Peripheral neuroblastic tumors with genotype-phenotype discordance: a report from the Children’s Oncology Group and the International Neuroblastoma Pathology Committee.

Pediatr Blood Cancer. 2013 Mar;60(3):363-70.

Suganuma R, Wang LL, Sano H, Naranjo A, London WB, Seeger RC, Hogarty MD, Gastier-Foster JM, Look AT, Park JR, Maris JM, Cohn SL, Amann G, Beiske K, Cullinane CJ, d’Amore ES, Gambini C, Jarzembowski JA, Joshi VV, Navarro S, Peuchmaur M, Shimada H.

Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Los Angeles, California 90027, USA.



BACKGROUND: Of 4,706 peripheral neuroblastic tumors (pNTs) registered on the Children’s Cancer Group and Children’s Oncology Group Neuroblastoma Study between 1989 and 2010, 51 cases (1.1%) had genotype-phenotype discordance characterized by MYCN amplification (indicating poor prognosis) and Favorable Histology (indicating better prognosis).

PROCEDURE: To distinguish prognostic subgroups in the genotype-phenotype discordant pNTs, two subgroups, “conventional” and “bull’s eye,” were identified based on the nuclear morphology. The “conventional” tumors (35 cases) included: Neuroblastoma, poorly differentiated subtype (NB-PD, 26 cases) with “salt-and-pepper” nuclei; neuroblastoma, differentiating subtype (4 cases); ganglioneuroblastoma, intermixed (3 cases); and ganglioneuroma, maturing subtype (2 cases). The “bull’s eye” tumors included NB-PD with prominent nucleoli (16 cases). Clinicopathologic characteristics of these two subgroups were analyzed. N-myc protein expression was tested immunohistochemically on available tumors.

RESULTS: No significant difference was found between these two subgroups in the distribution of prognostic factors such as age at diagnosis, clinical stage, histopathology category/subtype, mitosis-karyorrhexis index, ploidy, 1p LOH, and unbalanced 11q LOH. However, prognosis of the patients with “conventional” tumors (5-year EFS 85.7 ± 12.2%; OS 89.3 ± 10.3%) was significantly better than those with “bull’s eye” tumors (EFS 31.3 ± 13.0%; OS 42.9 ± 16.2%; P = 0.0010 and 0.0008, respectively). Immunohistochemically all (11/11) tested “conventional” tumors were negative, and 10/11 tested “bull’s eye” tumors were positive for N-myc protein expression.

CONCLUSIONS: Based on the presence or absence of prominent nucleoli (the putative site of RNA synthesis/accumulation leading to N-myc protein expression), two prognostic subgroups, “conventional” with a better prognosis and “bull’s eye” with a poor prognosis, were distinguished among the genotype-phenotype discordant pNTs. Copyright © 2012 Wiley Periodicals, Inc.

PMID: 22744966



Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) are known to offer one of the best models for investigating biologically and clinically significant relationships between molecular/genomic alterations and their morphologic/phenotypic manifestations. Tumors of this group have well-established prognostic factors such as age at diagnosis, clinical stage, histopathology classification, MYCN status, ploidy pattern, and chromosomal abnormalities (LOH’s). Among these prognostic factors, MYCN amplification, one of the strongest indicators of aggressive tumor progression, is reported to be a powerful driving force preventing tumor maturation and increasing mitotic and karyorrhectic activities [1, 2].  Accordingly MYCN-amplified neuroblastomas typically show the histologic feature of undifferentiated/poorly differentiated subtype with a high MKI (mitosis-karyorrhexis index), and are classified into the Unfavorable Histology Group according to the International Neuroblastoma Pathology Classification [3]. It is also reported that MYCN-amplified tumors are often associated with prominent nucleolar formation [4].

Through our central pathology review for the CCG (Children’s Cancer Group) and COG (Children’s Oncology Group) neuroblastoma cases from US, Canada, Australia, and New Zealand, we encountered a subset of rare tumors having genotype-phenotype discordance, i.e. MYCN-amplified tumors demonstrating histologic features classified into the Favorable Histology (FH) group.  Thorough investigation of those cases distinguished “conventional” tumors with an excellent prognosis and “bull’s eye” tumors with a significantly worse survival of the patients in this subset: “conventional” tumors had salt-and-pepper nuclei and “bull’s eye” tumor had one or few prominent nucleoli.  Further analysis demonstrated that the presence of prominent nucleoli (the putative site of RNA synthesis/accumulation) was critical for N-myc protein expression in the neuroblastic cells.  In contrast, those tumors without prominent nucleolar formation did not express N-myc protein.  The results of this study clearly show that the protein expression rather than DNA amplification is directly related to the aggressive tumor behavior of this rare subset of MYCN-amplified & FH neuroblastoma cases (see Figure 1).


Hiro Shimada-1

Figure 1: Genotype-Phenotype discordant (MYCN-amplified & Favorable Histology) Neuroblastoma: “Conventional” tumors with salt-and-pepper nuclei did not express N-myc protein and showed an excellent prognosis.  “Bull’s eye” tumors with prominent nucleoli expressed N-myc protein and linked to a poor prognosis.



1.      Shimada H, Stram DO, Chatten J, et al. Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J Natl Cancer Inst 1995:87:1470-1476.

2.      Goto S, Umehara S, Gerbing RB, et al. Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors. Cancer 2001:92:2699-2708.

3.      Shimada H, Ambros IM, Dehner LP, et al. The International Neuroblastoma Pathology Classification (the Shimada System). Cancer 1999:86:364-372.

4.      Kobayashi C, Monforte-Munoz HL, Gerbing RB, et al. Enlarged and prominent nucleoli may be indicative of MYCN amplification: A study of neuroblastoma (Schwannian stroma–poor), undifferentiated/poorly differentiated subtype with high mitosis-karyorrhexis index. Cancer 2005:103:174-180.



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