Discussion
GCTs represent a heterogenous group of tumors originating from primitive
germ cells distributed in sexual gland and the midline sites. Malignant
germ cell tumors (MGCT) are rare and constitute approximately 2% of all
malignant tumors in children[4]. The
insight into etiology and pathogenesis of pediatric GCTs is still
limited. Sacrococcygeal GCTs may be caused by apoptosis-related pathways
and associated with polymorphisms in
BAK1[5]. Pediatric extracranial GCTs
are divided into three subtypes: teratomas, malignant GCTs and mixed
GCT. Furthermore, malignant GCTs include seminomatous and
nonseminomatous GCT. Teratoma is one of the most frequent benign tumors
occurring in sacrococcygeal region in young children followed by yolk
sac tumor (YST), namely endodermal sinus tumor
[6]. According to limited data in our
study, children developing SYST were very young (median age 1.7 years)
and girls were more likely to develop SYSTs than boys similar with
sacrococcygeal teratomas[7].
More literatures were reported regarding
sacrococcygeal teratomas than
YSTs. The SYSTs presented a mass either protruding outward from the
buttocks from the tip of the sacrum, or impalpable mass within the
pelvic cavity compressing the bladder or rectum consistent with
teratoma[8]. Unlike teratoma, YSTs
secret AFP and serum half-life of AFP is 5 to 7 days. Elevated serum AFP
levels above age-related normal range can be viewed as a dynamic tumor
marker to assist diagnosis and monitor response to treatment.
Interestingly we observed AFP would show a transient elevation in one
week after initial chemotherapy, however, AFP would decline to lower
extent near to next cycle in most patients. Metastasis occurred in
46.2% patients at diagnosis demonstrating that SYSTs were highly
aggressive tumor[9] . Liver, lung and
bones were more frequent metastatic sites. The other rare distant
metastatic site including brain was also seen in one patient.
A multimodal approach in management of sacrococcygeal tumors was
recommended because of larger tumor size and advanced stage at
presentation as literature reported that malignant sacrococcygeal tumors
were usually very advanced at diagnosis and metastases were present in
50% of patients[9]. SYSTs are highly
sensitive to chemotherapy. Cisplatin-based chemotherapy has
significantly improved outcomes for most children with extracranial
GCTs. Platinum-containing chemotherapy with cisplatin, etoposide, and
bleomycin (PEB) is recommended as first-line chemotherapy. After a
median of four cycles of preoperative chemotherapy followed by delayed
tumor resection, the modality may
facilitate complete surgical resection in the setting of avoiding
rupture. However, more cycles of chemotherapy administered didn’t seem
to benefit surgical resection for surgeons because of high chemotherapy
sensitivity resulting in no definite tumor margin left. Chemotherapy
after incomplete resection has the benefit for survival, however,
complete resection of the coccyx is still the basic
principle[2,10].
Although the overall survival of SYST tumor was optimal, the RFS
remained still low. Literature reported the 5-year survival rate was
56.9% for sacrococcygeal tumors in the past
[11]. In our analysis the 5-year RFS
rate was 55.2%. The pediatric investigation on a small number of
patients identified sacrococcygeal tumors as high
risk[12]. Furthermore, the inferior
outcome has been attributed to delayed diagnosis and incomplete
resection at the time of original
surgery[13].
We conducted a retrospective cohort study investigating the prognostic
factors related with relapse. Boys were at higher risk of early relapse
in univariate analysis. An International Collaborative study also showed
boys (aged 11 years and older) with International Germ Cell Consensus
Classification (IGCCC) intermediate-risk or poor-risk features had
inferior outcomes[14]. Metastasis
didn’t play a significant role in the outcome of children with advanced
stage. This may be explained that high chemo-sensitivity of YST could
achieve durable complete remission of metastasis. Literature reported
risk factors associated with recurrence included gross or microscopic
incomplete resection, unresected coccyx, tumor rupture or spillage
before or during surgery[15].
However, some risk factors were still under
controversy[16]. Although
initial tumor size, AFP level and
pathological response did not show statistical differences in univariate
analysis, we could not preclude that these were acknowledged factors
associated with prognosis clinically. We selected the three clinical
significance variables combined with sex to classify the patients into
two groups as following: Group Ⅰ with 0-2 adverse factors and Group Ⅱ
with 3-4 adverse factors. The RFS difference between the two groups was
significant in analysis. We speculated that higher AFP level represented
higher tumor burden, greater initial tumor size resulted in increasing
difficulty in complete resection and poor pathological response may lead
to microscopic residuals. Boys tended to present larger tumor size at
diagnosis and have poor pathological response to neoadjuvant
chemotherapy. This hypothesis requires more evidence to support.
Salvage therapy could still benefit patients when patients relapsed.
Patients were still sensitive to second-line chemotherapy of other
platinum-based or paclitaxel-containing protocols. Salvage chemotherapy
was able to facilitate completeness of relapse tumor resection. We also
explored low-dose oral CTX and NVB or etoposide containing chemotherapy
as maintenance therapy in recurrent relapsed patients without overt
disease in terms of slight elevation of AFP. One patient didn’t follow
the doctor’s instructions strictly and prolonged maintenance therapy for
two years. The patient developed osteosarcoma and is receiving the
chemotherapy for second neoplasm.
Some limitations of our study lied in its retrospective character and
small sample size. The experience of surgeons had impact on the decision
making. Multicenter prospective studies are needed to determine
prognostic factors in large sample groups.
In conclusion, the present study demonstrated SYSTs occurred more
frequently in young children and RFS of
pediatric SYSTs remained still low
awaiting multidisciplinary effort. Salvage therapy can benefit the
survival. Male had inferior RFS. Greater initial tumor size, poor
pathological response to neoadjuvant chemotherapy and higher AFP level
in combination of male gender had negative impact on RFS.