Conventional Renal Cell Carcinoma Research Articles

Immunotherapy Applications for Thymine Dimers and WT1 Antigen in Renal Cancers: A Comparative Statistical Analysis

Renal cell carcinoma (RCC) remains incurable in advanced stages. Biomarkers have proven to be quite useful in cancer therapeutics. Herein, we provide a comparative/integrative statistical analysis of seminal immunohistochemistry (IHC) findings for Wilms’ Tumor 1 antigen (WT1) and thymine dimers (TDs), emerging as atypical, yet promising, potential biomarkers for RCCs. We assessed WT1/TD reactivity in adult RCC tumor cells, tumor microenvironment (TME), and tumor-adjacent healthy renal tissue (HRT). WT1 positivity was scarce and strictly nuclear in tumor cells, whereas TD-reactive tumor tissues were prevalent. We report statistically significant positive correlations between the density of reactive RCC cellularity and the intensity of nuclear staining for both biomarkers (WT1 − rho = 0.341, p-value = 0.036; TDs − rho = 0.379, p-value = 0.002). RCC stromal TME TD-positivity was much more frequent than WT1 reactivity, apparently proportional to that of the proper RCC cellularity and facilitated by extensive RCC inflammatory infiltration. TDs exhibited nuclear reactivity for most TME cell lines, while RCC TME WT1 expression was rare and inconsistent. In HRTs, TDs were entirely restricted to renal tubular cells, the likely cellular progenitor of most conventional RCC subtypes. In lieu of proper validation, these early findings have significant implications regarding the origins/biology of RCCs and may inform RCC therapeutics, both accounting for the high frequency of immunotherapy-permissive frameshift indels in RCCs, but also hinting at novel predictive clinical tools for WT1-targeted immunotherapy. Overall, the current study represents a meek yet hopefully significant step towards understanding the molecular biology and potential therapeutic targets of RCCs.

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.

FAPα and αSMA mark different subsets of fibroblasts in normal kidney and conventional renal cell carcinoma

Several studies suggested a correlation between cancer associated fibroblasts (CAF) and cancer progression, but data on conventional renal cell carcinoma (cRCC) is still lacking. We aimed to analyse the impact of αSMA positive myo-CAF and FAPα expressing i-CAF on postoperative relapse of cRCC. We applied immunohistochemistry on tissue-multiarray (TMA) containing 736 consecutively operated cRCC without metastasis at the time of diagnosis. We analysed the correlation between the amount and pattern of αSMA and FAPα expressing CAFs and tumour cells and postoperative tumour relapse. Stromal fibroblasts of each cRCC displayed αSMA immunreaction but only 142 of the 736 tumours showed positive FAPα staining. There was no correlation between the amount of αSMA and or FAPα positive CAFs and tumour progression. However, tumours with large tourtous vessels with strong αSMA positive immunreaction have more then two times higher risk of postoperative tumour relapse (RR=2.198, p = 0.005). Patients with cRCC (57) showing cytoplasmic αSMA staining of tumour cells had a nearly two times higher risk for postoperative progression (RR=1.776, p = 0.014).There is no significant correlation between the density of αSMA or FAPα positive CAFs and postoperative relapse of cRCCs, therefore CAFs in cRCC are not suitable targets for therapy. Further limitation of anti-CAF therapy of cRCC that stromal cells of normal kidney are positive with αSMA antibody.

A Rare and Unusual Renal Tumour: A Case Report

Introduction: Multilocular cystic renal cell neoplasm of low malignant potential is a rare histologically identified form of clear cell renal cell carcinoma included in 2016 Renal tumour classification of WHO. It is a low risk neoplasm with clear cells that have less expansile proliferation than other clear cell variants of renal cell carcinoma with no recurrence and metastasis with few exceptional cases. The incidence of multilocular cystic renal cell carcinoma is estimated to be 1-2 percent.6,12 Although the WHO classification of multilocular cystic renal cell carcinoma with low malignant potential was reported in 2004. The WHO 2016 categorization of renal cell tumour has been assessed as a special entity with no documented cases of metastasizing and recurrent tumour development.4 We present a rare clinical case of multilocular cystic renal cell neoplasm with low malignant potential, which should not be mistaken with other differential diagnoses such as cystic necrosis in conventional renal cell carcinoma, tubulo cystic renal cell carcinoma, multilocular cystic nephroma, clear cell variant of renal cell carcinoma and other benign multilocular renal tumors.

Transcription factor E3 renal cell carcinoma presenting as secondary hypertension.

Microphthalmia-associated transcription factor family (transcription factor E3 or transcription factor EB) translocation renal cell carcinomas (RCCs) are rare neoplasms. These renal neoplasms can be either asymptomatic and incidentally discovered on imaging or symptomatic, with the most common presenting symptoms being hematuria, pain, and abdominal mass, or paraneoplastic event. In conventional RCCs, hypertension is considered a risk factor and a possible paraneoplastic event, whereas, in translocation RCCs, prior exposure to cytotoxic chemotherapy is the only known risk factor, and hypertension as an isolated associated paraneoplastic event has never been reported. Interestingly, hypertension as the only presenting symptom in RCC is extremely rare. We report a case of transcription factor E3 positive RCC in a young adult presenting only with hypertension that normalized after radical nephrectomy. To the best of our knowledge, this is the first reported case of hypertension secondary to microphthalmia-associated transcription translocation RCC.

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.

This Month in Adult Urology

This Month in Adult Urology

Renal cell carcinoma with leiomyomatous stroma: A case report and a review of the literature of a provisional entity distinct from conventional renal cell carcinoma

Renal Cell Carcinoma with Leiomyomatous Stroma (RCCLMS) is a rare renal cancer with indolent behavior and favorable prognosis. We present a case of rare renal cell carcinoma with leiomyomatous stroma in a 49-year-old male, with an incidental finding of a 1.6 cm renal nodule on MRI scan. The patient underwent partial nephrectomy of the left kidney and subsequent histological examination showed an epithelial tumor composed of clear cell cytoplasm with low grade nuclear features, surrounded by an abundant smooth muscle stroma composed of fascicles of spindle cells. Immunohistochemistry revealed the positive reaction of tumor cells for CK7, CD10, CAIX, vimentin and desmin; negative for AMACR. Molecular testing via FISH study shows lack of 3p deletion. Final diagnosis of RCCLMS was made. The aim of this case report is to highlight the importance of awareness of this disease as well as to differentiate RCCLMS from other renal cancers with less favorable prognosis and higher degree of malignancy like clear cell renal cell carcinoma. Keywords: renal cell carcinoma; leiomyomatous stroma; kidney.

Clinicopathological features of non-conventional renal cell carcinoma histological subtypes: Learning points from a large contemporary series spanning over three decades.

PurposeTo perform a retrospective review of the clinicopathological features of patients with conventional and non-conventional renal cell carcinoma (cRCC and ncRCC).Materials and MethodsA large prospectively maintained uro-oncological registry was accessed to extract clinicopathological data of patients diagnosed with renal tumors who subsequently underwent nephrectomy from 1990–2019. Demographics and operative parameters were extracted. Analyses of overall survival (OS) and cancer-specific survival (CSS) were performed using the Kaplan–Meier method. Cox proportional-hazards analysis was used to identify risk factors which influenced survival.ResultsThere were a total of 1,686 consecutive nephrectomies which was retrieved, with 1,286 cRCC and 400 ncRCC. The commonest ncRCC subtypes were papillary (n=198, 11.7%), clear cell papillary (n=50, 3.0%) and chromophobe (n=49, 2.9%) RCC. Kaplan–Meier estimates of OS were higher in cRCC (0.74; 95% confidence interval [CI], 0.71–0.78) than ncRCC (hazard ratio, 1.47; 95% CI, 1.16–1.87). Among individual subtypes, chromophobe RCC had the highest 5-year OS (0.90; 95% CI, 0.79–1.0). Among ncRCC subtypes, acquired cystic RCC demonstrated the highest association with end-stage renal failure and hypertension, with the highest CSS. MiT family translocation RCC had the youngest mean age at presentation (45.6±12.8 y) and excellent CSS. Factors associated with increased OS in the entire cohort included shorter operative time, partial nephrectomy and lower tumor stages.ConclusionsThis study provides a comprehensive contemporary overview of ncRCCs which are yet poorly characterized, in comparison to cRCCs. Data from this study would contribute towards tailored patient counseling and healthcare resource planning.

Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results.

Simple SummaryIn the last 15 years, a deep improvement in the knowledge regarding the biological mechanisms responsible for neoplastic cell development and progression has led to a dramatic change in the treatment landscape of metastatic clear cell renal carcinoma. Nowadays, it is known that neo-angiogenesis is a key player in tumor growth and metastatic spread. In particular, the crucial role of the mutation of the von Hippel–Lindau (VHL) tumor suppressor gene, leading to angiogenesis through the transcription of multiple pro-angiogenic factors, is clearly recognized. On the basis of this biological evidence, three classes of targeted therapies with antiangiogenetic activity have received approval for the treatment of advanced disease: tyrosine kinase inhibitors (TKIs); a monoclonal antibody that interferes with vascular endothelial growth factor (VEGF); and two mammalian target of rapamycin (mTOR) inhibitors. These drugs showed impressive results in terms of progression-free survival and objective response rate. In addition, a “second therapeutic revolution” has recently started, due to the latest information on the immunogenic characteristics of renal cell carcinoma and the interplay between angiogenesis and immune surveillance systems. Consequently, immune checkpoint inhibitors, alone or in combination with TKIs, have been approved. In this review, we analyze the pharmacological characteristics and activity of antiangiogenic drugs approved for the treatment of metastatic clear cell renal carcinoma.Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed.

Expression of TXNIP is associated with angiogenesis and postoperative relapse of conventional renal cell carcinoma

One of the common mediator of tumour progression is the oxidative stress induced by inflammatory tumour microenvironment (TME). Activated fibroblasts, local and immune cells produce reactive oxygen species (ROS) supporting tumour cell proliferation and pave the way for metastatic tumour growth. TXNIP regulates ROS generation by inhibiting the antioxidative function of thioredoxin (TXN). The shift of TXNIP/TXN balance towards overexpression of TXNIP is associated with proliferation of endothelial cells during tumor angiogenesis. The oxidative stress activates the hypoxia inducible factor-1 (HIF-1), which plays an important role in the biology of conventional RCC (cRCC). Under oxydative stress TXNIP interacts with NLRP3 inflammasome leading to maturation and secretion of inflammatory cytokine IL1β. To establish the role of TXNIP and downstream genes HIF1α and IL1β in the biology of cRCC, we have applied immunohistochemistry to multi-tissue arrays containing tumours of 691 patients without detectable metastases at the time of operation. We found that cRCC displaying a fine organised capillary network with nuclear translocation of TXNIP and expressing IL1β have a good prognosis. In contrary, we showed a significant correlation between cytoplasmic TXNIP expression, inefficient vascularisation by unorganized and tortuous vessels causing tumour cell necrosis and postoperative tumour relapse of cRCC.

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.

Kidney Cancer: 12-years’ Experience of Sultan Qaboos University Hospital

Purpose: Kidney cancer is the 10th most common cancer in Omani males. Renal cell carcinoma (RCC) is found in 72% of kidney cancers in Oman. The aim is to study all nephrectomies performed in Sultan Qaboos University Hospital and know the charchectristics of RCC. Methods: Clinical, radiological and pathological data of 62 patients who underwent nephrectomy in Sultan Qaboos University Hospital over 12 years (1999-2011), were collected retrospectively. Kaplan-Meier, log-rank and chi-squared tests were used for statistical analysis. Results: A total of 27 patients operated for suspected kidney cancer, 74% were RCC. The mean (SE) tumor size was 8 (1.1) cm. There was a significant correlation between tumor size and mode of presentation, incidental or symptomatic, (Pearson chi-square 6.3, P = 0.04). The most common tumor location was upper pole of the kidney. The staging and grading were: T1 (52%), N0 (81.5%), M0 (100%), Fuhrman Grade 2 (59.3%). The most common histological type was conventional RCC (40.7%). Oncocytoma was found in (11%). Surgeries performed were radical nephrectomy (66.7%) and partial nephrectomy (33%). The mean (SE) follow up was 24.4 (5.9) months. The two-year overall and disease-free survivals were 85.7% and 66.7% respectively with a recurrence of 31.8%. The histological type had no significant effect on survival (P = 0.299). Conclusions: To improve the outcomes, referral and centralization of kidney caner surgery care is encouraged. Future long follow up studies in collaboration with ministry of health centers are needed to know the features of RCC in Oman.

P0553 - KIBRA plays as tumour suppressor via phosphorylation of LATS-2 in conventional renal cell carcinoma tissues

P0553 - KIBRA plays as tumour suppressor via phosphorylation of LATS-2 in conventional renal cell carcinoma tissues

Renal oncocytoma with prominent xanthomatous reaction. A rare histopathological variant of oncocytoma.

Renal oncocytoma (RO) is a distinctive neoplasm with a well-recognized gross and cytoarchitectural appearance. However, on some occasions, it may show uncommon, atypical, or worrisome gross and microscopic features potentially generating diagnostic difficulties. We herein review the oncocytoma variant characterized by a significant intraneoplastic xanthomatous reaction that produces a variegated macroscopic appearance. This feature may pose a genuine diagnostic problem with conventional (clear cell) renal cell carcinoma (RCC) because this reaction creates a departure from the typical uniform, tan-brown appearance of oncocytoma. The microscopic presence of foamy macrophages in RO may potentially lead to diagnostic difficulties with tumors exhibiting eosinophilic cells and significant infiltration for lipid-laden foamy macrophages such as cystic RCC, unclassified RCC rich in foamy macrophages, the solid variant of papillary RCC with oncocytic features, post-neuroblastoma RCC, succinate dehydrogenase-deficient RCC, mucinous-poor tubular and spindle cell carcinoma, and the oncocytic variant of the epithelioid angiomyolipoma. In conflictive cases, an immunohistochemical panel should help to solve the diagnostic problem. Therefore, the presence of abundant foamy macrophages should not dissuade the pathologist from establishing a diagnosis of RO. Prominent xanthomatous reaction despite its low frequency (4.3%) can be considered an additional feature of RO. Thus, RO should be added to the list of renal tumors that can show a significant reaction of lipid-laden foamy macrophages. Besides, Gamna–Gandy bodies can be present in this tumor.

OPEN PARTIAL NEPHRECTOMY FOR SMALL RENAL TUMOURS: TECHNICAL AND ONCOLOGICAL OUTCOMES

Objective: To assess the safety and oncological outcomes of Open Partial Nephrectomy in management of small renal tumours.
 Study Design: Case series.
 Place and Duration of Study: Armed Forces Institute of Urology, Rawalpindi, from Jan 2015 to Dec 2018.
 Methodology: We prospectively studied 61 patients with renal tumours either observed on computerized tomography (CT) scan or magnetic resonance imaging (MRI) having size ≤7cm and underwent open partial nephrectomy. The collected data included demographics, dimension of tumour, indication for surgery, cold ischemia time, hospital stay, complications and histopathological finding including involvement of margins. Patients were followed up for atleast 2 years.
 Results: Among 61, 39 patients were male and 22 females. The age of patients ranged from 20-72 years. Mean cold ischaemia time was 24.7 ± 6.37 minutes. Except for 2 patients with Von Hippel–Lindau (VHL) disease, all other patients had solitary renal growth. Nine (14.75%) patients had solitary kidney. The mean of maximum dimension of tumours was 3.84 ± 1.38 cm and mean hospital stay was 3.18 ± 2.19 days. Histopathological results showed 34 tumours to be conventional renal cell carcinoma (RCC) (55.73%) followed by 12 papillary renal cell carcinoma (19.67%). Two (3.27%) patients had positive surgical margin who were operated for >5 cm tumours and later managed expectantly. Twenty one patients had Grade I and II complications while 2 patients were stented post operatively for urine leak. At 2 years follow up there was no recurrence of tumour in any of the patient operated.
 Conclusion: Open ..........

The Evolution of Angiogenic and Inflamed Tumors: The Renal Cancer Paradigm

Gene expression analyses have identified subtypes of conventional renal cell carcinoma broadly distributed into angiogenic and proliferative/ immunogenic clades. Integration with genomic and functional experiments in animal models yields an evolutionary model. Evolutionary trajectories illustrate remarkable plasticity, particularly for a tumor that typically begins with inactivation of a single gene.

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.

Role of CAIX Expression in Conventional Renal Cell Carcinomas as a Diagnostic Marker and its Prognostic Importance.

Significant advances in understanding of the biology of renal cell carcinoma (RCC) have been achieved recently, which led to novel targeted therapies, revolutionising the management of patients with advanced disease. To date, there are no molecular markers which can reliably predict RCC outcome. We investigated whether a novel kidney cancer marker, carbonic anhydrase IX (CAIX), is associated with progression and survival. A retrospective study was done on patients diagnosed with renal cell carcinoma over a period of 5years. Immunohistochemical analysis using a CAIX monoclonal antibody was performed on paraffin-embedded blocks from patients treated with nephrectomy for clear cell RCC. Patients were segregated into two categories based on CA IX expression as CA IX ≤ 85% and CA IX > 85%. A comparison was made based on the survival (from date of diagnosis) with CA IX expression. Correlation of CA IX expression and TNM staging, nuclear grading, tumour volume and age was statistically studied using Student's t test. The association between survival and CA IX was done using Mann-Whitney test. The association of CA IX with rest of the prognostic variables were analysed using Fisher's exact test. In our study, CA IX expression > 85% had longer survival compared with those with lower expression ≤ 85%. A significant statistical association was seen with CAIX and lymphovascular emboli, major vessel, perinephric fat, renal sinus fat involvement and distant metastasis. CAIX reflects significant changes in tumour biology that predicts clinical outcome and identify high-risk patients for adjuvant immunotherapy and CAIX targeted therapies.

Molecular characteristics and markers of advanced clear cell renal cell carcinoma: Pitfalls due to intratumoral heterogeneity and identification of genetic alterations associated with metastasis.

To identify clear cell renal cell carcinoma-related gene mutations potentially associated with aggressive disease, sarcomatoid differentiation or poor prognosis. We carried out genomic analysis of 217 tumor foci from 25 patients with conventional clear cell renal cell carcinoma (14 patients), clear cell renal cell carcinoma with sarcomatoid differentiation (six patients) and non-clear cell renal cell carcinoma (five patients). Each tumor nodule on the tissue block that corresponded to the same focus on the slide was separated from the normal parenchyma and other histologically distinct areas of tumor. The isolated tumor foci were used for subsequent analyses and sequencing. Deoxyribonucleic acid from the formalin-fixed paraffin-embedded tissues was extracted. Multiplex bar-coded polymerase chain reaction amplification was carried out using next-generation sequencing libraries. Overall, 67 protein alterations, including amino acid alterations, frame shifts and splice site mutations in seven genes were identified in the cohort of renal cell carcinoma tumors included in this study. Fewer patients with clear cell renal cell carcinoma with sarcomatoid differentiation had clear cell renal cell carcinoma-related mutations in comparison with patients with conventional clear cell renal cell carcinoma. Additionally, the average number of unique clear cell renal cell carcinoma-related protein alterations per patient was significantly lower in clear cell renal cell carcinoma with sarcomatoid differentiation than in conventional clear cell renal cell carcinoma. Mutations in PBRM1 were identified in a higher proportion of patients with high-grade tumors (World Health Organization/International Society of Urological Pathology grade4) and in the primary tumors of six of 10 (60%) patients with metastatic disease. Although there are pitfalls due to intratumoral heterogeneity and sampling bias, mutations in PBRM1 may be associated with metastasis and aggressive disease in clear cell renal cell carcinoma.