Clear cell urothelial carcinoma: a rare but villainous and hostile subtype.

IntroductionThe occurrence of clear cell tumors in the bladder is not uncommon. Clear cell dysplasia is well-described and characterized by focal replacement of transitional mucosa by cells with abundant clear cytoplasm, nuclear enlargement, and a granular chromatin pattern. Clear cells can also be seen in clear cell adenocarcinoma, which is rare, comprising 0.5% to 2.0% of the reported bladder carcinomas. Other clear cell tumors found in the bladder to be considered in the differential diagnosis are tumors of Müllerian origin and metastatic lesions, such as renal cell carcinoma, clear cell sarcoma, and malignant melanoma. Clear cell urothelial carcinoma is exceedingly rare, with only nine clinical cases described in the literature.Case presentationWe report the case of a 75-year-old Caucasian man who presented with intermittent hematuria, in whom a bladder tumor was identified. A final histopathology examination of a cystoprostatectomy specimen revealed a pT3b, G3 urothelial carcinoma of clear cell type (>90% clear cells) and a prostatic adenocarcinoma of Gleason grade 3+3 (score=6). The bladder tumor consisted of sheets of malignant cells with severe nuclear atypia and abundant clear cytoplasm; no glandular or tubular structures were identified. Tumor cells were periodic acid-Schiff positive and negative after diastase treatment; additional mucicarmine and oil red O stains were negative. Immunohistochemical stains showed the tumor cells positive for cytokeratin 7 (CK7), p63 (>80% nuclei), p53 (about 30% nuclei), vimentin, E-cadherin, cluster of differentiation (CD10), and Ki-67 (>70% nuclei). Stains for cell adhesion molecule 5.2 (CAM 5.2), CD117, cytokeratin 20 (CK20), human melanoma black 45 (HMB-45), paired box protein (PAX 8), placental alkaline phosphatase (PLAP), prostate specific antigen (PSA), renal cell carcinoma (RCC), cancer antigen 25 (CA25), leukocyte common antigen (LC), S-100 protein, and uroplakin III were all negative.ConclusionsThe tumor marker profile was consistent with clear cell type carcinoma of urothelial origin. Within the differential diagnoses, we ruled out other possible tumor types such as urothelial carcinoma with focal clear cell differentiation, clear cell adenocarcinoma, Müllerian tumors, and metastatic disease.

Renal Cell Carcinoma: Diagnosis Based on Metastatic Manifestations

High expression of carbonic anhydrase IX (CAIX) is reported for clear cell renal cell carcinoma (RCC), with a paucity of data for non-renal genitourinary or adrenal tumours. This study investigated the immunohistochemical expression of CAIX throughout the genitourinary tract and adrenal gland. High expression in the renal cortex was restricted to clear cell, papillary and clear cell papillary RCC and carcinoid. Core biopsies of clear cell RCC were consistently positive. Positivity within the urothelial tract was seen in urothelial carcinoma including squamous, small-cell, sarcomatoid and adenomatous differentiation and clear cell adenocarcinoma. Signet ring and plasmacytoid variants of urothelial carcinoma were negative. Phaeochromocytoma, adrenal cortical adenoma, seminoma, yolk sac tumour, choriocarcinoma, Leydig cell tumour and prostatic adenocarcinoma were predominately negative, with variable reactivity in adrenal cortical carcinoma, embryonal carcinoma, teratoma and Sertoli cell tumour. Carbonic anhydrase IX is a sensitive marker for clear cell RCC in core biopsies. However, other genitourinary or adrenal tumours that can have a clear cell appearance including urothelial, squamous cell, clear cell adeno and adrenal cortical carcinoma and Sertoli cell tumour express CAIX. Knowledge of expression overlap between these entities may prevent incorrect interpretation of immunohistochemical results, particularly if limited tissue is available.

A 70-year-old woman was referred to our hospital with gross hematuria and diagnosed with right invasive ureteral cancer and bladder urothelial carcinoma in situ. Intravesical BCG therapy and neoadjuvant chemotherapy with carboplatin and gemcitabine were performed at the same time. Subsequently, laparoscopic right nephroureterectomy was performed. Urothelial carcinoma in situ persisted; however, most of the tumor was clear cell carcinoma. The clear cell carcinoma lesion had clear cytoplasm with round nuclei and visible nucleoli in an insular arrangement as is the case with clear cell renal cell carcinoma. No transitional lesion between clear cell adenocarcinoma and urothelial carcinoma was presented. The clear cell carcinoma lesion was GATA3 negative and HNF4α positive; however, the urothelial cancer lesion was GATA3 positive and HNF4α negative. Clear cell carcinoma was diagnosed as clear cell adenocarcinoma similar to clear cell renal cell carcinoma histology.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

A SCORING ALGORITHM TO PREDICT SURVIVAL FOR PATIENTS WITH METASTATIC CLEAR CELL RENAL CELL CARCINOMA: A STRATIFICATION TOOL FOR PROSPECTIVE CLINICAL TRIALS

BACKGROUND: GATA3 is a transcription factor involved in the development of several organs, including mammary gland, skin, and kidney and has been suggested as a marker of urothelial differentiation and urothelial carcinoma including upper tract urothelial tumors. Its expression in primary renal tumors has not been fully determined. We evaluated the expression of GATA3 in a set of 177 renal carcinomas including 136 primary tumors and 41 unrelated metastatic clear cell renal cell carcinomas. DESIGN: Formalin-fixed paraffin-embedded tissues from primary clear-cell (71), papillary (14), chromophobe (33) and collecting duct (18) renal cell carcinomas and (41) unrelated metastatic clear cell renal cell carcinomas were retrieved from our surgical pathology archives and used to build 5 tissue microarrays. Paired tumor and non-neoplastic kidney were spotted 4 times each. GATA3 nuclear expression was evaluated using standard immunohistochemistry (GATA3: clone L50-823, BioCare Medical, CA). Intensity and extent (percentage) of expression were assessed in each spot. For each tumor, median extent of expression was calculated and the highest intensity of expression was recorded. Several cut-off values (any positivity, >5% and >10%) were evaluated to indicate a positive GATA3 result. RESULTS: Median nuclear GATA3 expression was 0% (0%-16%). When considering any positivity, 2/136 (1.5%) cases of the primary renal cell carcinomas were positive for GATA3. These included one clear cell renal cell carcinoma (1%, 3+intensity) and one collecting duct carcinoma (16%, 2+ intensity). Only one case remained positive (0.7%) when using either 5% or 10% cut-off values (collecting duct carcinoma). All 41 cases of metastatic clear cell renal cell carcinomas were negative for GATA3 expression (0%). CONCLUSION: GATA3 is negative in renal cell carcinomas of papillary and chromophobe cell types and with a very rare exception clear cell, and collecting duct carcinomas. The findings are of great utility in excluding renal cell carcinoma as a primary site during the work-up of tumors of unknown primary. In addition, our findings further support the specificity of GATA3 labeling of urothelial carcinoma in the setting of difficult epithelial kidney tumors where the differential includes urothelial vs renal cell carcinoma.

15. Analysis of primary renal and urothelial neoplasia at royal north shore hospital from 1998–2013

Chromosomal abnormalities in renal cell carcinoma variants detected by Urovysion fluorescence in situ hybridization on paraffin-embedded tissue

Focus on kidney cancer

Clear cell adenocarcinoma and nephrogenic adenoma of the urethra and urinary bladder: A histopathologic and immunohistochemical comparison

Simple SummaryImmune checkpoint inhibition plays a pivotal role in the treatment of metastatic renal cell carcinoma and metastatic urothelial carcinoma. The association of chronic kidney disease with these tumors is well established. However, to what extent kidney failure modifies the efficacy or the toxicity profiles of checkpoint inhibitors has been poorly investigated. In this paper, we reviewed the files of 85 patients with renal cell carcinoma and 41 with urothelial cancer who had received checkpoint inhibitor treatment, and found that 37.6% and 41.5% had evidence of chronic kidney disease, respectively. We found that neither general treatment-related nor immune-related adverse events differed between patients with normal or impaired renal function. Using a multivariate analysis, we found that chronic kidney disease had no effect on progression-free survival. However, irrespective of the tumor entity, chronic kidney disease was found to positively influence overall survival. We conclude that treatment with checkpoint inhibitors in patients with chronic kidney disease is safe and efficient.Background: Checkpoint inhibitors are a standard of care in the treatment of advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC). Patients with these tumors often suffer from concomitant chronic kidney disease (CKD). Limited data are available on the efficacy and toxicity of checkpoint inhibitors in patients with CKD. Methods: We retrospectively analyzed 126 patients who received checkpoint inhibitors for RCC (n = 85) or UC (n = 41) and analyzed the frequency of treatment- and immune-related adverse events (AEs). We performed a multivariate analysis to determine progression-free survival (PFS) and overall survival (OS). Results: A total of 38.9% of patients had CKD. Frequencies of general AEs (49.0% in CKD vs. 48.1%, p > 0.99999) and immune-related AEs (28.6 vs. 24.7%, p ≥ 0.9999) did not significantly differ between the groups. There was no difference in PFS for patients with RCC or UC and CKD or without CKD (RCC: 6.81 vs. 7.54 months, HR 1.000 (95%CI 0.548–01.822), p = 0.999; UC:2.33 vs. 3.67 months, HR 01.492 (95%CI 0.686–3.247), p = 0.431). CKD appeared to be a potential effect modifier for OS in both RCC and UC (RCC: NR vs. 23.9 months, HR 0.502 (95%CI 0.219–1.152), p = 0.104; UC:18.84 vs. 15.42 months, HR 0.656 (95%CI 0.296–1.454), p = 0.299). Conclusions: Checkpoint inhibitor treatment in our cohort of patients with CKD was as safe and efficient as in the cohort of patients without CKD.

Cytogenetic and molecular genetic techniques have been used in demonstrating the chromosomal abnormalities which characterize specific subtypes of renal cell carcinoma (RCC). The aim of this study was to determine the efficiency of fluorescent in situ hybridization (FISH) technique in characterizing various subtypes of RCC based on the presence of specific chromosome abnormalities found in each RCC subtype. FISH was performed on touch imprint smears from eight renal cell carcinomas histologically confirmed by established criteria. In four tumors with histologic features of chromophobe renal cell carcinoma (ChRCC), interphase FISH was performed using centromeric probes for chromosomes 1, 2, 6, 10, 12, 17 and 21. All four ChRCC tumors showed one FISH signal corresponding to one copy number for each of these chromosomes. Two papillary RCCs included in this study showed trisomy 7 and 17, and loss of chromosome Y, using the corresponding chromosome centromeric probes. Similarly, we tested two clear cell RCCs for chromosome 3 short arm deletion with DNA probe 3p21.3. Both tumors showed loss of 3p21.3 signal. We conclude that interphase FISH performed on touch imprint smears is a relatively simple, rapid and reliable method for detecting chromosome abnormalities which are specific for various subtypes of RCC.

IntroductionUrine concentration of human kidney injury molecule-1 (KIM-1) is suggested to be increased in patients with renal cell carcinoma (RCC). However, it has never been tested in patients with urothelial tumors, while preoperative differentiation between RCC and upper tract urothelial carcinoma (UTUC) plays an essential role in therapeutic decisions.The aim of the study was to evaluate the role of urinary KIM-1 expression in preoperative differentiation between RCC and urothelial carcinoma (UC).Material and methodsSixty-four participants were enrolled in the study, including 30 patients with RCC and 27 with UC (16 with UTUC and 11 with bladder tumor). Preoperative urinary KIM-1 levels were measured using a commercially available ELISA kit and normalized to urinary creatinine levels.ResultsThe median concentration of urinary KIM-1 normalized to urinary creatinine was lower in patients with RCC compared to UC (1.35 vs 1.86 ng/mg creatinine, p = 0.04). The comparison between RCC and UTUC shows even more significant difference (1.33 vs 2.23 ng/mg creatinine, p = 0.02). Urinary KIM-1 concentration did not correlate with tumor stage nor grade in any of the groups. ROC analysis to identify UC revealed AUC of 0.657 with sensitivity 33.3% and specificity 96.7% at the cut-off value of 3.226 ng/mg creatinine. Among patients with eGFR ≥60 mL/min/1.73 m², ROC analysis to detect UC achieved AUC of 0.727 with sensitivity 69.5% and specificity 70.2%.ConclusionsUrine KIM-1 can potentially differentiate UC from RCC. However, a wide range of observed results and limited sensitivity and specificity requires caution in making clinical decisions before confirmatory studies.