Lack of N-MYC-Amplification and Normal Karyotype in Stage IV-N Neuroblastoma

Toren, Amos; Mandel, Mathilda; Passwell, Justeen; Biniaminov, Miriam; Neumann, Yoram; Rosenthal, Ester; Kende, G.; Kenet, Gili; Brok‐Simoni, Frida; Rechavi, Gideon

doi:10.3109/02841869609109931

Cited by 4 publications

(10 citation statements)

References 13 publications

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“…Similarly, in subsequent reports, all in the 1990s and with outmoded chemotherapy, the small number of 4N patients had superior EFS compared to other HR-NB stage 4 patients. [8][9][10] The same finding was noted in 4N patients >1-year-old (n = 11) identified in an analysis of the prognostic impact of metastatic sites in patients diagnosed 1989 to 1996. 12 A study of a select group of stage 4 patients who received MAT but no mAbs showed a better prognosis among those with only extra-skeletal disease and no bone/BM metastases.…”

Section: Introductionsupporting

confidence: 70%

“…[3][4][5][6] The large majority of stage 4 patients have metastatic involvement of cortical bone and/or BM but a subset is stage 4 by virtue of distant metastases limited to lymph nodes, so-called stage 4N or IV-N. Reports focused on this entity are few and do not cover recent experience. [7][8][9][10][11] In a large single institutional study of patients >1-year-old with metastatic NB treated 1970 to 1980 (ie, from the pre-MAT and pre-mAb era), 3/6 4N patients became long-term disease-free survivors vs 0/40 patients with extra-nodal NB (P < .0002). 7 MYCN status was not reported.…”

Section: Introductionmentioning

confidence: 99%

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Stage 4N neuroblastoma before and during the era of anti‐G_D2 immunotherapy

Kushner,

LaQuaglia,

Cardenas

et al. 2023

Intl Journal of Cancer

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Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high‐risk neuroblastoma (HR‐NB) before myeloablative therapy (MAT) and immunotherapy with anti‐GD2 monoclonal antibodies (mAbs) became standard. Because no report presents more recent results with 4N, we analyzed our large 4N experience. All 51 pediatric 4N patients (<18 years old) diagnosed 1985 to 2021 were reviewed. HR‐NB included MYCN‐nonamplified 4N diagnosed at age ≥18 months and MYCN‐amplified 4N. Among 34 MYCN‐nonamplified high‐risk patients, 20 are relapse‐free 1.5+ to 37.5+ (median 12.5+) years post‐diagnosis, including 13 without prior MAT and 5 treated with little (1 cycle; n = 2) or no mAb (n = 3), while 14 patients (7 post‐MAT, 8 post‐mAbs) relapsed (all soft tissue). Of 15 MYCN‐amplified 4N patients, 7 are relapse‐free 2.1+ to 26.4+ (median 11.6+) years from the start of chemotherapy (all received mAbs; 3 underwent MAT) and 4 are in second remission 4.2+ to 21.8+ years postrelapse (all soft tissue). Statistical analyses showed no significant association of survival with either MAT or mAbs for MYCN‐nonamplified HR‐NB; small numbers prevented these analyses for MYCN‐amplified patients. The two patients with intermediate‐risk 4N (14‐months‐old) are relapse‐free 7+ years postresection of primary tumors; distant disease spontaneously regressed. The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, where mAbs have proven efficacy. These findings plus curability without MAT, as seen elsewhere and at our center, support consideration of treatment reduction for MYCN‐nonamplified 4N.

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Section: Introductionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Stage 4N neuroblastoma before and during the era of anti‐G_D2 immunotherapy

Kushner,

LaQuaglia,

Cardenas

et al. 2023

Intl Journal of Cancer

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“…[2][3][4][5] Although an analysis of the prognostic significance of specific metastatic sites demonstrated that the presence of bone marrow metastases was predictive of poor outcome, 19 this report did not examine outcomes for patients with disease limited to a particular metastatic site, such as lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

“…In a separate case report, a 10-year-old patient with stage IV-N, non-MNA neuroblastoma was also a long-term survivor. 5 In an analysis of the prognostic impact of different metastatic sites in 434 patients older than 1 year of age with stage 4 neuroblastoma, 11 patients (2.5%) had 4N disease, with a nonsignificant trend toward improved event-free survival (EFS) for these individuals. 6 Loss of heterozygosity (LOH) at 19q13 has been suggested as a marker for locoregional disease with reported increased frequency in patients with stage 3 or stage 4N disease.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

“…1 Although the prognostic significance of metastatic spread to specific sites has not been extensively studied, case reports and small case series have raised the possibility that patients with metastatic disease confined to distant lymph nodes (4N disease; previously IV-N) may have a better outcome. [2][3][4][5][6] In a single-institution series of six patients with Evans stage IV neuroblastoma and extensive lymph node metastases but no extranodal disease, three patients were long-term survivors in comparison to none of the 40 patients with standard stage IV disease (extranodal involvement). 2 Subsequently,…”

Section: Introductionmentioning

confidence: 99%

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Metastatic Neuroblastoma Confined to Distant Lymph Nodes (stage 4N) Predicts Outcome in Patients With Stage 4 Disease: A Study From the International Neuroblastoma Risk Group Database

Morgenstern

London

Stephens

et al. 2014

JCO

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Purpose The presence of distant metastases is one of the most powerful predictors of outcome in patients with neuroblastoma. However, the pattern of metastatic spread is not incorporated into current risk stratification systems. Small case series have suggested that patients with neuroblastoma who have metastatic disease limited to distant lymph nodes (4N disease) may have improved outcomes. Patients and Methods We analyzed retrospective data from the International Neuroblastoma Risk Group database for patients diagnosed from 1990 to 2002. 4N patients were compared with the remaining stage 4 patients (non-4N), excluding those with missing metastatic site data. Results In all, 2,250 International Neuroblastoma Staging System stage 4 patients with complete data were identified, of whom 146 (6.5%) had 4N disease. For 4N patients, event-free survival (EFS; 5-year, 77% ± 4%) and overall survival (OS; 5-year, 85% ± 3%) were significantly better than EFS (5-year, 35% ± 1%) and OS (5-year, 42% ± 1%) for non-4N stage 4 patients (P < .001). 4N patients were more likely to be younger (P < .001) and have tumors with favorable characteristics, including absence of MYCN amplification (89% v 69%; P < .001). In a multivariable analysis, 4N disease remained a significant predictor of outcome (hazard ratio for non-4N v 4N: 3.40 for EFS and 3.69 for OS). Within subgroups defined by age at diagnosis and tumor MYCN status, 4N disease was significantly associated with improved outcomes. Conclusion 4N represents a subgroup with better outcome than that of other patients with metastatic disease. These findings suggest that the biology and treatment response of 4N tumors differ from other stage 4 tumors, and less intensive therapy should be considered for this cohort. Future exploration of biologic factors determining the pattern of metastatic spread is warranted.

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