Arun Z. Thomas

Surgical Management of Local Retroperitoneal Recurrence of Renal Cell Carcinoma after Radical Nephrectomy

PURPOSE Isolated local retroperitoneal recurrence after radical nephrectomy for renal cell carcinoma poses a therapeutic challenge. We investigated outcomes in patients with localized retroperitoneal recurrence treated with surgical resection. MATERIALS AND METHODS This was a retrospective, single institutional study of 102 patients with retroperitoneal recurrence treated with surgery from 1990 to 2014. Demographics, clinical and pathological features, location of retroperitoneal recurrence and perioperative complications are reported using descriptive statistics. We studied recurrence-free and cancer specific survival using univariate and multivariate analyses. RESULTS Median age at retroperitoneal recurrence diagnosis was 55 years (IQR 49-64). Cancer was pT3-4 in 62 patients (60.8%) and pN1 in 20 (19.6%). No patients had distant metastatic disease at retroperitoneal recurrence surgery. Median time from nephrectomy to retroperitoneal recurrence diagnosis was 19 months (IQR 5-38.8). The median size of the resected retroperitoneal recurrence was 4.5 cm (IQR 2.7-7). Median followup after recurrence surgery was 32 months (IQR 16-57). Metastatic progression was observed in 60 patients (58.8%) postoperatively. Neoadjuvant and salvage systemic therapy was administered in 46 (45.1%) and 48 patients (47.1%), respectively. On multivariate analysis pathological nodal stage at original nephrectomy and maximum diameter of retroperitoneal recurrence were identified as independent risk factors for cancer specific death. CONCLUSIONS Clinicopathological factors at nephrectomy as well as retroperitoneal recurrence surgery are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with retroperitoneal recurrence with acceptable complications and still has a dominant role in the management of isolated locally recurrent RCC.

The role of neoadjuvant therapy in the management of locally advanced renal cell carcinoma

In the past decade, the armamentarium of targeted therapy agents for the treatment of metastatic renal cell carcinoma (RCC) has significantly increased. Improvements in response rates and survival, with more manageable side effects compared with interleukin 2/interferon immunotherapy, have been reported with the use of targeted therapy agents, including vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (sunitinib, sorafenib, pazopanib, axitinib), mammalian target of rapamycin (mTOR) inhibitors (everolimus and temsirolimus) and VEGF receptor antibodies (bevacizumab). Current guidelines reflect these new therapeutic approaches with treatments based on risk category, histology and line of therapy in the metastatic setting. However, while radical nephrectomy remains the standard of care for locally advanced RCC, the migration and use of these agents from salvage to the neoadjuvant setting for large unresectable masses, high-level venous tumor thrombus involvement, and patients with imperative indications for nephron sparing has been increasingly described in the literature. Several trials have recently been published and some are still recruiting patients in the neoadjuvant setting. While the results of these trials will inform and guide the use of these agents in the neoadjuvant setting, there still remains a considerable lack of consensus in the literature regarding the effectiveness, safety and clinical utility of neoadjuvant therapy. The goal of this review is to shed light on the current body of evidence with regards to the use of neoadjuvant treatments in the setting of locally advanced RCC.

Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25-30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.

Percentage of sarcomatoid component as a prognostic indicator for survival in renal cell carcinoma with sarcomatoid dedifferentiation

OBJECTIVE Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with higher stage of presentation and worse survival. The objective of this study was to examine the clinicopathologic characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC). METHODS We reviewed clinicopathologic data for all nephrectomized patients with confirmed sRCC. Histologic slides were rereviewed by dedicated genitourinary pathologists to ascertain PSC. Patient characteristics were tabulated overall and by disease stage. Cutpoints in the PSC providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA). Factors selected included age group, gender, race, clinical stage, tumor histology, presurgical systemic therapy, lymphovascular invasion, and tumor size. The Kaplan-Meier method and log-rank test were used to assess differences in OS. RESULTS Among 186 patients with sRCC, 64 (34%) had localized, and 122 (66%) had metastatic disease at presentation. Patients had primarily clear cell histology (73%). Median follow-up was 12.1 months (range: 0.1-242.2mo). Median OS was 12.6 months (95% CI: 10.7-14.9mo). Univariate RPA identified a PSC cutpoint of 10% as prognostically significant. Patients with PSC>10% were at higher risk of death when compared with patients with PSC≤10% (45% vs. 61% 1-y OS; P = 0.04). Multivariate RPA revealed that tumor size, presence of metastatic disease, and PSC were significantly associated with OS. Among 4 identified groups, patients with localized disease and tumor size≤10cm were most likely to be alive at 1 year (89%), and patients with metastatic disease and PSC>40% were least likely to be alive at 1 year (28%; P<0.001). CONCLUSION PSC appears to be a prognostic factor in patients with sRCC, with larger percentage of involvement portending a worse survival, especially in patients with metastatic disease.

Role of metastasectomy in metastatic renal cell carcinoma

Purpose of review Management of patients with metastatic renal cell carcinoma is challenging and continues to be delivered in a multidisciplinary context. Even with the advent of systemic targeted therapy, complete remission with these new agents is rare using systemic therapy alone. Surgical resection of the primary tumor and metastatic deposits continues to play an important role in managing patients with metastatic renal cell carcinoma when aiming for complete remissions. To date, despite the lack of level 1 evidence, metastasectomy appears to prolong survival and achieve long-term cure in carefully selected patients. This review examines current evidence for the role of metastasectomy in renal cell carcinoma. Recent findings Studies continue to consistently support a benefit of complete metastasectomy for overall and cancer-specific survival at most sites for resection, with the exception of brain and bone, which tend to perform for symptomatic relief and palliation. Metastasectomy has not yet been examined in a randomized setting. The debate of survival benefit because of selection bias of patients or differences in tumor biology is relevant and has yet to be resolved in the literature. Clearly, careful patient selection remains paramount in optimizing survival benefit from metastasectomy. Summary Patients with isolated surgically resectable metastatic disease, with long disease-free intervals, and with good performance status are likely to benefit the most from metastasectomy.

Management of the Incidental Adrenal Mass

CONTEXT Incidentally discovered adrenal masses are becoming more common in clinical practice. OBJECTIVE To review the management of the incidental adrenal mass, including initial evaluation, surveillance, medical therapy, and surgical therapy. EVIDENCE ACQUISITION A literature search of English-language publications that included the keywords adrenal incidentaloma and incidental adrenal mass was performed through July 2015 using PubMed. Relevant original articles and guidelines on the management of the incidental adrenal mass were ultimately selected for analysis, with the consensus of all authors. EVIDENCE SYNTHESIS Data from the manuscripts included in this review were synthesized, and findings were categorized into metabolic evaluation, imaging, biopsy, surgical considerations, and follow-up recommendations. CONCLUSIONS Ideally, management of patients with adrenal incidentalomas should involve a multidisciplinary approach with experienced surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection. PATIENT SUMMARY Management of patients with adrenal incidentalomas should involve a multidisciplinary approach with surgeons, radiologists, and endocrinologists to determine whether such lesions are benign or malignant and functional or nonfunctional and/or whether they require surgical resection.

Prediction of Pulmonary Metastasis in Renal Cell Carcinoma Patients with Indeterminate Pulmonary Nodules

BACKGROUND Indeterminate pulmonary nodules (IPN) are of uncertain significance in patients with renal cell carcinoma. OBJECTIVE We sought to determine predictors of IPN progression to pulmonary metastasis and develop a tool for individualized risk stratification of patients who present with IPN on preoperative chest imaging in the setting of localized or locally advanced renal cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS We reviewed all patients who had radical nephrectomy with no evidence of distant metastases at a single institution from 2005-2009 who had ≥1 IPN on chest computed tomography that measured <2 cm. All chest computed tomographies were rereviewed by a radiologist who was blinded to outcomes, to independently determine number, size, and location of nodules. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary objective of the study was to develop a prognostic model to predict pulmonary metastases among radical nephrectomy patients who present with IPN based on readily available preoperative imaging and postoperative pathological criteria. Univariable and multivariable Cox regression models were used to assess the predictive factors for development of pulmonary metastasis. We developed a nomogram that predicted the 3-yr and 5-yr lung metastasis-free survival (LMFS), with assessment of discrimination and internal validation. RESULTS AND LIMITATIONS Among 251 patients with IPN who underwent nephrectomy, 72 (29%) developed pulmonary metastases. Median follow-up for the cohort was 36.6 mo. Three-yr and 5-yr probability of LMFS for the overall cohort was 71% (95% confidence interval 65-77%) and 65% (95% confidence interval 57-72%), respectively. The nomogram developed included number and size of IPN along with postoperative pathological variables, and showed calibration with a concordance index (c-index) of 0.81 and a bootstrap corrected c-index of 0.78. Limitations include retrospective study with no external validation. CONCLUSIONS We developed a nomogram to predict the individualized risk LMFS for patients who underwent nephrectomy for localized or locally advanced renal cell carcinoma. PATIENT SUMMARY We reviewed outcomes among kidney cancer patients who presented with small lung nodules and developed a clinical tool to predict risk of developing lung metastases.

Cytoreductive surgery in the era of targeted molecular therapy.

Cytoreductive nephrectomy (CN) was regarded standard of care for patients with metastatic renal cell carcinoma (mRCC) in the immunotherapy era. With the advent of targeted molecular therapy (TMT) for the treatment of mRCC, the routine use of CN has been questioned. Up to date evidence continues to suggest that CN remains an integral part of treatment in appropriately selected patients. This review details the original context in which the efficacy of CN was established and rationale for the continued use of cytoreductive surgery in the era of TMT.

Prognosticators and outcomes of patients with renal cell carcinoma and adjacent organ invasion treated with radical nephrectomy.

OBJECTIVE To study the natural history, prognosticators, and outcomes in patients with renal cell carcinoma (RCC) with extension of tumor beyond Gerota׳s fascia or invading contiguously into the adrenal gland (pT4) or both. PATIENTS AND METHODS From 1992 to 2012, we identified 61 patients who underwent radical nephrectomy and were found to have pT4 disease. Clinicopathologic variables were queried using univariate analysis to identify relevant prognostic variables. Cox proportional hazards model was used for multivariate analysis of predictors of cancer-specific survival. Survival plots were estimated using Kaplan-Meier method and survival analysis using log-rank test. RESULTS Median age was 56 years (interquartile range: 49-64) and 49 (81.7%) patients had Eastern Cooperative Oncology Group Performance Status 0 or 1. At diagnosis, 22 (36.1%) patients showed nonmetastatic and 39 (63.9%) patients showed metastatic RCC. Overall, 49 (80.3%) patients had clear cell RCC, 24 (39.3%) patients had sarcomatoid features, and 39 (69.6%) patients had Fuhrman grade 3 to 4. There were 26 (42.6%) patients with pN0, 16 (26.2%) patients with pN1, and 19 (31.1%) patients with pNx. Median cancer-specific survival was 37 months for patients with nonmetastatic and 8 months for patients with metastatic RCC. On multivariate analysis, preoperative lactate dehydrogenase and alkaline phosphatase, M stage, pN stage, and sarcomatoid dedifferentiation were significantly associated with survival. CONCLUSIONS Survival in patients with pT4 remains poor. The pT4 disease is associated with a locally and regionally invasive biology that requires specific attention and warrants careful study. Understanding the drivers of this unique phenotype would generate therapeutic interventions that can change the behavior of these uniquely aggressive tumors.

Primitive Neuroectodermal Tumors and Other Sarcomas of the Kidney

Although extremely rare, renal sarcomas can cause high rates of morbidity and death. The diagnosis of these entities remains challenging and findings illustrate the importance of obtaining a preoperative biopsy given the various range of prognosis. Furthermore, there is no standardized treatment for renal sarcomas, and evidence from the literature to help clinicians manage renal sarcomas is limited. Here, we summarize the clinical knowledge about the major clinicopathological characteristics, outcomes, and management of primary renal primitive neuroectodermal tumors and other rare types of kidney sarcomas, including leiomyosarcoma, liposarcoma, hemangiopericytoma, fibrosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, and primary renal synovial sarcoma.