Prognostic and Therapeutic Impact of the Histopathologic Definition of Parenchymal Epithelial Renal Tumors

Context

In the last few years, the treatment of renal cell carcinoma (RCC) has progressed significantly, and some histopathologic issues have become important for selection and follow-up after medical and surgical therapies.

Objective

The aim of this collaborative article is to review the most recent literature on the role of traditional histopathologic features obtained from renal core biopsy or nephrectomy specimens in the management of confined, locally advanced, and metastatic RCC.

Evidence acquisition

A nonsystematic review of the literature was performed in April 2010 using the Medline database. Multiple free-text searches were performed for the following items: renal cell carcinoma, clear cell, papillary, chromophobe, histologic* subtype*, histotype*, nuclear grade*, necrosis, sarcomatoid differentiation, biopsy, molecular marker*, and cytogenetic marker*. A total of 2369 records were retrieved from Medline, and 263 full-text studies were considered and partially included in the present review. A panel of experts reached consensus on the main subheadings of this paper.

Evidence synthesis

Core needle biopsies can provide important information that is useful to avoid the overtreatment of benign tumors and to help plan watchful waiting or minimally invasive treatments in selected patients. Tumor histotype is fundamental in the pathologic report. In the context of integrated prognostic systems, the combination of the most important clinical and pathologic factors (TNM stage, Fuhrman nuclear grade, presence of necrosis, microvascular invasion, and sarcomatoid dedifferentiation) allows us to reach a high prognostic accuracy. These models can be used to select patients suitable for adjuvant protocols, to design an appropriate follow-up schedule, and to provide careful patient counseling. Molecular and cytogenetic markers should be further evaluated.

Conclusions

The histopathologic definition of parenchymal epithelial renal tumors is fundamental to plan the management and follow-up of patients with locally confined, locally advanced, and metastatic RCC.     

Age-adjusted incidence, mortality, and survival rates of stage-specific renal cell carcinoma in North America: a trend analysis

Background

The rising incidence of renal cell carcinoma (RCC) has been largely attributed to the increasing use of imaging procedures.

Objective

Our aim was to examine stage-specific incidence, mortality, and survival trends of RCC in North America.

Design, setting, and participants

We computed age-adjusted incidence, survival, and mortality rates using the Surveillance Epidemiology and End Results database. Between 1988 and 2006, 43 807 patients with histologically confirmed RCC were included.

Measurements

We calculated incidence, mortality, and 5-yr survival rates by year. Reported findings were stratified according to disease stage.

Results and limitations

Age-adjusted incidence rate of RCC rose from 7.6 per 100 000 person-years in 1988 to 11.7 in 2006 (estimated annual percentage change [EAPC]: +2.39%; p < 0.001). Stage-specific age-adjusted incidence rates increased for localized stage: 3.8 in 1988 to 8.2 in 2006 (EAPC: +4.29%; p < 0.001) and decreased during the same period for distant stage: 2.1 to 1.6 (EAPC: −0.57%; p = 0.01). Stage-specific survival rates improved over time for localized stage but remained stable for regional and distant stages. Mortality rates varied significantly over the study period among localized stage, 1.3 in 1988 to 2.4 in 2006 (EAPC: +3.16%; p < 0.001), and distant stage, 1.8 in 1988 to 1.6 in 2006 (EAPC: −0.53%; p = 0.045). Better detailed staging information represents a main limitation of the study.

Conclusions

The incidence rates of localized RCC increased rapidly, whereas those of distant RCC declined. Mortality rates significantly increased for localized stage and decreased for distant stage. Innovation in diagnosis and management of RCC remains necessary.     

A review of integrated staging systems for renal cell carcinoma

Context

Several outstanding integrated staging systems (ISSs) have been devised for patients with renal cell carcinoma (RCC).

Objective

To review the available literature on existing ISSs.

Evidence acquisition

A nonsystematic search was conducted using Medline and PubMed databases. Original articles, review articles, and editorials addressing the development and validation of ISSs in RCC published up to February 2012 were identified. The search was limited to the English language. Keywords included kidney cancer, renal cell carcinoma, nomogram, risk group, prognosis, predictive accuracy, external validation, and discrimination. Links to related articles and cross-reading of citations in related articles were surveyed. All articles with a pertinent level of evidence were included and represent the basis for the current review article.

Evidence synthesis

In nephrectomy patients, a variety of models have been developed for prediction of recurrence and survival, both in the preoperative and postoperative settings. Several of those models relied on variables that are not routinely available in clinical practice. Not all tools were externally validated. In patients treated with systemic therapy, novel tools that were developed and validated in the targeted therapy era replaced tools devised during the cytokine era.

Conclusions

The development of ISSs for prediction of risk or prognosis in the context of RCC has evolved and improved. In the targeted therapy era, the urologic community should focus on direct comparisons of existing tools with the intent of identifying the optimal ISS for each specific end point.     

Is There a Need to Further Subclassify pT2 Renal Cell Cancers as Implemented by the Revised 7th TNM Version?

Background

The recently modified TNM classification of renal cell carcinoma (RCC) (7th edition) has implemented a subdivision of pT2 tumours into stage pT2a (>7 or ≤10 cm) versus pT2b disease (>10 cm).

Objective

Our aim was to evaluate whether this subdivision of pT2 RCC is justified due to a clinical prognosis divergence between the two groups (pT2a vs pT2b)

Design, setting, and participants

In total, 5122 patients were subjected to either radical nephrectomy or nephron-sparing surgery at three centres in Germany (University Hospitals of Hannover, Homburg/Saar, and Marburg). Patients were reclassified into stage pT2a and pT2b according to the maximum tumour diameter as suggested by the 7th revised version of the TNM classification system.

Measurements

The t test and Fisher exact test were applied to evaluate the comparability of the two groups (pT2a vs pT2b) regarding several additional patients’ and tumour-specific characteristics of known prognostic relevance for RCC. Univariable (Kaplan-Meier analysis) and multivariable statistical analyses (Cox proportional hazards regression model) were applied to identify a possible difference between the two groups (pT2a vs pT2b) regarding cancer-specific survival (CSS).

Results and limitations

Applying the new TNM classification, 579 previously pT2-staged patients were divided into 445 (76.9%) with pT2a and 134 (23.1%) with pT2b tumours. Kaplan-Meier curves revealed no significant difference in CSS between pT2a and pT2b patients; 5-yr CSS was 79.0% and 74.1%, respectively (p = 0.38). When applying multivariable analysis, unlike tumour grade and N/M status, pT2 subclassification failed to independently predict survival in RCC patients.

Conclusions

The new subclassification of pT2 RCC into two different subgroups as suggested by the latest modification of the TNM system does not yield additional/prognostic information.     

Hereditary Renal Cancer Syndromes: An Update of a Systematic Review

Context

Hereditary renal cancers (HRCs) comprise approximately 3–5% of renal cell carcinomas (RCCs).

Objective

Our aim was to provide an overview of the currently known HRC syndromes in adults.

Evidence acquisition

Data on HRC syndromes were analysed using PubMed and Online Mendelian Inheritance in Man with an emphasis on kidney cancer, clinical criteria, management, treatment, and genetic counselling and screening.

Evidence synthesis

Ten HRC syndromes have been described that are inherited with an autosomal dominant trait. Eight genes have already been identified (VHL, MET, FH, FLCN, TSC1, TSC2, CDC73, and SDHB). These HRC syndromes involve one or more RCC histologic subtypes and are generally bilateral and multiple. Computed tomography and magnetic resonance imaging are the best imaging techniques for surveillance and assessment of renal lesions, but there are no established guidelines for follow-up after imaging. Except for hereditary leiomyomatosis RCC tumours, conservative treatments favour both an oncologically effective therapeutic procedure and a better preservation of renal function.

Conclusions

HRC involves multiple clinical manifestations, histologic subtypes, genetic alterations, and molecular pathways. Urologists should know about HRC syndromes in the interest of their patients and families.     

EAU Guidelines on Renal Cell Carcinoma: The 2010 Update

Context and objectives

The European Association of Urology Guideline Group for renal cell carcinoma (RCC) has prepared these guidelines to help clinicians assess the current evidence-based management of RCC and to incorporate the present recommendations into daily clinical practice.

Evidence acquisition

The recommendations provided in the current updated guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials.

Evidence synthesis

A number of recent prospective randomised studies concerning RCC are now available with a high level of evidence, whereas earlier publications were based on retrospective analyses, including some larger multicentre validation studies, meta-analyses, and well-designed controlled studies.

Conclusions

These guidelines contain information for the treatment of an individual patient according to a current standardised general approach. Updated recommendations concerning diagnosis, treatment, and follow-up can improve the clinical handling of patients with RCC.     

Anoikis disruption of focal adhesion-Akt signaling impairs renal cell carcinoma

Background

Quinazoline-based α1-adrenoceptor antagonists suppress tumor growth by inducing apoptosis via an α1-adrenoceptor-independent action. Anoikis is a unique mode of apoptosis consequential to insufficient cell-matrix interactions.

Objective

This study investigated the apoptotic effect of novel quinazoline-based compounds on human renal cancer cells.

Design, setting, and participants

Two cell lines were used: renal cell carcinoma (RCC) 786-0, harboring a von Hippel-Lindau (VHL) tumor-suppressor gene mutation with a highly angiogenic phenotype, and Caki cells (no VHL mutation).

Measurements

The lead compound DZ-50 (10 μM) led to significant inhibition of tumor-cell adhesion, migration, and invasion at a lower dose than doxazosin (25 μM) in both RCC lines.

Results and limitations

Doxazosin induced death-receptor-mediated apoptosis, while DZ-50 led to anoikis via targeting of the focal adhesion complex and AKT signaling that subsequently increased RCC susceptibility to caspase-8-mediated apoptosis. Both quinazoline compounds, doxazosin and DZ-50, significantly reduced RCC metastatic potential in vivo.

Conclusions

Quinazoline-based drugs trigger anoikis in RCC by targeting the focal adhesion survival signaling. This potent antitumor action against human RCC suggests a novel quinazoline-based therapy targeting renal cancer.     

Critical Evaluation of the American Joint Committee on Cancer TNM Nodal Staging System in Patients with Lymph Node-Positive Disease after Radical Cystectomy

Background

The current 7th edition of the American Joint Committee on Cancer TNM staging system for bladder cancer stages lymph node (LN)–positive disease based on LN location rather than LN size. In addition, common iliac LNs are now considered regional LNs. Whether these changes improve prognostication for node-positive patients, however, remains unclear.

Objective

To investigate whether the 7th edition of the TNM nodal staging system provides superior prognostication compared with the 6th edition.

Design, setting, and participants

Patients between 2002 and 2008 with LN metastases after radical cystectomy combined with extended or superextended LN dissection were included. Patients were staged using both TNM staging systems. Median follow-up was 54 mo.

Outcome measurements and statistical analysis

Kaplan-Meier curves were used to estimate overall survival (OS) and recurrence-free survival (RFS). Log-rank tests and Cox proportional hazard regression models were used to test associations of pathologic variables with OS and RFS.

Results and limitations

Included were 146 patients with LN metastases of whom 131 patients underwent superextended LN dissection and 15 patients underwent extended LN dissection. Although in the 7th TNM edition many patients moved from the N2 category to the N3 category, RFS did not significantly differ within the nodal subgroups in either editions. LN metastases at or above the aortic bifurcation were not associated with decreased RFS (p = 0.67). On multivariable analysis, the presence of extravesical disease (hazard ratio [HR]: 2.84; p = 0.002), absence of adjuvant chemotherapy (HR: 0.32; p < 0.0001), and more than six positive LNs (HR: 2.72; p = 0.007) were associated with decreased RFS. This was a retrospective study with inherent limitations.

Conclusions

LNs at or above the aortic bifurcation should be considered regional LNs. Neither the 6th nor the 7th TNM staging system performed well as a prognostic tool. A better staging system for LN-positive bladder cancer needs to be developed.     

Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma

Background

The impact of capsular invasion on the survival of patients undergoing surgery for renal cell carcinoma (RCC) has attracted little attention in the literature and remains controversial.

Objectives

To evaluate the value of capsular invasion, without perirenal fat invasion, on the prognosis of patients with localized clear-cell RCC.

Design, setting, and participants

Between 1984 and 2007, we retrospectively reviewed the records of 317 consecutive patients with localized clear-cell RCC (pT1–T2N0M0) who underwent radical nephrectomy or nephron-sparing surgery at our institution. Overall, 299 patients were eligible for the study. We analyzed clinical (presentation and body mass index [BMI]) and pathologic (tumor size, Fuhrman nuclear grade, collecting system invasion, microvascular invasion, and capsular involvement) parameters.

Measurements

Recurrence-free survival (RFS) and cancer-specific survival (CSS) were investigated using the Kaplan-Meier method, and the Cox regression model was used to determine the significant prognostic factors based on multivariate analysis.

Results and limitations

Renal capsular invasion was observed in 106 of 299 patients (35.5%). Capsular invasion had a statistically significant association with age, symptomatic presentation, tumor diameter, pathologic stage, collecting system invasion, and microvascular invasion. The mean follow-up was 60.5 mo (range: 1–249). The 5-yr RFS and CSS rates for tumors with capsular invasion were significantly lower compared with rates for tumors without invasion (77.7% vs 92.3% and 85.5% vs 95.7%, respectively; p = 0.0004). Multivariate analysis showed that BMI (hazard ratio [HR] = 0.19), stage (HR = 2.45), and capsular invasion (HR = 3.36) were independent prognostic factors of disease recurrence. With respect to CSS, BMI (HR = 0.20), tumor size (HR = 1.13), and capsular invasion (HR = 4.03) were the factors related to death. Nevertheless, we recognize that these findings may be limited by the study's retrospective, single-institution design.

Conclusions

Our findings suggest that capsular invasion is associated with poor survival in patients with localized clear-cell RCC.     

Inflammatory Protein Serum Amyloid A1 Marks a Subset of Conventional Renal Cell Carcinomas with Fatal Outcome

Background

Conventional renal cell carcinoma (RCC) is the most common renal cancer. As the metastatic conventional RCC is practically incurable, there is a need for markers to estimate the tumour aggressiveness.

Objective

To identify and characterise new marker(s) associated with the poor prognosis of conventional RCC.

Design, Setting, and Participants

RNA from 24 conventional RCCs was analysed for global gene expression by Affymetrix U133 Plus 2.0 arrays. Tissue microarrays containing 224 renal tumours including 87 conventional RCCs were used for immunohistochemistry. Cell lines HD2, HD48, HA344 and HA465 established in our laboratory were used for invasion assay and zymography.

Measurements

Serum amyloid A 1 (SAA1) was found to be upregulated in conventional RCCs and it has been analysed by quantitative RT-PCR and immunohistochemistry on TMAs to establish the correlation between SAA1 protein expression and patient survival by uni and multivariate analysis. The effect of SAA1 on tumour cell behaviour in vitro has also been examined by invasion assay and zymography.

Results and Limitations

SAA1 RNA is expressed in conventional RCC samples of patients with poor prognosis. Immunohistochemistry of 72 conventional RCCs with a 5 yr follow up showed a correlation between SAA1 expression and the clinical outcome of disease. Stimulation of conventional RCC cell lines with recombinant SAA1 increased the expression of metalloproteinase (MMP)-9 and the invasive potential of tumour cells. Limitation of the study is a relatively small number (72) of patients having follow up.

Conclusion

SAA1 seems to be a useful marker to estimate the prognosis of conventional RCCs.     

Vaccine Therapy in Patients with Renal Cell Carcinoma

Context

Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans. Although immunotherapy is currently much less used than in the past, it remains an important option that warrants further exploration.

Objective

To examine the current status of vaccine therapy for RCC and to provide information on relevant clinical studies.

Evidence acquisition

We reviewed recent literature on Medline (2003–2008, using the keywords renal cell carcinoma, cancer vaccines, active immunotherapy, and dendritic cells). Subsequent references were identified from reference list of retrieved articles. Quality assessment included prospective phase 1–3 trials and critical evaluations with low numbers of patients.

Evidence synthesis

Therapeutic vaccines can be divided in autologous tumour cell–based vaccines, genetically modified tumour cell–based and dendritic cell (DC)–based vaccines, and peptide-based vaccines. To date, only two randomised, adjuvant, phase 3 studies investigating RCC vaccines have been published. Autologous tumour cell vaccine (Reniale) improved the 5-yr progression-free survival (PFS) for high-risk nonmetastatic RCC patients at all tumour stages when administered after nephrectomy. The benefit was clearer in the T3 group. A per-protocol analysis revealed a statistically significant PFS and overall survival (OS) in favour of the vaccine. Autologous tumour-derived heat shock protein peptide complex (HSPPC-96; vitespen) could not significantly improve recurrence-free survival in RCC patients at high risk for recurrence after nephrectomy, but did so in intermediate risk patients. DC vaccination in metastatic RCC (mRCC) patients is safe and can induce antigen-specific immune response and obtain tumour regression in a subset of patients.

Conclusions

RCC vaccines have much less toxicity than other current therapies and remain an important area for further research. Reniale has shown significant benefit as an adjuvant RCC vaccine. Vitespen seems promising as an adjuvant treatment in earlier stage disease. A possible area of research is the use of RCC vaccines with immune-enhancing or antiangiogenic agents in the adjuvant setting.     

Expression of aquaporin 1 in primary renal tumors: a prognostic indicator for clear-cell renal cell carcinoma

Background

Aquaporin 1 (AQP1) is a water channel expressed in many epithelial tissues and endothelium, including the proximal nephron of the kidney.

Objective

We measured AQP1 expression in primary renal cell carcinomas (RCCs) and evaluated its significance and prognostic utility.

Design, setting, and participants

We examined AQP1 expression in 559 sporadic renal tumors as well as in 43 normal kidney tissue samples and collected clinicopathologic and prognostic data.

Measurements

AQP1 expression was measured by using real-time quantitative polymerase chain reaction (PCR).

Results and limitations

All normal kidney samples presented substantial AQP1 expression. Among tumor subtypes, AQP1 expression was significantly higher in clear-cell and papillary RCCs, whereas it was lower in chromophobe RCCs, oncocytomas, and collecting-duct carcinomas. In clear-cell RCC, AQP1 was significantly higher in patients without symptomatic presentation or whose tumors were smaller, lower grade, or either lower stage or lacking in microvascular invasion. Von Hippel-Lindau (VHL) tumor suppressor gene mutational status did not affect expression level. Cox univariate and multivariate analyses strongly associated high AQP1 expression with better prognosis in cancer-specific and cancer-free survival tests in all patient cohorts, as well as in cancer-specific survival in a cohort of patients with advanced metastatic RCC. The time-dependent receiver operation characteristic (ROC) analyses, combined with logistic regression models, revealed that the addition of the AQP1 parameter to the University of California Los Angeles Integrated Staging System (UISS) prognostic score can improve the accuracy of predictions of both cancer death and recurrence for all patient cohorts as well as of cancer death for advanced cases within a 5-yr follow-up period in clear-cell RCC. High AQP1 expression was also associated with better outcome in a univariate cancer-specific survival test in papillary RCCs.

Conclusions

AQP1 shows RCC subtype-specific expression, and its expression level provides useful prognostic information for patients with clear-cell RCC.     

Validation of the AJCC TNM Substaging of pT2 Bladder Cancer: Deep Muscle Invasion Is Associated with Significantly Worse Outcome

Background

The current TNM bladder cancer staging system stratifies bladder muscle invasion into superficial (pT2a) and deep (pT2b). Controversy exists regarding the significance of the extent of muscle invasion on clinical outcome.

Objective

Our aim was to compare the cancer-specific outcomes of patients with pT2 urothelial carcinoma of the bladder (UCB) at radical cystectomy (RC) in a large international cohort of patients.

Design, setting, and participants

The records of patients treated with RC for UCB at six centers were reviewed. Of the 2605 reviewed patients, 565 (21.7%) had pT2 disease. None of the patients received preoperative systemic chemotherapy or radiotherapy.

Measurements

Patients’ characteristics and outcome were evaluated.

Results and limitations

The median patient age in the entire group was 66.2 yr. Of the 565 patients with pT2 UCB, 249 patients (44.1%) had substage pT2a; 316 patients (55.9%) had pT2b. One hundred and eleven patients (19.6%) had metastases to regional lymph nodes. Median follow-up was 50.5 mo. Recurrence-free survival (73.2% vs 58.7%) and cancer-specific survival (78.0% vs 65.1%) estimates were significantly better for pT2a patients compared with those with pT2b (p = 0.002 and p = 0.001, respectively). Pathologic T2 substaging was associated with worse recurrence-free and cancer-specific survival after adjusting for the effects of standard pathologic features (p = 0.011 and p = 0.006, respectively). The statistical significance of these associations was reconfirmed in subgroup analysis limited to those patients with pathologically negative lymph nodes.

Conclusions

In this large international cohort, pathologic substaging helped to stratify patients with lymph node–negative pT2 UCB into statistically significantly different risk groups. These data support the value of the current American Joint Committee on Cancer TNM staging.     

A Critical Analysis of the Actual Role of Minimally Invasive Surgery and Active Surveillance for Kidney Cancer

Context

The incidence of renal cell carcinomas (RCCs) has increased steadily—most rapidly for small renal masses (SRMs). Paralleling the changing face of RCC in the past 2 decades, new, less invasive surgical options have been developed. Laparoscopic radical nephrectomy (LRN) is an established procedure for the treatment of RCC. Treatment of SRMs includes open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN), thermal ablation, and active surveillance.

Objective

To present an overview of minimally invasive treatment options and data on surveillance for kidney cancer.

Evidence acquisition

Literature and meeting abstracts were searched using the terms renal cell carcinoma, minimally invasive surgery, laparoscopic surgery, thermal ablation, surveillance, and robotic surgery. The articles with the highest level of evidence were identified with the consensus of all the collaborative authors and reviewed.

Evidence synthesis

Renal insufficiency, as measured by the glomerular filtration rate, occurs more often after radical nephrectomy than partial nephrectomy (PN). OPN and LPN show comparable results in long-term oncologic outcomes. The treatment modality for SRMs should therefore be nephron-sparing surgery (NSS). In select patients, thermal ablation or active surveillance of SRMs is an alternative.

Conclusions

LRN has become the standard of care for most organ-confined tumours not amenable to NSS. Amongst NSS options, PN is the treatment of choice, yet remains underutilised in the community. Initial data during its learning curve revealed that LPN had higher urologic morbidity. However, current emerging data indicate that in experienced hands, LPN has shorter ischaemia times, a lower complication rate, and equivalent long-term oncologic and renal functional outcomes, yet with decreased patient morbidity compared to OPN. Robotic partial nephrectomy is being explored at select centres, and cryotherapy and radiofrequency ablation are options for carefully selected tumours. Active surveillance is an option for selected high-risk patients. Percutaneous needle biopsy is likely to gain increasing relevance in the management of small renal tumours.     

Diagnostic and Prognostic Molecular Markers for Renal Cell Carcinoma: A Critical Appraisal of the Current State of Research and Clinical Applicability

Context

Earlier detection of renal cell carcinoma (RCC) and the recent expansion of treatment possibilities have positively influenced the outlook for patients with this disease. However, progression and treatment response are still not sufficiently predictable. Molecular markers could help to refine individual risk stratification and treatment planning, although they have not yet become clinically routine.

Objective

This review presents an overview of diagnostic and prognostic molecular markers for RCC and a subgrouping of these markers for different clinical issues.

Evidence acquisition

Literature and recent meeting abstracts were searched using these terms: renal (cell) carcinoma, molecular/tumor markers, biopsy, blood, urine, disease progression/prognosis, immunohistochemistry, risk factors, and survival.Due to the resulting large number of articles, studies were subjectively selected according to the importance of a study on the field, number of investigated patients, originality, multivariate analyses performed, contrast with previously published data, actuality, and assumed clinical applicability of the described results. More then 90% of the selected studies originated from the past 10 yr; >50% of the articles were written in 2006 or later.

Evidence synthesis

These data were predominantly obtained via nonrandomized, retrospective, but often controlled studies. Thereby, the resulting level of evidence is 2A/2B. The broad spectrum of described molecular markers (MMs) for RCC consists of markers already extensively studied in other malignancies (eg, p53), as well as MMs typically associated with specific RCC-altered gene functions and pathways (eg, von Hippel–Lindau [VHL]). The main goal of using MMs is to refine the prediction of clinical end points like tumor progression, treatment response, and cancer-specific and/or overall survival. Further, MMs might facilitate the clinical work-up of undefined renal masses and prove to be more convenient tools for screening and follow-up in blood and urine.

Conclusions

Presently, there are a number of promising MMs for diverse clinical questions, but the available data are not yet valid enough for routine, clinical application. We should comply with the demand for large multicenter prospective investigations, stratified for RCC type and treatment modalities, to lift the use of molecular markers in RCC to a practical level, thereby providing a better consultation for our patients regarding diagnosis, treatment, and follow-up.     

A contemporary update on pathology reporting for prostate cancer: biopsy and radical prostatectomy specimens

Context

The diagnosis of and reporting parameters for prostate cancer (PCa) have evolved over time, yet they remain key components in predicting clinical outcomes.

Objective

Update pathology reporting standards for PCa.

Evidence acquisition

A thorough literature review was performed for articles discussing PCa handling, grading, staging, and reporting published as of September 15, 2011. Electronic articles published ahead of print were also considered. Proceedings of recent international conferences addressing these areas were extensively reviewed.

Evidence synthesis

Two main areas of reporting were examined: (1) prostatic needle biopsy, including handling, contemporary Gleason grading, extent of involvement, and high-risk lesions/precursors and (2) radical prostatectomy (RP), including sectioning, multifocality, Gleason grading, staging of organ-confined and extraprostatic disease, lymph node involvement, tumor volume, and lymphovascular invasion. For each category, consensus views, controversial areas, and clinical import were reviewed.

Conclusions

Modern prostate needle biopsy and RP reports are extremely detailed so as to maximize clinical utility. Accurate diagnosis of cancer-specific features requires up-to-date knowledge of grading, quantitation, and staging criteria. While some areas remain controversial, efforts to codify existing knowledge have had a significant impact on pathology practice.     

Prognostic heterogeneity in T3aN0M0 renal cell carcinoma according to the site of invasion

Purpose

We investigated the influence of the site of invasion on recurrence and survival in patients with pT3aN0M0 renal cell carcinoma (RCC).

Histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma

Background

The oncologic safety of blunt tumor enucleation (TE) of renal cell carcinoma (RCC) depends on the presence of a continuous pseudocapsule (PS) around the tumor and on the possibility of obtaining negative surgical margins (SMs).

Objective

To investigate the PS and SMs after TE to define the real need to take a rim of healthy parenchyma around the tumor to avoid the risk of positive SMs. The risk of PS invasion related to other clinical and pathologic variables was also evaluated.

Design, setting, and participants

Between September 2006 and December 2007, data were gathered prospectively from 187 consecutive patients who had kidney surgery. Overall, 90 consecutive patients who had TE for RCC were eligible for the study. All specimens were evaluated using an image analyzer by a dedicated uropathologist.

Intervention

TE was done by blunt dissection using the natural cleavage plane between the tumor and the normal parenchyma.

Measurements

PS, SM, and routinely available clinical and pathologic variables were recorded.

Results and limitations

In 60 RCC tumors (67%) the PS was intact and free from invasion (PS−) while in 30 (33%) there were signs of penetration within its layers, with or without invasion beyond it. Indeed, 26.6% had PS that had been penetrated on the parenchymal side and 6.6% had penetration on the perirenal fat tissue side. The odds of having PS penetration increased significantly with an increase in clinical tumor size. PS penetration was also significantly associated with pathologic tumor dimensions and grade. In all cases the SMs were negative after TE. The present patients, followed for >2 yr, will enable us to correlate the risk of local recurrence with PS status.

Conclusions

The risk of PS penetration is associated with clinical and pathologic tumor dimensions and grade. If there is PS invasion into normal parenchyma, the presence of a thin layer of tissue allows for negative SM even if a TE is performed.     

Novel Immunotherapeutic Strategies in Development for Renal Cell Carcinoma

Context

The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase.

Objective

To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm.

Evidence acquisition

A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy.

Evidence synthesis

Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host–tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies.

Conclusions

It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.     

Long-Term Oncologic Outcomes After Radiofrequency Ablation for T1 Renal Cell Carcinoma

Background

Radiofrequency ablation (RFA) of renal cell carcinoma (RCC) is used to obtain local control of small renal masses. However, available long-term oncologic outcomes for RFA of RCC are limited by small numbers, short follow-up, and lack of pathologic diagnoses.

Objective

To assess the oncologic effectiveness of RFA for the treatment of biopsy-proven RCC.

Design, setting, and participants

Exclusion criteria included prior RCC or metastatic RCC, familial syndromes, or T2 RCC. We retrospectively reviewed long-term oncologic outcomes for 185 patients with sporadic T1 RCC. Median follow-up was 6.43 yr (interquartile range [IQR]: 5.3–7.7).

Outcome measurements and statistical analysis

The chi-square test and Wilcoxon rank-sum tests were used to compare proportions and medians, respectively. Disease-specific survival and overall survival (OS) were calculated using Kaplan-Meier analysis, then stratified by tumor stage, and comparisons were made using log-rank analysis. The 5-yr disease-free survival (DFS) and OS rates are reported. A p value <0.05 was considered statistically significant.

Results and limitations

Median tumor size was 3 cm (IQR: 2.1−3.9 cm). Tumor stage was T1a: 143 (77.3%) or T1b: 42 (22.7%). Twenty-four patients (13%) were retreated for residual disease. There were 12 local recurrences (6.5%), 6 recurrences in T1a disease (4.2%) and 6 in T1b disease (14.3%) (p = 0.0196). Median time to recurrence was 2.5 yr. Local salvage RFA was performed in six patients, of whom five remain disease free at 3.8-yr median follow-up. Tumor stage was the only significant predictor of DFS on multivariate analysis. At last follow-up, 164 patients (88.6%) were disease free (T1a: n = 132 [92.3%]; T1b: n = 32 [76.2%]; p = 0.0038). OS was similar regardless of stage (p = 0.06). Five patients developed metachronous renal tumors (2.7%). Four patients developed extrarenal metastases (2.2%), three of whom died of metastatic RCC (1.6%).

Conclusions

In poor surgical candidates, RFA results in durable local control and low risk of recurrence in T1a RCC. Higher stage correlates with a decreased disease-free survival. Long-term surveillance is necessary following RFA. Patient selection based on tumor characteristics, comorbid disease, and life expectancy is of paramount importance.