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.