Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy.

BACKGROUND: With treatment leading to nearly uniform cure in clinical stage I nonseminomatous testicular cancer (CSI-NSGCT), diminishing treatment-related morbidity has become the primary concern. This study examined feasibility and outcome of active surveillance as treatment in an unselected CSI patient population. MATERIALS AND METHODS: All patients with CSI-NSGCT referred from 1998 to 2007 to the British Columbia Cancer Agency and the Oregon Testis Cancer Program were retrospectively reviewed. A total of 233 patients were identified, of which 223 chose active surveillance. RESULTS: Vascular invasion (VI) was absent, present and unknown in 66%, 27% and 7% of cases, respectively. Overall, 49% of patients had embryonal predominant disease. Fifty-nine patients (26%) relapsed, all but one with good prognosis disease. VI was present in 30 relapsed patients. Most patients relapsed within 2 years (88%). Only 7 of 223 patients (3%) relapsed beyond 2 years. All relapses were in long-term remission following chemotherapy with or without retroperitoneal lymph node dissection (RPLND). Only 17 of 223 patients (8%) required postorchiectomy surgery. Disease-specific survival is 100% after a median follow-up of 52 months (3-136). No patient has required second-line chemotherapy. CONCLUSIONS: Active surveillance for all CSI-NSGCT patients is associated with excellent outcomes comparable with the best results reported with primary RPLND or adjuvant chemotherapy. Nearly 75% of patients are spared any therapy after orchiectomy.

Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors.

BACKGROUND: This investigation evaluates prognostic variables in patients with seminomatous and non-seminomatous extragonadal germ-cell tumors (EGCT) in order to identify relevant factors for long-term outcome following cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients from six countries treated at 11 centers in Europe and the USA from 1975 to 1996 were evaluated retrospectively. Uni- and multivariate analyses of prognostic variables for survival and for response to chemotherapy were performed. RESULTS: Data were available for 635 EGCT patients, 104 with seminomatous and 524 with non-seminomatous EGCT (n = 7 not specified). For non-seminomatous EGCT the following independent adverse factors were identified: presence of either liver, lung or central nervous system metastases, primary mediastinal tumor or elevation of pretreatment beta-human gonadotropin; for extragonadal seminoma (only univariate) adverse factors were: presence of liver metastases, two or greater metastatic sites or International Germ Cell Cancer Collaborative Group (IGCCCG) grouping (intermediate versus good). Integration of these variables produced the following prognostic risk groupings: 'excellent prognosis', all seminomatous EGCT (89% 5-year survival rate); 'intermediate low', 'intermediate high' and 'poor', all non-seminomatous EGCT with a 69, 55 and 17% 5-year survival rate, respectively. The decreased survival among the different groups was due to a lower rate of favorable objective remissions and a higher rate of relapses. Classification and regression tree (CART) modeling confirmed histology and location of primary tumor as the major prognosticators. For the subgroup of patients with mediastinal non-seminoma, the 2-year survival rate ranged from 34 to 84%. Multivariate testing for the probability to respond to chemotherapy revealed non-seminomatous histology, primary mediastinal tumor site, and the presence of liver, lung or CNS metastases as independent adverse factors. CONCLUSIONS: In EGCT, prognostic variables for the outcome and for the response to chemotherapy could be identified, which in part differ from gonadal GCT. The proposed model might help to better understand the specific prognosis of EGCT and to tailor risk-adapted treatment strategies. In addition, CART analysis demonstrated the heterogenous prognosis of patients with mediastinal non-seminoma.

Incidence of metachronous testicular cancer in patients with extragonadal germ cell tumors.

BACKGROUND: The frequency of subsequent testicular cancer (referred to as metachronous testicular cancer) in men who have had previous testicular cancer is relatively high. The rate of metachronous testicular cancer in men with extragonadal germ cell tumors (EGCTs), however, is largely unknown. We conducted a retrospective study of EGCT patients to determine the incidence, cumulative risk, and specific risk factors for metachronous testicular cancers. METHODS: A standardized questionnaire about patient characteristics, the extent of EGCT disease, any second malignancies, and treatments received was completed for 635 patients with EGCTs identified from the medical records of 11 cancer centers in Europe and the United States from 1975 through 1996. Comparisons with age group-specific data from the Saarland, Germany, population-based cancer registry were used to calculate the standardized incidence ratio (SIR). The Kaplan-Meier method was used to analyze survival data and cumulative risk. All statistical tests were two-sided. RESULTS: Sixteen EGCT patients (4.1%) developed metachronous testicular cancers, with a median time between diagnoses of 60 months (range, 14-102 months). The risk of developing metachronous testicular cancers was statistically significantly increased in patients with EGCTs (observed = 16; expected = 0.26; SIR = 62; 95% confidence interval [CI] = 36 to 99) and in subsets of EGCT patients with mediastinal location (SIR = 31; 95% CI = 8 to 59), retroperitoneal location (SIR = 100; 95% CI = 54 to 172), and nonseminomatous histology (SIR = 75; 95% CI = 43 to 123). The cumulative risk of developing a metachronous testicular cancer 10 years after a diagnosis of EGCT was 10.3% (95% CI = 4.9% to 15.6%) and was higher among patients with nonseminomatous EGCTs (14.3%; 95% CI = 6.7% to 21.9%) and retroperitoneal EGCTs (14.2%; 95% CI = 5.6% to 22.8%) than among patients with seminomatous EGCTs (1.4%; 95% CI = 0.0% to 4.2%) and mediastinal EGCTs (6.2%; 95% CI = 0.1% to 12.2%). CONCLUSIONS: Patients with EGCTs, particularly those with retroperitoneal or nonseminomatous tumors, but also those with primary mediastinal EGCTs, are at an increased risk of metachronous testicular cancer.

Chemotherapy of disseminated germ cell tumors.

The success of management of germ cell tumors puts an extraordinary burden on the physician and health care system to assure that cure is achieved in all patients except the small proportion that present with advanced refractory disease. New prognostic systems can define groups of patients who have excellent outcomes with treatment and a group of patients for whom treatment less reliably results in cure. Good risk disseminated disease should be treated with three cycles of bleomycin, etoposide, and cisplatin, whereas those with more advanced disease should receive four cycles. Postchemotherapy resection of residual disease is commonly required. In patients who recur after primary chemotherapy, salvage treatments can result in cure in 30% to 40% of patients.

Current concepts in risk factor assessment for advanced germ cell cancer.

Disseminated germ cell tumors (GCT) have come to represent the model for a curable malignancy, as cure rates with cisplatin-based chemotherapy coupled with appropriate surgery are 70% to 80%. For patients with favorable prognostic factors who achieve and maintain a complete response, the outlook is good. However, despite advances in the treatment of this disease, a significant number of patients with metastatic GCT fail to respond either primarily or secondarily. Being able to identify poor-risk patients up front would allow for appropriate selection of candidates for high-risk trials. Several different classification systems were previously developed at several treatment centers in the United States and Europe. These models recognized different clinical variables as prognosticators and had unique functional properties. However, these served as precursors to the International Germ Cell Consensus Classification that was developed to establish a universally accepted standard. The development of this system has allowed for valid comparisons of ongoing and future trials. Furthermore, this system will serve to encourage international collaboration for the study of high-risk GCT.

Chemotherapy of disseminated germ cell tumors.

The fact that germ cell tumors can be successfully managed puts an extraordinary burden on the physician and health care system to ensure that the promise of cure is achieved in all patients except the small proportion that present with advanced refractory disease. Good risk disseminated disease should be treated with three cycles of bleomycin, etoposide and cisplatin (BEP) whereas those with more advanced disease should receive four cycles. Postchemotherapy resection of residual disease is commonly required. In patients in whom disease recurs after primary chemotherapy, salvage treatments can result in cure in 30-40% of patients. Physicians managing these patients should be aware of some of the pitfalls encountered when determining relapse and should be versed in the indications for salvage conventional dose chemotherapy, high dose chemotherapy, and the role of aggressive desperation surgery.

Viable malignant cells after primary chemotherapy for disseminated nonseminomatous germ cell tumors: prognostic factors and role of postsurgery chemotherapy--results from an international study group.

PURPOSE: To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. PATIENTS AND METHODS: The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. RESULTS: The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. CONCLUSION: A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

Extragonadal seminoma: an international multicenter analysis of prognostic factors and long term treatment outcome.

BACKGROUND: The objectives of this study were to evaluate the long term outcome of patients with extragonadal seminomatous germ cell tumors (GCT) so that prognostic variables for disease recurrence and patient survival could be identified and to access the efficacy of different treatment modalities. METHODS: Six hundred thirty-five patients with extragonadal GCT who were treated consecutively at 11 centers in the United States and Europe during the cisplatin-based chemotherapy era between 1975 and 1996 were evaluated retrospectively. RESULTS: Fifty-two patients with primary retroperitoneal GCT (50%) and 51 patients with primary mediastinal GCT (49%) of pure seminomatous histology were identified (n = 1 patient with a primary cervical lymph node) representing 16.4% of 635 patients with extragonadal GCT who were included in the data base. The median age was 37 years (range, 18-70 years). Treatment consisted of platin-based chemotherapy in 77 patients (74%), radiotherapy in 9 patients (9%), and combined modality in 18 patients (17%). Ninety-two percent of patients (95% confidence interval, 87-97%) achieved a favorable response to primary therapy. After a median follow-up of 61 months (range, 1-211 months), 18 patients (17%) have had recurrent disease: 14% of those who received chemotherapy and 67% of those who received radiation therapy. The 5-year progression free survival rate favored the chemotherapy group, with 87% compared with 33% for irradiated patients (P = 0.006), whereas the overall survival rates were equal (90% vs. 67%; P = 0.13). No differences in overall survival or progression free survival were observed among patients with primary retroperitoneal and mediastinal seminoma. Prognostic factors that were identified to influence survival negatively were liver metastases (P = 0.01) and two or more metastatic sites (P = 0.04). CONCLUSIONS: In patients with extragonadal seminoma, a survival rate of > 90% at 5 years is achieved with adequate cisplatin-based chemotherapy. Compared with patients with nonseminomatous extragonadal GCT, no difference in long term survival exists between patients with primary retroperitoneal or mediastinal seminoma location. Primary radiotherapy seems to be associated with a significantly higher rate of disease recurrence, although most patients will be salvaged by subsequent chemotherapy.

Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis.

PURPOSE: Relapsed extragonadal germ cell tumors patients (EGGCT) are treated with identical salvage chemotherapy regimens, as are patients with metastatic testicular cancer. This investigation evaluates the results of second-line chemotherapy in nonseminomatous EGGCT and tries to identify prognostic factors for survival. PATIENTS AND METHODS: We conducted a retrospective review of 142 patients treated at eleven European and American centers between 1975 and 1996. All had received cisplatin-containing regimens as induction treatment. RESULTS: Twenty-seven of 142 patients (19%) were long-term disease-free, 11% with primary mediastinal and 30% of patients with primary retroperitoneal disease. Median follow-up since start of salvage treatment was 11 months (range, 1 to 157) for all patients and 45 months (range, 6 to 157) for surviving patients. Forty-eight patients (34%) received high dose chemotherapy with autologous bone marrow transplant at relapse, and 10 of these patients (21%) are continuously disease-free. Primary mediastinal location (P =.003), sensitivity to cisplatin (P =.003), elevated beta-HCG at relapse (P: =.04), and normal LDH at diagnosis (P =.01) were shown to be significant negative prognostic factors for overall survival in univariate; mediastinal location [relative risk ratios (HR) = 1.9; 95% confidence intervals (CI), 1.2 to 3.0] and sensitivity to cisplatin [HR = 2.4; 95% CI, 1.1 to 5.2] were significant negative prognostic factors in multivariate analysis. CONCLUSION: Although current salvage strategies will cure between 20% and 50% of recurrent metastatic testicular cancer, relapsed nonseminomatous EGGCT patients appear to have an inferior survival rate, in particular in case of primary mediastinal location. Mediastinal primary tumor and inadequate response to cisplatin-based induction chemotherapy have been identified as independent negative prognostic factors, both associated with an approximately two-fold higher risk for failure of salvage treatment.

High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer.

PURPOSE: To assess the role of high-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. PATIENTS AND METHODS: From August 1992 to April 1998, 65 patients with testicular cancer were treated with high-dose carboplatin and etoposide followed by peripheral-blood stem-cell transplantation or autologous bone marrow transplantation rescue as initial salvage chemotherapy at Indiana University. An identical course was given after hematopoietic reconstitution. Postchemotherapy resection of residual disease was performed in selected patients with incomplete radiographic response associated with normalization of markers. The median follow-up was 39 months (range, 16 to 91 months). RESULTS: Thirty-seven (57%) of the 65 patients are continuously disease-free. Three additional patients are disease-free with subsequent surgery. High-dose chemotherapy was associated with significant morbidity but no treatment-related mortality. CONCLUSION: High-dose chemotherapy as initial salvage chemotherapy achieved impressive long-term survival with acceptable toxicity in patients with relapsed testicular cancer.

The relative risk of second nongerminal malignancies in patients with extragonadal germ cell tumors.

BACKGROUND: Apart from a recognized association between extragonadal mediastinal germ cell tumors (GCT) and the occurrence of hematologic malignancies, the risk of developing second nongerminal solid tumors after the diagnosis or treatment of extragonadal GCT is unknown. METHODS: Six hundred thirty-five consecutive patients with extragonadal GCT treated at 11 centers in the U.S. and Europe during the era of cisplatin-based chemotherapy (1975-1996) were included into a large database. These patients were evaluated for the occurrence of second malignancies. RESULTS: No treatment-related leukemia was observed in 611 patients treated with chemotherapy. In 7 patients, second solid tumors were observed, resulting in a frequency of 1.86% (95% confidence interval [95% CI], 1.79-1.93%) after a median follow-up of 55 months (95% CI, 50-60 months) (annual incidence, 0.30% [95% CI, 0.14-0.59]). Four solid tumors (57%) developed in patients with primary mediastinal and 3 tumors (43%) developed in patients with retroperitoneal GCT. Three patients (43%) had a nonseminomatous and 4 patients (57%) had a seminomatous histology. Six patients had been treated with chemotherapy and one patient with radiotherapy. Six of 7 solid tumors (86%) had developed within 5 years and 7 of 7 solid tumors within 10 years of diagnosis. The median time period to the occurrence of neoplasia was 47 months (range, 9-145 months). Four cutaneous tumors were observed (melanoma, two patients; basal cell carcinoma, one patient; and squamous cell carcinoma, one patient); the other three tumors were angiosarcoma, nonsmall cell lung carcinoma, and colorectal carcinoma. The overall risk for developing a second tumor was not increased compared with an age-matched general population with a standard incidence ratio (SIR) of 1.49 (95% CI, 0.60-3.06). An elevated risk for skin tumors was observed in all extragonadal GCT patients (SIR, 4.00 [95% CI, 1. 09-10.24]), as well as in the subgroup of patients treated with chemotherapy (SIR, 5.33 [95% CI, 1.45-13.65]). CONCLUSIONS: This analysis excludes an increased biologic risk of developing second solid malignancies in patients with extragonadal GCT except for the previously reported association between primary mediastinal nonseminoma and hematologic disorders. The overall risk of developing second malignancies in extragonadal GCT patients appears to be comparable to that in patients with primary testicular carcinoma. The incremental occurrence of skin malignancies in patients treated with chemotherapy should be investigated further.

Adjuvant bleomycin, etoposide and cisplatin in pathological stage II non-seminomatous testicular cancer. the Indiana University experience.

Two cycles of bleomycin, etoposide, and cisplatin (BEP) were evaluated as adjuvant chemotherapy for patients with pathological stage II non-seminomatous germ cell tumours. Between 1985 and 1995, 86 patients with pathological stage II non-seminomatous testicular cancer were treated with two cycles of BEP. At retroperitoneal lymph node dissection (RPLND) 49 patients (57%) had pathological stage II(A) (microscopic nodal metastases) and 37 (43%) had stage II(B) (gross nodal metastases). After RPLND, the patients received bleomycin, 30 units weekly for 8 weeks, etoposide (100 mg/m(2)) and cisplatin (20 mg/m(2)) each for 5 days every 28 days for two cycles as adjuvant chemotherapy. 4 patients were lost to follow-up. 10 patients (12%) developed granulocytopenic fever during their chemotherapy. Of the 82 evaluable patients all remained with no evidence of disease except for a single patient with a cervical nodal relapse of teratoma. This was resected and he remains disease free. Median follow-up has been 85 months (range: 42-173 months). In patients with fully resected stage II non-seminomatous germ cell tumour, two cycles of BEP were almost universally effective in preventing relapse.

Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors.

BACKGROUND: The association between primary germ cell tumors of the mediastinum (the space between the lung pleura that contains the heart and other chest viscera) and hematologic malignancies has been described by retrospective analysis of patients treated at individual clinical centers. To better characterize the risk of hematologic disorders in patients with extragonadal germ cell tumors and to describe the clinical and biologic features of the disorders, we studied an unselected population in a large, international, multicenter database. METHODS: Six hundred thirty-five patients treated at 11 centers in the United States and Europe from 1975 through 1996 were evaluated retrospectively. RESULTS: A hematologic disorder was observed in 17 patients with germ cell tumors. All cases developed among the 287 patients with primary mediastinal nonseminomatous germ cell tumors, giving an incidence rate in this group of 2.0% (95% confidence interval [CI] = 1.1%-3.1%) per year over a median follow-up time of 3 years. The risk of developing hematologic disorders was statistically significantly increased in patients with primary mediastinal nonseminomatous germ cell tumors in comparison with the age-matched general population (standardized incidence ratio = 250; 95% CI = 140-405). The median time to onset of hematologic neoplasia was 6 months (range, 0-47 months), and the median survival after diagnosis of the hematologic disorder was 5 months (range, 0-16 months) (two-sided P<.0001, comparing survival from the time of diagnosis of the germ cell tumor of patients with and without hematologic disorders). CONCLUSION: In our study, approximately one in 17 patients with primary mediastinal nonseminomatous germ cell tumors was affected by a hematologic disorder, whereas no cases were seen among 334 patients with other extragonadal germ cell tumors. The hematologic disorder had a statistically significant impact on prognosis, with none of the 17 reported patients surviving for more than 2 years.

Successful treatment of aggressive post transplant lymphoproliferative disorder using rituximab.

A 52 year -old female developed a histologically aggressive, Epstein-Barr virus positive, lymphoproliferative disorder involving the brain and liver 4 months following a combined kidney/pancreas transplant. Following a brief trial of reduced immunosuppression, she was treated with rituximab. Despite subsequent re-intensification of immunosuppression, the lesions showed continued regression with almost complete disappearance by 5 months. Rituximab appears to be a safe, effective treatment for post transplant lymphoproliferative disorder.

Treatment of recurrent germ cell tumors.

Treatment of recurrent germ cell tumors is a complex undertaking. There are a number of clinical scenarios that can mimic relapse and, as such, a great deal of experience with management of germ cell tumors is required to recognize these rare but important situations that simulate recurrence. If recurrence is proven, standard chemotherapy with cisplatin, ifosfamide, and etoposide can result in approximately 30% of patients being long-term, disease-free survivors. Emerging technologies, e.g., high-dose chemotherapy and new drugs, may augment our current ability to salvage this patient population. Desperation surgery offers an additional opportunity for selected patients with localized chemotherapy-resistant relapse or those patients with late relapse of germ cell tumor.

Testicular cancer: what's new in staging, prognosis, and therapy.

Improvements in the clinical staging of testicular cancer may permit the identification of clinical stage I patients at low risk of harboring metastatic disease, who could be spared treatment and observed only. Both retrospective, single-institution studies and studies of unselected, consecutive patients have confirmed that vascular invasion, lymphatic invasion, and percentage of embryonal carcinoma are predictive of metastasis in patients with low-stage nonseminoma. Whether patients with these risk factors have a worse outcome if managed with surveillance, rather than with aggressive therapy, is unclear. Low MIB-1 staining (which identifies the Ki-67 antigen) in conjunction with a low percentage of embryonal carcinoma in the testicular specimen appears to be predictive of a low probability of metastasis. Computed tomography (CT) is a useful staging tool. A new prognostic classification system for seminomas and nonseminomas was recently developed by an international consensus conference. Laparoscopic retroperitoneal lymphadenectomy appears to be a feasible staging tool with acceptable short-term morbidity. Whether laparoscopic lymph node dissection is equivalent to the open procedure when used as a therapeutic modality is not yet known. At present, laparoscopy should be used only in selected patients in a study setting. Primary chemotherapy is not recommended currently because it has not yet been proven to be superior in patients with high-risk clinical stage I nonseminoma and can cause significant long-term sequelae.

Dietary cholesterol-induced xanthomatosis in atherosclerosis-susceptible Japanese quail (Cotunix japonica).

Japanese quail of a strain (SUS) susceptible to dietary cholesterol-induced atherosclerosis were fed a diet supplemented with cholesterol (0.5% w/w) for 4, 8 or 12 weeks. Plasma cholesterol increased significantly from 240-1550 mg/dl at 4 weeks and remained at that concentration for 8 and 12 weeks on the same diet. Plasma triglycerides (TGs) increased from 112-384 mg/dl after 4 weeks but showed no significant increases thereafter. Striking eruptive xanthomatous lesions were noticed on the feet of 50% of these birds at 4 weeks, and the percentage of birds affected increased to 85 after 12 weeks on the cholesterol-supplemented diet. This is the first report of xanthomatosis in birds. These birds had also developed atherosclerotic plaques in the aorta and brachiocephalic arteries by 4 weeks. There was no significant correlation between xanthoma scores and plasma cholesterol and TG concentrations at any of the three sampling periods (4, 8 and 12 weeks of cholesterol feeding). There was, however, a significant negative correlation (r = -0.61) between xanthoma scores and atherosclerotic plaque scores at 4 weeks. The correlation became non-significant at later stages of cholesterol exposure. Similarities between mammalian and SUS Japanese quail xanthomatosis may make the SUS quail a useful model for the study of this disorder.

Evaluation and management of the "new" lymphoma entities: mantle cell lymphoma, lymphoma of mucosa-associated lymphoid tissue, anaplastic large-cell lymphoma, and primary mediastinal B-cell lymphoma.

Non-Hodgkin's lymphomas (NHL) represent a major health problem worldwide, and incidence has been on the rise continuously for the last few decades. It is estimated that approximately 55,000 new cases of NHL will be diagnosed in the United States in 1998 and that slightly fewer than 25,000 patients will die of treatment failure or recurrent disease. The rising incidence of NHL is related not only to the acquired immunodeficiency syndrome epidemic but to also a steady increase in the number of cases diagnosed in older patients without immunosuppression. The new pathologic classification of NHL (revised European-American lymphoma classification, REAL) developed by the International Lymphoma Study Group (ILSG) is already resulting in more accurate disease-specific epidemiologic and clinical investigations. These studies have brought a new awareness of the existence and the relative prevalence of discrete NHL subtypes that appear to predominate among patients in different populations according to age, sex, geographic distribution, and predisposing conditions. This developing database has also the potential to result in the discovery of specific environmental causes, predisposing genetic factors, and therapeutic approaches. Some of the entities defined in the REAL classification, such as follicular lymphomas, diffuse B large-cell lymphomas, and T-cell lymphoblastic lymphomas, were already well described in the older classification systems (Kiel and Working Formulation). Others, such as mantle cell lymphoma, (MCL) anaplastic large-cell lymphoma (ALCL), lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), and primary mediastinal B-cell lymphoma (PMBCL) are relatively new members of the family, and accurate data on their clinicopathologic features and natural histories have only recently begun to emerge. This review presents in detail the most recent data on the clinical presentation of, diagnostic evaluation of, and treatment options for the most common of the new NHL entities: MCL, MALT lymphoma, CD30+ (Ki-1+) ALCL, and PMBCL. These four entities combined represent approximately 20% of all cases of NHL and exemplify well the broad clinicopathologic spectrum of NHL and the diagnostic and therapeutic challenges facing those who care for patients affected by these conditions.

Testicular cancer.

The following article provides a comprehensive review of male germ cell tumors; the pathology and the clinical manifestations of the tumors are discussed, as are the modern concepts of clinical staging. Patients with bulky stage II and stage III non-seminomatous germ cell tumors are treated with chemotherapy. The new international classification system has provided a very useful way to categorize these patients by prognosis. Patients with good- or intermediate-risk tumors may be treated with 3 courses of cisplatin, etoposide, and bleomycin (BEP) or 4 courses of etoposide and cisplatin (EP), and more than 90% of these patients will survive. Randomized trials have shown that, if only 3 courses of chemotherapy are to be given, the substitution of carboplatin for cisplatin and the omission of bleomycin are deleterious to outcome. Patients who still have a significant residual mass and normal markers after treatment should undergo a surgical resection of the residual tumor. Patients who are classified by the international classification system as having poor-risk tumors have about a 50% likelihood of survival, and many of these patients will require surgical resection of a residual tumor after chemotherapy. No randomized trial has proved a regimen to be superior to that of 4 courses of BEP. Currently, an ongoing trial is evaluating the effect of the early use of high-dose therapy in combination with hematopoietic rescue in patients with these types of tumors. Patients with small-volume stage II tumors are generally treated with retroperitoneal lymph node dissection (RPLND). About 25% of the patients selected for this procedure will actually have pathologically negative nodes. Those with positive nodes may elect to receive adjuvant chemotherapy (2 courses of BEP), which will almost always prevent relapse. An alternate approach for patients willing to comply with monthly follow-up is surveillance, with chemotherapy deferred until relapse is noted. About 50% of these patients will be cured with surgery (as many as 75% have microscopic disease only). With careful follow-up, those destined to relapse can be treated promptly and at a time when they have small-volume tumors and an excellent prognosis if they go on to receive chemotherapy. Patients with clinical stage I nonseminomatous germ cell tumors may also undergo RPLND, although an acceptable alternative for these patients is surveillance. The advantages and the disadvantages of each approach are discussed. The overall risk of recurrence is about 30%, but there have been patient groups defined that may vary in risk from 10% to 15% up to 50% or more. Patients with advanced seminoma are treated with chemotherapy. When this procedure is used, outcomes are favorable and all patients are either in good- or intermediate-risk groups, according to the international classification system. Patients with small-volume stage II tumors are treated with radiotherapy. Radiation is also generally used for the treatment of clinical stage I patients, although surveillance is growing in prominence as a means to treat these patients. Late effects of treatment are also discussed in this article. Ejaculatory function can be preserved in most patients who have early stage tumors and who undergo RPLND and in some patients who undergo surgery after chemotherapy. The most troubling effect of chemotherapy is the development of etoposide-induced leukemia, a unique--and fortunately rare--clinical entity.

Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor.

PURPOSE: This study was designed to assess the effectiveness of vinblastine, ifosfamide, and cisplatin (VeIP) as second-line therapy in patients with recurrent germ cell tumors with previous treatment with cisplatin plus etoposide, usually in combination with bleomycin. PATIENTS AND METHODS: From July 1984 through December 1989, 135 patients with progressive, disseminated germ cell tumors after cisplatin-etoposide-based combination therapy induction chemotherapy were treated with VeIP. Patients who progressed within 3 weeks of previous cisplatin therapy were not eligible. Progression was documented by biopsy or increasing serum markers. No exclusion was made on the basis of metastatic site or performance status. The dosages were vinblastine 0.11 mg/kg/d (days 1 and 2), ifosfamide 1.2 gm/m2/d (days 1 through 5), and cisplatin 20 mg/m2/d (days 1 through 5), with courses repeated every 21 days for four cycles. RESULTS: Sixty-seven (49.6%) patients achieved a disease-free status after chemotherapy with or without surgical resection of residual carcinoma or teratoma. Overall, 42 (32%) patients are alive and 32 (23.7%) are continuously free of disease. None of the 32 patients with nonseminomatous extragonadal tumors are disease-free compared with 30 of 100 patients with gonadal primaries. Two of three extragonadal seminomas are continuously disease-free. CONCLUSION: VeIP is capable of producing durable complete remissions in patients with disseminated germ cell cancer who relapse after cisplatin-etoposide-based induction therapy. Long-term disease-free survival is not seen in those patients with extragonadal nonseminomatous germ cell tumors.