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.