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Neuroblastoma Treatment (PDQ®)

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Cellular Classification of Neuroblastic Tumors

Neuroblastomas are classified as one of the small, round, blue cell tumors of childhood. They are a heterogenous group of tumors composed of cellular aggregates with different degrees of differentiation, from mature ganglioneuromas to less mature ganglioneuroblastomas to immature neuroblastomas, reflecting the varying malignant potential of these tumors.[1]

There are two cellular classification systems for neuroblastoma.

  • International Neuroblastoma Pathology Classification (INPC) System: The INPC system involves evaluation of tumor specimens obtained before therapy for the following morphologic features:[2-5]
    • Amount of Schwannian stroma.
    • Degree of neuroblastic maturation.
    • Mitosis-karyorrhexis index of the neuroblastic cells.

    Favorable and unfavorable prognoses are defined on the basis of these histologic parameters and patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.[2-4]

    In the future, the INPC system is likely to be replaced by a system that does not include patient age as a part of cellular classification.

Table 1. Prognostic Evaluation of Neuroblastic Tumors According to the International Neuroblastoma Pathology Classification (Shimada System)a
International Neuroblastoma Pathology classification Original Shimada classification Prognostic group 
Neuroblastoma(Schwannian stroma-poor)bStroma-poor
FavorableFavorableFavorable
<1.5 yrsPoorly differentiated or differentiating & low or intermediate MKI tumor
1.5–5 yrsDifferentiating & low MKI tumor
UnfavorableUnfavorableUnfavorable
<1.5 yrsa) undifferentiated tumorc
b) high MKI tumor
1.5–5 yrsa) undifferentiated or poorly differentiated tumor
b) intermediate or high MKI tumor
≥5 yrsAll tumors
Ganglioneuroblastoma, intermixed(Schwannian stroma-rich)Stroma-rich Intermixed (favorable)Favorabled
Ganglioneuroma(Schwannian stroma-dominant)
MaturingWell differentiated (favorable)Favorabled
MatureGanglioneuroma
Ganglioneuroblastoma, nodular(composite Schwannian stroma-rich/stroma-dominate and stroma-poor)Stroma-rich nodular (unfavorable)Unfavorabled

MKI: mitosis-karyorrhexis index.
aReprinted with permission. Copyright © 1999 American Cancer Society. All rights reserved.[2] Hiroyuki Shimada, Inge M. Ambros, Louis P. Dehner, Jun-ichi Hata, Vijay V. Joshi, Borghild Roald, Daniel O. Stram, Robert B. Gerbing, John N. Lukens, Katherine K. Matthay, Robert P. Castleberry, The International Neuroblastoma Pathology Classification (the Shimada System), Cancer, volume 86, issue 2, pages 364–72.
bSubtypes of neuroblastoma were described in detail elsewhere.[6]
cRare subtype, especially diagnosed in this age group. Further investigation and analysis required.
dPrognostic grouping for these tumor categories is not related to patient age.

Most neuroblastomas with MYCN amplification in the INPC system also have unfavorable histology, but about 7% have favorable histology. Of those with MYCN amplification and favorable histology, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those who do express MYCN.[7]

  • International Neuroblastoma Risk Group (INRG) Classification System: The INRG used a decision-tree analysis to compare 35 prognostic factors in more than 8,000 patients with neuroblastoma from a variety of clinical trials. The following INPC (Shimada system) histologic factors were included in the analysis:[8,9]
    • Diagnostic category.
    • Grade of differentiation.
    • Mitosis/karyorrhexis index.

    Because patient age is used in all risk stratification systems, a cellular classification system that did not employ patient age was desirable, and underlying histologic criteria, rather than INPC or Shimada Classification, was used in the final decision tree. Histologic findings discriminated prognostic groups most clearly in two subsets of patients, as shown in Table 2.

Table 2. Histologic Discrimination of International Neuroblastoma Risk Group Subsets of Neuroblastoma Patientsa
INSS Stage/Histologic Subtype Number of Cases EFS (%)  OS (%) 
INSS stage 1, 2, 3, 4S5,13183 ± 191 ± 1
GN, maturing16297 ± 298 ± 2
GNB, intermixed
NB4,97083 ± 190 ± 1
GNB, nodular
INSS stage 2, 3; age >547 d26069 ± 381 ± 2
11q normal and differentiating1680 ± 16100
11q aberration or undifferentiated4961 ± 1173 ± 11

EFS = event-free survival; GN = ganglioneuroma; GNB = ganglioneuroblastoma; INSS = International Neuroblastoma Staging System; NB = neuroblastoma; OS = overall survival.
aAdapted from Cohn et al.[8]

References
  1. Joshi VV, Silverman JF: Pathology of neuroblastic tumors. Semin Diagn Pathol 11 (2): 107-17, 1994.  [PUBMED Abstract]

  2. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999.  [PUBMED Abstract]

  3. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (9): 2451-61, 2001.  [PUBMED Abstract]

  4. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (10): 2699-708, 2001.  [PUBMED Abstract]

  5. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003.  [PUBMED Abstract]

  6. Shimada H, Ambros IM, Dehner LP, et al.: Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer 86 (2): 349-63, 1999.  [PUBMED Abstract]

  7. Suganuma R, Wang LL, Sano H, et al.: Peripheral neuroblastic tumors with genotype-phenotype discordance: a report from the Children's Oncology Group and the International Neuroblastoma Pathology Committee. Pediatr Blood Cancer 60 (3): 363-70, 2013.  [PUBMED Abstract]

  8. Cohn SL, Pearson AD, London WB, et al.: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27 (2): 289-97, 2009.  [PUBMED Abstract]

  9. Okamatsu C, London WB, Naranjo A, et al.: Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG. Pediatr Blood Cancer 53 (4): 563-9, 2009.  [PUBMED Abstract]