clear cell papillary renal cell carcinoma (CCPRCC) is a novel tumor entity that was recently recognized as a new distinct epithelial tumor within the current classification system. Nonclassic morphologic variants have rarely been reported. We present six challenging cases of CCPRCC with prominent (>75 %) tubular, acinar, and/or solid component and angioleiomyomatous stroma. The tumors lacked well-organized papillary architecture. All tumors had a variously thick capsule formed by a layer of bands of smooth muscle. The leiomyomatous tissue often entirely encased patches of tubular structures, or it formed only small leiomyomatous islands within the epithelial component. There was a remarkable relationship between the vascular network and the epithelial component in the sense that every single tubule or acinus was associated with a fine capillary network, with the capillaries intimately surrounding the tubular or acinar circumference. CCPRCC with variant morphology expressed carbonic anhydrase IX (CA-IX) in cup-shaped distribution. In addition, the tumor cells stained positive for cytokeratin 34betaE12, CK7, and vimentin. Renal cell carcinoma (RCC), P504s/AMACR, Melan A, and HMB45 were negative in tumor cells in all cases examined. Fluorescence in situ hybridization studies showed the presence of a normal copy number for chromosomes 7, 17, 3q, and 3p. CCPRCC with variant morphology seems to have a favorable prognosis. In the current series, tumor stage was low at presentation, and none of the patients had local recurrence or metastatic disease. The distinction between CCPRCC with variant morphology and clear cell RCC is critical because no case of CCPRCC has behaved aggressively.     

Useful immunohistochemical panel for differentiating clear cell papillary renal cell carcinoma from its mimics

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described low-grade renal cell tumor. In this study, we investigated the expression of paired box 8 (PAX-8), carbonic anhydrase IX (CA IX), CK7, and α-methylacyl-CoA-racemase (AMACR) in this tumor by immunohistochemistry in a group of 20 cases of CCPRCC. Clear cell papillary renal cell carcinoma showed diffuse (70%) or intermediate (30%) nuclear positivity for PAX-8 in each case, with predominantly moderate intensity (50%). Ninety percent of the cases showed some degree of cytoplasmic staining for CA IX, predominantly with moderate intensity (50%). In addition, each case of CCPRCC also showed diffuse membranous staining for CK7. Most CCPRCCs (95%) were negative for AMACR. PAX-8, CA IX, CK7, and AMACR comprise a concise panel for distinguishing CCPRCC from its mimics. PAX-8 positivity helps to confirm the renal origin of this tumor. Positivity for CA IX and CK7 differentiate CCPRCC from conventional clear cell renal cell carcinoma, which is usually CA IX positive while CK7 negative. The CK7-positive and AMACR-negative pattern seen in CCPRCC differentiates it from papillary renal cell carcinoma, which is usually positive for both AMACR and CK7.     

Clear cell papillary renal cell carcinoma: Incidence,morphological features,immunohistochemical profile,and biologic behavior: A single institution study

This study was undertaken to determine the incidence and the clinicopathologic characteristics of those tumors that qualify as clear cell papillary renal cell carcinoma (CCPRCC) by the current definitions. From January 1, 2003 to April 30, 2013, a total of twenty-eight CCPRCC were identified (28/648, 4.3%). CCPRCC showed variable architectural patterns including cystic, papillary, tubular, and acinar. Irrespective of the architecture, the tumors were composed of cuboidal or columnar cells with clear cytoplasm, small vesicular, round or oval nuclei, and inconspicuous nucleoli. Variably thick bundles of smooth muscle actin-positive soft tissue encircled the whole tumors, forming a continuous pseudocapsule. CCPRCC strongly expressed PAX8, CA-IX, CK7, cytokeratin 34betaE12, and vimentin, and were negative for RCC, P504s/AMACR, and TFE3. On ultrastructural examination, CCPRCC showed short microvilli, cytoplasmic interdigitations, nuclear pseudoinclusions, and stromal myofibroblasts. To the best of our knowledge, this is first comprehensive ultrastructural study of CCPRCC in the literature. The major differential diagnostic considerations are clear cell renal cell carcinoma, multilocular cystic renal cell carcinoma, papillary renal cell carcinoma with clear cell changes, and Xp11.2 translocation renal cell carcinoma. CCPRCC seems to have a favorable prognosis. In the current series, none of the patients had local recurrence or metastatic disease.     

Targeted next‐generation sequencing and non‐coding RNA expression analysis of clear cell papillary renal cell carcinoma suggests distinct pathological mechanisms from other renal tumour subtypes

Clear cell tubulopapillary renal cell carcinoma (CCPRCC) is a recently described rare renal malignancy that displays characteristic gross, microscopic and immunohistochemical differences from other renal tumour types. However, CCPRCC remains a very poorly understood entity. We therefore sought to elucidate some of the molecular mechanisms involved in this neoplasm by carrying out targeted next‐generation sequencing (NGS) to identify associated mutations, and in addition examined the expression of non‐coding (nc) RNAs. We identified multiple somatic mutations in CCPRCC cases, including a recurrent [3/14 cases (21%)] non‐synonymous T992I mutation in the MET proto‐oncogene, a gene associated with epithelial‐to‐mesenchymal transition (EMT). Using a microarray approach, we found that the expression of mature (n = 1105) and pre‐miRNAs (n = 1105), as well as snoRNA and scaRNAs (n = 2214), in CCPRCC cases differed from that of clear cell renal cell carcinoma (CCRCC) or papillary renal cell carcinoma (PRCC) tumours. Surprisingly, and unlike other renal tumour subtypes, we found that all five members of the miR‐200 family were over‐expressed in CCPRCC cases. As these miRNAs are intimately involved with EMT, we stained CCPRCC cases for E‐cadherin, vimentin and β‐catenin and found that the tumour cells of all cases were positive for all three markers, a combination rarely reported in other renal tumours that could have diagnostic implications. Taken together with the mutational analysis, these data suggest that EMT in CCPRCC tumour cells is incomplete or blocked, consistent with the indolent clinical course typical of this malignancy. In summary, as well as describing a novel pathological mechanism in renal carcinomas, this study adds to the mounting evidence that CCPRCC should be formally considered a distinct entity. Microarray data have been deposited in the GEO database [GEO accession number (GSE51554)]. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Hereditary and Sporadic Papillary Renal Carcinomas with c-met Mutations Share a Distinct Morphological Phenotype

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.     

Oncocytic renal cell carcinoma having papillotubular growth: rare morphological variant of papillary renal cell carcinoma

Herein is described a unique renal cell tumor with previously unreported morphological and immunohistochemical features. The patient was a 78-year-old Japanese man. A huge left renal tumor was found on ultrasound during evaluation of left abdominal distention. The tumor was macroscopically characterized by a non-infiltrative border, pale yellow to grayish color, foci of hemorrhage and partial edematous change. Histologically the tumor had an extensive small tubular growth pattern often with papillary fronds mainly composed of oncocytic cells with deeply eosinophilic granular cytoplasm. Clear vacuolated cells were scattered among the oncocytic cells. The present case had an unusual immunohistochemical profile for all known types of renal cell tumors, but both the oncocytic cells and the clear vacuolated cells were strongly immunoreactive for α-methylacyl-coenzyme A racemase. It is concluded that the tumor may be a candidate for a rare variant of papillary renal cell carcinoma. Further cases having similar features are awaited for a definitive classification of this tumor as a previously undescribed tumor type.     

Clear cell papillary renal cell carcinoma: a review

The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type.     

Multilocular cystic renal cell carcinoma

Multilocular cystic renal cell carcinoma (MCRCC) appears to be a distinct subtype of renal cell carcinoma with characteristic gross and microscopic features. The authors' ten-year experience (1977-1987) included six cases of MCRCC that were followed for a minimum of two years, with neither recurrence nor metastasis observed in any of the cases. During this period, there were 855 urologic procedures for the upper urinary tract, with 256 neoplasms or cysts identified. These included 32 simple cysts, 41 transitional cell carcinomas, 133 renal cell carcinomas, 17 papillary renal cell carcinomas, and 33 miscellaneous tumors. Histologically, the MCRCCs were well-demarcated multicystic lesions containing variably sized aggregates of neoplastic clear cells showing grade 1 nuclear features and little or no mitotic activity. The cyst walls were densely fibrotic, and the lining was often devoid of epithelium. Flow-cytometric analysis performed in five of the six cases with the use of paraffin-embedded tissue showed the tumors to be diploid in all instances, with low proliferative activity. The authors believe that this tumor is a low-grade variant of renal cell carcinoma and should be studied further to determine appropriate therapy.     

Metastatic renal cell carcinoma presenting as a gallbladder polyp

Clear cell renal cell carcinoma accounts for approximately 3% of all adult malignancies and 85% of all primary renal malignancies. Clear cell renal cell carcinoma (ccRCC) metastasis to the gallbladder is extremely rare and often presents as a metachronous metastasis following several years of tumour free disease. We report a case of a 78-year-old female with metastatic ccRCC to the gallbladder. During follow-up ultrasound imaging, a polypoid gallbladder mass was discovered incidentally. The previous medical history is significant for total nephrectomy for left-sided ccRCC 6 years ago. A new suspicious intraluminal polypoid gallbladder mass in a patient with a history significant for clear cell renal cell carcinoma should alert the physician to consider metastatic clear cell renal cell carcinoma.     

Primary renal glomus tumor with concurrent papillary renal cell carcinoma and multiple papillary adenomas in a patient with end stage renal disease: a case report and clinicopathologic analysis

Glomus tumors are mesenchymal tumors commonly seen in the extremities, and rarely seen in deep visceral organs. This is due to the lack of glomus bodies in visceral organs. Here, we describe an unusual association between glomus tumor and co-existing papillary renal cell carcinoma, multiple papillary adenomas, and end stage renal disease. We discuss our diagnostic approach and differential diagnoses, along with an extensive review of all reported benign and malignant primary glomus tumors. A 63-year-old male with a known history of a kidney transplant, end-stage renal disease, and previous nephrectomy of his right kidney due to a renal mass (papillary renal cell carcinoma) presented with a renal mass. Microscopic examination showed papillary carcinoma, multiple papillary adenomas, and a small nodule with uniform, round to oval cells. Immunohistochemical work-up revealed the small nodule to be a glomus tumor. Only 28 cases of primary renal glomus tumors have been reported in the literature. Most were discovered incidentally. None of the reported cases have occurred along with other renal tumors. This is the first case of the unusual combination of primary renal glomus tumor arising in the native kidney of a renal transplant patient with concurrent papillary renal cell carcinoma and multiple papillary adenomas (renal adenomatosis). We also explore the possible genetic basis behind this association.     

Oncocytic papillary renal cell carcinoma: a clinicopathological study emphasizing distinct morphology,extended immunohistochemical profile and cytogenetic features

Papillary renal cell carcinoma (PRCC) is traditionally classified into type 1 and type 2. Recently, an oncocytic variant of PRCC has been described. We report a series of 6 oncocytic renal papillary tumors (OPRCC) which tended to occur in older patients (mean, 56.8 years) with a male preference (male-to-female ratio is 5:1). All 6 patients are alive with no evidence of disease after initial resection, showing an indolent clinical behavior. Histologically, tumors exhibited predominant papillary structure with delicate fibrovascular cores. Papillae were lined by single layers of cells with large, deeply eosinophilic and finely granular cytoplasms and round regular nucleus. The phagocytosis of tumor cells was frequently and evidently seen in our cases that hemosiderin-laden tumor cells and foamy tumor cells were noticed in five and four cases respectively. All tumors were immunoreactive for racemase, vimentin, CD10, and MET and negative for CD117. While E-cadherin, EMA, and cytokeratin 7 exhibited variable immunopositivity. FISH analysis was performed in five of six cases and found heterogeneous results. Trisomy of chromosomes 7 was found in three cases and trisomy of chromosomes 17 in two cases. Loss of chromosome Y was noted in one of four tumors in male patients. MET gene status was also investigated by direct sequencing in all 6 cases and found no distinct mutation in any case. These results suggest that OPRCC shows distinct morphology, indolent clinical behavior, and similar immunohistochemical and cytogenetic features with PRCC, seems to be a variant in the PRCC group. Whether the strong expression of MET indicates a potential therapeutic target is still unknown and requires further investigation in clinical trials.     

Fine-needle aspiration cytology of papillary renal cell carcinoma: the association with concomitant secondary malignancies

Papillary renal cell carcinoma is a rare type of renal malignancy. Cytogenetic findings characteristic for this tumor have been described as well as mutations of the proto-oncogene c-met. Secondary malignancies occurring together with papillary renal cell carcinomas are rare, and are often of genitourinary tract origin. We describe two cases of papillary renal cell carcinoma occurring in association with two other visceral malignancies, gastrointestinal stromal tumor and colon adenocarcinoma.Two cases of papillary renal cell carcinoma diagnosed by fine-needle aspiration (FNA), occurring in association with gastrointestinal malignancies were reviewed.Both aspirates showed cytologic features characteristic for papillary renal cell carcinoma, namely papillary structures, foamy histiocytes, intracytoplasmic hemosiderin, and nuclear grooves. Subsequent histology and immunohistochemical stains supported the cytologic diagnosis. The histologic diagnosis of gastrointestinal stromal tumor and colon adenocarcinoma were confirmed.Papillary renal cell carcinoma is a type of renal carcinoma that can be often accurately diagnosed by FNA. The occurrence of associated visceral malignancies has never been reported. The possible role of the protooncogene c-met in the development of these tumors was explored.     

Renal cell carcinoma with intratumoral calcium oxalate crystal deposition in patients with acquired cystic disease of the kidney

We describe 2 cases of renal cell carcinoma arising in acquired cystic disease of the kidney (ACDK) in patients with end-stage renal disease undergoing hemodialysis for more than 5 years and provide a brief review of the complications of ACDK. In both cases, abundant calcium oxalate crystals were observed within the tumors. Histologically, one of the tumors was a conventional (clear cell) renal cell carcinoma. The other tumor was a bilateral papillary renal cell carcinoma. Both tumors were high-grade carcinomas with extensive oncocytic (acidophilic) features. Also noted within the kidneys were cysts with atypical papillary hyperplasia. The clinicopathologic findings along with review of the literature suggest a relationship between tumor growth and calcium oxalate crystal deposition in patients undergoing hemodialysis with ACDK.     

Clear cell papillary renal cell carcinoma and clear cell renal cell carcinoma arising in acquired cystic disease of the kidney: an immunohistochemical and genetic study

Clear cell papillary renal cell carcinoma (RCC) is a recently established disease entity. However, there are few reports on genetic study of this entity. We report such a case with focus on genetic study. A 57-year-old Japanese man was found to have 3 renal tumors. Histologically, two tumors showed findings of clear cell RCC; and the other tumor showed findings of clear cell papillary RCC that was characterized by papillary growth pattern of neoplastic cells in cystic space with purely clear cell cytology. Immunohistochemically, tumor cells of clear cell papillary RCC were diffusely positive for PAX2 and cytokeratin 7, but negative for CD10, RCC Ma, and AMACR. In fluorescence in situ hybridization study for one clear cell papillary RCC, we detected polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20. In addition, we detected mutation of VHL gene in clear cell RCC, but found no VHL gene mutation in clear cell papillary RCC. Finally, our results provide further evidence that clear cell papillary RCC may be both morphologically and genetically distinct entity from clear cell RCC and papillary RCC.     

Osteopontin is differentially expressed in renal cell tumors

ABSTRACT

Osteopontin (OPN) has been shown to play a significant role in regulating the aggressiveness of cancer cells and promote tumor growth. Evaluation of this phosphorylated extracellular glycoprotein expression may help estimate its use as a potential prognostic marker in tumorigenesis of different renal tumors. The objective of the present study was to characterize for the first time the expression pattern of OPN in primary renal tumors and correlate its association to tumor progression and survival. A total of 68 primary renal tumors (clear cell renal cell carcinoma, oncocytoma, renal cell carcinoma, invasive urothelial carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, papillary urothelial carcinoma) were analyzed by immunohistochemical staining and Western blot methods. Expression of OPN in relation to grading, histologic type of tumor, and survival was statistically assessed. Study data demonstrated that OPN is differentially expressed in various renal tumor cells types. It was shown that OPN is predominantly expressed at the protein level in clear cell renal cell carcinoma when compared to other types of renal tumors. In conclusion, osteopontin may be involved in the pathogenesis of renal tumors. However, the role of OPN expression in predicting the biological response requires further evaluation.     

Tubulocystic renal cell carcinoma with poorly differentiated foci is indicative of aggressive behavior: clinicopathologic study of two cases and review of the literature

Tubulocystic renal cell carcinoma (TCRCC) is a rare, recently characterized RCC subtype with distinctive clinicopathologic and genetic characterizations as well as typical behaviors in an indolent fashion. However, sporadic case reports in the literature have indicated that TCRCC with sarcomatoid differentiation or poorly differentiated (PD) foci could behave aggressively. Herein, we reported two cases of TCRCC with PD foci indentified from our consultative service. Both patients were male and aged 66 y and 47 y, respectively. The first patient experienced radical nephrectomy while the other was treated by partial nephrectomy. Macroscopically, both tumors were described as partly cystic and solid with the greatest diameter measuring of 12-cm and 4.5-cm, respectively. Histologically, both lesions had classic areas of TCRCC occupying most part of the tumor with small papillary RCC component. In case one, PD foci were scatteredly distributed and mixed with TCRCC and papillary RCC components, while in the other case the PD foci were adjacent to the areas of TCRCC. In both tumors, the PD foci were composed of irregular, often angulated, small tubules lined by atypical eosinophilic cells and surrounded by desmoplastic stroma, resembling collecting duct carcinoma. Immunohistochemistry, in both tumors, both TCRCC component and PD foci showed the similar immunoprofiles, i.e., labeling strongly and diffusely with PAX8, AMACR and Vimentin, and focally with CK34βE12 but not with renal cell carcinoma marker or P63. In case one, the tumor invaded extensively into the adjacent renal parenchyma and focally into both renal sinusal and perirenal adipose tissues. The patient had metastasis in the pelvic cavity at the time of diagnosis and succumbed to the disease without further treatment 3 months later. The other case was organ confined but with focal positive renal parenchymal margin. The patient subsequently underwent radical nephrectomy and was in a good status without evidence of tumor recurrence or metastasis at a follow-up of 8 months.     

Expression of prostate-specific membrane antigen in renal cortical tumors.

Prostate-specific membrane antigen is a type II membrane glycoprotein that is expressed in benign and neoplastic prostatic tissue and has been recently shown to be also expressed in the neovasculature of various solid malignant tumors including renal cell carcinoma. Renal cell carcinoma is a heterogeneous group of tumors with distinct morphologic and genetic characteristics and clinical behaviors. We performed immunohistochemical studies on formalin-fixed, paraffin-embedded archival material from 75 nephrectomies, using antibodies 13D6 against prostate-specific membrane antigen and CD31 against endothelial cells. The study included 30 clear cell renal cell carcinomas, and 15 of each of papillary and chromophobe renal cell carcinoma and oncocytoma. The extent and intensity of staining were assessed semiquantitatively. In all cases, immunoreactivity was detected only in the tumor-associated neovasculature and not in tumor cells. Clear cell renal cell carcinoma showed the most diffuse staining pattern, where 24/30 cases or 80% had >50% reactive vessels, followed by chromophobe renal cell carcinoma (9/15; 60%) and oncocytoma (5/15, 33%). No diffuse staining was detected in any of the papillary renal cell carcinomas and only focal staining was detected in 11 cases (11/15; 73%). Staining intensity was the strongest in clear cell renal cell carcinoma (25/30; 83%) followed by chromophobe renal cell carcinoma (9/15; 60%), oncocytoma (8/15, 53%) and papillary renal cell carcinoma (5/15; 33%). In summary, prostate-specific membrane antigen is expressed in tumor-associated neovasculature of the majority of renal cortical tumors and is most diffusely and intensely expressed in clear cell renal cell carcinoma and least in papillary renal cell carcinoma. The differences in the expression of prostate-specific membrane antigen in renal cell carcinoma subtypes provide further evidence of the biological diversity of these tumors, and diagnostic and therapeutic applications of such expression can be expanded to include subtypes of renal cell carcinoma.