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Purpose: Fibrosis accounts for approximately 50% of histological findings at post-chemotherapy retroperitoneal lymph node dissection, and is associated with reported relapse rates of 10% to 15%. We characterized patients with fibrosis at post-chemotherapy retroperitoneal lymph node dissection and identified predictors of adverse outcomes in this group., Materials and Methods: We reviewed the medical records of men who underwent post-chemotherapy retroperitoneal lymph node dissection between 1989 and 2013 with histological findings of necrosis/fibrosis. With few exceptions post-chemotherapy retroperitoneal lymph node dissection after 1999 was performed with a bilateral template. Clinical, pathological and treatment related data were reported. Cox regression models were built to identify predictors of disease recurrence., Results: The study cohort included 598 men with a median age of 32 years (IQR 25-38). Most cases (397 of 547, 73%) were classified as IGCCCG good risk, with no significant differences in risk classification before and after 1999 (p=0.55). Median followup was 7.3 years (IQR 3.2-12.3). The 5-year recurrence-free and overall survival rates were 94% and 96%, respectively. Overall 36 patients had disease recurrence, most of which was distant or outside the retroperitoneal lymph node dissection template. Procedures performed after 1999 and the presence of embryonal cell carcinoma on primary histology were associated with improved recurrence-free survival on multivariate analysis (p <0.01)., Conclusions: Disease recurrence in patients with fibrosis at post-chemotherapy retroperitoneal lymph node dissection is an uncommon yet significant event, which is less likely to occur in patients treated after 1999 and in those with embryonal carcinoma on primary histology., Competing Interests: and Disclosure Statement All authors have nothing to disclose., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We analyzed the 23-year Memorial Sloan Kettering Cancer Center experience with surgical resection, and concurrent adrenalectomy and lymphadenectomy for locally advanced nonmetastatic renal cell carcinoma., Materials and Methods: We retrospectively reviewed the records of 802 patients who underwent nephrectomy with or without concurrent adrenalectomy or lymphadenectomy for locally advanced renal cell carcinoma, defined as stage T3 or greater and M0. Patients who received adjuvant treatment within 3 months of surgery or had fewer than 3 months of followup or bilateral renal masses at presentation were excluded from analysis. Five and 10-year progression-free and overall survival was estimated by the Kaplan-Meier method. Differences between groups were analyzed by the log rank test., Results: A total of 596 (74%) and 206 patients (26%) underwent radical and partial nephrectomy, respectively. Renal cell carcinoma progressed in 189 patients and 104 died of the disease. Median followup in patients without progression was 4.6 years. Symptoms at presentation, ASA(®) classification, tumor stage, histological subtype, grade and lymph node status were significantly associated with progression-free and overall survival. On multivariate analysis adrenalectomy use decreased with time but lymphadenectomy use increased (OR 0.82 vs 1.16 per year). Larger tumors were associated with a higher likelihood of concurrent adrenalectomy and lymphadenectomy., Conclusions: In our series of patients with locally advanced nonmetastatic renal cell carcinoma survival was favorable in those in good health who were asymptomatic at presentation with T3 tumors and negative lymph nodes. Further, there has been a trend toward more selective use of adrenalectomy and increased use of lymphadenectomy., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with good risk nonseminomatous germ cell tumors received induction chemotherapy with 4 cycles of etoposide and cisplatin (EPx4) or 3 cycles of bleomycin, etoposide and cisplatin (BEPx3). We report the histological results at post-chemotherapy retroperitoneal lymph node dissection after induction chemotherapy in patients treated with etoposide and cisplatin or bleomycin, etoposide and cisplatin for good risk nonseminomatous germ cell tumors., Materials and Methods: Post-chemotherapy retroperitoneal lymph node dissection was performed in 579 patients after induction chemotherapy. Of these patients 505 were treated with EPx4 and 74 were treated with BEPx3 or BEPx4. Clinical and pathological features are reported., Results: No difference in the frequency of viable residual cancer was observed with bleomycin, etoposide and cisplatin vs etoposide and cisplatin (5% vs 6%, respectively, p=not significant). Teratoma was more prevalent in the bleomycin, etoposide and cisplatin group vs etoposide and cisplatin group (57% vs 34%, respectively, p <0.001). On multivariate analysis patients who received induction bleomycin, etoposide and cisplatin had a twofold greater risk of harboring teratoma at post-chemotherapy retroperitoneal lymph node dissection (OR 2.0; 95% CI 1.0, 4.0; p=0.04). When excluding patients from analysis who received BEPx4, those who received BEPx3 still had a 3.7-fold increased risk of teratoma in the retroperitoneum (OR 3.7; 95% CI 1.5, 8.9; p=0.004). Relapse-free and disease specific survival was not different between the 2 regimens., Conclusions: Viable cancer was equally uncommon after treatment with both regimens. Overall, relapse-free and disease specific survival did not differ between the groups. The discrepancy between regimens in the frequency of teratoma is not explained but may be due to an unrecognized selection bias rather than an effect of the regimen., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated pathological variables of testicular sex cord-stromal tumors, management options and clinical outcomes., Materials and Methods: We retrospectively reviewed the records of 48 patients with testicular sex cord-stromal tumors treated at Memorial Sloan-Kettering Cancer Center between 1997 and 2012. Clinical outcomes were compared based on treatment and previously described pathological factors associated with metastatic potential., Results: Of the 48 patients 37 underwent surveillance without retroperitoneal lymph node dissection, including 34 with no high risk feature and 3 with 1. Median followup was 14.5 months (IQR 6.9-32.5). No patient experienced recurrence. Retroperitoneal lymph node dissection was performed in 11 patients, including 6 with clinical stage I disease and 2 or more high risk features who underwent early dissection, 2 with clinical stage IIa disease at diagnosis who underwent early dissection and 3 with clinical stage I disease and 2 or more high risk features who were observed elsewhere but referred to our institution due to retroperitoneal disease. Six patients with clinical stage I disease underwent early dissection, 4 had no evidence of disease at a median followup of 6.6 years and 2 experienced recurrence and died of disease. Neither of the 2 patients with IIa disease at diagnosis experienced relapse. All 3 patients with delayed dissection experienced relapse and 1 died of disease., Conclusions: Patients with testicular sex cord-stromal tumors and 1 or no high risk feature can be safely observed without retroperitoneal lymph node dissection but longer followup is needed. Given the lack of effective alternative treatments, early retroperitoneal lymph node dissection may be beneficial in those with 2 or more high risk features, or clinical stage IIa disease., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Several recently reported recurrent genomic alterations in clear cell renal cell carcinoma are linked to pathological and clinical outcomes. We determined whether any recurrent cancer gene mutations or copy number alterations identified in the TCGA (The Cancer Genome Atlas) clear cell renal cell carcinoma data set could add to the predictive accuracy of current prognostic models., Materials and Methods: In 413 patients who underwent nephrectomy/partial nephrectomy we investigated whole exome, copy number array analyses and clinical variables. We identified 65 recurrent genomic alterations based on prevalence and combined them into 35 alterations, including 12 cancer gene mutations. Genomic markers were modeled using the elastic net algorithm with preoperative variables (tumor size plus patient age) and in the postoperative setting using the externally validated Mayo Clinic SSIGN (stage, size, grade and necrosis) prognostic scoring system. These models were subjected to internal validation using bootstrap., Results: Median followup in survivors was 45 months. Several markers correlated with adverse cancer specific survival and time to recurrence on univariate analysis. However, most of them lost significance when controlling for tumor size with or without age in the preoperative models or for SSIGN score in the postoperative setting. Adding multiple genomic markers selected by the elastic net algorithm failed to substantially add to the predictive accuracy of any preoperative or postoperative model for cancer specific survival or time to recurrence., Conclusions: While recurrent copy number alterations and cancer gene mutations are biologically significant, they do not appear to improve the predictive accuracy of existing models of clinical cancer specific survival or time to recurrence for clear cell renal cell carcinoma., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We assessed temporal shifts in the frequency of risk factors for patients with metastatic renal cell carcinoma in a multicenter, international data set., Materials and Methods: An international database of 3,748 patients treated with systemic therapy for metastatic renal cell carcinoma from 1975 to 2002 was constructed by pooling clinical trial data. Proportions of previously identified risk factors were examined during 6 specified time cohorts. Overall survival for each cohort was examined using the Kaplan-Meier method. Trends in overall survival from 1973 to 2008 were also examined in 25,271 patients from the SEER (Surveillance, Epidemiology and End Results) database., Results: Median overall survival from start of treatment increased with each consecutive time cohort group. In the earliest cohort median overall survival was 0.5 years (95% CI 0.43-0.57), which increased to 1.63 years (95% CI 1.28-1.79) in 2001 to 2002. More patients had a history of nephrectomy in the most recent cohort (p = 0.001). The proportion of patients with low performance status, high lactate dehydrogenase and high adjusted calcium decreased by study entry year (each p <0.01). Analysis of overall survival from the SEER database showed similar improvement in the more contemporary diagnosis cohorts (p <0.001). Two-year overall survival in the earliest and latest diagnosis cohort was 14% (95% CI 13-14) and 22% (95% CI 21-24), respectively., Conclusions: Higher representation of favorable risk factors in recent years may have partly contributed to the improvement in overall survival observed in more recent metastatic renal cell carcinoma clinical trials. These shifts could affect the outcome interpretation., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We analyzed characteristics in patients with recurrent renal cell carcinoma 5 years or later after nephrectomy and determined predictors of survival after recurrence., Materials and Methods: From July 1989 to October 2008 at total of 2,368 nephrectomies were done for clinically localized, unilateral renal cell carcinoma at our institution. Of 256 patients with disease recurrence 44 had recurrence 5 years or more after nephrectomy. We compared clinicopathological characteristics in patients with disease recurrence before vs after 5 years. Survival from time of recurrence was assessed based on Memorial Sloan-Kettering Cancer Center risk score, symptoms at recurrence, metastasectomy, tumor diameter, and recurrence stage and site., Results: Patients with late recurrence tended to have fewer symptoms at presentation, smaller tumors (median 8.5 vs 7 cm) and less aggressive disease (pT1 in 18% vs 39%). Median overall survival was 6.1 years from time of recurrence. Five-year actuarial survival was 85% in 28 patients at favorable risk and 14% in 10 at intermediate risk (log rank p <0.001). The 5-year estimated overall survival rate was 72% in 31 patients with incidentally detected recurrence and 39% in 11 with symptoms at recurrence (log rank p = 0.01)., Conclusions: Data suggest that patients with cancer recurrence 5 years after nephrectomy are at favorable risk and have long-term median survival. A favorable Memorial Sloan-Kettering Cancer Center risk score and absent symptoms related to metastasis are associated with longer survival in these patients., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the prognostic roles of metastasectomy and an established risk stratification system in patients with disease recurrence following nephrectomy for nonmetastatic renal cell carcinoma., Materials and Methods: A retrospective analysis was performed in 129 patients with localized renal cell carcinoma treated with partial or radical nephrectomy and subsequently diagnosed with disease recurrence. At recurrence a previously validated risk score based on Karnofsky performance status, interval from nephrectomy, and serum hemoglobin, calcium and lactate dehydrogenase was used to categorize patients as being at favorable, intermediate or poor risk. Survival from time of recurrence was assessed based on risk categorization and metastasectomy., Results: Median time from nephrectomy to recurrence was 16 months. The risk score was strongly associated with median survival and the 2-year survival rate, including 73 months and 81% for favorable risk, 28 months and 54% for intermediate risk, and 6 months and 11% for poor risk, respectively (log rank <0.001). Metastasectomy performed in 44 patients (34%) was found to be of clinical benefit across the various risk categories (interaction analysis p = 0.8). On multivariate analysis a better risk category and metastasectomy were each independently associated with more favorable survival (each p <0.001). When combined, they provided 6 risk categories with an estimated 2-year survival of 0% to 93%., Conclusions: The clinical course in patients with recurrent renal cell carcinoma following nephrectomy can be variable. It is independently impacted by an objectively determined risk score and whether the patient undergoes metastasectomy.

Purpose: We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma., Materials and Methods: Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review)., Results: Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months., Conclusions: The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation.

Purpose: Sarcomatoid renal cell carcinomas, highly aggressive variants of renal cell carcinoma subtypes, often present with or develop metastases soon after the primary diagnosis. Most metastatic cases do not respond to immunotherapy or aggressive chemotherapy. Recently targeted therapies, particularly those targeting hypoxia inducible pathway molecules, have been tested clinically on metastatic clear cell renal cell carcinoma with promising initial results. No such studies are available on sarcomatoid renal cell carcinoma. We investigated the hypoxia inducible pathway marker immunohistochemical expression profile, and any potential therapeutic implications that such expression may have, in these tumors., Materials and Methods: Immunohistochemical staining for hypoxia inducible factor-1alpha, glucose transporter 1, carbonic anhydrase IX and vascular endothelial growth factor was performed in 22 clear cell and 12 nonclear cell sarcomatoid renal cell carcinomas. The immunoreactivity in the tumors was graded from 0 to 3+ (0-no staining, 1+-1% to 25% cells positive, 2+-26% to 50% cells positive and 3+-greater than 50% cells positive). The results were then compared with various clinical parameters to assess for associations., Results: Most clear cell renal cell carcinomas over expressed (2+ or 3+) hypoxia inducible factor-1alpha (in 59%), carbonic anhydrase IX (95%), glucose transporter 1 (91%) and vascular endothelial growth factor (95%). None of the nonclear cell sarcomatoid renal cell carcinomas showed 2+ or 3+ expression of hypoxia inducible factor-1alpha, carbonic anhydrase IX or glucose transporter 1, but 92% showed diffuse positivity for vascular endothelial growth factor. Over expression of carbonic anhydrase IX showed no association with survival, unlike that reported in (nonsarcomatoid) clear cell renal cell carcinoma. There was significant discordance in the staining grades among hypoxia inducible factor-1alpha, carbonic anhydrase IX and glucose transporter 1 in clear cell renal cell carcinoma, suggesting that mechanisms other than hypoxia inducible pathway may be involved in some sarcomatoid clear cell renal cell carcinoma., Conclusions: Hypoxia inducible pathway markers continue to be over expressed in sarcomatoid clear cell renal cell carcinoma, and can be of diagnostic usefulness in such high grade tumors. Over expression of vascular endothelial growth factor in the clear and nonclear cell groups raises the possibility that vascular endothelial growth factor targeted therapies may have a role in the management of sarcomatoid renal cell carcinoma, and deserve further investigation.

Purpose: We identified differentially expressed genes associated with response to pegylated interferon-alpha treatment in patients with renal cell carcinoma., Materials and Methods: We performed expression profiling on renal cell carcinoma specimens isolated from 23 patients with metastatic disease who were subsequently treated with interferon. Significance Analysis for Microarrays software was used to identify genes that were differentially expressed between patients with partial response compared to those with disease progression., Results: A candidate gene approach looking at VHL and known target genes did not identify any genes whose expression correlated with patient response. A global analysis of approximately 54,000 probe sets identified 4 genes that had expression correlated with response. Reverse transcriptase-polymerase chain reaction analysis of 2 of these genes confirmed that they were more highly expressed in tumors from patients who responded to interferon-alpha. Interestingly, both of these genes mapped to 4q31-32, a region that has been implicated as the site of a potential tumor suppressor gene in renal cell carcinoma., Conclusions: We have identified 4 genes (3 uncharacterized and 1 known) that may prove useful in predicting response to interferon-alpha treatment in patients with renal cell carcinoma.

Purpose: We evaluated the incidence, sites and histology of disease outside 5 modified retroperitoneal lymph node dissection templates for patients with low stage nonseminomatous germ cell tumors of the testis., Materials and Methods: Our cohort consisted of 500 consecutive patients with clinical stage I to IIA nonseminomatous germ cell tumors who underwent primary retroperitoneal lymph node dissection from 1989 to 2004. We analyzed 191 patients with pathological stage II disease and defined the incidence of disease outside 5 modified retroperitoneal lymph node dissection templates, 3 described for open surgery (Testicular Tumor Study Group, Indiana University and Memorial Sloan-Kettering Cancer Center) and 2 for laparoscopic surgery (University of Innsbruck and The Johns Hopkins University)., Results: Of 191 patients with pathological stage II disease, 111 (58%) had clinical stage I disease and 80 (42%) had clinical stage IIA disease. Depending on the template applied, extra-template disease ranged from 3% to 23% of all patients and was 1% to 11% of patients with pN1 disease. Regardless of template, histological distribution of extra-template disease was not significantly different from in-template disease with approximately 90% viable germ cell tumor, 10% teratoma only and 20% with any teratoma. For right side templates inclusion of para-aortic, preaortic and right common iliac regions decreased the incidence of extra-template disease to 2%. For left side templates inclusion of interaortocaval, precaval, paracaval and left common iliac regions decreased the incidence of extra-template disease to 3%., Conclusions: A significant number of men with clinical stage I to IIA nonseminomatous germ cell tumors and retroperitoneal metastases have disease present outside the limits of modified templates, including 20% to 30% with chemoresistant teratomatous elements. The data suggest that more extensive nerve sparing templates optimize oncological efficacy and ejaculation preservation, and minimize overall treatment morbidity.

Purpose: The biological potential of teratoma remains unpredictable, therefore identifying its presence in the retroperitoneum remains important. We evaluated patients undergoing post-chemotherapy retroperitoneal lymph node dissection for nonseminomatous germ cell tumors to determine predictors of teratomatous elements in the retroperitoneum., Materials and Methods: We identified 532 patients from 1989 to 2003 who underwent retroperitoneal lymph node dissection following chemotherapy for nonseminomatous germ cell tumors at our institution. Multiple clinical and pathological variables were reviewed from our prospective retroperitoneal lymph node dissection database. A logistic regression model was designed based on preoperative variables to predict the presence of teratomatous elements in the retroperitoneal lymph node dissection specimen., Results: Of the 532 patients in our series 450 (85%) received only induction chemotherapy and 82 (15%) required salvage chemotherapy. Teratomatous elements were identified in the orchiectomy specimen in 42% of patients. Retroperitoneal nodal pathology revealed teratomatous elements in 235 (44%) patients and only teratoma in 210 (40%) patients. By multivariate analysis testicular yolk sac tumor (p = 0.046), teratoma in the orchiectomy specimen (p <0.005), relative change in nodal size before and after chemotherapy (p <0.005), and no requirement for salvage chemotherapy (p = 0.03) were independent predictors for the presence of teratoma in the retroperitoneum., Conclusions: Teratoma remains a common histological finding in the retroperitoneal lymph nodes following chemotherapy. We have identified several pre-retroperitoneal lymph node dissection variables that predict the finding of teratoma in the retroperitoneum for men treated with chemotherapy for metastatic nonseminomatous germ cell tumors.

Purpose: The outcome after primary retroperitoneal lymph node dissection (RPLND) was analyzed in patients with clinical stage I-IIA nonseminomatous germ cell testicular cancer with embryonal carcinoma predominance (ECP) or lymphovascular invasion (LVI)., Materials and Methods: Between 1989 and 2002, 267 patients with clinical stage I-IIA nonseminomatous germ cell testicular cancer, and ECP and/or LVI underwent RPLND. Patient information was obtained from a prospective database. Median followup was 53 months., Results: Overall 42% of patients had pathological stage (PS) II disease, of whom 54% had low volume (PN1) disease and 16% had retroperitoneal teratoma. The 5-year progression-free probability was 90% overall, 90% for PS I and 86% for PN1. All patients with relapse were continuously free of disease following standard chemotherapy with or without resection of residual masses and the 10-year actuarial overall survival was 100%. When adjuvant chemotherapy was restricted to patients with PN2 disease, the estimated 5-year relapse rate was 9% and an estimated 72% of patients avoided chemotherapy., Conclusions: The low risk of systemic relapse in patients with PS I and PN1 after RPLND alone combined with the 16% incidence of retroperitoneal teratoma and the favorable morbidity profile supports RPLND over primary chemotherapy for the treatment of patients with low stage disease with ECP and/or LVI who are not candidates for surveillance. An estimated 72% of patients are spared the potential toxicity of chemotherapy if adjuvant therapy is restricted to patients with PN2. After primary RPLND and selective adjuvant chemotherapy late recurrence is distinctly uncommon and long-term cancer control is anticipated in essentially all patients.

Purpose: We determined the pathological findings and clinical outcome of patients with pure embryonal carcinoma (EC) of the testis managed by primary retroperitoneal lymph node dissection., Materials and Methods: From January 1989 to February 1998, 45 patients with pure EC underwent primary retroperitoneal lymph node dissection at our institution. Patients presented as clinical stage I in 26, IIA in 17 and IIB in 2. Lymphovascular invasion was present in 29 (64%). Median followup was 36.8 months., Results: Overall the pathological stage was pN0 in 11, pN1 in 10 (4 with microscopic disease) and pN2/N3 in 24 patients (8 with extranodal extension). Nineteen of 26 patients (73%) with clinical stage I and 13 of 17 (77%) patients with clinical stage IIA had retroperitoneal disease. No patient with negative lymph nodes (pN0) has had relapse. Only 1 of 9 (11%) patients with pN1 treated without adjuvant chemotherapy has had relapse. Of 24 patients with pN2/N3 disease only 3 (12%) have required more than 2 cycles of postoperative chemotherapy for persistent or recurrent disease despite complete resection of the retroperitoneum., Conclusions: Patients with low stage pure EC of the testis are at high risk for retroperitoneal disease. However these patients do not appear to be at increased risk for high volume (pN2/N3) retroperitoneal disease, systemic relapse in pN0 or pN1 disease managed without adjuvant chemotherapy (although the number of evaluable patients in this subset is somewhat small), or persistent or recurrent disease in completely resected high volume (pN2/N3) retroperitoneal disease compared to patients with mixed nonseminomatous germ cell tumors.

Purpose: We determined the incidence and clinical outcome of patients with clinical stages I and IIA nonseminomatous germ cell tumors (NSGCT), and teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection (RPLND)., Materials and Methods: Between January 1989 and February 1998, 294 patients with clinical stages I (209) and IIA (85) underwent primary RPLND at our institution. The primary tumor had teratomatous elements in 179 (61%) cases. Median followup was 27.8 months., Results: The overall incidence of teratoma in the retroperitoneum was 9% (25 of 294), and 21% (25 of 118) in patients with pathological stage II disease. The incidence of teratoma in the retroperitoneum increased from 3% (6 of 209) in clinical stage I to 22% (19 of 85, chi-square test p <0.0001) in clinical stage IIA. The incidence of teratoma in patients with pN1/N2/N3 disease increased from 9% (6 of 64) in clinical stage I to 35% (19 of 54) in clinical stage IIA (chi-square test p = 0.0006). All 25 patients with pathological stage II and teratoma in the retroperitoneum have no evidence of disease., Conclusions: The incidence of teratoma in the retroperitoneum increases with clinical and pathological stage. Teratomatous elements in the orchiectomy specimen predict teratoma in clinical and pathological stage II NSGCT. The absence of teratoma in the primary tumor does not preclude its presence in the retroperitoneum. Primary RPLND avoids the persistence of chemoresistant teratoma in the retroperitoneum, contributes to the high cure rate of patients with low stage NSGCT and decreases the potential for late relapse.

Purpose: Few published studies have combined prognostic factors to predict the likelihood of recurrence after surgery for renal cell carcinoma. We developed a nomogram for this purpose., Materials and Methods: With Cox proportional hazards regression analysis, we modeled pathological data and disease followup for 601 patients with renal cell carcinoma who were treated with nephrectomy. Predictor variables were patient symptoms, including incidental, local or systemic, histology, including chromophobe, papillary or conventional, tumor size, and pathological stage. Treatment failure was recorded when there was either clinical evidence of disease recurrence or death from disease. Validation was performed with a statistical (bootstrapping) technique., Results: Disease recurrence was noted in 66 of the 601 patients, and those in whom treatment was successful had a median and maximum followup of 40 and 123 months, respectively. The 5-year probability of freedom from failure for the patient cohort was 86% (95% confidence interval 82 to 89). With statistical validation, predictions by the nomogram appeared accurate and discriminating with an area under the receiver operating characteristic curve, that is a comparison of the predicted probability with the actual outcome of 0.74., Conclusions: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among patients with newly diagnosed renal cell carcinoma. The nomogram may be useful for patient counseling, clinical trial design and patient followup planning.

Purpose: We review the status of systemic therapy for patients with advanced renal cell carcinoma., Materials and Methods: A literature search was performed on MEDLINE and CANCERLIT to identify results of systemic therapy for patients with renal cell carcinoma published from January 1990 through December 1998. Treatment results of chemotherapy agents, immunotherapy, combination programs and adjuvant therapy were reviewed., Results: No chemotherapy agent has produced response rates that justify its use as a single agent. Interferon-alpha and interleukin (IL)-2 demonstrated low response rates ranging from 10% to 20%. The results of 2 randomized trials suggest that treatment with interferon-alpha compared to vinblastine or medroxyprogesterone achieves a small improvement in survival. Response rates in patients treated with low dose IL-2 are similar to those achieved with a high dose bolus schedule but whether the responses are as durable is being addressed in an ongoing randomized trial. A randomized trial of interferon-alpha plus IL-2 compared to monotherapy with either agent showed increased toxicity but no improvement in survival. In 3 randomized trials no survival benefit was associated with adjuvant interferon-alpha therapy following complete resection of locally advanced renal cell carcinoma., Conclusions: Despite extensive evaluation of many different treatment modalities, metastatic renal cell carcinoma remains highly resistant to systemic therapy. A few patients exhibit complete or partial responses to interferon and/or IL-2 but most do not respond, and there are few long-term survivors. Preclinical research, and clinical evaluation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.

Purpose: Teratoma with malignant transformation refers to a form of germ cell tumor in which a somatic teratomatous component becomes morphologically malignant and develops aggressive growth. We evaluated the spectrum of histologies, chromosomal abnormalities and clinical outcome in patients with teratoma with malignant transformation., Materials and Methods: We identified 46 patients with germ cell tumor meeting morphologic criteria for malignant transformation. Histology, disease extent and treatment were correlated with survival. Tumors in 12 patients were studied by conventional cytogenetics or molecular genetic techniques for the isochromosome 12p [i(12p)], a marker for germ cell tumor, as well as other chromosomal abnormalities., Results: The site of first detection of malignant transformation occurred in the primary tumor of 21 cases (44%), at a metastatic site in 20 (43%) and in both sites in 5 (10%). Sarcoma was the most frequent histology, identified in 29 patients (63%) with rhabdomyosarcoma the most common subtype. Seventeen tumors (37%) contained a solid tumor histology other than sarcoma, with adenocarcinoma and primitive neuroectodermal tumor as the most common histologies. Four patients with mediastinal germ cell tumor containing sarcoma also had hematological malignancies, including a focus of nonHodgkin's lymphoma in the mediastinal primary tumor (1) and nonlymphocytic leukemia in spleen or bone marrow (3). Patients who had teratoma with malignant transformation components confined to the testis or retroperitoneum completely resected experienced a longer survival than those with distant metastases or incompletely resected tumors (p = 0.003). Chromosomal abnormalities associated with germ cell tumor (i[12p]) were identified in 11 of 12 tumors containing adenocarcinoma, primitive neuroectodermal tumor, sarcoma and leukemia. In addition to i (12p), chromosomal rearrangements characteristic of the transformed histology were detected in 4 tumors., Conclusions: A variety of nongerm cell histologies, including sarcoma, adenocarcinoma, primitive neuroectodermal tumor and leukemia, may occur in association with germ cell tumor. Chromosomal abnormalities in these tumors include i (12p), reflecting germ cell tumor clonality, as well as chromosomal abnormalities associated with the transformed histology. These tumors do not respond like germ cell tumor to cisplatin-containing chemotherapy regimens. Treatment should be tailored according to that used in standard management of the transformed histology, and surgical resection is the mainstay of therapy.

Purpose: We attempted to select patients for surgery of post-chemotherapy residual mass in advanced seminoma., Materials and Methods: A total of 55 patients with advanced seminoma underwent surgical exploration of a mass seen on computerized tomography (CT) after chemotherapy. Residual masses were defined radiographically as smaller or larger than 3 cm. and as well defined or poorly defined. Surgery consisted of complete resection of the mass and surrounding lymph nodes or multiple biopsies at sites of disease., Results: Of the 55 patients 32 (58%) had masses resected and 23 (42%) underwent multiple biopsies. Of 27 patients with a post-chemotherapy 3 cm. or larger mass on CT 8 (30%) had residual tumor (seminoma in 6 and teratoma in 2), whereas necrotic tissue was found in the other 28 patients having a mass smaller than 3 cm. Well defined masses on CT were resected in 78% of patients and poorly defined masses could be resected in only 44%. Of the 8 patients with positive histology 6 remain alive and disease-free after complete resection of a well defined, larger than 3 cm. mass containing viable tumor, and 2 with a poorly defined mass died after biopsy only of residual seminoma despite salvage therapy. Three other patients who underwent complete resection of necrotic masses subsequently had relapse at distant sites and died. Median followup was 47 months (range 5 +/- 153+ months)., Conclusions: Patients with advanced seminoma who have a residual mass smaller than 3 cm. after chemotherapy do not benefit from surgery. For patients with a residual mass 3 cm. or larger we prefer surgery to define response, resect viable tumor when possible and direct further treatment.

For patients with advanced nonseminomatous germ cell tumors a retroperitoneal lymph node dissection is routinely performed following chemotherapy if the serum tumor markers have returned to normal. Bilateral retroperitoneal lymph node dissection has been recommended because metastatic deposits may be widespread. The aim of this study was to describe the distribution of retroperitoneal metastases following chemotherapy in patients with nonseminomatous germ cell tumor and determine if the extent of the retroperitoneal lymph node dissection can be modified. We studied 113 patients who had initially bulky retroperitoneal disease and underwent retroperitoneal lymph node dissection following chemotherapy. For the purposes of this study teratoma and malignant germ cell tumor are referred to as tumor. The most common location of tumor was the para-aortic area (91%) in patients with a left primary tumor and the interaortocaval area (78%) in those with a right tumor. Tumor was located outside the boundaries of a modified retroperitoneal lymph node dissection in 14 of the 60 patients with residual disease but the tumor was present within a palpable mass in 6 of these 14 patients. If the residual mass was removed and a modified retroperitoneal lymph node dissection was performed only 9 of the 113 patients (8%) would have tumor left in the retroperitoneum. For a select group of patients with advanced nonseminomatous germ cell tumor treated with chemotherapy, resection of the residual mass combined with modified retroperitoneal lymph node dissection is appropriate.

The role of ras oncogenes in the pathogenesis of renal cell carcinoma is unclear. We have previously shown that insertion of a mutated ras oncogene into cultured human proximal tubular cells, the normal counterpart of renal cell carcinomas, initiates a series of transformation events which results in cells possessing a renal cancer phenotype. These data suggested a role for mutated ras genes in the initiation and maintenance of this disease. Therefore, to assess the involvement of ras genes in renal carcinogenesis, 51 primary and metastatic renal carcinomas, including three oncocytomas, were analyzed for point mutations in codons 12, 13 and 61 of the Ha-ras, Ki-ras and N-ras proto-oncogenes using polymerase-catalyzed chain reaction methodology. A mutated Ha-ras gene was found in one renal cancer metastatic to lung for an overall incidence of 2%. These data indicate that ras oncogenes, activated by point mutations, do not play a major role in the initiation, maintenance or metastases of renal carcinomas.