A total of 37 NGC patients were recruited, all of Chinese origin. The median age at disease onset was 22 (range 9-44) years. As of March 2020, the follow-up period of this cohort amounted to 41 (range 1-269) months. Twenty-three patients had no pregnancy history, including 7 premenarchal girls, and 20 patients declared no previous history of sexual activity (Table 1).
All 37 patients underwent surgery and thus had a histopathological confirmation of choriocarcinoma. Thirty patients exhibited pure type NGC with no other germ cell tumor components. A mixture of mononucleated cells and variable levels of multinucleated syncytiotrophoblasts were observed. Tumor cells typically surrounded a central area of necrosis and hemorrhage. Three cases had primarily necrosis with limited tumor cells on the periphery. Immunohistochemistry results for hCG, HSD3B1, CD10, CD146 and HLA-G were usually positive. Seven patients presented with histopathologically confirmed mixed type NGC (1 in pituitary, 5 in ovary, 1 in stomach). Apart from choriocarcinoma, other components included dysgerminoma, embryonal carcinoma, teratoma and adenocarcinoma.
For 37 NGC patients, ovary was the most commonly affected location, with ratio of 11:22:1 for left:right:bilateral. Two patients had NGC in the pituitary, and another presented with NGC in the stomach. Twenty-one (56.8%) patients had metastatic lesions of which lungs were the most commonly observed (40.5%) location. Other locations of metastatic lesions included the brain in two patients, and the liver in two patients. Two patients had extensive lesions in both the abdomen and pelvic cavity. Another two patients only had extensive metastasis in the abdominal cavity, and two only had extensive pelvic cavity metastases.
Symptoms of these NGC patients were relatively nonspecific. Abdominal pain was reported by 24 patients, 6 of whom presented with acute abdominal pain and underwent emergency surgery. Sixteen postpubertal patients presented with abnormal uterine bleeding, such as irregular menstruation and amenorrhea. Two pituitary patients presented with insipidus. Other tumor-related manifestations, such as fever, pregnancy symptoms, palpable mass, headache, cough, hemoptysis, and melena were only rarely observed. No choriocarcinoma or any other type of tumor history in primary relatives were reported by these 37 NGC patients.
Serum β-hCG levels of each patient were regularly measured. The median of each patient’s highest value of serum β-hCG during the whole disease course was 77,278 (range 89.1-386,274) mIU/ml. AFP was tested in 13 patients. Only one mixed germ cell NGC tumor with dysgerminoma and embryonal carcinoma exhibited elevated AFP.
Staging of NGC remains unclear. There are no standard guidelines for gastric and pituitary NGC staging. For 34 ovarian NGC subjects in this study, 14 were in stage I, 2 were in stage II, 2 were in stage III, and 16 were in stage IV, according to the International Federation of Gynecology and Obstetrics (FIGO) 2013 standard of ovarian cancer, with a 5-year survival rate of 92.9%, 100%, 0% and 68.8%, respectively. In view of FIGO’s 2000 classification of choriocarcinoma, 14 were in stage II, 11 in stage III, and 9 in stage IV. The CR rates for these cases were 92.9%, 81.8%, and 44.4%, respectively (Table 1).
Treatments included chemotherapy, surgery, radiotherapy and intrathecal injection. All patients received multiple-drug combined chemotherapy. The primary regimens chosen were EMA/CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, Vincristine for 20 patients), FAEV (Floxuridine, Actinomycin-D, Etoposide, Vincristine for 15 patients), BEP (Bleomycin, Etoposide, Cisplatin for 7 patients), PVB (Bleomycin, Vincristine, Cisplatin for 4 patients), and ICE (Ifosfamide, Carboplatin, Etoposide for 2 patients). Nine patients received chemotherapy prior to surgery. The overall median courses and courses to reach CR were 7.5 and 4.0, respectively. Three to four consolidation chemotherapies were recommended after hCG levels had returned to normal. For 7 mixed NGC patients, 2 primarily received the BEP protocol and another 3 were administered the EMACO protocol, all of whom exhibited CR. BEP, EMACO and FAEV protocols were prescribed for another ovarian mixed NGC patient but were unable to control her disease. The stomach mixed NGC patient obtained CR after FAEV therapy but experienced disease relapse 2 years later.
Twelve patients showed drug resistance to primary chemotherapy. Five patients were resistant to FAEV chemotherapy. EMACO, PEB, and ICE regimens were then prescribed for these different patients. Two patients exhibited resistance to the EMACO regimen but responded to the FAEV regimen. Two patients were prescribed the PEB/PVB regimen prior to being seen in our clinic, at which time they received the EMACO/FAEV regimen due to unsatisfactory decreases in hCG levels. Another 3 patients were resistant to nonstandard multiagent chemotherapies.
Myelosuppression was a commonly observed adverse effect of chemotherapy, but only one patient experienced life-threatening myelosuppression. Other conditions, such as liver injury, dental ulcer, and anorexia, were rarely reported by sporadic patients.
All 37 patients underwent surgery. Of 34 ovarian NGC patients, 16 underwent cytoreductive surgery, and 18 received fertility-preserving surgery. The scale of cytoreductive surgery includes the uterus, bilateral ovary, bilateral fallopian tube, omentum, pelvic and para-aortic lymph nodes, appendix, and any other abdominal/pelvic metastases. Fertility-preserving surgery preserved the uterus, unilateral ovary, and unilateral fallopian tube, including unilateral salpingo-oophorectomy, unilateral salpingo-oophorectomy with partial omentectomy, and unilateral salphingo-oophorectomy with pelvic and para-aortic lymphadenectomy, omentectomy, and appendectomy. Among 16 patients who received cytoreductive surgery, 6 initially underwent fertility-preserving procedures. However, a debulking surgery was performed at our medical center because of unsatisfactory decreases in β-hCG or due to disease relapse. Even though 15 patients had lung metastases, only three of them received pulmonary lobectomy. The gastric NGC patient received subtotal gastrectomy with lymphadenectomy.
As an adjunct to chemotherapy, one pituitary NGC patient completed 25 radiotherapy treatments (total 45 Gray). Another patient with cerebral metastasis received 3 methotrexate intrathecal injections (Table 2).