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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7641-7645 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.00.8110 Rhabdoid Tumor of the Kidney in The National Wilms' Tumor Study: Age at Diagnosis As a Prognostic FactorFrom the University of Texas Southwestern Medical Center, Dallas, TX; Department of Biostatistics, University of Washington, Seattle; Fred Hutchinson Cancer Research Center, Seattle, WA; St Jude Children's Research Hospital, Memphis, TN; Bayfront Cancer Care Center, St Petersburg, FL; Children's Memorial Medical Center, Chicago, IL; Loma Linda University, Missoula, MT; University of Pennsylvania, Philadelphia, PA; and Roswell Park Cancer Institute, Buffalo, NY. Address reprint requests to Gail E. Tomlinson, MD, PhD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8593; e-mail: Gail.Tomlinson{at}UTSouthwestern.edu
PURPOSE: The objective of this study is to determine prognostic factors in rhabdoid tumor of the kidney (RTK), including both demographic and treatment variables. PATIENTS AND METHODS: A total of 142 patients studied on National Wilms' Tumor Studies 1, 2, 3, 4, and 5 were analyzed. Patients were enrolled between the years 1969 and 2002. Variables examined included sex, age of diagnosis, tumor stage, presence of CNS lesions, as well as treatment variables, including the use of doxorubicin and/or radiotherapy (RT). RESULTS: No survival differences were observed between males and females, between those treated with or without doxorubicin, or with or without RT. Patients with tumors of lower stage had an overall survival rate of 41.8%, whereas, tumors of higher stage were associated with a 15.9% survival (P < .001). A highly significant difference in survival was noted when patients were stratified according to age of diagnosis. Survival at 4 years in infants under 6 months of age at diagnosis was 8.8%, whereas, survival in patients 2 years of age or older was 41.1% (P < .0001). Stratification into intermediate age brackets demonstrated a strong correlation of increasing survival with increasing age at diagnosis. All patients with a CNS lesion, except one, died. CONCLUSION: Age at diagnosis is a highly significant prognostic factor for survival of children with RTK. Infants have a dismal prognosis, whereas, older children have a more favorable outcome. Higher tumor stage and presence of a CNS lesion were both factors predictive of a poor survival rate.
Rhabdoid tumor of the kidney (RTK), a rare aggressive cancer occurring in infancy and early childhood, was recognized as a distinct tumor type in 1978, although initially it was classified as a possible rhabdomyosarcomatoid variant of Wilms' tumor.1,2 Subsequent studies confirmed its distinctive nature and the designation rhabomyosarcomatoid pattern was shortened to rhabdoid. To date, the exact cell type of derivation remains unknown. An interesting feature of RTK is the occasional occurrence of separate CNS primary tumors.3 Previous studies have reported that 10% to 15% of RTK patients also develop CNS lesions, now designated atypical teratoid-rhabdoid tumors.4 Both RTK and atypical teratoid-rhabdoid tumors of the CNS are genetically characterized by mutation of the hSNF5/INI1 gene.5,6 RTK is considered one of the most deadly malignant solid tumors of childhood with overall survival rates of not more than 20% to 25%. Given the observed rapid progression of these tumors in some infants as well as reports of anecdotal cases of RTK patients who survive despite widespread disease,7 we sought whether certain clinical or demographic features were of prognostic importance. Variables considered were sex, age at diagnosis, tumor stage, and presence or absence of CNS lesions. We also analyzed the effect of treatment with or without doxorubicin and with or without RT within the limits of small sample sizes, as treatment regimens varied according to the National Wilms' Tumor Study (NWTS) Group trials as described elsewhere.8-12
Patients studied were those registered on the NWTS 1 to 5 with a confirmed diagnosis of RTK between the years 1969 and 2002. A total of 142 patients with RTK made up 1.5% of the 9,232 patients with a childhood tumor of the kidney registered on study during that period. All patients enrolled onto the study had an informed consent approved by the referring hospital's institutional review board signed by a parent allowing outcome study. Histologic slides were reviewed at the time of diagnosis and again on retrospective review by one of two pathologists (JBB, EP). All histologic materials used for diagnosis were obtained before administration of therapy. Follow-up data were available for 142 patients and these form the basis of the present report. Survival at 4 years was estimated by actuarial methods after stratification separately for age at diagnosis, sex, stage, presence of CNS lesions, and treatment with or without doxorubicin and/or RT.13 Differences in survival rates among patient subgroups were analyzed using the log-rank test, with and without stratification on other factors.14,15 Relative risks (RR) of death, (ratios of mortality rates in different subgroups), were estimated from the Cox model with or without adjustment for other factors.16
Eighty-two patients were male and 60 were female, giving a male to female ratio of 1.37 (P = .01). The ages of patients at diagnosis ranged from newborn (two patients) to older than 8 years (1 patient) with a median age of 10.6 months and a mean age of 15 months. As shown in Figure 1, the distribution of ages at diagnosis was skewed and younger ages predominated. Fifteen patients had stage I tumors, 25 patients were stage II, 58 patients were stage III, 41 patients were stage IV, and three patients had stage V (bilateral) tumors. Among the stage IV patients, metastatic sites included lung (34 patients), liver (three patients), bone (two patients), and brain (see Analysis of CNS Tumor Development and Survival section). Seven patients had metastases at multiple sites at presentation. The vast majority of lung metastases were multiple involving both lungs and none of the metastatic sites were judged to be resectable. The tumor staging system used was that of the NWTS Group.8-12
Overall survival at 4 years for the 142 patients analyzed was 23.2%. No significant difference in survival was noted between males and females. Of the 82 male patients the survival at 4 years was 20.1%. Of the 60 female patients survival at 4 years was 27.4% (P = .55).
Analysis of Tumor Stage and Survival
Analysis of Age at Diagnosis and Survival
Analysis of CNS Tumor Development and Survival A total of 30 out of the 142 patients studied (21%) had CNS involvement at some time as demonstrated by an intracranial mass on imaging studies. In 10 patients, tissue analysis of CNS lesion was obtained. In six of these patients, histologic analysis of the CNS mass was consistent with a second malignant neoplasm (primitive neuroectodermal tumor in four patients, anaplastic astrocytoma in one patient, and atypical teratoid-rhabdoid tumor in one patient). One of these confirmed second malignant neoplasms was diagnosed at the time of the original evaluation of the renal mass and the other five were diagnosed 5 to 12 months after the original diagnosis. In the remaining four patients, histologic analysis was interpreted as metastatic rhabdoid tumor of the kidney. In five other patients, the imaging studies were highly suspicious for a second malignant neoplasm, however, no biopsy material was obtained. In the remainder, it was not possible to determine whether the CNS lesions represented dissemination from the primary renal tumor or second primary tumor. Many of the patients with CNS lesions on the earlier studies predated the distinction of rhabdoid tumor as a distinct entity and were interpreted only as metastatic Wilms' tumor, so that further work-up and therapy was discontinued. In several cases, the presence of CNS disease was in conjunction with widespread disease involving other sites and was presumed to represent wide-spread disease progression. Patients with any type of CNS involvement ranged in age from 1 to 26 months with 26 of the 30 patients (86%) less than 1 year of age at diagnosis. All but one infant with evidence of a second primary CNS tumor involvement died as did all of the patients thought to have CNS metastases.
Analysis of Treatment and Survival We evaluated the effect of treatment with doxorubicin on outcome. Of the 142 patients analyzed, 71 received doxorubicin and 71 did not. In NWTS 2 and 3, administration of doxorubicin was determined by randomization. In NWTS 4 the choice of treatment regimen was entirely determined by institution, physician, or family preference. Doxorubicin was not included in the recommended regimen for RTK in NWTS 5. There was no difference in the survival rate of patients with RTK who did or did not receive doxorubicin. There were 52 deaths in the group that received doxorubicin and 57 deaths in the group that did not receive doxorubicin (P = .45). Of the 142 patients analyzed, 100 received radiation therapy to the primary tumor bed and 36 did not. In six patients, data regarding use of radiation was missing. The overall survival at 4 years was 28.5% among the irradiated patients and 12.2% among the unirradiated patients. (P = .25) The effect of radiation was difficult to analyze in part because radiation use and dose varied by age and stage. In analyzing the group as a whole and ignoring age as a prognostic factor, patients who received a radiation dose of 25 Gy or more to the operative bed appeared to have a better outcome. (Table 2) This effect, however, was confounded by age. Older patients were more likely to receive radiation therapy and those who did received a higher dose. Patients under and over the age of 1 year at diagnosis were, therefore, further analyzed separately.
For infants under the age of 1 year, only one received a dose greater than 25 Gy and there was no suggestion of improved survival with intermediate versus lower radiation doses. For infants over the age of 1 year, those receiving 25 Gy or more appeared to have an improved outcome with overall survival at 4 years estimated at 54.2%. However, the highest doses were received by the oldest children. After adjusting for age and stage, the RR of death comparing 25+ Gy with no RT was 0.85 (P = .83) so the apparent effect of RT on survival was much reduced and no longer statistically significant (Table 3).
RTK overall is associated with a poor prognosis. This has also been observed within a study from the United Kingdom.17 Like other pediatric renal tumors, low stage tumors have a better outcome. The age at diagnosis, however, is a previously unrecognized important prognostic factor. Patients less than a year of age at diagnosis have a dismal outlook as well as a tendency to develop CNS tumors, while those older than 1 year of age at diagnosis have a modestly better prognosis. The higher survival rate in older children should be useful in counseling parents of older children with RTK, because this disease has previously been considered a tumor with a uniformly poor outcome. One could argue that in older patients, aggressive therapy with existing agents is appropriate, albeit further development of combination therapy is needed. In the youngest patients who, as a group, had an almost uniformly poor outcome, new and different approaches to treatment are needed. Early discussion of palliative care and hospice measures are also appropriate in the youngest of patients. The role of radiation was most difficult to define. One might argue that radiation contributed to the improved survival observed in the older subgroups that were irradiated to higher doses than the younger patients. However, when corrected for age, no clear benefit for RT was observed. A randomized study of radiation versus no radiation in older patients with rhabdoid tumor might serve to clarify this point. However, because of the rarity of RTK, such a study would take many years, possibly decades, to complete. An international collaboration could, however, help to facilitate such a study. Many other tumor types occur in both a hereditary and nonhereditary form, with the hereditary form characterized by, among other factors, a younger age of onset and the occurrence of second primary site tumors. With the identification of cancer predisposition genes, it is increasingly possible to identify predisposing germ-line mutations in cancer genes and to determine the contribution of genetic predisposition to early onset cancers. Versteege et al5 reported the isolation of the hSNF5/INI1 gene, which is mutated in many rhabdoid tumors as well as the associated atypical teratoid-rhabdoid tumors of the CNS. Biegel et al6 demonstrated that both acquired mutations and germ-line mutations can be identified in patients with rhabdoid tumors. Savla et al18 demonstrated germ-line mutation in two infants who developed both rhabdoid tumors of the kidney as well as histologically distinct CNS tumors, whereas two other older patients with rhabdoid tumors of the kidney without CNS tumors who survived 4 years or more did not have germ-line mutations. It is possible that the younger patients were more likely to harbor germ-line mutations. However, data from the literature suggest that within tumor tissue, mutations are found in a high proportion of all rhabdoid tumors, not all of which are necessarily germ-line.6,19 Tumors from patients with predisposing mutations in cancer genes such as RB1 or TP53, although diagnosed at an early age, are not generally associated with a poorer outcome. It is interesting to speculate as to whether the genetic predisposition to some rhabdoid tumors in young infants might contribute to the observed poor outcome. Germ-line DNA was not available for analysis for most of the patients in this study, including all of the patients on NWTS 1, 2, and 3. Future work will involve defining the possible correlation between germ-line mutation and demographic characteristics of patients as well as the influence of the mutated hSNF5/INI1 gene on the aggressive nature of rhabdoid tumors.
The authors indicated no potential conflicts of interest.
Supported by NIH CA42326. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Beckwith J, Palmer N: Histopathology and prognosis of Wilms' tumor: Results of the First National Wilms' Tumor Study. Cancer 41:1937-1948, 1978[CrossRef][Medline] 2. Palmer N, Sutow W: Clinical aspects of the rhabdoid tumor of the kidney: A report of the National Wilms' Tumor Study Group. Med Pediatr Oncol 11:242-245, 1983[Medline] 3. Weeks D, Beckwith J, Mierau G, et al: Rhabdoid tumor of the kidney: A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol 13:439-458, 1989[Medline] 4. Rorke LB, Packer R, Biegel J: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J Neurooncol 24:21-28, 1995[CrossRef][Medline] 5. Versteege I, Sevenet N, Lange J, et al: Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394:203-206, 1998[CrossRef][Medline]
6. Biegel JA, Zhou JY, Rorke LB, et al: Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59:74-79, 1999 7. Waldron PE, Rodgers BM, Kelly MD, et al: Successful treatment of a patient with stage IV rhabdoid tumor of the kidney: Case report and review. J Pediatr Hematol Oncol 21:53-57, 1999[Medline] 8. D'Angio G, Evans A, Breslow N, et al: The treatment of Wilms tumor: Results of the National Wilms' Tumor Study. Cancer 38:633-646, 1976[CrossRef][Medline] 9. D'Angio G, Evans A, Breslow N, et al: The treatment of Wilms' tumor: Results of the second National Wilms' Tumor Study. Cancer 47:2302-2311, 1981[CrossRef][Medline] 10. D'Angio G, Breslow N, Beckwith J, et al: Treatment of Wilms tumor: Results of the Third National Wilms' Tumor Study. Cancer 64:349-360, 1989[CrossRef][Medline]
11. Green D, Breslow N, Beckwith J, et al: A comparison between single dose and divided dose administration of dactinomycin and doxorubicin: A report from the National Wilms' Tumor Study Group. J Clin Oncol 16:237-245, 1998
12. Green DM, Breslow NE, Beckwith JB, et al: The effect of duration of treatment on outcome and cost of the treatment for Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 16:3744-3751, 1998 13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assn 53:456-481, 1958 14. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 15. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J Royal Stat Soc (Series A) 135:185-206, 1972 16. Cox DR: Regression models and life-tables (with discussion). J Royal Stat Soc (Series B) 34:187-220, 1972 17. Mitchell C, Jones PM, Kelsey A, et al: The treatment of Wilms' tumor: Results of the United Kingdom Children's Cancer Study Group (UKCCSG) second Wilms' tumour study. Br J Cancer 83:602-608, 2000[CrossRef][Medline]
18. Savla JCT, Schneider NR, Timmons CF, et al: Mutations of the hSNF5/INI1 gene in renal rhabdoid tumors with second primary brain tumors. J Natl Cancer Inst 92:648-650, 2000
19. Biegel JA, Tan L, Zhang F, et al: Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8:3461-3467, 2002 Submitted December 4, 2004; accepted July 15, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
