Eric C. Kauffman

Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers

Despite nearly two decades passing since the discovery of gene fusions involving TFE3 or TFEB in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis of these genes remain largely unclear. The recently published findings of The Cancer Genome Atlas Network reported that five of the 416 surveyed clear cell RCC tumours (1.2%) harboured SFPQ–TFE3 fusions, providing further evidence for the importance of gene fusions. A total of five TFE3 gene fusions (PRCC–TFE3, ASPSCR1–TFE3, SFPQ–TFE3, NONO–TFE3, and CLTC–TFE3) and one TFEB gene fusion (MALAT1–TFEB) have been identified in RCC tumours and characterized at the mRNA transcript level. A multitude of molecular pathways well-described in carcinogenesis are regulated in part by TFE3 or TFEB proteins, including activation of TGFβ and ETS transcription factors, E-cadherin expression, CD40L-dependent lymphocyte activation, mTORC1 signalling, insulin-dependent metabolism regulation, folliculin signalling, and retinoblastoma-dependent cell cycle arrest. Determining which pathways are most important to RCC oncogenesis will be critical in discovering the most promising therapeutic targets for this disease.

Gleason 6 prostate cancer: Translating biology into population health

PURPOSE Gleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management. MATERIALS AND METHODS Members of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes. RESULTS The Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes. CONCLUSIONS The definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening.

Germline PTEN Mutation Cowden Syndrome: An Underappreciated Form of Hereditary Kidney Cancer

PURPOSE Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. MATERIALS AND METHODS Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. RESULTS Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. CONCLUSIONS Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience

BACKGROUND Long-term oncologic outcomes following robot-assisted radical cystectomy (RARC) remain scarce. OBJECTIVE To report long-term oncologic outcomes following RARC at a single institution. DESIGN, SETTINGS, AND PARTICIPANTS Retrospective review of 99 patients who underwent RARC for urothelial carcinoma of bladder between 2005 and 2009. INTERVENTION RARC was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS), measured by the Kaplan-Meier method. The association between primary outcomes and perioperative and pathologic factors was assessed using a multivariable Cox proportional hazards model. RESULTS AND LIMITATIONS Fifty-one (52%) patients had stage pT3 or higher disease. Eight (8%) patients had positive margins and 30 (30%) had positive lymph nodes (LNs), with a median of 21 LNs removed. Median follow-up for patients alive was 74 mo. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively. Tumor stage, LN stage, and margin status were each significantly associated with RFS, CSS, and OS. On multivariable analysis, tumor and LN stage were independent predictors of RFS, CSS, and OS, while positive margin status and Charlson comorbidity index predicted worse OS and CSS. Adjuvant chemotherapy predicted RFS only. Retrospective design and lack of open comparison are main limitations of this study. CONCLUSIONS Long-term oncologic outcomes following RARC demonstrate RFS and CSS estimates similar to those reported in literature for open radical cystectomy. Randomized controlled trials can better define outcomes of any alternative technique. PATIENT SUMMARY Survival data 5 yr after RARC for bladder cancer demonstrate that survival outcomes are dependent on the same oncologic parameters as previously reported for open surgery.

Clinical significance of prospectively assigned Gleason tertiary pattern 4 in contemporary Gleason score 3+3=6 prostate cancer

To determine the oncologic impact of prospectively assigned tertiary pattern 4 in contemporary Gleason score (GS) 3 + 3 = 6 radical prostatectomy (RP) specimens.

Efficacy of robot-assisted radical cystectomy (RARC) in advanced bladder cancer: results from the International Radical Cystectomy Consortium (IRCC)

To characterise the surgical feasibility and outcomes of robot‐assisted radical cystectomy (RARC) for pathological T4 bladder cancer.

External validation of preoperative and postoperative nomograms for prediction of cancer-specific survival, overall survival and recurrence after robot-assisted radical cystectomy for urothelial carcinoma of the bladder

To externally validate currently available bladder cancer nomograms for prediction of all‐cause survival (ACS), cancer‐specific survival (CSS), other‐cause mortality (OCM) and progression‐free survival (PFS).

Incidence of Clear Cell Papillary Renal Cell Carcinoma in Low-Grade Renal Cell Carcinoma Cases A 12-Year Retrospective Clinicopathologic Study From a Single Cancer Center

Clear cell papillary renal cell carcinoma (CCPRCC) is a recently recognized subtype of renal cell carcinoma entity after 2004 World Health Organization classification of renal tumors. CCPRCC has unique histomorphological and immunohistochemical characteristics. The distinction of CCPRCC from renal cell carcinoma (RCC) with clear cell morphology is crucial because the former is considered to have a favorable clinical outcome. CCPRCC may be interpreted in the past as other renal cell carcinomas, particularly low-grade clear cell RCC. In this study, the frequency of CCPRCC in previously diagnosed low-grade RCC and its clinicopathologic features were examined. A total of 126 cases of stage T1a with low nuclear grade RCC were identified from 625 consecutive RCCs removed by radical/partial nephrectomy over 12-year period (2000-2011). Archival tissue sections were retrospectively reviewed along with patient medical charts. Eight cases (1.3% of all RCC, 6.3% of pT1a low grade RCC) with characteristic histologic features of CCPRCC were confirmed by immunohistochemical studies. Seven cases were previously diagnosed as clear cell RCC and one as multilocular cystic RCC. Radiographically, CCPRCC favored a mid-pole location in the kidneys. At a median follow-up period of 52 months (range 20-114.5 months), there were no cases of local or distant recurrence. In conclusion, CCPRCC is not uncommon among small low-grade RCC tumors. CCPRCC can be correctly recognized by its unique histomorphological features and confirmed by immunohistochemistry studies, which is important due to the excellent clinical outcome following resection.

Cancer of the kidney

Surgical resection is the cornerstone of therapy for patients both with localized and metastatic renal cell carcinoma, given the ineffectiveness of chemotherapeutic and radiotherapeutic strategies against these tumors. Traditionally, the surgical approach to the kidney has been through a flank, subcostal, or midline incision. With the advent of minimally invasive surgery, laparoscopic techniques have been applied to the kidney. Both radical and nephron-sparing surgery of the kidney are now routinely performed laparoscopically for patients with renal masses without compromising oncological principles. This chapter will provide an overview of the indications and technical considerations for the various forms of minimally invasive surgical options that are currently available to patients with renal mass.

Blinded review of archival radical prostatectomy specimens supports that contemporary Gleason score 6 prostate cancer lacks metastatic potential

Retrospective identification of Gleason pattern 4 in metastatic Gleason score 3 + 3 = 6 (GS6) radical prostatectomy (RP) specimens has suggested true GS6 prostate cancer (CaP) lacks metastatic potential. However, pathologist awareness of study design and metastasis outcomes at the time of RP review might have introduced upgrading bias. We used pathologist‐blinded methodology for unbiased characterization of metastasis rates for contemporarily defined pathologic GS6 (pGS6) CaP.