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© 2000 American Society for Clinical Oncology Natural Course of Neuroblastoma Detected by Mass Screening: A 5-Year Prospective Study at a Single InstitutionFrom the Divisions of Oncology, Pathology, Radiology, Hematology, and Surgery, Kanagawa Children’s Medical Center, Yokohama, Japan. Address reprint requests to Yukichi Tanaka, MD, Division of Pathology, Kanagawa Children’s Medical Center, Mutsukawa 2–138-4, Minami-ku, Yokohama 232-8555, Japan; email p-cmck{at}gd5.so-net.ne.jp
PURPOSE: To describe various favorable courses of neuroblastoma (NBL) detected by mass screening and to present our observation program as a temporary treatment option, to be used until a final decision is made regarding the mass screening program for 6-month-old infants. PATIENTS AND METHODS: Between October 1993 and November 1999, 26 of 51 patients with NBL detected by mass screening were enrolled in our observation program. The criteria for observation included urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels less than 50 µg/mg creatinine, smaller tumor size (< 5.0 cm), preoperative status, and granted informed consent. Patients were divided into four groups according to changes in urinary VMA and HVA values and tumor size. Patients who no longer fulfilled criteria underwent surgery. RESULTS: The observation period ranged from 4 to 73 months. Urinary VMA and HVA levels decreased in 19 of 26 patients, often by age 16 months. Eighteen patients had regressing tumors, and in 10 of these cases, the tumor was undetectable or barely detectable by imaging techniques. Four patients younger than 12 months had increased tumor marker levels and tumor volume, histologically reflecting neuroblastic proliferation. The remaining three patients, all older than 18 months, had varied tumor marker levels but increased tumor volume, histologically reflecting an increase in Schwann cells. No upgrading of tumor stage or unfavorable biologic factor was noted in any patient. CONCLUSION: None of our patients showed evidence of transition from favorable to unfavorable prognosis, a finding that points to a reduction in the significance of screening as a public health measure. Until results of ongoing screening trials involving older patients have been evaluated, the observation program can be used as a temporary measure to avoid, with little risk, unnecessary surgical intervention.
NEUROBLASTOMA (NBL) is extremely variable in terms of biologic and clinical behavior.1-5 Some tumors, localized or even widespread (stage IV-S or International Neuroblastoma Staging System [INSS] stage 4S), regress and/or mature spontaneously.2,3 However, approximately 60% of patients with clinically diagnosed NBL have stage IV or INSS stage 4 disease and have a very poor prognosis; the 5-year survival rate is no more than 30%, even with aggressive therapy.4,5 To decrease the number of cases of advanced disease and mortality, a nationwide mass-screening program for 6-month-old infants (MS6M) was introduced in Japan 15 years ago.6 The total number of NBL cases has increased markedly, but there has been no apparent decrease in the number of cases of advanced disease.7-10 Between October 1985 and September 1993, we treated 57 patients with NBL detected through MS6M and found that all of the resected tumors, regardless of stage, had no biologic risk factors, including N-myc amplification and unfavorable histology. All of these patients were alive without disease after 6 to 15 years of follow-up, although a few had had surgical complications, mostly postoperative adhesive ileus. In the hope of avoiding unnecessary treatment, we observed a patient whose NBL had been detected through MS6M. In 1991, we reported this first trial case.11 The patient showed spontaneous regression after 10 months of observation without treatment. In 1993, on the basis of this experience, we proposed new observation criteria for NBL found through MS6M, and we reported preliminary results in 1995.12 After our trial, similar attempts were made at other institutions. Yamamoto et al13 used nearly identical criteria and reported similar results after a relatively short (between 4 and 27 months) observation period. Whether to continue the screening program for NBL is the subject of repeated debate, and the recent trend is toward abolishing the program.14,15 In the present report, a report of the largest series of NBL patients, we describe the various favorable courses of NBL detected through MS6M.
Mass screening was performed by sending specimen kits containing instructions and filter papers to families with 6-month-old children. After the filters were soaked with urine, they were sent back to the Institute of Public Health, where vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels were measured quantitatively using high-performance liquid chromatography. Families of children whose VMA and HVA levels were higher than the cutoff values were required to submit a second sample. If test results were again positive, the families were referred to appropriate institution for further examinations. Our previous experience with MS6M suggested that many patients screened for NBL and found to have smaller tumors (< 5 cm) and lower urinary VMA and HVA values (< 50 µg/mg creatinine) had stage I or II disease.12,13 Based on these data, observation criteria for patients with NBL detected through MS6M were proposed (Table 1). Patients who fulfilled the criteria were observed untreated. The criteria were approved by the institutional tumor board of Kanagawa Children’s Medical Center. Written consent for observation without treatment was obtained from each patient’s guardian.
VMA and HVA tests and ultrasonography or magnetic resonance imaging were performed every month for the first 3 months of observation. If the tumor marker level or the tumor volume started decreasing, the tests and imaging were performed every 2 to 3 months. After a year, the tests and imaging were performed at an interval of 4 to 6 months. The volume of the mass was calculated as follows: [4/3]  x height/2 x width/2 x depth/2 = height x width x depth x 0.5215.16 Fifty-one patients with NBL detected through MS6M were referred to Kanagawa Children’s Medical Center between October 1993 and November 1999, and 26 patients (51%) fulfilled the criteria and joined the observation program. The remaining 25 patients were treated according to the protocol at our institution.17 The 10 tumors surgically removed after several months of observation, as well as the tumors of the 25 patients who did not enroll in the program, were staged according to the Evans staging system18 and INSS19 and were examined for histopathology,20 N-myc amplification,21 and ploidy pattern.22
Clinical data from the 26 patients enrolled in the observation program are summarized in Table 2. The 18 boys and eight girls were 6 to 11 months old at the time of diagnosis. Twenty-five patients had presumed Evans stage I or II disease, and one patient had presumed Evans stage IV-S disease.
The 26 patients were divided into four groups. The four patients in group A (patients no. A1 through A4) had normalized urinary VMA and HVA levels and their tumors had regressed markedly and were undetectable by imaging techniques. The observation period in this group ranged from 36 to 65 months (mean, 46.8 months). Urinary VMA and HVA levels normalized between 9 and 16 months of age (VMA level: mean age, 11.8 months; HVA level: mean age, 10.5 months), and tumors became undetectable by 16 months of age. In patient no. A1, for example, the tumor disappeared completely after 8 months of observation (Fig 1).
The 14 patients in group B (patients no. B1 through B14) had normalized urinary VMA and HVA levels, and their tumors had regressed but were still detectable by imaging techniques. The tumors of patients no. B13 and B14 were removed at 12 and 10 months of age, respectively, by parent request (patient no. B13) or because the patient’s family was moving abroad (patient no. B14). The histologic diagnosis in both cases was differentiating NBL and favorable by Shimada histopathologic classification (stroma poor, differentiating, low mitosis karyorrhexis index, age < 1.5 years).23 The 12 patients whose tumors were not removed were observed for 6 to 73 months (mean, 30.9 months). Urinary VMA and HVA levels normalized between 9 and 18 months of age (VMA level: mean age, 13.0; HVA level: mean age, 11.8 months). In eight of 12 cases, the tumor decreased to less than 4 cm3 by 24 months of age and the size did not change much thereafter. The four patients in group C (patients no. C1 through C4) had varied urinary VMA and HVA levels (all < 50 µg/mg creatinine) and their tumors increased in size. In patient no. C3, the tumor was resected by parent request. In the remaining three cases, the tumors were resected because of the significant increase in size. The changes in the tumor of patient no. C4 are shown in Fig 2. The increase in tumor size in this group most probably reflected the increase in Schwann cells. In the three patients who were 18 months old or older at the time of surgery, the tumors were ganglioneuroblastoma and ganglioneuroma. The tumor of patient no. C4 was removed at the age of 12 months. Although the histologic diagnosis was differentiating NBL, an increase of Schwann cells was evident.
The characteristic features of group D, which included four patients (patients no. D1 through D4), were an increase in urinary VMA and HVA levels (40 to 110 µg/mg creatinine) and an increase in tumor size. Patients were observed for a relatively short period and were 12 months old or younger at the time of surgery. The histologic diagnosis in all cases was poorly differentiated NBL and favorable by Shimada histopathologic classification (stroma poor, undifferentiated, low or intermediate mitosis karyorrhexis index, age < 1.5 years). The increased urinary VMA and HVA values and tumor volume most likely reflected the proliferation of the neuroblasts. In summary, urinary VMA and HVA levels gradually decreased in 19 (73%) of 26 patients. The mean ratio of VMA level to HVA level was 0.92. Urinary VMA and HVA values were normalized by 16 months of age in 16 (62%) of 26 patients, and urinary HVA values seemed to normalize faster than did urinary VMA values. Two patients had urinary HVA values that were within normal limits at the time of initial diagnosis. A decrease in tumor volume was observed in 18 (95%) of 19 patients with decreased urinary VMA and HVA values. In four of 19 patients, the tumors were no longer detectable by imaging techniques. In the additional six patients with tumors measuring less than 3.0 cm3, these lesions were detected only because of prior knowledge of their existence. Before 12 months of age, increased tumor volume most often correlated with increased urinary VMA and HVA values, reflecting the proliferation of the neuroblasts. In the cases of increased tumor volume after the age of 12 months, the age at surgery was correlated with the maturing features of the tumor. Adrenal glands and the retroperitoneum were the common primary sites; although disease in the mediastinum or pelvis often has a good prognosis, the regressing tumors did not tend to be located in these sites. In the surgically resected samples, no unfavorable biologic factors, including N-myc amplification and diploidy or tetraploidy, were found. Also, no upgrading of the presumed tumor stage was confirmed.
The findings of the present study indicate that a considerable number of NBLs detected through MS6M may regress completely or decrease markedly in size. Examinations of the resected tumors revealed no unfavorable biologic factors or upgrading of the presumed tumor stage in any of the study patients. If the urinary VMA and HVA levels normalized, an increase in the tumor size indicated maturation (not progression) of the tumor. Spontaneous partial regression has been reported11,13; however, there has been no reported case of complete regression as demonstrated by the tumors of the patients in our study group A. The natural course of the tumors of our group D patients was unpredictable. However, given that clinicopathologic studies, conducted at our institution24 and elsewhere,8,13 of NBL detected by mass screening have suggested a proliferative stage in some NBLs (most often occurring before 12 months of age) during their natural favorable course of development, rapid and life-threatening growth of the tumors of our group D patients was unlikely. The original intention of MS6M was to detect potentially aggressive NBL at an early stage, thus reducing the number of cases of advanced disease. However, the number of cases of NBL detected by other means and the mortality rate have changed little, and only the number of cases of NBL detected through MS6M has increased.8,9 A large, population-based study in Quebec did not find mass screening in infancy to be useful.7 Several reports have referred to the unfavorable biologic factors of NBL detected through MS6M; the percentage of tumors with various unfavorable factors ranged from 0% to 20%.10,25,26 However, N-myc amplification, considered the most significant unfavorable factor for infantile NBL, is rare in NBL detected through MS6M; the rate of amplification with more than 10 copies is presumed to be less than 1%.27 Moreover, a lack of correlation between N-myc amplification and prognosis was recently reported in localized NBL.28 A review of the nationwide occurrence rate of NBL and the associated mortality shows that only a small percentage of the patients have clearly merited from MS6M. Nationwide, death due to NBL has been noted in eight (0.5%) of 1,593 patients with NBL detected through MS6M; death due to surgical complications or severe chemotherapeutic side effects has been reported in 18 cases (1.1%).27 Recently, some investigators warned of overdiagnosis and overtreatment of infantile NBL, including NBL detected through MS6M.28,29 Since the early 1990s, we have treated patients with INSS stage 1, 2, or 4S NBL with surgery alone. For patients with stage III or IV disease with no N-myc amplification, surgery and chemotherapy have been scheduled and the total chemotherapy dose has been reduced to half the dose planned for patients with NBL detected by other means than MS6M.17 With this therapeutic regimen, we have achieved a 100% survival rate without life-threatening complications in the 106 patients with NBL detected through MS6M (October 1985 to November 1999). In Japan, more than 10% of patients undergoing surgery for NBL detected through MS6M experienced major or minor postoperative complications, and eight patients died from surgical complications.4,27,28 Our first trial of the observation program in 1991 was primarily planned and performed by surgeons who were concerned about the possibility of surgical complications and noted the high frequency of favorable biologic features in NBL detected through MS6M.11 It is stressful for a patient’s guardians and medical staff to observe a tumor for a long period without having a complete guarantee of a favorable biologic course. The wish to perform surgery, regardless of possible surgical complications, is understandable. Yet considering the favorable biologic features in most infantile NBL, the need for surgical intervention to pinpoint the biologic risk factors in all tumors is questionable. Even though the screening program may be useful for detecting NBL that might otherwise ultimately have an unfavorable prognosis, in our study we noted no transition from favorable to unfavorable prognosis. At present, there is no persuasive evidence that such a transition occurs nor that early treatment may have an effect on this transition. The potential risk associated with a tumor that is often capable of spontaneous regression should be balanced against the risk associated with therapeutic intervention. At a recent Consensus Conference on Neuroblastoma Screening, it was reported that NBL screening at less than 7 months cannot be recommended as a public health measure.14,15 Screening at a later age has been performed in some areas, and preliminary results have not indicated a dramatic improvement in mortality.29-31 Additional data from ongoing screening trials are needed. More time probably will pass before a final decision can be made regarding the significance of mass screening as a public health measure. In the meantime, our observation program, which can be used to avoid unnecessary surgical intervention to a considerable extent with little risk, can be adopted in cases of infantile NBL.
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Yamamoto K, Hayashi Y, Hanada R, et al: Mass screening and age-specific incidence of neuroblastoma in Saitama Prefecture, Japan. J Clin Oncol 13:2033–2038, 1995 9. Bessho F, Hashizume K, Nakajo T, et al: Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children. J Pediatr 119:237–241, 1991[Medline] 10. Kaneko Y, Kanda N, Maseki N, et al: Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: A chromosome and N-myc amplification study. J Clin Oncol 8:2005–2013, 1990[Abstract] 11. Matsumura M, Tsunoda A, Nishi T, et al: Spontaneous regression of neuroblastoma detected by mass screening. Lancet 338:447–448, 1990 (letter) 12. Nishihira H, Toyoda Y, Iguchi M, et al: An observation program on neuroblastoma cases detected by mass screening at 6 months of age. Jpn J Pediatr Surg 31:424, 1995
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Yamamoto K, Hanada R, Kikuchi A, et al: Spontaneous regression of localized neuroblastoma detected by mass screening. J Clin Oncol 16:1265–1269, 1998 14. Philip T: Early detection of neuroblastoma in infants: Research? Yes. Routine screening? No. Med Pediatr Oncol 33:355–356, 1999 (editorial)[Medline] 15. Berthold F, Brodeur G, Favrot MC, et al: Report of the 1998 Consensus Conference on Neuroblastoma Screening. Med Pediatr Oncol 33:357–359, 1999[Medline] 16. Gobel V, Jurgens H, Etspuler G, et al: Prognostic significance of tumor volume in localized Ewing’s sarcoma of bone in children and adolescents. J Cancer Res Clin Oncol 113:187–191, 1987[Medline] 17. Nishihira H, Toyoda Y, Goto H, et al: Clinical and biological studies on 97 neuroblastoma cases. Jpn J Pediatr Oncol 31:33–37, 1994 18. Evans AE, D’Angio GJ, Randolph J: A proposed staging for children with neuroblastoma. Cancer 27:374–378, 1971[Medline]
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Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466–1477, 1993 20. Shimada H, Ambros I, Dehner LP, et al: Terminology and morphologic criteria of neuroblastic tumors: Recommendations by the International Neuroblastoma Pathology Committee. Cancer 86:349–363, 1999[Medline] 21. Seeger RC, Brodeur GM, Sather H, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313:1111–1116, 1985[Abstract] 22. Look AT, Hayes FA, Nitschke R, et al: Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 311:231–235, 1984[Abstract] 23. Shimada H, Chatten J, Newton WA, et al: Histopathologic prognostic factors in neuroblastic tumors: Definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 73:405–416, 1984 24. Ijiri R, Tanaka Y, Misugi K, et al: Clinicopathological study of mass-screened neuroblastoma with special emphasis on untreated observed cases: A possible histological clue to tumor regression. Am J Surg Pathol 24:807–815, 2000[Medline] 25. Erttmann R, Tafese T, Berthold F, et al: 10 years’ neuroblastoma screening in Europe: Preliminary results of a clinical and biological review from the Study Group for Evaluation of Neuroblastoma Screening in Europe (SENSE). Eur J Cancer 34:1391–1397, 1998 26. Woods WG, Tuchman M, Brodeur GM, et al: Clinical and biologic parameters from patients diagnosed with neuroblastoma as part of the Quebec Screening Project: Differences between cases detected by screening and those diagnosed clinically. 4th International Symposium on Neuroblastoma Screening, Stuttgart, Germany, 1995 27. Suita S, Sawada T, Kaneko M, et al: Annual report on neuroblastoma mass screening in Japan: Report of the Committee on neuroblastoma. Jpn J Pediatr Oncol 36:107–117, 1999 28. Ikeda H, Suzuki N, Takahashi A, et al: Surgical treatment of neuroblastomas in infants under 12 months of age. J Pediatr Surg 33:1246–1250, 1998[Medline] 29. Esteve J, Parker L, Roy P, et al: Is neuroblastoma screening evaluation needed and feasible? Br J Cancer 71:1125–1131, 1995[Medline] 30. Craft AW, Parker L: Screening for neuroblastoma: 20 years and still no answer. Eur J Cancer 32:1540–1543, 1996 31. Nishi M, Miyake H, Takeda T, et al: Mass screening for neuroblastoma targeting children age 14 months in Sapporo City. Cancer 82:1973–1977, 1998[Medline]
Submitted December 23, 1999;
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
