Renal Cell Carcinoma: Prognostic Factors and Patient Selection

Renal cell carcinoma (RCC) accounts for 2% of all new cancer cases worldwide. Staging systems for RCC are a valuable tool for guiding patient selection for the various treatment regimens and clinical trials. Integration of pathologic tumour stage with histologic and clinical features has led to the development of a number of comprehensive prognostication systems to predict patient outcomes. More recent work has highlighted the additional prognostic value of a range of molecular markers, which may correlate disease status with likely response to treatment. For example, results from a number of studies have indicated that the expression of carbonic anhydrase IX and the vascular endothelial growth factor family of proteins and receptors may be important for predicting the survival rate of patients with distant metastases. Incorporation of molecular markers into staging systems is expected to enhance the prediction of individual tumour behaviours and help to stratify patients into more sophisticated risk categories to improve accurate prognostication. Furthermore, use of molecular markers to direct targeted therapies to the patients who would gain most benefit may ultimately enable improved treatment success and, thus, maximise survival benefits.     

Current staging of renal cell carcinoma

Most (>80%) cancers involving the kidney are renal cell carcinoma (RCC). One third of patients diagnosed with kidney cancer have evidence of metastatic disease at the time of diagnosis, and as many as half of patients treated for localized disease eventually relapse. As is true for any other malignancy, one must determine which tumor features, patient factors, and laboratory techniques will provide diagnostic and prognostic information for patients with RCC. This article focuses on the history and rationale of the current staging systems for RCC as well as the potential for improvements by the addition of other clinical, pathologic, and molecular prognostic markers.     

Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine

What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti‐angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. ? A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. ? RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. ? Alteration of the product of the Von Hippel–Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. ? However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. ? Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. ? Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. ? Recent technological developments, such as large‐scale analysis and high‐speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.     

Tissue-based molecular markers for renal cell carcinoma

Since the introduction of targeted therapies in renal cell carcinoma (RCC), more individualized treatment options have become available. Molecular markers might support treatment planning due to more accurate individual risk stratification. Current molecular markers in RCC were reviewed to elucidate clinical impact and future perspectives. An English-language literature review of the Medline database (1990 to September 2010) of published data on tissue-based molecular markers and RCC was undertaken. Histological types, clinical and oncological behaviour are variable in renal masses. Molecular markers offer potential for additional information in tumour detection and diagnosis, prognostic and predictive values, as well as determination of therapeutic targets. Investigations on molecular biomarkers in RCC include hypoxia inducible factor (HIF-α), vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX), mammalian target of rapamycin (mTOR), survivin, B7-H1, p53, matrix metalloproteinases (MMP), Insulin-like growth factor II mRNA-binding protein 3 (IMP3), Ki-67, C-reactive protein (CRP), Vimentin, Fascin, platelet count, hemoglobin level and combinations of these factors. Although some markers offer promising results, utilization in daily practice is compromised due to limited specificity, predictive accuracy and tumour histology variablity. There is an imminent need for novel molecular markers that allow accurate histologic and biologic classification of RCC to improve upon current outcomes. It is very likely that a panel of molecular markers will be used to achieve a sufficient degree of certainty in order to guide clinical decisions. A large concerted effort is required to advance the field of RCC molecular marker through systematic discovery, verification, and validation.     

Pathology,Molecular Biology,and Prognosis of Penile Squamous Cell Carcinoma: What Can We Learn from the Specimen?

In the treatment of penile cancer, there is a need for prognostic and predictive factors allowing assessment of the likelihood of lymph node metastasis, as this would greatly facilitate clinical decision-making for invasive staging of inguinal nodes. Furthermore, systemic chemotherapy in metastatic disease has limited efficacy and more effective additional or second-line therapies are needed. There is a great interest in personalised and targeted therapies at present, but do we have any indications that these will be useful in penile cancer? This review examines the well-proven predictors of prognosis that pathologists can take from specimens, and reports which molecular markers are of proven value in penile cancer.     

Independent validation of the 2002 American Joint Committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort

PURPOSE: The primary tumor classification for renal cell carcinoma (RCC) was updated by the American Joint Committee on Cancer in 2002. To date the new classification has not been validated using an independent group of patients and, therefore, its accuracy for predicting patient outcome is unknown. In the current study we evaluated the 2002 primary tumor classification and compared its predictive ability with that of the 1997 classification. MATERIALS AND METHODS: We studied 2,746 patients treated with radical nephrectomy or nephron sparing surgery for unilateral, sporadic RCC between 1970 and 2000. Cancer specific survival was estimated using the Kaplan-Meier method. The predictive abilities of the 1997 and 2002 classifications were compared using the concordance index. RESULTS: There were 812 deaths from RCC a mean of 3.3 years following nephrectomy. Median followup in patients still alive at last followup was 9 years. Estimated 5-year cancer specific survival rates by the 2002 tumor classification were 97%, 87%, 71%, 53%, 44%, 37% and 20% in patients with pT1a, pT1b, pT2, pT3a, pT3b, pT3c and pT4 RCC, respectively. The concordance index for the association between the 2002 classification and death from RCC was 0.752 compared with 0.737 for the 1997 classification, indicating that the 2002 version contained more predictive ability. CONCLUSIONS: Our data suggest that the 2002 primary tumor classification with pT1 cancers subclassified into pT1a and pT1b provides excellent stratification of patients according to cancer specific survival and it has a predictive ability that is superior to that of the 1997 classification.     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

Novel concepts in the staging of renal cell carcinoma

The incidence of renal cell carcinoma (RCC) continues to rise steadily; unfortunately, our ability to cure patients with metastatic RCC remains limited. When developing and evaluating new treatment protocols, it is important to consider the role of prognostic factors, often defined as pretreatment features, that are predictive of outcome. The complexity and variability of patients’ individual clinical outcome and the recently recognized limitation of conventional staging systems have lead to the formulation of integrated prognostic staging systems. In this review, we discuss the evolution of various clinically relevant integrated staging systems for RCC.     

Update on chemotherapy for advanced bladder cancer

PURPOSE: Recent years have seen several advances in the treatment of locally advanced and metastatic bladder cancer. We summarize the current state of the art for advanced bladder cancer treatment. MATERIALS AND METHODS: A comprehensive review of published, prospective phase II/III clinical trials and retrospective analyses of patients with advanced bladder cancer was performed. RESULTS: Adjuvant and neoadjuvant chemotherapeutic strategies around the time of radical cystectomy have been used to decrease the risk of subsequent metastatic disease. Although the benefit of adjuvant chemotherapy remains unproven, neoadjuvant chemotherapy is associated with a modest 5% to 6% absolute survival benefit in 2 meta-analyses of the available data. Chemoradiation is feasible and effective in some patients, allowing bladder preservation with an acceptable risk of progression. Randomized, phase III data comparing methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy to gemcitabine/cisplatin showed similar response proportions and overall survival with less toxicity in the gemcitabine/cisplatin arm. This has led to the widespread use of gemcitabine/cisplatin as first line chemotherapy for metastatic bladder cancer. The optimal agents and regimens for second line chemotherapy remain undefined. Similarly biological and targeted therapies for advanced bladder cancer remain investigational. CONCLUSIONS: Combination cisplatin based neoadjuvant chemotherapy may benefit patients with locally advanced bladder cancer. Gemcitabine/cisplatin has replaced methotrexate, vinblastine, doxorubicin and cisplatin as the regimen of choice in patients with good renal function. The optimal regimens for the medically unfit patient and second line chemotherapy remain undefined. The development of targeted therapies, less toxic regimens and improved cytotoxic agents are necessary to improve outcomes.     

Prognostic factors and predictive models in renal cell carcinoma: a contemporary review

Context

The natural history of renal cell carcinoma (RCC) is highly unpredictable. Small renal masses may be accompanied by metastatic disease. Conversely, patients with locally advanced disease may enjoy long-term disease-free survival.

Objective

To review the status of prognostic factors in RCC.

Evidence acquisition

A literature review was performed using the PubMed, MEDLINE, and Cochrane databases for articles published as of February 15, 2010. Electronic articles published ahead of print were also considered. Search was limited to the English language. Search was conducted using the following keywords: renal cell carcinoma, molecular, tissue, markers, blood, urine, progression, prognosis, risk factor, and survival. Studies were selected according to the relevance of the study, the number of patients included, originality, actuality, and clinical applicability of the results.

Evidence synthesis

Four areas of prediction were examined: (1) new RCC diagnostics, (2) RCC grade and stage at diagnosis, (3) disease progression, and (4) disease-specific mortality. All identified reports represented either case series or controlled studies. Although a large number of markers were identified, only a few were validated. Several prognostic factors were integrated in predictive or prognostic models.

Conclusions

Several prognostic factors can help discriminate between favourable and unfavourable RCC phenotypes. Of those, several clinical, pathologic, and biologic markers have been tested and validated, and they are used in predictive and prognostic models. Nonetheless, the search continues, especially for informative markers predicting the response to targeted therapies.     

Risk stratification and prognostication of renal cell carcinoma

Objectives To review the most recent data on prognostic factors and describe the characteristics and prognostic accuracy of the most important prognostic systems available to predict the risk of recurrence, progression, and mortality in patients with renal cell carcinoma (RCC). Methods The study was based on a non-systematic review of literature. Results Clinical (performance status, and mode of presentation), anatomical (size and extension of the primary tumor, lymph node involvement, and distant metastasis), and histological factors (histological subtypes, nuclear grade, and tumor necrosis) are the most largely evaluated prognostic factors in RCC. Valuable prognostic accuracy has been shown for several laboratory parameters (erythrocyte sedimentation rate, platelet count, serum calcium, hemoglobin, and lactate dehydrogenase levels) and a few genetical and molecular markers (CAIX, B7-H1, and B7-H4). A few integrating systems have been proposed and validated, integrating both clinical and pathological (UCLA Integrating Staging Systems, Kattan nomogram, and Sorbellini nomogram) or only pathological variables (SSIGN score). Conclusions Several large and methodologically consistent studies have been published. The chance to integrate the data derived from each prognostic factor into prognostic algorithms and scores has allowed improving significantly the stratification of the prognosis of patients with RCC. The currently available prognostic systems can be further improved through the inclusion of molecular and genetic variables. Integrating prognostic systems should be used to design randomized controlled trials (RCTs), which will evaluate the efficacy of the new-targeted therapies in either neoadjuvant, adjuvant, or salvage treatments of patients with RCC.     

Looking Ahead in Renal Cell Carcinoma: Integrating New Agents in the Armamentarium of the Urologist

Urologists play a pivotal role in many aspects of the care of patients with renal cell carcinoma (RCC). However, until recently, in some European countries, they have rarely been involved in the systemic treatment of this disease or in the design of clinical trials. This is undoubtedly set to change with the emergence of new oral, molecularly targeted therapies for RCC. Sorafenib (Nexavar^®; Bayer Healthcare, West Haven, CT, USA) is one such therapy, which has already been shown to be efficacious and well tolerated for the treatment of RCC. Although targeted agents show great promise for the treatment of RCC, their precise role in the treatment of metastatic disease, and in adjuvant and neoadjuvant settings has yet to be defined. Drawing from their extensive experience of RCC, urologists will be instrumental in the design and application of clinical studies to define the role of targeted therapies in all settings of RCC and, ultimately, to integrate targeted therapies into clinical practice. Through increased understanding of the molecular pathways involved in RCC, research into diagnostic and prognostic markers, and commitment to clinical trials, urologists can be at the forefront of this progress.     

Current insights in renal cell cancer pathology

In recent years molecular biologists and pathologists have described new entities of renal cell cancer (RCC) with a totally different morphology and biology among the histotypes of renal carcinoma, but always referring to the same renal cancer disease. The evidence of a distinct biological behavior and long-term prognosis among these makes the correct pathological diagnosis of renal cancer critically important for the clinician. Advances in understanding of the pathogenesis, behavior, and importance of prognostic factors for RCC have paved the way for a revision of its classification and staging. We reviewed the role of histological classification, microscopic tumor necrosis, microscopic venous invasion, lymph node involvement and, particularly, pathological stage. In our series of patients who underwent renal surgery for neoplasm, a retrospective study established the predictive role of tumor size on recurrence rate, compared with other known prognostic factors, and we conclude that histological grade, pathological stage and tumor size remain relevant prognosticators in early stage RCC patients. In order to optimize the management of patients with RCC it is necessary to develop an interdisciplinary approach (surgeon, radiologist, pathologist, oncologist) and find new prognostic parameters at molecular and cellular levels. Many efforts are ongoing to integrate molecular data (from tissue microarrays) and clinical data (traditional prognosticators) into a molecular integrated staging system. In the postgenomic era, new tumor-associated antigens and molecules can be identified at the protein level using proteomics, providing a major opportunity for screening and finding novel targets that are the basis of new emerging therapies for RCC.     

Classical pathology versus molecular pathology in renal cell carcinoma

Renal cell carcinoma (RCC) has been characterized based on histology, stage, and grading to predict behavior and guide therapy; however, RCC is still unpredictable, with poor prognosis in metastatic disease. The classification of RCC has been revised to account for molecular characteristics, and there has been an increasing understanding of the hereditary forms of RCC. This has led to further elucidation of pathways in the development of RCC including the hypoxia-inducible pathway and angiogenesis. Many other promising molecular modalities are in development, including gene expression profiling, nuclear parameters, and proliferation/apoptotic markers. This article discusses the current understanding of the classical pathologic features of RCC and highlights recent developments in the cellular and molecular characterization of RCC, which aim to improve the classification, prognostication, and treatment of RCC.     

Renal cell carcinoma with renal vein and inferior vena caval involvement: clinicopathological features, surgical techniques and outcomes

PURPOSE: We present a contemporary review of patients with renal cell carcinoma (RCC) in whom renal vein/inferior vena caval thrombus was treated with radical nephrectomy and thrombectomy. MATERIALS AND METHODS: A total of 220 patients underwent radical nephrectomy for RCC at our institution from 1998 to 2002. Of them 49 patients with renal vein/inferior vena caval involvement (T3b/c) were selected for review. We evaluated demographics, presenting symptoms, imaging modalities, clinical staging, pathological features, adjuvant treatment and clinical outcomes. We also evaluated surgical incisions, liver mobilization procedures, blood loss, transfusion requirements and perioperative mortality/morbidity. RESULTS: Gross hematuria was the most common presenting symptom, seen in 22 patients (45%), followed by constitutional symptoms in 8 (16%). Stage T3b/c was clinically diagnosed in 44 patients, while 2 had T2 and 2 had T4 disease. A subcostal incision was made in 30 patients, a chevron incision was made in 18, and a sternotomy and flank incision were made in 1. Liver mobilization was necessary in 13 patients and 2 required a Pringle maneuver. Cardiopulmonary bypass was performed in a single patient. Lymph node involvement was seen in 4 patients (8%) and distant metastases were present in 10 (20%). Median tumor size was 10 cm. Clear cell carcinoma was most common, as seen in 42 patients. Early (30-day) mortality in this series was 8%. At a median followup of 15 months 21 patients (43%) were without evidence of disease, 14 (29%) had disease, 8 (16%) had died of disease and 2 (4%) had died of other causes. None of the patients with lymph node involvement survived beyond 8 months after surgery. Tumor grade and T stage were found to be significant negative predictors of survival on univariate analysis. CONCLUSION: Most patients with RCC and tumor thrombus are symptomatic at presentation and metastatic disease at presentation is not uncommon. These results support the role of aggressive surgical treatment as the best initial management of these tumors. The majority of tumors can be approached and safely controlled without the need for a thoracoabdominal incision. While surgery provides modest disease-free survival, most patients should be offered immunotherapy, particularly those with advanced stage, grade, nodal involvement or metastases.     

Minimal residual marrow disease: Detection and significance of isolated tumour cells in bone marrow

Background : Detection of malignant cells in bone marrow and peripheral blood of patients with solid tumours at the time of surgery is increasingly emerging as a prognostic factor for disease progression and a way of monitoring adjuvant therapies. Furthermore, isolation and characterization of these cells provide insight into the early metastatic process, with potential therapeutic implications. This article reviews the current knowledge about the clinical significance of minimal residual marrow disease (MRMD) and its methods of detection, outlining some of their specific technical problems. Methods : A comprehensive review of articles cited in the largest medical databases was conducted. Results : The sensitivity of the methods of detecting MRMD has improved substantially in the past decade, resulting in higher detection rates. In many solid tumours MRMD has been found to correlate with disease‐free and overall survival; however, the importance of this as an independent prognostic variable remains contentious. Conclusions : There is a need for a standardized approach to the detection of these cells before they become integrated into the current staging systems. The challenge remains to establish which of these tumour cells have the capacity to progress and develop metastatic disease, what are the early genetic and molecular mechanisms underlying this process and to apply novel, better targeted therapies against them.     

Recent advances in the treatment of advanced renal cell carcinoma: towards multidisciplinary personalized care

What's known on the subject? and What does the study add? With recent improvements in the prognosis for patients with metastatic renal cell carcinoma (mRCC), focus is now shifting towards maximising clinical benefit from targeted therapies. Factors other than efficacy data are increasingly being considered when selecting a treatment strategy, with a view towards optimising clinical outcomes. This review examines the development and efficacy of targeted agents for the management of mRCC and discusses the potential factors, including resistance mechanisms, sequential therapy, prognostic and predictive markers of response, and adverse event management, that may contribute to successful individually tallored treatment of patients with this disease.

• ? Targeted agents have substantially improved outcomes for patients with metastatic renal cell carcinoma (mRCC).
• ? Treatment focus is now shifting towards achieving a continuum of care such that long‐term benefit and extended survival may be achieved through the optimal use of targeted agents.
• ? To achieve this goal, a number of factors which impact on treatment selection and outcomes need to be considered when treating patients with mRCC, such as the optimal sequence of targeted therapies (and the related issue of resistance mechanisms).
• ? Recent advances are also likely to impact on the future treatment of mRCC. Examples include the identification of predictive biomarkers as well as a consideration of patient risk profiles or the safety profile of the selected targeted agent. In addition, attention is focusing on re‐defining the role of surgery for the treatment of RCC in the context of targeted therapies.
• ? This review examines the recent and future advances that offer the potential for personalizing treatment by selecting the most appropriate treatment for each patient with a view towards optimizing clinical outcomes.

     

Prostate specific antigen only progression of prostate cancer

PURPOSE: Introduction of the prostate specific antigen (PSA) serum marker for prostate cancer and the subsequent PSA era from 1988 to the present have dramatically altered the diagnosis of the disease. The early to mid 1990s diagnosis boom resulted in a huge increase in clinically localized and early stage disease treatments. Radical prostatectomy rates increased from 17.4 to 54.6/100,000 between 1988 and 1992, and age adjusted rates increased 2 to 4-fold for men in the fifth and sixth decades of life. Since the late 1990s clinicians have been seeing the effects of this diagnosis and localized treatment boom, in that many men each year are experiencing PSA only disease recurrence. Given that the majority are relatively young and otherwise healthy, treatment of PSA only recurrence requires approaches that not only improve survival, but also preserve quality of life. A comprehensive overview of the definition of PSA only recurrence, staging controversies and the wide variety of treatments to be considered is provided. MATERIALS AND METHODS: A literature review and overview of the topic of PSA only recurrence after prior clinically localized prostate cancer treatment were performed. RESULTS: For radical prostatectomy cases PSA only recurrence is broadly defined as any elevation of PSA postoperatively. For radiation treated patients the 1997 American Society for Therapeutic Radiology and Oncology guidelines specify 3 consecutive elevations of PSA after posttreatment PSA nadir is achieved. As localized treatment series in the PSA era have matured, and database and statistical support have improved, a number of useful models to predict PSA only recurrence have emerged. These models are based on traditional prognostic markers, such as pretreatment PSA, and grade and stage of disease as well as emerging molecular and cellular biomarkers. Although bone scans and pelvic computerized tomography are commonly used for re-staging at PSA only recurrence, recent study suggests that their value is limited unless PSA recurrence exceeds 30 to 40 ng./ml. 111Indium capromab pendetide radionuclide scan, which has been approved for radical prostatectomy PSA only recurrence, may be helpful to determine cases best suited for salvage radiotherapy versus systemic hormonal therapy, although more study is needed. Treatment of PSA only recurrence is divided into 2 main categories of salvage local treatments and systemic therapy. The principal dilemma is the inability to determine definitively whether PSA only recurrence is solely due to local progression or distant micrometastases. External beam radiation is the main local salvage treatment for radical prostatectomy recurrence, and cryotherapy, salvage prostatectomy and salvage brachytherapy are options for radiation recurrence. Proper patient selection is critical to the success of all salvage local treatments. Traditional hormonal therapy is the mainstay of systemic treatment for PSA only recurrence, although nontraditional approaches, such as intermittent and low dose hormonal therapy, are under study. Emerging chemopreventive agents, such as vitamins, minerals and other supplements, may have a future role in treatment. CONCLUSIONS: PSA only recurrence after prior local prostate cancer treatment remains a common problem facing clinicians.     

pT2 classification for renal cell carcinoma. Can its accuracy be improved?

PURPOSE: The 2002 tumor classification for renal cell carcinoma (RCC) classifies pT2 tumors as more than 7 cm in greatest dimension, limited to the kidney. In this study we determined whether a size cutoff point exists within pT2 tumors and whether such subclassification would further improve the accuracy of the current tumor classification. MATERIALS AND METHODS: We studied 544 patients with unilateral, sporadic pT2 RCC treated with radical nephrectomy or nephron sparing surgery between 1970 and 2000. The association of tumor size with death from RCC was examined using martingale residuals from a Cox proportional hazards regression model to determine the optimal size cutoff point. RESULTS: There were 204 deaths from RCC a median of 3.8 years following nephrectomy. Univariately tumor size was significantly associated with death from RCC (risk ratio 1.08, 95% CI 1.04 to 1.13, p <0.001). A scatterplot of tumor size vs expected risk of death per patient suggested that a cutoff point between 9 and 10 cm was appropriate. When adjusted for regional lymph node involvement and distant metastases, the 10 cm cutoff point performed better than the 9 cm point (risk ratio 1.42, 95% CI 1.07 to 1.90, p = 0.017 vs 1.22, 95% 0.86 to 1.72, p = 0.268). Therefore, we propose using a 10 cm cutoff point to subclassify patients into pT2a and pT2b. CONCLUSIONS: Our data suggest that the prognostic accuracy of the 2002 pT2 tumor classification can be further improved by subclassifying patients with tumors greater than 7 and less than 10 cm into a pT2a category, and those with tumors 10 cm or greater into a pT2b category.     

Biomarkers of renal cell carcinoma

The incidence of renal cell carcinoma (RCC) has increased steadily in past few decades and is partially attributable to the increased utilization of cross-sectional imaging. Many of these carcinomas are small incidental discoveries, although a subset leads to locally advanced or distant disease. Although its molecular pathophysiology is not completely understood, knowledge of hereditary RCCs has shed light on some of the pathways involved. More recently, the rapid advances in genomics, proteomics, and metabolomics have allowed for a deeper and more nuanced understanding of the genetic aberrations that lead up to and result from the transformation of a renal tubular epithelial cell into a carcinoma. These discoveries have allowed for the development of novel therapeutics that target these pathways. They have also led to the development of diagnostic, prognostic, and predictive biomarkers that could radically change the way RCC is diagnosed and treated. Although some of the current investigations are nascent and it remains to be seen which biomarkers will become clinically available, many candidate biomarkers show promise and require external validation. Ultimately, biomarkers may allow for cost-effective screening of high-risk patients, the identification of aggressive cancers among small renal masses, the identification of high-risk patients, the detection of recurrences postoperatively with minimal imaging, and the ability to choose appropriate targeted therapies for patients with metastatic disease.