Management of pediatric renal tumor: Past and future trials of the Japan Wilms Tumor Study Group

The Japan Wilms Tumor Study group (JWiTS) was founded in 1996 to improve outcomes for children with renal tumor in Japan, and a nationwide multicenter cooperative study was initiated thereafter. JWiTS‐1 (1996–2005) was analyzed, and JWiTS‐2 (2005–2014) is now under analysis; the following problems have been identified and used to decide future study protocol: (i) there has been a decline in survival rate for patients with rhabdoid tumor of the kidney (RTK) and new treatment strategies are required; (ii) the survival rate for bilateral Wilms tumors (BWT) has improved, but results for renal preservation are unsatisfactory; (iii) the prognosis of stage IV favorable nephroblastoma is very good, suggesting that the current protocols provide overtreatment, particularly for patients with lung metastasis; and (iv) no effective biological risk factors exist for predicting the outcome of Wilms tumor, and a study of the genetic changes of these tumors is necessary to determine biological markers for use in risk classification. To solve these issues, the development of a new risk classification of pediatric renal tumors is required. In addition, different study protocols should be developed according to the risk‐based classification of the patients. Further, a new study protocol for BWT began in 2015, and new study protocols are being prepared for RTK, and for Wilms tumor with lung metastasis. In addition, an analysis of biological markers with regard to risk classification is to be performed. Furthermore, to create new protocols for patients with rare renal tumors, international collaboration with Children's Oncology Group and International Society of Pediatric Oncology is necessary.     

Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor

BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP trials and studies largely focus on the issue of preoperative therapy to facilitate surgery of a shrunken tumor and to treat metastasis as early as possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor were registered. 847 of them had a histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173 tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative chemotherapy in benign tumors was given to 1.3 % of the patients. The main objective of the trial was the randomized question, if the postoperative two drug chemotherapy for stage I in intermediate risk or anaplasia can be reduced from conventional 3 courses to an experimental 1 course without loss of efficacy. RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive preoperative chemotherapy. The histology in this group of patients was of intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7 %) high risk. The stage distribution of the tumors was stage I in 315 (61 %), stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %) patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was measured in 487 patients before and in 402 after preoperative chemotherapy. The median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction depends on the histological subtype. The event free survival (EFS) after 5 years was 91 % for all patients with unilateral Wilms tumor without distant metastasis. Randomisation was done in 43.7 % for stage I patients and there was no difference in EFS for both treatment arms (90 versus 91 %). The EFS is identical for patients with stage I and II N- (0.92), as well as for stage II N+ and III (0.82). The tumor volume after chemotherapy is a prognostic factor for intermediate risk tumors with the exception of epithelial and stromal predominant tumors. These two subtypes often present as large tumors, they do not shrink during preoperative chemotherapy but they still have an excellent prognosis. On the other hand the prognosis of patients with blastemal predominant subtype after preoperative chemotherapy is worse than in any other patient group of intermediate risk tumors. There are less blastemal predominant tumors compared to primary surgery, but they are chemotherapeutic resistant selected by the preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor without metastasis have an excellent prognosis. The post-operative chemotherapy in stage I can be reduced to 4 weeks without worsening treatment outcome. The reduction of the tumor volume could be identified as a helpful marker for stratification of post-operative treatment. Post-chemotherapy blastemal predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal anaplasia has a better prognosis than diffuse anaplasia and will be classified as intermediate risk tumor.     

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??Childhood kidney tumors account for about 7% of all childhood cancers. Most childhood kidney tumors are Wilms tumor??but in the 15- to 19-year age group??most tumors are renal cell carcinoma. In medically developed countries??clinical trials in Wilms tumor??WT?? have resulted in overall survival rates of greater than 90%. Children’s Oncology Group Renal Tumor Committee??COG-RTC?? is one of the clinical study groups internationally known for its clinical research in childhood kidney tumor. Its standard treatment for children with Wilms tumor consists of initial nephrectomy??when feasible?? followed by chemotherapy and??in some patients??radiation therapy. This summary reviewed peer-reviewed??evidence-based reports about the treatment for Wilms tumor published recently and intended to be a resource to assist clinicians who care for children with Wilms tumor.     

Pitfalls in the differential diagnosis of renal tumor in an adolescent

The differential diagnosis of renal tumors, particularly in adolescents, may be challenging. We describe an 11‐year‐old female with a primary intra‐renal mass. Initial differential diagnoses included primitive neuroectodermal tumor (PNET), desmoplastic small round cell tumor (DSRCT), and Wilms Tumor (WT). Extensive pathologic and molecular analysis on initial and relapsed tumor samples confirmed WT. The EWS‐WT1 and EWS‐FLI1 rearrangements, distinctive of DSRCT and PNET were negative. The differential diagnosis on monophasic blastemal WT may be complex. Primary renal DSRCT and PNET have been rarely described. Nevertheless, molecular confirmation for these rare conditions may be necessary in selected cases. Pediatr Blood Cancer 2010;54:319–321. © 2009 Wiley‐Liss, Inc.     

Management of Wilms tumors in Drash and Frasier syndromes

Background

Children with WT1 gene‐related disorders such as Denys–Drash syndrome (DDS) and Frasier syndrome (FS) are at increased risk of Wilms tumor and end‐stage renal disease. We investigated whether Wilms tumors in these patients displayed a specific phenotype or behavior and whether nephron‐sparing surgery was beneficial.

Procedure

We retrospectively studied all patients with DDS, FS, or other WT1 mutations treated at our institutions between 1980 and 2007.

Results

We identified 20 patients, of whom 18 had benign or malignant tumors. Wilms tumors occurred in 15 patients, being unilateral in 10 and bilateral in 5 (20 tumors). Median age at Wilms tumor diagnosis was 9 months. No patients had metastases. According to the International Society of Pediatric Oncology Working Classification, there were 19 intermediate‐risk tumors and one high‐risk tumor; no tumor was anaplastic. In patients with nephropathy who underwent unilateral nephrectomy for Wilms tumor or nephron‐sparing surgery for bilateral Wilms tumor, mean time to dialysis was 11 or 9 months, respectively. Other tumors included three gonadoblastomas (in two patients), one retroperitoneal soft‐tissue tumor, and one transitional cell papilloma of the bladder. Two patients, both with stage I Wilms tumor, died from end‐stage renal disease‐related complications. The median follow‐up time for the 18 survivors was 136 months (range, 17–224 months).

Conclusion

Most Wilms tumors in children with WT1‐related disorders were early‐stage and intermediate‐risk tumors, with a young age at diagnosis. In patients without end‐stage renal disease, nephron‐sparing surgery should be considered for delaying the onset of renal failure. Pediatr Blood Cancer 2009;52:55–59. © 2008 Wiley‐Liss, Inc.     

Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk: report of the international society of paediatric oncology (SIOP) nephroblastoma trial and study 9

BACKGROUND: The SIOP Nephroblastoma therapeutic protocols include a period of preoperative chemotherapy followed by nephrectomy and a period of postoperative chemotherapy. From the outset, identification of low-risk groups has been an aim of the SIOP Nephroblastoma Trials and Studies. Now that 90% of children with Wilms tumor can be cured, attention is even more focused on the identification of patients who could benefit from less aggressive postoperative therapy, thus minimizing the morbidity and late effects associated with treatment. The prognostic implications of total necrosis in nephroblastoma after chemotherapy have not been investigated hitherto. PROCEDURE: Between November 1, 1987 and June 30, 1993, 599 patients referred to the SIOP-9 Nephroblastoma Trial and Study were preoperatively treated and classified as stages I-IV nonanaplastic Wilms tumor. RESULTS: Of these 599 patients, pathologic examination of the nephrectomy specimen revealed a completely necrotic Wilms tumor (CNWT) with no viable tumor remaining in 59 (10%): these comprised 37 stages I-III and 22 stage IV. Of these patients, 58 (98%) had no evidence of disease at 5 years vs. 90% for the rest of the cohort (P < 0.05). Stages I-III patients represented 63% of CNWT and had a 97% overall survival rate. The only death was related to veno-occlusive disease and occurred in a stage I patient in the month following nephrectomy. Stage IV patients represented 37% of CNWT (vs. only 10% of all other cases of unilateral nonanaplastic Wilms tumor) and had a 100% rate of survival. Children with CNWT were older (mean 59 months vs. 43 months); their tumor at diagnosis was larger and had regressed more significantly at subsequent ultrasound examination. The data also uphold the hypothesis that Wilms tumors of blastemic pattern are most aggressive, but also are extremely responsive to chemotherapy. CONCLUSIONS: Patients with unilateral nonanaplastic WT that showed total necrosis following preoperative chemotherapy had excellent outcome and should benefit from less aggressive postoperative treatment in further trials. Other very responsive tumors, such as Wilms with <10% viable tumor, should also be assessed.     

Imaging of pediatric renal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper focused on Wilms tumor and nephrogenic rests

Malignant renal tumors account for approximately 6% of pediatric malignancies, with Wilms tumor (WT) representing approximately 90% of pediatric renal tumors. This paper provides consensus-based imaging guidelines for the initial evaluation of a child with suspected WT and follow-up during and after therapy co-developed by the Children's Oncology Group (COG) Diagnostic Imaging and Society for Pediatric Radiology (SPR) oncology committees. The guidelines for Wilms Tumor Imaging in the Society of International Pediatric Oncology (SIOP) are briefly discussed to highlight some of the differences in imaging approach.     

Anaplastic histology Wilms’ tumors registered to the Japan Wilms’ Tumor Study Group are less aggressive than that in the National Wilms’ Tumor Study 5

Purpose

To evaluate the clinical features and treatment results of anaplastic histology (AH) Wilms’ tumor (WT) patients registered in the Japan Wilms’ Tumor Study (JWiTS) group to elucidate the clinical characteristics of AH in the Japanese population.

Patients and methods

Of 344 WT patients who were enrolled in JWiTS between 1995 and 2013, 17 had AH. Treatment using the JWiTS protocols was similar to the fifth National Wilms’ Tumor Study 5 (NWTS-5) protocols. Clinical characteristics and mutation status of TP53 gene were evaluated and compared with those in NWST-5 study.

Results

AH incidences in JWiTS were 4.9 %, lower than that in NWTS-5. Seven tumors had focal AH and 10 had diffuse AH. Clinical stages of AH patients were stage I in seven, stage II in three, stage III in five, stage IV in one and unknown in one. Four-year event-free survival and overall survival rates were 90.9 and 86.7 %, respectively. Two patients with diffuse AH and none with focal AH had TP53 mutation.

Conclusion

Japanese patients presented with higher incidence, earlier stages and may have better outcomes than American patients, indicating a possible biological heterogeneity of AH WT. Further analysis is necessary to elucidate the different characteristic of AH WT between Japanese and American populations.

     

The role of biopsy in the diagnosis of renal tumors of childhood: Results of the UKCCSG Wilms tumor study 3

BACKGROUND: The United Kingdom Children's Cancer Study Group (UKCCSG) Wilms Tumor Study 3 has adopted preoperative chemotherapy for Wilms tumors (WT), but required prechemotherapy biopsy for histologic diagnosis. The aims of this review were to assess the usefulness and safety of prechemotherapy biopsy and to compare histologic features of WT before and after chemotherapy. PROCEDURE: There were 286 eligible patients but only 241 biopsies and 226 nephrectomy case slides were submitted for panel review. The presence of different histologic components of WT before and after chemo therapy was retrospectively assessed. RESULTS: Among the 241 cases, the biopsy material in 9 (4%) was not diagnostic, in 28 (12%) that were clinically and radiologically consistent with WT, the biopsy revealed tumors other than WT, and in the remaining 204 (85%) WT was confirmed. Of 188 WT suitable cases, blastema was found in 89% of tumors at biopsy, but in only 50% at nephrectomy; the remainder were either completely necrotic (17%) or showed only epithelial and/or stromal elements (33%). Of 182 children who had percutaneous cutting needle biopsy (PCNB), a fall in haemoglobin (20% of cases) and local pain (19%) were the most common complications. One child required emergency nephrectomy due to massive intratumoral bleeding, another had tumor rupture and subsequently died, and a third developed a needle track recurrence 8 months after the biopsy. CONCLUSIONS: A number of renal tumors (12%) can have the correct histologic diagnosis made by PCNB. Preoperative chemo therapy markedly decrease in the number of samples with preserved blastema. The morbidity associated with PCNB is small. Needle biopsy of any renal mass prior to initiation of chemotherapy is recommended.     

儿童肾肿瘤多中心协作组288例诊治报告

目的:总结中国小儿肿瘤专业委员会(CCCG)肾母细胞瘤(WT)-2015方案的疗效。方法:前瞻性研究,在CCCG-WT-2009方案基础上修正建立WT-2015方案。总结2015年9月至2018年12月在14家协作组成员单位明确诊断的288例初发肾肿瘤患儿的临床资料。分析儿童肾肿瘤的发病年龄、病理亚型分布、分期、疗效及预后因素。生存曲线应用Kaplan-Meier法,单因素分析应用Log-Rank法。结果:288例肾肿瘤中WT 261例,其中良好组织学型(FH)WT 254例,占97.3%,间变型(UFH)WT 7例,占2.7%。FHWT、UFHWT 3年无事件生存率(EFS)分别为(88.9±2.1)%、(80.0±17.9)%,优于WT-2009方案的81.2%、71.7%。Ⅲ、Ⅳ期FHWT有放疗指征者96例,其中76例实施放疗,20例因未放疗升至M方案化疗(环磷酰胺、依托泊苷、更生霉素、长春新碱、阿霉素),放疗与未放疗患儿3年EFS分别为(84.7±4.3)%及(84.7±8.1)%,预后差异无统计学意义(χ2=0.015,P=0.902)。肾肉瘤包括肾透明细胞肉瘤22例和肾横纹肌样瘤5例。3年EFS分别为(94.4±5.4)%及(20.0±17.9)%。将年龄、性别、病理类型、分期、手术中破溃否、治疗结束是否达到完全缓解(CR)、放疗否进行预后单因素分析,结果发现病理类型(χ2=44.329,P<0.01)和治疗结束时是否达到CR(χ2=49.459,P<0.01)是独立预后影响因素。结论:CCCG-WT-2015方案与WT-2009方案相比,预后改善,可扩大协作组对象应用本方案。     

Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group

PURPOSE: This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. PATIENTS AND METHODS: The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. RESULTS: Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin (6) or etoposide (1), and six were treated with infradiaphragmatic irradiation. The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. CONCLUSIONS: The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.     

Clinical presentation of rhabdoid tumors of the kidney

PURPOSE: We designed this study to differentiate the clinical presentation, particularly the incidence of hematuria, of a rhabdoid tumor of the kidney (RTK), a rare but highly malignant tumor, from a Wilms tumor. PATIENTS AND METHODS: We reviewed patient flow charts from the National Wilms Tumor Study Group and queried participating hospitals to obtain additional information regarding presenting symptoms and laboratory data for fifty patients. Patient ages ranged from 2 days to 3.5 years with a mean of 11 months. We documented the presence of gross and microscopic hematuria, fever, and hypercalcemia. RESULTS: Whereas 75% of children with rhabdoid tumor of the kidney (RTK) had stage III (44%), IV (27%), or V (4%) tumors, 67% of children with Wilms tumors had stage I (41%) or II (26%) tumors. Either gross or microscopic hematuria was present in 84.4% (27/32) of the patients with RTK. Gross hematuria was present in 59% (22/37) of children with RTK compared with 18% previously reported with Wilms tumor. Microscopic hematuria was present in 76% (22/29) of children with RTK compared with 24% previously reported with Wilms tumor. Fever was found in 44% (16/36) of children with RTK, compared with 22% of children previously reported with Wilms tumor. Hypercalcemia was seen 26% (6/23) of children with RTK. CONCLUSION: Although diagnosis of any renal mass still must be confirmed with histopathologic features, a distinct clinical presentation with fever, hematuria, a young age, and high-tumor stage at presentation suggests the diagnosis of RTK.     

Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood

The previous International Society of Paediatric Oncology (SIOP) trials and studies recognized three prognostic groups of renal tumors of childhood: low risk, intermediate risk, and high risk tumors, which were further defined in the SIOP (Stockholm) Working Classification of Renal Tumors of Childhood (1994). The results of the latest SIOP Trials and Studies showed that certain histological features which remain after preoperative chemotherapy, such as blastema, are of prognostic significance while others are not. Therefore, in the next SIOP Trials and Study a revised classification of renal tumors will be followed. It still recognizes the three tumor risk groups with different types in each of them, but for treatment purposes, only three major types of nephroblastoma need to be recognized: completely necrotic (low risk tumor), blastemal (high risk tumor), and others (intermediate risk tumors). Patients will be treated according to tumor histology and stage. Trials which include preoperative chemotherapy have shown that the presence of necrotic tumor or chemotherapy induced changes in the renal sinus or perirenal fat can be ignored for distinguishing between stage I and II, but if present at resection margins or lymph nodes, it should be regarded as stage III. Prognostic significance of all histological component of Wilms tumors will be studied prospectively in the new trial.     

Sudden death due to pulmonary embolism as presenting symptom of renal tumors

In 4-6% of patients with renal tumors in children intravascular infiltration is found. Tumor emboli are even rarer, and sudden death as presenting symptom has only been described at presentation in Wilms tumor (WT) in six cases so far. This report describes two recent cases of sudden death in patients with renal tumors in which a fatal pulmonary embolus was the first presentation.     

Decrease in LDL receptor-related protein expression and function correlates with advanced stages of Wilms tumors

BACKGROUND: The molecular processes responsible for the invasive phenotype of pediatric Wilms tumors (WT) are poorly understood. A candidate WT suppressor gene (WT1) has been found mutated in a number of these pediatric kidney tumors. However, the disruption of normal WT1 protein function cannot solely explain WT growth. The aim of the present study is to identify new molecular players that regulate the invasive character of WT. PROCEDURE: Fresh frozen samples from 45 renal tumors of Wilms were obtained from the National Wilms Tumor Study Group's Biological Samples Bank. Gelatin zymography, Western blotting, and immunodetection were used to compare tissue biopsies originating from the infiltrating (stage III), metastatic (stage IV), and anaplastic phenotype of Wilms tumors (WT). RESULTS: The expression of the low-density lipoprotein receptor-related protein (LRP) diminished in stage IV and anaplastic WT. Moreover, the expression of RAP, an LRP intracellular chaperone, was also decreased. The diminished expression of LRP and RAP correlated with increased levels of several known extracellular ligands that LRP usually recycles from the extracellular matrix (ECM) environment, including PAI-1, MMP-9, and TIMP-1. The proteolytic processing of MT1-MMP, a functional regulator of LRP, also correlated with the WT invasive phenotype. CONCLUSIONS: The low expression of LRP, whose function is regulated by MT1-MMP and whose activity in recycling ECM-associated proteolytic enzymes becomes drastically diminished in advanced stages of WT, may in part explain the acquired invasive potential of the developing WT pediatric cancer.     

Children's Oncology Group's 2013 blueprint for research: Renal tumors

Renal malignancies are among the most prevalent pediatric cancers. The most common is favorable histology Wilms tumor (FHWT), which has 5‐year overall survival exceeding 90%. Other pediatric renal malignancies, including anaplastic Wilms tumor, clear cell sarcoma, malignant rhabdoid tumor, and renal cell carcinoma, have less favorable outcomes. Recent clinical trials have identified gain of chromosome 1q as a prognostic marker for FHWT. Upcoming studies will evaluate therapy adjustments based on this and other novel biomarkers. For high‐risk renal tumors, new treatment regimens will incorporate biological therapies. A research blueprint, viewed from the perspective of the Children's Oncology Group, is presented. Pediatr Blood Cancer 2013; 60: 994–1000. © 2012 Wiley Periodicals, Inc.     

Recent advances in Wilms tumor genetics

The past decade has witnessed substantial growth in our knowledge of the genes and loci that are altered in Wilms tumor. Although Wilms tumor was one of the original paradigms of Knudson's two-hit model of cancer formation, it has become apparent that several genetic events contribute to Wilms tumorigenesis. Recent research has identified targets and regulators of the first Wilms tumor gene, WT1, has uncovered several candidate genes at the second Wilms tumor locus, WT2, and has identified two familial Wilms tumor loci, FWT1 and FWT2. The recent discovery of activating beta-catenin mutations in some Wilms tumors has also implicated the Wnt signaling pathway in this neoplasm. Recurrent abnormalities of other loci, including 16q, 1p, and 7p, have indicated that these sites may harbor Wilms tumor genes. An enhanced understanding of these and other genetic lesions will provide the foundation for novel targeted Wilms tumor therapies.     

儿童复发性肾母细胞瘤临床特点和治疗经验

目的 探讨儿童复发性肾母细胞瘤临床特点和治疗经验.方法 回顾性研究2003年1月-2011年4月收治的17例儿童复发性肾母细胞瘤临床资料.其中9例采用手术联合术前术后化疗、放疗治疗方法.采用SPSS 17.0软件进行统计学处理,运用Kaplan-Meier曲线进行生存率分析.结果 本组病例按美国肾母细胞瘤研究组织(MWTSG)临床分期分为Ⅰ期4例、Ⅱ期8例、Ⅲ期3例、Ⅳ期1例、V期1例.原发瘤与复发瘤病理类型一致,其中预后良好型12例,预后不良型5例.全组有9例共接受12次再次手术,其中根治性切除1次,肿瘤单纯切除11次,术后化疗9例,放疗3例.再次手术组1 a累积生存率高于未再次手术组,差异有统计学意义(P＜0.05).结论 尽管肾母细胞瘤可能反复复发,但病理类型仍然与原发瘤保持一致.治疗策略在于尽可能完整切除复发瘤和转移瘤,同时联合术前术后化疗、放疗可以提高患者生存率.     

Pediatric Germ Cell Tumors: Protocol Update for Pathologists

The therapy for pediatric germ cell tumors has historically been widely variable and institution dependent. The efforts to provide consistent, biology-driven therapy through Intergroup protocols has been a relatively recent phenomenon that has provided the framework for future protocol designs. The first Intergroup protocols confirmed that stage I malignant testicular germ cell tumors and immature teratomas at all sites in children could be treated with surgery alone followed by close observation. Future protocols currently in the planning stages may extend this low-risk category to stage I ovarian germ cell tumors of all histologic types. Low-stage extragonadal germ cell tumors may be placed in a new intermediate risk category. Particular pathologic issues that were raised and reported during the first protocols and that may impact on future protocol design include the presence and size of foci of endodermal sinus tumors within low-stage immature teratomas at all sites. Accurate staging will grow more critical in future protocols. The ability to recruit international cooperative groups will determine the success of chemotherapy tailored to specific subgroups that now must be lumped for statistical purposes. Lastly, companion biologic studies will be critical to defining the different subtypes of germ cell tumors and to determining predictors of biologic behavior.