Abstract
Aim: To assess prognosis of gestational trophoblastic neoplasia (GTN) and obstetric outcome after chemotherapy. Patients and Methods: Sixty-six patients had diagnosis of hydatiform mole on curettage and 18 developed GTN. Two patients were referred with pathological diagnosis of GTN. Chemotherapy was tailored according to International Federation of Gynecology and Obstetrics risk scoring system. Results: All patients with GTN but one, were recovered by chemotherapy and had no evidence of disease after a median follow-up of 80 months. Only the patient with epithelioid trophoblastic tumor died of disease. Seven out of the eight women who tried to conceive after chemotherapy became pregnant. Ten conceptions occurred, resulting in no molar pregnancy, three miscarriages and seven term-live healthy births (70.0%). All seven babies showed normal development and growth after a median follow-up of 38 months. Conclusion: The prognosis of women with GTN is very good, and obstetric outcomes of those who conceive after chemotherapy are similar to those of the general population.
- Gestational trophoblastic neoplasia
- βhCG
- choriocarcinoma
- epithelioid trophoblastic tumor
- methotrexate
- combination chemotherapy
Gestational trophoblastic disease includes hydatidiform mole and gestational trophoblastic neoplasia (GTN), which encompasses invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor (1-4). Hydatidiform mole usually has a benign behavior after dilation and curettage (D&C) (5-8). Post-molar weekly monitoring of the β subunit of human chorionic gonadotropin (βhCG) guarantees an early diagnosis of GTN, and histopathological confirmation of the precise nature of the GTN is not usually available (4, 9, 10). However, GTN may also present clinically as primary or metastatic disease. The currently available chemotherapy regimens have drastically changed the natural history of GTN, from nearly 100% fatality to nearly 100% cure rates (11). Given the very high curability of trophoblastic disease, the risk of further molar pregnancy as well as fertility issues after chemotherapy represent major concerns (8, 12-20).
In this study, we analyzed the prognosis of patients with GTN treated at our Department and the obstetric outcome of those who conceived after chemotherapy.
Patients and Methods
We reviewed the hospital records of 68 women with gestational trophoblastic disease treated at the Department of Gynecology and Obstetrics of the University of Pisa between 1998 and 2015.
Sixty-six women had a diagnosis of hydatiform mole on surgical samples of D&C, and two patients were referred to our Department with a pathological diagnosis of GTN (choriocarcinoma on the uterus removed for presumed leiomyoma in one case, and epithelioid trophoblastic tumor on surgical samples of D&C and cervical biopsy in the other).
Of the 66 women with diagnosis of hydatiform mole, four underwent primary total hysterectomy and the pathological examination showed hydatiform mole in three cases and choriocarcinoma in one. The other 62 patients underwent weekly monitoring of βhCG. The women with persistently stable or rising βhCG levels (persistent gestational trophoblastic disease), as well as those with pathological diagnosis of GTN, underwent pelvic and trans-vaginal ultrasound, chest x-rays, chest- and abdominal computed tomography (CT) scan, and brain CT scan or magnetic resonance imaging (MRI). The patients with GTN were classified according to the International Federation of Gynecology and Obstetrics (FIGO) risk factor scoring system and received tailored chemotherapy (21).
Chemotherapy regimens used were as follows: single-agent methotrexate (MTX) plus folinic acid (FA) (22); combination of etoposide plus MTX plus actinomycin-D (EMA) alternating with cyclophosphamide plus vincristine (CO) (23, 24); combination of EMA alternating with etoposide plus cisplatin (EP) (25); low-dose weekly chemotherapy with etoposide (100 mg/m2) plus cisplatin (20 mg/m2) (days 1 and 2) (26); and alternating two weekly doublet of paclitaxel (135 mg/m2) plus cisplatin (60 mg/m2) and paclitaxel (135 mg/m2) plus etoposide(150 mg/m2) (27).
Response to treatment was assessed by serum βhCG assays with commercially available kits. Chemotherapy was administered until serum βhCG levels decreased below 5 mIU/ml [defined as complete response (CR)]. Two to four additional cycles were given as consolidation treatment. Pelvic and trans-vaginal ultrasound was usually repeated every two or three cycles of chemotherapy, whereas CT scan was performed in patients who developed resistance to chemotherapy (persistently stable or rising βhCG levels), as well as in those who had achieved a CR at the end of treatment.
The present investigation assessed the clinical outcome of the 20 patients with GTN. The woman with epithelioid trophoblastic tumor died within 9 months from diagnosis. The remaining 19 patients were followed-up at our Department until February 2016, with a median follow-up of 80 months (range=3 to 213 months) from the end of treatment.
Results
The median age of the 68 patients was 36 years (range=15 to 52 years). Sixty-three women (92.6%) were Caucasian and five (7.4%) were Asian. Forty-one (60.3%) were nulliparous and 27 (39.7%) were pluriparous.
Of the 62 women with hydatiform mole who underwent weekly monitoring of βhCG, 48 (77.4%) had βhCG normalization and none of them developed recurrent disease. Conversely, 14 women (22.6%) developed persistent gestational trophoblastic disease. Thirteen patients had a FIGO score of 6 or less (low-risk) and one patient had a FIGO score higher than 6 (high-risk). Of the four women with hydatiform mole who underwent primary total hysterectomy, three had low-risk disease and one had high-risk disease. Both patients referred to our Department with a pathological diagnosis of GTN had high-risk disease.
Of the 16 women with low-risk disease, one of those who underwent primary total hysterectomy had serum βhCG less than 5 mIU/ml two weeks after surgery. She had no further treatment and is still alive with no evidence of disease after 107 months. The other 15 patients with low-risk disease received MTX/AF and 10 (66.7%) achieved a CR after a median of 3 cycles (range, 2 to 10) (Table I).All complete responders are still alive with no evidence of disease after a median of 80 months (range, 14 to 190 months) from the end of treatment.
Five low-risk patients became resistant to MTX/FA and received second-line EMA/CO. Four (80.0%) obtained a CR (Table I).The patient resistant to EMA/CO underwent EMA/EP which induced a CR.
As far as the four women with high-risk disease are concerned, one patient (who underwent primary total hysterectomy with a pathological diagnosis of chorio-carcinoma) refused EMA/CO regimen and received MTX/FA, which achieved a CR (Table I). One patient with high-risk persistent gestational trophoblastic disease obtained a CR after EMA/CO.
The patient referred with a diagnosis of choriocarcinoma after total hysterectomy and left salpingo-oophorectomy performed for presumed myoma had a serum βhCG level of 1.180.322 mIU/ml at admission (Table I). Chest and abdominal CT scan showed a right paravesical mass measuring 10 cm, pelvic enlarged lymph nodes and multiple bilateral lung metastases, most of which had largest diameter exceeding 2 cm. Positron-emission tomography (PET)/CT scan revealed pathological 18F-fluorodeoxy-glucose(FDG) uptake in paravesical area, pelvic nodal lesions, and lung nodules. Brain CT scan detected one metastatic lesion in the right parietal-temporal-occipital area. The patient received three cycles of low-dose weekly EP, plus two intrathecal injections of 12.5 mg of MTX and 30 mg of FA rescue 24 h later every 2 weeks, with sharp decrease of serum βhCG to 838 mIU/ml. Afterwards, the brain metastasis was treated with one- single fraction of 24 Gy stereotactic radiotherapy delivered with a TrueBeam™ LINAC (Varian Medical System Palo Alto US) and RapidArc® technique. Then the patient commenced EMA/CO regimen, with intravenous MTX given at the dose of 1 g/m2 over 24 h followed by FA rescue (30 mg orally every 12 h for 3 days starting 24 h after MTX). βhCG levels after the first, second, third, fourth and fifth cycles of EMA/CO were 43, 14, 9, 7, and 6 mUI/ml, respectively. Chest and abdominal CT scan showed a sharp decrease in the size of paravesical lesion as well as in the number and size of lung metastases. PET/CT scan confirmed the good response, associated with a significant decrease in 18FDG uptake of target lesions. The patient underwent laparotomy, with removal of paravesical lesion, right ovaro-salpingectomy, pelvic lymphadenectomy, omentectomy, and multiple peritoneal random biopsies. The histological examination revealed the presence of foci of GTN only in the paravesical lesion. Currently, serum βhCG is persistently less than 5 U/ml, PET/CT scan is negative, and brain CT and MRI show the disappearance of the metastatic lesion, with residual area of radionecrosis surrounded by scar tissue.
The patient with epithelioid trophoblastic tumor had locally advanced disease, with cervical and vaginal involvement, multiple lung metastases at presentation, and a serum βhCG level of 514,967 mUI/ml. The histological diagnosis was supported by diffuse immunohistochemical positivity for E-cadherin, cytokeratin 7, and epidermal growth factor receptor (EGFR) (Figure 1). She was given three cycles of weekly low-dose EP, plus cranial prophylaxis with two intrathecal injections of MTX, with decrease of serum βhCG to 43,000 mUI/ml. Then the patient received EMA/CO followed by EMA/EP, with serological (βhCG=238.000 mUI/ml), clinical and radiological progression of both local and lung disease (Table I). Following chemoembolization of uterine arteries to control extensive vaginal bleeding, the woman underwent alternating paclitaxel plus cisplatin and paclitaxel plus etoposide for two cycles but died of disease 1 month after the last cycle of chemotherapy.
Response to chemotherapy in patients with gestational trophoblastic neoplasia.
Seven (87.5%) out of the eight patients who tried to conceive after chemotherapy became pregnant. A total of 10 conceptions occurred, resulting in no molar pregnancy, three miscarriages and seven term-live births (70.0%), with APGAR score of 9 or more. Five babies were delivered vaginally and two were delivered with cesarean section. There were neither antepartum nor postpartum complications, nor congenital abnormalities, and all seven babies show normal development and growth after a median follow-up of 38 months (range=12-115 months). It is noteworthy that the woman who achieved a CR after third-line chemotherapy with EMA/EP delivered two babies.
Discussion
Hydatiform mole usually has a benign behavior, since only 10-20% of cases will progress to GTN after D&C (5-8). The risk of GTN after βhCG normalization is usually less than 1% (5-7, 28, 29). In our experience, 77.4% of the 62 women with hydatiform mole who underwent βhCG monitoring had antigen normalization after D&C and none of them subsequently developed recurrent disease.
Patients with low-risk GTN are treated with MTX/FA, whereas those with high-risk disease usually receive EMA/CO (11, 22-24, 30-32). Approximately 30% of low-risk patients become resistant to single-agent chemotherapy and need combination chemotherapy most commonly in the form of EMA/CO (30). EMA/CO-resistant patients usually achieve a CR with a salvage chemotherapy with EMA/EP or bleomycin plus EP (25, 32, 33). In the present series, five out of the 15 patients (33.3%) with low-risk disease failed to respond to MTX/FA, but all were recovered by combination chemotherapy. The only patient who became resistant to EMA/CO achieved a CR with EMA/EP.
In the presence of multiple, large lung metastases, primary treatment with EMA/CO can cause an early death due to lung failure and hemorrhage secondary to rapid chemotherapy-induced tumor destruction (23). In the experience of Charing Cross Hospital, the use of low-dose weekly chemotherapy with EP before EMA/CO allowed to achieve a more gradual reduction of bulky lung disease and to decrease early death rates from 7.8% to only 0.7% (26). In our experience, this low-dose regimen was safely and successfully employed before EMA/CO in two patients with very large, multiple lung metastases.
Microscopic features of epithelioid trophoblastic tumor. The neoplasm is composed of a uniform population of mononucleate intermediate trophoblastic cells, with typical round nuclei and eosinophilic cytoplasm, arranged in cords and nests that are strictly associated with fibrillar, hyaline-like material and necrotic debris (a). At immunohistochemistry, the tumor was found to be diffusely positive for E-cadherin (b), cytokeratin-7 (c), and epidermal growth factor receptor (d). Original magnification, ×5.
Epithelioid trophoblastic tumor is an extremely rare form of GTN arising from chorionic-type intermediate trophoblast, with approximately 100 cases reported to data (2, 34-37). In some cases, the tumor trophoblastic cells replace the endocervical surface epithelium, giving the appearance that the neoplasia is derived from the cervix. Immunohistochemically, this tumor is diffusely positive for cytokeratin, E-cadherin, and EGFR. Its clinical behavior is difficult to predict, and although most cases follow a benign course following resection, there is a potential for metastatic disease in approximately 25% of patients (2, 34). Epithelioid trophoblastic tumor is chemoresistant and surgery is the standard of care for localized disease (35, 37), In the series of the New England Trophoblastic Disease Center, all three patients with extra-uterine disease who received chemotherapy had stable or progressive disease at follow-up, whereas two out of the four patients who presented with localized disease and underwent hysterectomy were alive with no evidence of disease (37). Currently, it is thought that epithelioid trophoblastic tumor behaves very similarly to placental site trophoblastic tumor, but in reality few data are available on this issue (32). These two tumor types are so rare that it is unlikely that their treatment will ever be fully optimized, hence the International Society of the Study of Trophoblastic Diseases has launched an international database to pool cases (https://pstt.shef.ac.uk).Our patient with epithelioid trophoblastic tumor had both locally advanced and distant disease at presentation, failed to respond to different sequential chemotherapy regimens, and died within 9 months of diagnosis. This case report confirms the chemoresistance of this tumor type and the poor prognosis of patients with extra-uterine disease.
Literature data show that the overall risk for molar pregnancy after hydatiform mole ranges from 0.7% to 2.6% (8, 11-14) and that chemotherapy regimens used for GTN have minimal impact on the subsequent childbearing potential (8, 13, 15-20). Term-live birth rates higher than 70% without increased risk of congenital abnormalities have been reported in women who conceived after chemotherapy for GTN. Obstetric complications are comparable to those of the general population, except for a slightly increased risk of stillbirth (approximately 1.3% versus 0.8%) (13, 15, 16). In our experience, seven out of the eight patients who tried to conceive after chemotherapy became pregnant, resulting in three miscarriages and seven term-healthy babies, who showed normal development and growth after a median follow-up of 38 months. No patient had a subsequent molar pregnancy.
In conclusion, the prognosis of patients with GTN is very good, with all the cases recovered by chemotherapy except for one harboring advanced epithelioid trophoblastic tumor, and the obstetric outcomes of those who conceive after chemotherapy are similar to those of the general population.
- Received April 14, 2016.
- Revision received May 24, 2016.
- Accepted May 25, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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