DISCUSSION
Although a high-risk treatment is generally recommended for NB cases of Stage 2,3, and 4S with MYCN -A in young patients (within 18 months),8 these patients often suffer with late adverse-effects of radiotherapy and high-dose chemotherapy. Therefore, the treatment strategy is commonly decided according to several prognostic factors. A tumor with MYCN -A and FH, which represents genotype–phenotype discordance, is very rare and has been characterized based on specific features and prognosis.6 In the present study, we reported two NB discordant pediatric cases (under 18-months-old; Stages 4S and 2B) with negative results for N-myc staining, and good prognosis under conventional therapy.
We reviewed seven previously published cases of Stage 4S NB with discordance features (Table 1).9-12 Four cases survived for more than 24 months with conventional therapy without autologous stem cell rescue or radiotherapy. Because N-myc expression finding was not reported in any of these cases, an association between N-myc expression and prognosis in Stage 4S NB remained controversial until Suganuma report.6
Goto et al. classified the discordance feature of MYCN -A andMYCN -nonamplified (MYCN -NA) NBs into four categories (MYCN -A+FH, MYCN -NA+UH, MYCN -A+UH, andMYCN -NA+FH), and discussed their specific clinical and pathological features, and prognosis. Both of our cases involvedMYCN -A+FH tumors.13 In the Children’s Cancer Group and Children’s Oncology Group Neuroblastoma Study,6 the prognosis of MYCN -A+FH (51 of 5962 cases registered) was reported as 5-year event-free survival (5yEFS) of 65.2±11.6% and an overall survival (OS) of 72.6±11.0%. This was better than MYCN -A+UH cases, where 5yEFS was estimated of 41.4±3.2% and OS of 48.2±3.2%. When discordance cases are further categorized into ”conventional” or ”Bull’s eye” tumors by nucleoli form,6 ”conventional” tumors (5yEFS: 85.7±12.2%, OS: 89.3±10.3%) had significantly better outcomes than ”Bull’s eye” tumors (5yEFS: 31.3±13.6%, OS: 42.9±16.2%), and the prognosis was similar toMYCN -A+FH group. They concluded that among MYCN -A+FH tumors, two prognostic subgroups could be identified based on the nuclear morphology and immunohistochemistry. In particular, ”conventional” tumors with undetectable N-myc expression were associated with an excellent prognosis. The NBs in both our cases wereMYCN -A+FH and ”conventional” tumors; therefore, good prognosis was inferred.
Despite of MYCN- A was observed, N-myc was not detected in both our cases and the nucleoli, where MYCN transcripts are located, were inconspicuous (not visible). Inconspicuous nucleoli in ”conventional” tumors may be due to a lack of mRNA synthesis. The downregulation of N-myc in the ”conventional” tumor promotes cell differentiation, blocks cell proliferation and, therefore, accelerates tumor maturation. Indeed, a differentiated tumor, such as intermixed subtype of ganglioneuroblastoma and maturing subtype of ganglioneuroma, were included in the subgroup of ”conventional” tumors in older children. On the contrary, it is believed that excessive N-myc expression in “Bull’s eye” tumors results in the formation of the MYC-MAX heterodimer that is responsible for the aggressive behavior of this type of NB.6
Elizabeth et al. recently validated that high MKI remains a valuable prognostic factor and that it can be treated as an independent risk factor.14 Moreover, MKI along with other histologic features can replace the INPC score, which is believed to be a cofounding factor to define risk.14 Therefore, because our two cases had low/intermediate MKI, it was expected for them to have a good prognosis.
In conclusion, morphology and immunohistochemical expression of N-myc should be evaluated to identify different prognostic groups, i.e., ”conventional” and ”Bull’s eye” tumor, in genotype-phenotype discordant NB (MYCN -A+FH) cases. These pathological genetic and cellular features should be considered to optimize the treatment approach applied in such cases.
Ethical Statement: The parents of the infants included in this study provided written informed consent for publication.
Conflict of Interest Statement: The authors have no conflict of interest to declare.
Acknowledgments: We thank Takehiko Kamijo, MD, PhD (Saitama Cancer Center, Saitama, Japan) for their technical support in FISH and RT-PCR tests. We also thank Shota Tanaka, MD; Sayaka Suzuki, MD; Shun Yanai, MD; Masaki Matsuoka, MD; Kazumasa Mitsui, MD; Yasuko Kojima, MD; and Tsutomu Saji, MD, PhD (Department of Pediatrics, Toho University, Tokyo, Japan) for their encouragement and insightful discussions.