Histologic classification and tumor markers According to the World Health Organization (WHO) classification, germ cell tumors are classified into the following seven categories: asexual cell tumors, yolk sac tumors, embryonal carcinomas, pleomorphic tumors, choriocarcinomas, teratomas, and gonadoblastomas, but because many types are rare in children, GCTs in children are now commonly classified internationally into mature teratomas, immature teratomas, and malignant germ cell tumors Three categories are used. Mature teratomas are the most common tissue subtype, and well-differentiated tissue from the three germ layers, endoderm, mesoderm and ectoderm, can be seen within the tumor, which is benign. Immature teratoma is also derived from three germ layers, but immature tissue and primitive neuroepithelium can be seen, and is classified as grade 0-3 according to the degree of tissue differentiation. Immature teratomas tend to occur outside the gonads of young children and close to the ovaries of adolescent girls, but the histological grading is not related to the age of the child [5,6]. In clinical management, immature teratomas are usually classified as malignant germ cell tumors. The majority of malignant germ cell tumors are of germ cell origin, although the presence of malignant tissue of somatic cell origin has been reported in rare cases. The vast majority of neonatal GCTs are teratomas (mature and immature teratomas) occurring at midline sites such as the sacrococcygeal, retroperitoneal, mediastinal and cervical regions, and Isaacs reported that the sequence of GCTs in the neonatal period was teratoma, yolk sac tumor, choriocarcinoma and germoblastoma, with approximately 5.8% of children containing a yolk sac tumor component [3]. Malignant germ cell tumors can occur alone or in combination with immature teratomas [7], but there are no reports of combined choriocarcinoma or embryonal carcinoma in teratomas of the fetal and neonatal periods [3]. Yolk sac tumors can secrete alpha-fetoprotein (AFP), and asexual cell tumors, seminoma and especially choriocarcinoma can produce beta-human chorionic gonadotropin (ß-HCG), for which GCTs containing the above components are GCTs containing these components are specific tumor markers and can be used for continuous follow-up after tumor treatment. Stage IV: metastases in lung, liver, brain, bone, and distant lymph nodes A large number of experiments have confirmed that the main prognostic factors affecting extracranial GCTs in children include histological type, age, primary site, stage, and chemotherapy regimen [9,10], and in order to maximize the survival of children with GCTs while minimizing treatment-related sequelae, the POG (Pediatic Oncology Group (POG) and CCG (Children Cancer Group) have developed a more detailed risk grading scheme that takes into account the primary site and Brodeur’s stage. germ cell tumors; mature and immature teratomas at any site; intermediate risk group, stage II-IV gonadal and stage II extragonadal germ cell tumors; high risk group, stage III-IV extragonadal germ cell tumors. Treatment Surgery and chemotherapy are currently the main treatment options for extracranial germ cell tumors. Complete tumor resection and an appropriate chemotherapy regimen are the most important factors affecting the outcome and prognosis of malignant germ cell tumors in children. The survival rate of postoperative microscopic residual cases is only about half of that of residual-free cases, and the 5-year survival rate of GCTs has improved to more than 90% after the application of platinum-based drugs [11-14]. In contrast, the recurrence and progression rates of malignant germ cell tumors treated with regimens such as VAC before platinum-based drugs were 47% and 89%, respectively [16]. Therefore, the PEB regimen is still the “gold standard” regimen widely used internationally, but the JEB regimen with carboplatin instead of cisplatin has the same effect because of the ototoxicity and nephrotoxicity of cisplatin [13,15]. (i) Mature and immature teratomas The treatment of mature and immature teratomas is surgical resection alone, with as wide a margin as possible and close postoperative follow-up. The 3-year recurrence-free survival rates for completely resected immature teratomas outside the ovaries, testes and gonads are 97.8%, 100% and 80%, respectively [19]. Some sacrococcygeal teratomas are dumbbell-shaped and can grow into the pelvis causing bladder and rectal compression, which should be alerted preoperatively and require perfect preoperative imaging and adequate preoperative preparation. Mature teratomas and epidermoid cysts of the testis can be removed simply by removing the mass and preserving the testis. Some immature teratomas contain an epidermoid cyst component, and preoperative AFP can be abnormally elevated. Postoperative testing should be performed on a regular and continuous basis to be able to detect tumor recurrence or progression as soon as possible. It has been reported in the literature that the postoperative recurrence rate of teratomas is about 10-21%, mostly occurring within 3 years after surgery [17,18]. Therefore including local examinations and serum AFP tests should be followed up for at least 3 years. About half of the recurrent cases are malignant and adjuvant chemotherapy should be administered in this group of cases. (ii) Malignant germ cell tumors 1 Testicular malignant germ cell tumors occur mostly before the age of 4. Trans-scrotal biopsy may increase the chance of inguinal lymph node metastasis, and radical orchiectomy + high spermatic cord resection via inguinal incision is the best choice for testicular malignant germ cell tumor procedure. Retroperitoneal lymph node dissection does not improve outcome in young children, whereas CT, MRI and elevated tumor markers are sufficient for clinical staging [20,21]. studies by CCG and POG have shown that 6-year event-free survival was 82% in stage I testicular GCTs under close observation after surgery, and 6-year survival after 4 cycles of standard-dose PEB regimen chemotherapy in stage II and recurrent stage I cases was 100% [11,20,21], and children under 15 years of age with stages III and IV treated surgically followed by 4 cycles of standard-dose or high-dose PEB regimen chemotherapy had a 6-year survival rate of 100% and an event-free survival rate of 100% and 94%, respectively [12]. The European collaborative group obtained essentially consistent results using the JEB regimen of chemotherapy [13]. The recommended treatment regimen for malignant germ cell tumors of the testis is: Stage I: radical surgery (transinguinal orchiectomy + high spermatic cord resection without retroperitoneal lymph node dissection) with regular postoperative local review and continuous monitoring of tumor marker AFP changes. Stage II-IV: radical surgery with 4-6 cycles of standard-dose PEB regimen chemotherapy (or 6 cycles of JEB regimen) postoperatively. Due to the high survival rate of testicular GCTs, several clinical studies of reduced-dose chemotherapy are currently underway in order to reduce the ototoxicity and nephrotoxicity caused by platinum-based chemotherapeutic agents. 2 Ovarian GCTs are rare in newborns, with a gradual increase in incidence after 8 or 9 years of age, peaking at 19 years of age. Multiple large case statistics of surgery plus PEB (JEB) chemotherapy regimens have achieved long-term survival rates of more than 90% [11,12,22]. The recommended treatment regimen for ovarian GCTs is: Stage I-IV: surgical removal of the affected ovary with preservation of the uterus and contralateral ovary, 4-6 cycles of standard-dose PEB regimen chemotherapy (or 6 cycles of JEB regimen) postoperatively, neoadjuvant chemotherapy after biopsy for unresectable tumors, and deferred surgery after evaluation to preserve as many organs and functions as possible while complete removal of the tumor. Laparoscopic surgery has not been systematically evaluated and is not recommended for use in children at this time. 3 Neonatal GCTs occur primarily extragonadal, with sacrococcygeal tumors accounting for the majority of cases. For extragonadal GCTs, age is an important prognostic factor, with the younger the age the better the prognosis, and the risk of death in children older than 12 years is six times higher than in children younger than 12 years [9]. For extra-gonadal GCTs, preoperative chemotherapy is more important than gonadal tumors. Extra-gonadal malignant GCTs mostly show progressive nature and 1/3 present with metastases, so preoperative neoadjuvant chemotherapy can significantly improve surgical resection rates and survival and reduce serious complications or disability due to surgery.POG and CCG statistics show overall survival rates of 80-90% and event-free survival rates of 75-85% for extra-gonadal GCTs [23]. Recommended treatment regimen for extragonadal GCTs: Stage I-II: surgery + 4-6 cycles of postoperative standard-dose PEB regimen chemotherapy (or 6 cycles of JEB regimen). Stage III-IV: biopsy + preoperative chemotherapy + surgery + 4-6 cycles of postoperative standard-dose PEB regimen chemotherapy (or 6 cycles of JEB regimen). Surgery for sacrococcygeal GCTs at any stage must remove the coccyx. 4 Chemotherapy regimen: PEB: cisplatin 20mg/m2/d, d1-5; etoposide 100mg/m2/d, d1-5; bleomycin 15mg/m2/d, d1; one cycle every 21 days. JEB: carboplatin 600 mg/m2/d, d2; etoposide 100 mg/m2/d, d1-5; bleomycin 15 mg/m2/d, d3; one cycle every 21-28 days. A histologic diagnosis must be obtained for unresectable tumors prior to the administration of preoperative neoadjuvant chemotherapy; otherwise, many cases are undiagnosed due to tumor necrosis in specimens after deferred surgery. (iii) For the treatment of recurrent GCTs, secondary surgery and salvage chemotherapy with PEB regimen can be implemented; preoperative chemotherapy can help complete tumor resection; if salvage surgery still does not allow complete tumor resection, radiation therapy can be considered, and high-dose chemotherapy with reference to paclitaxel and gemcitabine regimen and autologous stem cell support for adult GCTs can also be considered, but only small samples have been reported so far [24].