Conventional Clear Cell Renal Carcinoma Research Articles

EphrinB2: Expression of a novel potential target in renal cell carcinoma.

Renal cell carcinoma (RCC) is primarily managed by surgery with the use of systemic targeted therapy in a metastatic setting. Newer targeted therapeutic options are evolving; Eph-ephrin is a potential new pathway. The therapeutic potential of targeting the EphB4-EphrinB2 pathway has been demonstrated in many solid tumors; however, its expression in RCC has only been evaluated in a few studies with limited cases. We herein determine the immunohistochemical expression of EphrinB2 in RCC. A tissue microarray comprising 110 cases of different histological subtypes of RCC and 10 normal kidney tissues were stained with monoclonal anti-EphrinB2 antibody (Abcam, AB201512). The tumor and endothelial cells expressing the EphrinB2 were examined and its expression was correlated with sex, histological subtypes, and tumor nodes metastasis (TNM) stage. Twenty cases of urothelial carcinoma and two unsatisfactory conventional clear cell RCC cases were excluded, and EphrinB2 expression was interpreted in the remaining 88 tumors. EphrinB2 was expressed in 42 out of 88 tumors (47.7%) and was negative in the normal renal parenchyma. There was a statistically significant difference in the expression of EphrinB2 in males (55%) and females (32%). However, no such difference of expression was noted for the histological subtypes and the stages. Half (51%) of Stage 1 (n = 30) and Stage 2 (n = 11) tumors showed EphrinB2 positivity. EphrinB2 is expressed in approximately half of RCC cases. EphrinB2 expression in the early stage cancer might indicate its induction as an early event.

Abstract 158: A combination therapy of atypical protein kinase C inhibitors and phosphatidylinositol-3-kinase inhibitor reduces resistance & invasiveness in renal cell carcinoma (RCC)

Abstract Renal Cell Carcinoma (RCC) is the most common type of kidney cancer (85%) of which 75% of the cases involve conventional clear cell RCC (ccRCC). Choice of treatments recommended for clear cell carcinoma and non-clear cell carcinoma are partial nephrectomy (Stage I), radical nephrectomy (Stage II and III) and chemotherapy (stage IV). Phosphatidylinositol-3- kinase (PI3K) inhibitors can be a viable candidate in the chemotherapy of ccRCC as the PI3K/PDK1 pathway is frequently activated in RCC. Hence, PI3K inhibitors like Alpelisib (BYL 719) can be a choice of treatment. In addition, aPKCs, PKC ί/λ and PKC ζ are overexpressed in most cancer cells and play a central role in tumor progression and metastasis of different type of cancers. Treatment of ccRCC metastatic clear cells with a combination of aPKC inhibitor [8-hydroxynaphthalene-1, 3, 6-trisulfonic acid] ζ-stat, or ICA-1 and BYL 719 inhibits PKC ί/λ and PKC ζ with the downstream inhibition of c-Myc (a major protein controlling cell survival and cell cycle progression in RCC). Inhibition of the aPKCs (PKC ί/λ and PKC ζ) also reduces the activation of other important proteins, for example, Mitogen-Activated Protein Kinase Kinase (MEK) and extracellular signal regulated kinase (ERK1/2). It is observed that treatment with ζ-stat, or ICA-1 disrupts the aPKC-AKT1 association which in turns reduces the activation of AKT1 through phosphorylation. ζ-stat, or ICA-1 treatment also disrupts association between aPKC and c-Myc. Inhibition of aPKCs and other downstream effector proteins by combination therapy is more pronounced compared to the single therapy. These effects contribute to reduced cell growth, cell survival and eventually induction of apoptosis. Boyden Chamber assay also suggested that there is decreased invasiveness of the cells when treated with the combination treatment. This can be due to the inactivation of both ERK1/2 and AKT by the combination treatment. In addition, efflux proteins, (p-glycoprotein (P-gp) and ATP-binding cassette sub-family G member 2 (ABCG2), responsible for developing cell resistance, had reduced expression in the cells when treated with ζ-stat as a single therapy along with the combination of Alpelisib and ζ-stat. Hence, combination therapy of Alpelisib and an aPKC inhibitor for metastatic ccRCC can reduce expression of multi drug resistance (MDR) proteins/efflux transporter P-gp and ABCG2. Therefore, a combination of Alpelisib and an aPKC inhibitor is an effective approach to reducing cell proliferation, invasion and resistance eventually inducing apoptosis. Citation Format: Khandker Mohammad Khalid, Wishrawana S. Ratnayake, Christopher A. Apostolatos, Luke Lajmi, Sloan Breedy, Nuzhat N. Oishee, Mildred Acevedo-Duncan. A combination therapy of atypical protein kinase C inhibitors and phosphatidylinositol-3-kinase inhibitor reduces resistance & invasiveness in renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 158.

Immunoexpression of SDHB, FH, and CK20 among eosinophilic renal tumors: A tissue microarray study

BackgroundDifferential diagnosis can be a challenge for eosinophilic subtypes of renal cell tumors due to their overlapping histomorphological and immunohistochemical features. We aimed to investigate the frequency of rare variants of renal cell carcinomas (RCCs) such as succinate dehydrogenase-deficient RCC (SDDRCC), hereditary leiomyomatosis and RCC (HLRCC)-associated RCC, and eosinophilic, solid, and cystic RCC (ESCRCC) in our population. Materials and methodsRenal tumors which could be considered in the eosinophilic tumor category were included: 91 conventional clear cell RCCs with eosinophilic cytoplasm, 72 papillary RCCs, 74 chromophobe RCCs, 88 oncocytomas, and 37 other rare subtypes. Using the tissue microarray method, succinate dehydrogenase B (SDHB), fumarate hydratase (FH), and cytokeratin 20 (CK20) antibodies were performed by immunohistochemistry. Immunohistochemistry was repeated on whole block sections for selected cases. The utility of these antibodies in the differential diagnosis was also investigated. ResultsLoss of SDHB expression was detected in three tumors, two of which showed typical morphology for SDDRCC. In additional two tumors, SDHB showed weak cytoplasmic expression without a mitochondrial pattern (possible-SDHB deficient). None of the tumors showed loss of FH expression. Heterogeneous reactions were observed with SDHB and FH antibodies. Only one ESCRCC was detected with diffuse CK20 positivity. ConclusionSDDRCCs, HLRCC-associated RCCs, and ESCRCCs are very rare tumors depending on the population. Possible weak staining and focal loss of SDHB and FH expression should be kept in mind and genetic testing must be included for equivocal results.

A Case of Carney Triad Complicated by Renal Cell Carcinoma and a Germline SDHA Pathogenic Variant

Background: Carney triad is a rare multiple-neoplasia syndrome presenting as an association of paragangliomas (PGL), gastrointestinal stromal tumors (GIST), and pulmonary chondromas (CHO). Succinate dehydrogenase deficiency has been associated with several neoplasias, including Carney triad, renal cell carcinoma (RCC) and those associated with hereditary PGL/ pheochromocytoma (PHEO) syndromes. Clinical Case: A 57-year-old male diagnosed with hypertension at age 49, presented with a gradual increase in blood pressure over a period of 12 months. For seven years following his diagnosis of hypertension, the patient experienced episodic increases in blood pressure, to a systolic pressure greater than 180 mmHg associated with a tight band sensation around his forehead lasting half a day. Abdominal computed tomography (CT) revealed a left adrenal adenoma, a 5.1 cm para-aortic mass, and a right renal superior pole lesion measuring 2.5 cm, which was suspicious for a carcinoma. 123I-metaiodobenzylguanidine (123I-MIBG) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scans were performed, which suggested the para-aortic mass to be consistent with a PGL. Additionally, 18F-FDG uptake was noted in the gastroesophageal region and was suspicious for a GIST. The left adrenal mass was not associated with 123I-MIBG or 18F-FDG activity. Chest CT demonstrated a right middle lobe lung lesion suggestive of a CHO, although no biopsy was performed. A diagnosis of Carney triad was made. The patient underwent surgical resection of the PGL and GIST, as well as a partial right nephrectomy. The PGL and GIST were positive for SDHA and negative for SDHB by immunohistochemical (IHC) staining. Pathology from the renal lesion was consistent with a 2.3 cm conventional clear cell renal carcinoma, with positive staining for SDHA and SDHB by IHC. The patient was found to harbor a germline heterozygous pathogenic variant (c.91 C>T, p.R31X) in SDHA which has been previously reported and results in loss of function of SDHA. SHDC hypermethylation was not detected in the PGL, GIST, or RCC. Additionally, DNA sequencing of the RCC did not indicate loss of heterozygosity at the variant region of interest. Although the SDHA disease-causing variant is responsible for the patients Carney triad phenotype, it is unclear if this variant is causative of the RCC. Conclusion: This is a novel presentation of a germline inactivating SDHA pathogenic variant in a patient with Carney triad complicated by RCC. However, an SDHA disease-causing variant was previously reported in a patient with comorbid GIST and RCC. This case provides further support to the increasing evidence that SDHx pathogenic variants may predispose patients to develop renal neoplasms.

BAP1-Mutated Clear Cell Renal Cell Carcinoma.

While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC. We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features. BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases. Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.

Collision Tumor of the Kidney with Clear Cell Renal Cell Carcinoma and Papillary Renal Cell Carcinoma Components: Report of a Rare Case

Abstract Introduction/Objective Collision tumors refer to the phenomenon where distinct, well-defined tumor subtypes are present within a single lesion. While this phenomenon has been described in different organs, it has been rarely encountered in renal tumors outside the context of rare tumor susceptibility syndromes. Collision tumors of the kidney may encompass any known benign or malignant renal tumor types. However, a collision tumor of two different renal cell carcinoma (RCC) subtypes is remarkably rare. Methods A 43-year-old male was referred to our institution for the management of a right lower pole renal mass. The right radical nephrectomy specimen revealed a 6.5 x 5.0 x 4.0 cm well circumscribed, yellow-orange and hemorrhagic cortical mass abutting the renal capsule and extending into the renal sinus fat. A grossly distinct 1.5 x 1.4 x 1.2 cm pale, nodular area was demonstrated at the periphery of the tumor. Results Microscopically, the tumor displayed two distinct, neoplastic components within the same mass, without transitional morphology. The majority of the tumor consisted of a nuclear-grade-2 conventional clear cell RCC, while the peripheral nodule represented a type-2 papillary RCC component. Immunostains further supported these findings: The papillary component was strongly and diffusely positive for CK7 and P504S/AMACR with variable EMA and vimentin expression, and negative for CAIX, while the clear cell component was positive for CAIX, EMA and vimentin with only focal and weak staining for CK7 and faint nonspecific P5O4S/AMACR staining. TFE3 Mart1 and HMB45 immunostains were negative in the tumor. Conclusion Collision tumor of the kidney with two distinct RCC subtypes is an exceedingly rare finding. Careful gross examination may be the first clue to identify such lesions, and sampling of all grossly distinct tumor areas is crucial. The identification of collision tumors may have important therapeutic implications, given the difference in pathophysiology and outcome between RCC subtypes.

Abstract 1783: A combination therapy of atypical protein kinase inhibitor and phosphatidylinositol-3- kinase inhibitor reduces multidrug resistance in renal cell carcinoma (RCC)

Abstract Renal Cell Carcinoma (RCC) is the most common type of kidney cancer (85%) of which 75% of the cases involve conventional clear cell RCC (ccRCC). Choice of treatments recommended for clear cell carcinoma and non-clear cell carcinoma are partial nephroctomy (Stage I), radical nephoroctomy (Stage II and III) and chemotherapy (stage IV). Phosphatidylinositol-3- kinase (PI3K) inhibitors are one of the most prospective candidate in the therapy of ccRCC as the PI3CA gene for p110α (a class of the catalytic sub unit of PI3K) is mutated in most of the cases. Hence, PI3K inhibitors like Alpelisib (BYL 719) can be a treatment. But current therapeutic prospects are limited to the fact that RCC is a chemotherapy-resistant cancer type that acts as a barrier for successful treatment with this inhibitor. In addition, of all the other aPKCs, PKC ί/λ and PKC ζ are reported to be frequently overexpressed in most cancer cells and to have different significant roles in tumor progression and carcinogenesis of different type of cancers. Caki-1 metastatic clear cells were treated with PKC ζ inhibitor [8-hydroxynaphthalene-1,3,6-trisulfonic acid] or ζ-stat, Alpelisib and combination of both ζ-stat and Alpelisib at different doses. The results of WST-1 shows that the combination of ζ-stat (7.5 µM) and Alpelisib (10.0 µM) has the most cytotoxicity compared to the single therapy of Alpelisib. Annexin-V/PI assay also suggested that the combination therapy caused greater percentage of apoptosis and cell death compared to the single therapy of Alpelisib. The efflux proteins, (p-glycoprotein (P-gp) and ATP-binding cassette sub-family G member 2 (ABCG2), are responsible for developing cell resistance in Caki-1 cells had reduced expression in the cells when treated with the combination treatment of Alpelisib and ζ-stat. Therefore, combination therapy of Alpelisib and an aPKC inhibitor for metastatic ccRCC can reduce expression of multi drug resistance (MDR) proteins/efflux transporter P-gp and ABCG2. Hence, this combination may be a possible treatment that might help eradicating MDR of ccRCC. Thus, a combination of Alpelisib and an aPKC inhibitor can be a two pronged approach reducing the cell proliferation and resistance. Citation Format: Khandker Mohammad Khalid. A combination therapy of atypical protein kinase inhibitor and phosphatidylinositol-3- kinase inhibitor reduces multidrug resistance in renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1783.

Abstract 3417: Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway

Abstract Tumors arising from the nephron of the kidney are collectively called renal cell carcinomas (RCCs). Recent high-throughput genomics endeavors, such as the TCGA initiative, have provided a roadmap for a deepened molecular understanding of these tumor types. With the aim to characterize RCCs that do not conform to the most common subtypes of RCC we scrutinized RNA-Seq transcriptomes of kidney tumor samples supplied by the TCGA project. Dimensionality reduction analyses revealed one defined a transcriptional subset of RCCs, which upon re-review of tissue histology could be classified as clear cell papillary RCC (ccpRCC). In line with previous analyses, samples were defined by overexpression of KRT7, CA9, CCND1 and GATA3 and harbored few genomic alterations as well as a limited number of gene mutations; only mTOR was found recurrently mutated. We observed upregulation of the Hypoxia inducible factor (HIF) pathway, possibly caused by VHLinactivation by gene promoter methylation in the majority of ccpRCCs. This may explain the morphological resemblance of ccpRCCs to VHL driven conventional clear cell RCCs. Further, the methylomes of ccpRCCs were distinct from other tumors and transcription factors specific for epithelial cells of the distal nephron were overexpressed, thus suggesting distinct tumor ontogeny of ccpRCCs compared to other renal tumors. Citation Format: David Lindgren, Jonas Sjolund, Helen Nilsson, Borje Ljungberg, Martin Johansson, Hakan Axelson. Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3417.

Renal Cell Carcinoma With Leiomyomatous Stroma: A Group of Tumors With Indistinguishable Histopathologic Features, But 2 Distinct Genetic Profiles: Next-Generation Sequencing Analysis of 6 Cases Negative for Aberrations Related to the VHL gene.

We have studied a cohort of renal cell carcinomas (RCCs) with smooth-muscle stroma (N=6), which lacked any of following genetic aberrations: mutations in the VHL-gene-coding sequence, loss of heterozygosity of chromosome 3p, or hypermethylation of VHL. Using targeted next-generation sequencing, no intronic VHL mutations or mutations in selected genes involved in angiogenesis and genes frequently mutated in clear cell RCC were identified. Tumors were also tested for the presence of hotspot mutations in the TCEB1 gene with negative results in all cases. We conclude that there exists a group of RCCs with abundant leiomyomatous stroma, where the epithelial component is indistinguishable from conventional clear cell RCC and distinct from clear cell (tubulo-) papillary RCC and that these tumors lack aberrations related to the function of the VHL gene, mutations in genes involved in angiogenesis, and hotspot mutations in the TCEB1 gene.

Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma

IntroductionBRCA1-associated protein 1 (BAP1) is a gene situated on chromosome 3p in a region that is deleted in more than 90% of renal cell carcinomas (RCCs). In the present study, we studied BAP1 immunohistochemical expression in a large series of conventional clear cell RCCs (ccRCCs) treated with radical nephrectomy; we assessed the prognostic value of their expression in terms of patients׳ survival at long-term follow-up. Materials and methodsA total of 154 consecutive patients with ccRCC were selected from a prospective database and considered for the study purpose; all patients were treated with radical nephrectomy and lymphadenectomy at our Institute of Urology between 1983 and 1985.The features considered in this study were tumor size, grade and stage, vascular and capsular invasion, incidence of metastasis, and patient-specific survival; all these parameters were correlated with immunohistochemical cytoplasmic and nuclear expression of BAP1 in tumoral tissue. ResultsMedian follow-up was 196.18 months and median survival was 125.34 months. Nuclear BAP1 expression showed a high frequency of loss in tumoral cells; nuclear BAP1-negative tumors had higher tumor size, higher Fuhrman grade, and higher stage, a greater amount of vascular and capsular invasion and a higher incidence of metastases. In multivariate analysis, pathological stage and nuclear BAP1 expression resulted independent prognostic factors. ConclusionWe have demonstrated that nuclear BAP1 expression is a marker of prognosis in ccRCC, having an influence on cancer-specific survival. The clinical importance for BAP1 will be realized with the identification and application of targeted therapies and with individualized approaches in the adjuvant setting or in the metastatic setting or in both the settings.

Cytopathologic features of clear cell papillary renal cell carcinoma: A recently described variant to be considered in the differential diagnosis of clear cell renal epithelial neoplasms.

Clear cell papillary renal cell carcinoma (CCPRCC) is a distinctive variant of renal cell carcinoma that has been formally adopted by the new Word Health Organization classification. An emerging consensus has documented its particularly indolent course and emphasized its separation from conventional clear cell renal cell carcinoma (CCRCC) for treatment planning. CCPRCC features in cytologic preparations have not been studied. This study retrospectively identified a series of CCPRCCs that had cytology samples before the histopathologic diagnosis and reviewed corresponding cytologic materials, including aspirate smears, cell block materials, touch preparations, and core biopsy samples. The identified clinicopathologic and cytologic features were tabulated. Five cases of CCPRCC with cytopathologic materials were identified from 4 women and 1 man aged 34 to 70 years (2 with end-stage renal disease), and the sampled lesions were 1.8 to 11.0 cm. The original cytopathologic diagnostic considerations ranged from atypical cyst-lining cells to angiomyolipoma to CCRCC and CCPRCC. The aspirate and touch preparation samples showed scant cellularity with scattered sheets and clusters of small, bland epithelial cells (much smaller than admixed renal tubular cells) with optically clear cytoplasm (lacking conspicuous cytoplasmic vacuolization) and small, grade 1 nuclei. The cell block materials and the core biopsy samples showed cyst walls with prominent myomatous stroma lined by low-grade epithelium with optically clear cytoplasm, inverse nuclear polarization, and a characteristic cytokeratin 7-positive/carbonic anhydrase IX-positive phenotype. Three cases were treated with resection, 1 case was treated with ablation, and 1 case was under surveillance. CCPRCC demonstrates recognizable cytomorphologic features and merits consideration in the cytologic differential diagnosis for kidney lesions. With increasing experience, more conservative management may be contemplated. Cancer Cytopathol 2016;124:565-72. © 2016 American Cancer Society.

Histological subtype of renal cell carcinoma significantly affects survival in the era of partial nephrectomy

ObjectivesTo analyze whether the histological subtype of renal cell carcinoma (RCC) affects survival after surgical resection in contemporary patients, and if so, whether prognostic significance differs according to the type of surgical resection or tumor stage. Materials and methodsFrom 2006 to 2014, 2,237 patients underwent surgical resection (25% radical nephrectomy and 75% partial nephrectomy [PN]) for nonmetastatic RCC at a tertiary referral center. Estimated survival function curves and Cox regression models evaluated the effect of histological subtype on recurrence-free survival (RFS) and overall survival (OS). Interaction analyses tested whether the effect of histological subtype depends on the type of surgical resection or tumor stage. ResultsPatients with RCC stage T2 or lower and those with low-grade conventional clear cell, papillary or chromophobe RCC of any stage had 5-year RFS probabilities>90%. Patients with clear cell papillary RCC stage T3 or greater had predicted 5-year RFS of 81%. However, 5-year OS probabilities were>94% for clear cell papillary RCC of any stage. High-grade conventional clear cell and papillary RCC stage T2 or lower, low-grade conventional clear cell and chromophobe RCC of any stage conferred 5-year OS probabilities of >93%. Unclassified RCC demonstrated the lowest OS probabilities at any stage.In multivariable analyses, histological subtype affected RFS (P<0.0001) and OS (P = 0.026) following surgical resection, with no differences in this association for radical nephrectomy vs. PN (RFS, P = 0.2; OS, P = 0.4), and across pathologic stages (RFS, P = 0.1; OS, P = 0.3). Compared with low-grade conventional clear cell RCC, chromophobe (hazard ratio [HR] = 0.72, 95% CI: 0.30–1.75) and papillary RCC (HR = 0.30, 95% CI: 0.09–0.97) conferred lower risk of recurrence. Chromophobe (HR = 0.67, 95% CI: 0.30–1.52) and clear cell papillary RCC (HR = 0.91, 95% CI: 0.12–6.78) conferred the lowest risk of all-cause mortality. ConclusionsIn the era of PN for RCC, histological subtype remained a significant predictor of survival, regardless of type of surgical resection or tumor stage.

Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma

BAP1 is a gene situated on chromosome 3p in a region that is deleted in over 90% of Renal Cell Carcinomas (RCCs) (1,2). In the present study we studied BAP1 immunohistochemical expression in a large series of conventional clear cell RCCs (ccRCCs) treated with radical nephrectomy and we assessed the prognostic value of their expression in terms of patients survival at long-term follow-up. 154 consecutive patients with ccRCC were selected from a prospective database and considered for the study purpose; all patients were treated with radical nephrectomy and lymphadenectomy at our Institute of Urology between 1983 and 1985. The features considered in this study were tumor size, grade and stage, vascular and capsular invasion, incidence of metastasis and patient specific survival; all these parameters were correlated with immunohistochemical cytoplasmic and nuclear expression of BPA-1 in tumoral tissue. Median follow-up was 196.18 months (range 5 to 274); median survival was 125.34 months (range 5 to 274 months). We found that nuclear BAP1 expression showed a high frequency of loss in tumoral cells; nuclear BAP1 negative tumors had higher tumor size, higher Fuhrman grade, and higher stage, a greater amount of vascular and capsular invasion and a higher incidence of metastases. We have demonstrated that nuclear BAP1 expression is a marker of prognosis in ccRCC, having an impact on cancer-specific survival. The clinical importance for BAP1 will be realized with the identification and application of targeted therapies and with individualized approaches in the adjuvant and/or metastatic setting.

Clear cell papillary renal cell carcinoma: a potential mimic of conventional clear cell renal carcinoma on core biopsy.

Clear cell papillary renal cell carcinoma (CCP-RCC) is a recently described, relatively uncommon variant of renal cell carcinoma (RCC) with a reported incidence of 4.1%. Thought to only arise in those with end stage renal disease, CCP-RCC is increasingly identified in those without renal impairment. CCP-RCCs have unique morphologic, genetic, and immunohistochemical features distinguishing them from both conventional clear cell renal cell carcinomas and papillary renal cell carcinomas. Immunohistochemically, these tumors are positive for CK7 and negative for CD10 and racemase. This is in contrast to conventional cell renal cell carcinomas (CK7 negative, CD10 positive) and papillary cell carcinomas (CK7, CD10, and racemase positive). These tumours appear to be indolent in nature, with no current documented cases of metastatic spread. We present the case of a 42-year-old female who presented with an incidental finding of a renal mass that on a core biopsy was reported as clear cell carcinoma, Fuhrman grade 1. She subsequently underwent a radical nephrectomy and further histological examination revealed the tumor to be a clear cell papillary renal cell carcinoma, Fuhrman grade 1.

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

The accurate pathological diagnosis of renal neoplasia both guides treatment and underlies translational research. We searched the electronic database of the department of anatomical pathology Royal North Shore Hospital for all cases of renal neoplasia and urothelial neoplasia treated by nephrectomy from 1998 to 2013. We reviewed the pathology reports to both restage according to the 7th edition 2009 staging system and to reclassify according to the ISUP Vancouver 2013 classification of renal carcinoma. The restaging and reclassification was based on review of the reports rather than slide review. We identified 415 cases and divided them in to three broad groups of renal parenchymal tumours, urothelial carcinoma and stromal tumours (angiomyolipoma, leiomyoarcoma and synovial sarcoma). Of these, 322 (77.6%) were renal parenchymal tumours, 77 (18.6%) were urothelial carcinoma and 16 (3.9%) were stromal tumours (12 angiomyolipomas, 3 leiomyosarcomas and 1 synovial sarcoma). Of the renal parenchymal tumours, 231 (71.7%) were conventional clear cell renal carcinoma, 29 (9.0%) were papillary renal cell carcinoma, 20 (6.2%) were oncocytoma, 16 (5.0%) were chromophobe renal cell carcinoma, 4 (1.2%) were sarcomatoid carcinoma, 3 (0.9%) were clear cell tubulopapillary renal cell carcinoma, 2 (0.6%) were metanephric adenoma, 2 (0.6%) were acquired cystic disease associated renal carcinoma, 1 was hereditary leiomyomatosis associated renal cell carcinoma and 1 was a mucinous and tubular spindle cell carcinoma. For 15 cases (4.7%) further subclassification into different types of renal carcinoma could not be made based on the report. The median age of patients at the time of nephrectomy were 68.0 years for renal parenchymal tumours and 75.0 years for urothelial carcinoma. Clear cell renal cell carcinoma presented with a median age of 67.0 years, papillary carcinomas 67.0 years, oncocytoma 73.0 years, and chromophobe 63.5 years.

Clinicopathologic Patterns of Adult Renal Tumors in Pakistan

Renal cancer is a serious public health problem which may be under reported and registered in our setup, since the Karachi cancer registry documented only 43 cases out of 4,268 incident cancer cases over 3 year duration. Therefore we aimed to determine the clinicopathologic characteristics of adult renal tumors in our setup. The study was conducted in histopathology department, Liaquat National Hospital and included total of 68 cases of adult renal tumors over 4 years. Detailed histopathologic characteristics of tumors were analyzed. Mean age of patients was 56.4 (18-84) years. Renal cell carcinoma (RCC) was the most common cell type (78%) cases; followed by transitional/urothelial carcinoma (12.5%), leiomyosarcoma (4.7%), oncocytoma (1.6%), squamous cell carcinoma (1.6%) and high grade pleomorphic undifferentiated sarcoma (1.6%). Among 50 RCC cases; 62% were conventional/clear cell RCC (CCRCC) type followed by papillary RCC(PRCC), 24%; chromophobe RCC(CRCC), 6% and sarcomatoid RCC(SRCC), 8%. Mean tumor size for RCC was 7.2 cm. Most RCCs were intermediate to high grade (60% and 40% respectively). Capsular invasion, renal sinus invasion, adrenal gland involvement and renal vein invasion was seen in 40%, 18%, 2% and 10% of cases respectively. We found that RCC presents at an earlier age in our setup compared to Western populations. Tumor size was significantly larger and most of the tumors were of intermediate to high grade. This reflects late presentation of patients after disease progression which necessitates effective measures to be taken in primary care setup to diagnose this disease at an early stage.

Spontaneous regression of metastatic pulmonary renal cell carcinoma in the setting of sarcomatoid differentiation of the primary tumour

We present a case of spontaneous regression of pulmonary metastases from renal cell carcinoma (RCC) with sarcomatoid differentiation, prior to intervention. The patient presented with conventional type RCC with Furhman Grade 4/4 and sarcomatoid differentiation, complicated by pulmonary metastases. Palliative systemic therapy was planned, but prior to the onset of treatment, serial computed tomography scans demonstrated regression of metastatic disease. Spontaneous regression of metastases is rare, but well-documented in conventional clear cell RCC. To the best of our knowledge, this has not previously been described in the setting of sarcomatoid differentiation of the primary tumour.

MicroRNA profiles classify papillary renal cell carcinoma subtypes

Background:Besides the conventional clear-cell renal cell carcinoma (ccRCC), papillary RCC (pRCC) is the second most common renal malignancy. Papillary RCCs can further be subdivided into two distinct subtypes. Although a clinical relevance of pRCC subtyping has been shown, little is known about the molecular characteristics of both pRCC subtypes.Methods:We performed microarray-based microRNA (miRNA) expression profiling of primary ccRCC and pRCC cases. A subset of miRNAs was identified and used to establish a classification model for ccRCC, pRCC types 1 and 2 and normal tissue. Furthermore, we performed gene set enrichment analysis with the predicted miRNA target genes.Results:Only five miRNAs (miR-145, -200c, -210, -502-3p and let-7c) were sufficient to identify the samples with high accuracy. In a collection of 111 tissue samples, 73.9% were classified correctly. An enrichment of miRNA target genes in the family of multidrug-resistance proteins was noted in all tumours. Several components of the Jak-STAT signalling pathway might be targets for miRNAs that define pRCC tumour subtypes.Conclusion:MicroRNAs are able to accurately classify RCC samples. Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC. Furthermore, our results indicate that pRCC type 2 tumours could be dependent on oncogenic MYC signalling.

Abstract 1964: MicroRNA expression profiles classify renal cell carcinoma subtypes.

Abstract Introduction. Renal cell carcinoma (RCC) accounts for nearly 4% of all malignancies worldwide. According to the WHO classification of tumors of the urinary system, RCC is a collection of different subtypes rather than one entity. Besides the conventional clear cell RCC (ccRCC), the papillary RCC (pRCC), with an incidence of 10%-15%, is the second most common entity among renal malignancies. By histological characteristics, pRCCs can further be sub-divided into two distinct subtypes. Hereby, pRCCs type 2 are correlated with a worse clinical outcome. To date, little is known about the molecular characteristics within the pRCC subtypes. Material and Methods. We used commercial miRNA microarrays (GeneChip miRNA arrays, Affymetrix) to perform whole miRNome profiling in a set of seven cases of ccRCC and pRCC subtypes 1 and 2 each. The expression of a selected subset of miRNAs was validated by quantitative PCR. The best discriminating miRNAs of this initial set were used to establish a classification model for tissue samples. This core set of miRNAs was analyzed in a second, independent patient cohort of 69 tissue samples. Using the pre-defined classification rules, the samples of the independent patient cohort were classified in a double-blind fashion solely by their miRNA expression. Results. Microarray results showed, that every RCC entity and subtype displayed a characteristic pattern of miRNA expression. Ten miRNAs were selected based on their ability to discriminate between tumor and normal tissue or between different subtypes of RCC. Binary logistic regression identified a core set of only five miRNAs that was able to fully classify any given sample with an overall accuracy of 88%. This classification scheme was applied to an independent patient cohort. Here, the five discriminating miRNAs (miRNAs miR-145, -200c, -210, -502-3p, and let-7c) were able to classify the samples with an overall accuracy of 64%. A pathway analysis indicated that target genes of deregulated miRNAs are members of the family of multidrug-resistance proteins (MRPs) or components of the Jak-STAT signaling pathway. Conclusions. Every entity or subtype of RCC displays a characteristic and unique pattern of miRNA expression. Characteristic miRNAs can be used to distinguish not only between tumor and normal tissue samples but also between different tumor entities with high accuracy. Target genes of these characteristic miRNAs might contribute to the tumor biologic and clinical behavior of RCC entities and subtypes. Citation Format: Sven Wach, Elke Nolte, Anne Theil, Christine Stoehr, Tilman Rau, Arndt Hartmann, Arif B. Ekici, Bastian Keck, Helge Taubert, Bernd Wullich. MicroRNA expression profiles classify renal cell carcinoma subtypes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1964. doi:10.1158/1538-7445.AM2013-1964

Importance of local data on occurrence and outcomes of renal cell cancer

Background: In comparatively socioeconomically deprived areas male cancer mortality is often above the national average. Given this, we explored the pattern of presentation and outcomes of men with conventional clear cell renal cell carcinoma (CCRCC) undergoing nephrectomy at a North East of England regional tertiary referral centre. Patients and methods: A retrospective review of CCRCC patients treated with nephrectomy between 2004 and 2008 was performed. Risk of progression for men and women was calculated using Mayo, Memorial Sloan-Kettering (MSK) and Kattan prognostic scores. Outcomes of disease free progression and overall survival were measured. Results: 292 patients with complete local follow up were identified that had undergone radical nephrectomy for conventional clear cell histology. The median (range) follow up was 36 months (10–65 months), and men accounted for 64% of these cases. At presentation, 45% of cases presented with stage III–IV (&gt;T2, N0/1, M0/1) disease compared with 32% nationally (BAUS cancer registry). At diagnosis men had more advanced tumours compared with women (54% vs. 22% for stage &gt;T2, N0/1, M0/1; p &lt; 0.001) and had higher risk of progression based on prognostic scores ( p &lt; 0.01) despite similar risk factors and clinical symptoms. Early outcome analysis comparing men to women revealed both lower disease-free survival (82% vs. 89%) and overall survival (87% vs. 93%) in men at 24 months ( p &lt; 0.01). However, stage for stage comparisons between men and women demonstrated no significant difference in survival. Discussion: Men in the North East of England presented later with more advanced CCRCC. The reason for this remained undefined in this study. This pattern is consistent with reports of adverse male cancer-related outcomes in deprived areas and highlights the importance of local data in planning local health care.