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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 695-699 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.00.8631 Prognostic Value of International Neuroblastoma Pathology Classification in Localized Resectable Peripheral Neuroblastic Tumors: A Histopathologic Study of Localized Neuroblastoma European Study Group 94.01 Trial and ProtocolFrom the Departamento de Patologia, Universidad de Valencia, Spain; Klinisches Institut für Pathologie der Medizinischen Universität Wien, Austria; Avdeling for Patologi, Rikshospitalet, Oslo, Norway; Histopathology Department, Leeds Teaching Hospitals National Health Service Trust, United Kingdom; Unita Ospedaliera di Anatomia Patologica, Ospedale San Bortolo, Vicenza; Unita Ospedaliera di Anatomia Patologica, Istituto G. Gaslini; Unita Ospedaliera di Oncoematologia Pediatrica, Istituto G. Gaslini, Genova, Italia; Service de Biostatistiques and Département d'Oncologie Pédiatrique, Institut Curie; and Service de Pathologie, Hôpital R. Debré AP-HP and EA3102 Université Paris 7, Paris, France Address reprint requests to Samuel Navarro, MD, Department of Pathology, University of Valencia, Medical School, Valencia, Avda Blasco Ibañez 17, 46010 Valencia, Spain; e-mail: samuel.navarro{at}uv.es
PURPOSE: To assess the prognostic value of clinical, biologic, and morphologic data in peripheral neuroblastic tumors, International Neuroblastoma Staging System (INSS) stages 2A and 2B MYCN nonamplified, a multinational protocol entitled Localized Neuroblastoma European Study Group trial 94.01, with a trial of surgery as the only treatment, was initiated in 1995. We present the prognostic value of the revised International Neuroblastoma Pathology Classification (INPC) applied to the patients included in this protocol until its closure in 1999. MATERIALS AND METHODS: A total of 120 neuroblastic tumors from trial patients were reviewed by the European International Society of Pediatric Oncology neuroblastoma pathology panel and assigned to a favorable or unfavorable prognostic category according to the INPC guidelines. Overall survival and relapse-free survival (RFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: A total of 115 of 120 patients were assessable and were assigned to the favorable (90 patients; 78.3%) or unfavorable (25 patients; 21.7%) category. The 60-month survival rate was 97.7% in favorable patients compared with 73.8% in unfavorable patients (P = .0002). RFS analysis showed a 60-month relapse rate of 13.4% and 32% in favorable and unfavorable patients (P < .025), respectively. Statistical analysis demonstrated a significant association of unfavorable INPC category and high lactate dehydrogenase level (P < .045). CONCLUSION: This European study shows for the first time that the INPC prognostic categorization has a significant impact on outcome prediction in INSS stage 2 localized peripheral neuroblastic tumors.
Children with peripheral neuroblastic tumors present with localized resectable disease without metastases in 20% to 30% of the occurrences (International Neuroblastoma Staging System [INSS] stages 1 and 2).1 The outcome of these patients is good, with overall survival (OS) ranging from 80% to 100%.2 The relapse-free survival (RFS) of patients with INSS stage 1 disease treated by surgery alone is close to 100%.2,3 However, this is not true for patients with INSS stage 2 disease. Factors such as abdominal localization, tumor rupture during surgery, regional lymph node involvement, unfavorable histopathology, or MYCN amplification have been regarded as indicators of relapse.4-6 To assess the prognostic value of clinical, biologic, and pathologic data, a European protocol entitled Localized Neuroblastoma European Study Group (LNESG) 94.01, with a trial of surgery as the only treatment for MYCN nonamplified INSS stages 2A and 2B peripheral neuroblastic tumors, was initiated in 1995. Here we present the results of the prognostic categorization according to the International Neuroblastoma Pathology Classification (INPC)7-9 and the correlation with the clinical outcome of these patients.
The LNESG trial included 123 patients with tumors staged 2A and 2B, MYCN nonamplified, and a median follow-up of 62 months (range, 10 to 101 months). The median age was 11 months (range, 0 days to 171 months). A patient/parent/guardian consent form was provided in the guidelines of LNESG 94.01 protocol; informed consent was obtained and the consent form was signed for each patient. The study was approved by an international review board. Representative sections stained with hematoxylin and eosin (median, four slides) of 120 stage 2A and 2B resected tumors were obtained from local pathology departments and reviewed by the pathology panel of the European International Society of Pediatric Oncology neuroblastoma group (G.A., K.B., C.J.C., E.S.G.D.A., C.G., S.N., M.P.). Three patient cases had to be excluded because no slides were available. The histopathologic study was performed in accordance with the guidelines of INPC. Consensus (here defined as agreement of at least five of seven pathologists) on the morphologic features was achieved by review at a multiheaded microscope. The tumors were classified as neuroblastoma (undifferentiated, poorly differentiated, and differentiating), ganglioneuroblastoma intermixed, ganglioneuroblastoma nodular, ganglioneuroma (maturing and mature), peripheral neuroblastic tumor not classifiable, neuroblastoma not otherwise specified, and ganglioneuroblastoma not otherwise specified. Other parameters analyzed in the stroma poor component were mitotic-karyorrhexis index and mitotic index. Prognostic categories of the samples analyzed were established according to the age-linked INPC categorization. Nodular ganglioneuroblastomas were categorized according to the recent revision of the INPC.9
Statistical Analysis The relationship of the INPC with serum lactate dehydrogenase (LDH) was assessed by the two-sided Fisher's exact test to take into account the small number of patients.
For the histopathologic analysis, a total of 120 patient cases were evaluated in accordance with INPC criteria. The distribution of different histologic categories and subtypes is shown in Figure 1.
In five patients, the prognostic categorization was not possible because of either necrosis/hemorrhage or poor quality of the diagnostic material. Of the remaining 115 patients, 90 patients (78.3%) were assigned to the favorable category and 25 patients (21.7%) were assigned to the unfavorable prognostic category. The 60-month OS and RFS of all the 123 patients was 93.0% (range, 88.2% to 97.7%) and 82.8% (range, 76.2% to 89.5%), respectively (Table 1).
Table 1 and Figure 2A show the relationship between INPC categorization and OS. There were eight deaths. Six occurred in the unfavorable histology group and were related to disease. Two deaths were in the favorable histology group; one was due to tumor progression and the other was due to sepsis. No surgery-related death was observed in our series.
The 60-month OS rate was 97.7% (range, 94.7% to 100%) for the favorable category compared with 73.8% (range, 55.3% to 92.4%) for the unfavorable category (P = .0002). The relative risk of death for INPC unfavorable category was 11.4-fold that for the favorable category. Table 2 and Figure 2B show the relationship between INPC categorization and RFS. Twelve of 90 tumors with favorable histology relapsed compared with eight of 25 with unfavorable histology. Nineteen of 20 patients relapsed within the first 18 months; individual patients may have had several relapses. The relapse rate at 60 months was 13.4% (range, 6.3% to 20.4%) and 32.0% (range, 13.7% to 50.3%) for patients with favorable and unfavorable classifications, respectively (P < .025). The relative risk of relapse for the INPC unfavorable category was 2.7-fold that for the favorable category.
Moreover, there was no statistical difference between INSS stages 2A and 2B with regard to the OS (with a 60-month survival rate of 94.3% and 92%, respectively) and the RFS (with a 60-month relapse rate of 17% and 17.3%, respectively). There was no difference in the distribution of favorable and unfavorable revised INPC categories in INSS stages 2A and 2B, with 22.4% of unfavorable revised INPC in stage 2A and 21.2% of unfavorable revised INPC in stage 2B (P > .87). Moreover, no RFS/OS difference was observed according to the degree of tumor resection at initial surgery, as defined by complete resection with ipsilateral positive lymph nodes (stage 2B), complete resection with microscopic residue (stage 2B), or presence of macroscopic residue (stages 2A, 2B). LDH data were available in 103 patients, but comparison with INPC categorization could only be performed in 97 patients. A significant association (P < .045) was demonstrated. High LDH levels (at least two-fold increase) were more frequent in the unfavorable (four of 22 patients; 18.2%) than in the favorable prognostic category (three of 75 patients; 4%). Moreover, a two-fold fold increased value of LDH level was also statistically correlated with OS (P < .0001) and relapse-free interval (P < .045). Age as independent variable showed no correlation with either OS or RFS in this cohort of patients (Tables 1 and 2).
The clinical, pathologic, and biologic heterogeneity of peripheral neuroblastic tumors directs the different therapeutic strategies used in the management of patients enrolled onto cooperative trials and protocols. For ganglioneuroma and ganglioneuroblastoma intermixed, the histopathologic diagnosis is sufficient for prognostication and therapeutic management. For ganglioneuroblastoma nodular and neuroblastoma, several other prognostic indicators such as patient age and stage of disease, as well as biologic factors (especially MYCN oncogene amplification), influence the therapy.10 Advanced stage of disease (INSS stage 4) requires aggressive multimodal therapy, with the exception of infants younger than 12 months of age. Regarding localized disease, controversy surrounded the use of multimodal treatment in these patients until 1994.2 The objectives of the European cooperative protocol LNESG 94.01 were to establish a trial for patients with localized neuroblastic tumors stages 2A and 2B, treated only by surgical resection, and to define clinical and biologic factors that predict tumor relapse. The histopathologic confirmation of diagnosis was recognized as an integral component of the trial, and subsequently, a panel of pathologists (European International Society of Pediatric Oncology neuroblastoma pathology panel) was established to review the histomorphology of all trial patients. The prognostic importance of morphologic parameters in neuroblastic tumors has been suggested by many authors.11-13 Shimada et al14 introduced an age-linked morphologic classification that assigned tumors to favorable or unfavorable categories. The evolution of the classification lead to the establishment of the INPC or Shimada system.6,7 A recent modification was the subdivision of nodular ganglioneuroblastoma into favorable and unfavorable prognostic subsets9,15 based on the morphology and mitotic-karyorrhexis index of the stroma-poor component (revised INPC). To date, the INPC has not been applied to a series of localized neuroblastic tumors. In 2002, Ikeda et al16 demonstrated the prognostic significance of the 1999 INPC in a large series of patients from Japan. We provide the first application of the revised INPC (includes the changes in the ganglioneuroblastoma nodular categorization) to a cohort of European patients and thus validate this revised INPC outside the United States. By application of the revised INPC to the LNESG 94.01 patients, we found a statistically significant difference in both OS and RFS between favorable and unfavorable categories. One of the most striking findings is the higher death rate for patients who experienced relapse with unfavorable histology (six of eight died) compared with patients who experienced relapse with favorable histology (10 of 12 are alive) in this INSS stage 2 group. Thus, we demonstrate the prognostic value of the INPC on a group of patients with localized disease where MYCN is not amplified. Furthermore, this study shows that age as an independent parameter is not prognostically significant in localized neuroblastic tumors. An increased level of LDH proved to be a strong prognostic indicator of adverse outcome and correlated with unfavorable histopathology in previous reports.17-19 Other biologic parameters such as DNA index and 1p loss of heterazygosity are not included in this article and will be the subject of a separate report (manuscript in preparation). Histopathologic prognostication permits early identification of the patient at risk of relapse and/or fatal outcome. It offers the possibility of tailoring the treatment of the individual patient, especially in the event of relapse, given that the probability of an event remains at 32.0% with a large CI. In this context, a second European cooperative protocol of localized neuroblastic tumors opened in 2004.20 It enrolls patients with resectable INSS stage 1 to 3 tumors without MYCN amplification, as well as patients with stage 1 disease and MYCN amplification. This new protocol requires INPC classification of the primary tumor as the principal indicator for the use of aggressive chemotherapy in patients who experience relapse, even if it is only localized.
The authors indicated no potential conflicts of interest.
We thank the pathologists, surgeons, and oncologists of participating centers and the Localized Neuroblastoma European Study Group National Coordinators: V. Castel, Spain; B. De Bernardi, Italy; J. De Kraker, the Netherlands; A. Lacerda, Portugal; A. Foot, United Kingdom; R. Ladenstein, Austria; G. Laureys, Belgium; M. Nenadov Beck, Switzerland; and H. Rubie, France.
Supported by the Association pour la Recherche sur le Cancer, France; United Kingdom Children Cancer Study Group, UK Grant No. G03/89 from Instituto Carlos III, Madrid, Spain; Italian Neuroblastoma Foundation, Italy; and European Society of Pediatric Oncology Neuroblastoma Research Network, European Community. All of the authors contributed equally to this study. Presented in part at the Advances in Neuroblastoma Research Meeting, 11th Conference, June 16-19, 2004, Genova, Italy. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Berthold F, Brandeis W, Lampert F: Neuroblastoma: Diagnostic advances and therapeutic results in 370 patients. Monogr Paediatr 18: 206-223, 1986 2. de Bernardi B, Rogers D, Carli M, et al: Localized neuroblastoma: Surgical and pathologic staging. Cancer 60: 1066-1072, 1987[CrossRef][Medline] 3. Castleberry RP, Kun LE, Shuster JJ, et al: Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol 9: 789-795, 1991[Abstract] 4. Seeger R, Brodeur G, Sather H, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastoma. N Engl J Med 313: 1111-1116, 1985[Abstract] 5. Rosen E, Cassady J, Kretschmar C, et al: Influence of local-regional lymph node metastases on prognosis in neuroblastoma. Med Pediatr Oncol 12: 260-263, 1984[Medline] 6. Perez CA, Matthay KK, Atkinson JB, et al: Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: A Children's Cancer Group study. J Clin Oncol 18: 18-26, 2000 7. Shimada H, Ambros IM, Dehner LP, et al: Terminology and morphologic criteria of neuroblastic tumors: Recommendations by the International Neuroblastoma Pathology Committee. Cancer 86: 349-363, 1999[CrossRef][Medline] 8. Shimada H, Ambros IM, Dehner LP, et al: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86: 364-372, 1999[CrossRef][Medline] 9. Peuchmaur M, d'Amore E, Joshi V, et al: Revision of the International Neuroblastoma Pathology Classification: Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma nodular. Cancer 98: 2274-2281, 2003[CrossRef][Medline] 10. Brodeur GM: Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer 3: 203-216, 2003[CrossRef][Medline] 11. Beckwith JB, Martin RF: Observations on the histopathology of neuroblastomas. J Pediatr Surg 3: 106-110, 1968[CrossRef][Medline] 12. Joshi VV, Cantor AB, Altshuler G, et al: Recommendations for modification of terminology of neuroblastic tumors and prognostic significance of Shimada classification: A clinicopathologic study of 213 cases from the Pediatric Oncology Group. Cancer 69: 2183-2196, 1992[CrossRef][Medline] 13. Joshi VV, Rao PV, Cantor AB, et al: Modified histologic grading of neuroblastomas by replacement of mitotic rate with mitosis karyorrhexis index: A clinicopathologic study of 223 cases from the Pediatric Oncology Group. Cancer 77: 1582-1588, 1996[CrossRef][Medline] 14. 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[Medline] 15. Umehara S, Nakagawa A, Matthay KK, et al: Histopathology defines prognostic subsets of ganglioneuroblastoma, nodular. Cancer 89: 1150-1161, 2000[CrossRef][Medline] 16. Ikeda H, Iehara T, Tsuchida Y, et al: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86: 1110-1116, 2002[CrossRef][Medline] 17. Joshi VV, Cantor AB, Brodeur GM, et al: Correlation between morphologic and other prognostic markers of neuroblastoma: A study of histologic grade, DNA index, N-myc gene copy number, and lactic dehydrogenase in patients in the Pediatric Oncology Group. Cancer 71: 3173-3181, 1993[CrossRef][Medline] 18. Joshi VV, Tsongalis GJ: Correlation between morphologic and nonmorphologic prognostic markers of neuroblastoma. Ann N Y Acad Sci 824: 71-83, 1997[Medline] 19. Shuster JJ, McWilliams NB, Castleberry R, et al: Serum lactate dehydrogenase in childhood neuroblastoma: A Pediatric Oncology Group recursive partitioning study. Am J Clin Oncol 15: 295-303, 1992[Medline] 20. Nenadov-Beck M: LNESG 2 study: Guidelines for the treatment of patients with localized resectable neuroblastoma and analysis of prognostic factors. Presented at E-SIOP Neuroblastoma Meeting, October 21-23, 2004, Cracow, Poland Submitted December 9, 2004; accepted October 4, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
