DISCUSSION
In 1998, Satge et al. reported that GCTs make up nearly a third
of intracranial tumors in patients with DS, whereas they account for
<4% in the general pediatric population.3Though a mechanism for this interaction is unestablished, DS is known to
predispose to the development of gonadal GCTs through various
mechanisms.3 Few patients with DS and CNS GCTs have
since been reported.4 This study includes the largest
reported cohort of patients with DS and CNS GCTs and provides insight
into the characteristics, management and outcomes of this population.
Genetic and environmental differences influence the occurrence of CNS
GCTs, as evidenced by differences in incidence by geographical location.
Germ cell tumors account for <5% of all childhood CNS tumors
in the United States, Germany and Canada.33-35 In
contrast, GCTs account for 2.1-9.4% in Japan and the Far
East.36,37 Race and ethnicity also play a role, as an
analysis of the SEER database by Poynter et al. showed higher
incidence rates of CNS GCTs in patients of Asian/Pacific Islander
descent irrespective of gender, tumor location and
histology.38 Consistent with these findings, the
majority of studies we identified in the literature (22/26) originated
from Japan or China. Consistent with prior studies, CNS GCTs were also
seen most frequently in male patients.34 Male sex has
been strongly associated with pineal involvement, whereas suprasellar
involvement has been associated with female sex.39,40In our study, pineal localization showed a slight male predominance
(5/9; 55.6%), whereas sellar/suprasellar involvement showed a female
predominance (5/8; 62.5%). Overall, CNS GCTs in the general population
most commonly occur in the pineal or suprasellar
region.1,36,37 Interestingly, the most common site of
tumor involvement in our patients was the basal ganglia (13/41; 31.7%).
Germ cell tumors arising in the basal ganglia or thalamus are relatively
rare, representing only 5-10% of all primary intracranial
GCTs.41
Comparable to prior studies, patients in our cohort displayed symptoms
for an average of 6.9 months prior to diagnosis.42 In
a retrospective review of 30 patients with CNS GCTs, Crawford et
al . reported a mean symptom duration of 8.4 months; symptoms including
movement disorders, enuresis, anorexia, and psychiatric complaints led
to delayed diagnosis (>6 months) in nine patients, whereas
headache, nausea, vomiting and visual changes led to earlier
diagnosis.42 Similarly, patients in our cohort with
symptoms >6 months had movement disorders (n=3) or
polyuria/polydipsia (n=3) on presentation.
The Brain Tumor Registry of Japan reported a 5-year OS of 97% for
patients with pure germinomas (n=200) from 2001 to 2004; within their
database, germinomas made up 64% of all CNS GCTs.37In our study, germinomas accounted for 39% of all tumors and had a poor
3-year OS of 62%. Localized germinomas have historically been managed
with WBRT/WVI followed by primary tumor boost, with CSI being reserved
for disseminated germinomas.43 More recently,
chemotherapy has been incorporated to reduce the late adverse-effects
caused by RT.44,45 In an analysis of the
SIOP-CNS-GCT-II trial, Calaminus et al. showed that following CR
to induction chemotherapy, patients with localized germinomas (n=58) who
received 24 Gy WVI without a tumor boost had a 4-year event-free
survival of 98%.45 Furthermore, Bartels et al.demonstrated that 18 Gy WVI with 12 Gy tumor boost was associated with
an excellent 3-year progression-free survival rate of
94.5.44 In our cohort, most germinoma patients
received RT or combined chemotherapy/RT.
In contrast to germinomas, NGGCTs are less common and associated with
worse outcomes.46 In an analysis of the European
SIOP-CNS-GCT-96 trial by Calaminus et al. , 5-year OS for patients
with localized NGGCTs (n =116) was 82%.46 More
recent trials have shown better outcomes – In a phase II trial for
patients with newly-diagnosed NGGCTs, Goldman et al. demonstrated
a 5-year OS of 93% when neoadjuvant chemotherapy was followed by 36 Gy
CSI with 54 Gy tumor-bed boost. In comparison, Fangusaro et al.showed that reduced RT (30.6 Gy WVI and 54 Gy tumor-bed boost) resulted
in a similar OS of 92.4% at 3 years, though it is important to note
that all patients who had treatment failure were in the
spine.47 In our cohort, 3-year OS for NGGCTs was 79%.
The mainstay of treatment for teratomas is maximal surgical resection,
while adjuvant chemotherapy and RT is recommended for some patients
depending on each case and residual disease.43 Huanget al. reported a 5-year OS of 40% in 13 immature teratoma
patients treated with maximal possible resection, and no difference in
outcomes were found between patients who received chemotherapy and/or RT
versus those who did not.48 Three-year OS for
teratomas (five immature, one mature, two unspecified) in the present
study was comparable at 53%; notably, all three patients who underwent
biopsy-only died from tumor progression within one year, whereas all
four patients who underwent GTR were alive at follow-up.
The SIOP-96 trial reported grade 3-4 toxicities in 27/83 patients (33%)
receiving combined chemotherapy/RT and 26/154 patients (17%) receiving
RT only; there were no treatment-related deaths.49 In
contrast, while 16/41 patients (39%) in the present study experienced
grade 3-4 toxicities, 50% died from their toxicity (n=8). Moreover,
five of the 16 germinoma patients (31%) died from treatment-related
toxicity, which resulted in a poor 3-year OS of 62%. Trisomy-21 is
associated with functional deficiencies in B-cell, T-cell and phagocytic
cell systems, resulting in an increased risk of developing and
succumbing to various infectious diseases.5,7 In an
analysis of the AML-BGM-93 trial for AML, Lehrnbecher et al.found that patients with DS had significantly higher rates of
infection-associated fatal complications (5/28; 17.9%) than children
without DS (15/276; 5.4%).5 Notably,
infection-related mortality significantly decreased in the subsequent
AML-BFM 2004 trial (3/61; 4.9%), in which a reduced-intensity
chemotherapy regimen was utilized.7
Craniofacial abnormalities, increased secretions and hypotonia
associated with DS contribute to higher rates of upper-airway
obstruction, particularly after the induction of
anesthesia.50 After tonsillectomy or adenoidectomy
surgeries, Goldstein et al. found that children with DS more
frequently required airway management or observation in the pediatric
intensive care unit compared to controls (25% versus0%).50 Finally, patients with DS are at a particular
risk of developing Moyamoya due to cranial RT, potentially because
several proteins encoded on chromosome 21 including superoxide dismutase
1, interferon gamma receptor and cystathionine beta-synthase affect
arterial physiology as well as DNA repair.6
Our study has multiple limitations; despite being the largest cohort of
patients with DS and CNS GCTs, the small number of patients limits our
conclusions regarding treatment approach. Moreover, our reliance on
multiple institutions limits the consistency of pathology or radiology
reports, as well as tumor marker levels. The inconsistency of data
reporting by previously published studies also limits the thoroughness
of our retrospective cohort.