Gestational trophoblastic neoplasia: experience at Salah Azaiez Institute

Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization. It includes benign trophoblastic disease (hydatidiform moles (HM)) and the malignant trophoblastic diseases or gestational trophoblastic neoplasia (GTN). The frequency of the GTD in Tunisia is one per 918 deliveries. The aim of this study is to analyze the clinical characteristics, treatment and outcomes of GTD at Salah Azaiez Institute (ISA). Medical records of women diagnosed with GTD at ISA from January 1st, 1981 to December 31st, 2012 were retrospectively reviewed. FIGO score was determined retrospectively for patients treated before 2002. One hundred and nine patients with GTN were included. Patients presented with metastases at 43% of cases. The most common metastatic sites were lung (30%) and vagina (13%). Fifty six (56 (51%) patients had low-risk and 21 (19%) cases had high-risk, the FIGO score was not assessed in 32 cases. After a median follow-up of 46 months, 21 patients were lost to follow-up, 12 patients died, 19 progressed and 8 relapsed. At 10 years, the OS rate was 85% and the PFS rate 79%. OS was significantly influenced by the presence of metastases at presentation (M0 100 % vs. Metastatic 62 %; p < 0.0001), FIGO stage (I-II 100% VS 61% and 65% for stage III and IV; p < 0.001), FIGO score (low-risk 99 % vs. high-risk 78 %; p < 0.001). GTN is a significant source of maternal morbidity with increased risk of mortality from complications if not detected early and treated promptly.


Introduction
Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization. It includes benign trophoblastic disease (hydatidiform moles (HM)) and the malignant trophoblastic diseases or gestational trophoblastic neoplasia (GTN). The frequency of the GTD in Tunisia is one per 918 deliveries [1]. The aim of this study was to analyze the clinical characteristics, treatment and outcomes of GTD at Salah Azaiez Institute (ISA).

Methods
Medical records of women diagnosed with GTD at ISA from January 1 st , 1981 to December 31 st , 2012 were retrospectively reviewed.
Patients with incomplete records were excluded from the study.
Disease diagnosis, treatment, follow-up data, overall survival (OS) and progression free survival (PFS) were analyzed. FIGO score was determined retrospectively for patients treated before 2002. The data processing and analysis were carried out using the SPSS software version 20. Survival probabilities were estimated using Kaplan-Meier method. 126 patients were reported and included during 31 years . Of these cases, 17 (13%) were diagnosed hydatidiform mole and were excluded from this study. One hundred and nine (109) patients presented with GTN and were included.

Results
During the study period, 109 patients presented with GTN and were included. Their ages ranged between 18 and 53 years with an average of 34 years. Consanguinity was found in 33 cases (45% first degree).
The median delay to diagnosis was 3 months (0-36). Sixty eight patients presented with amenorrhea followed by bleeding per vaginally or abortion followed by irregular bleeding per vaginally. GTN occurred after full-term pregnancy in two cases (after one and 14 months). Initial presenting features and reproductive history are summarized in Table 1  . Other potential risk factors have also been reported for example; blood group A, past history of hydatidiform mole and maternal age [4]. GTN is a highly vascular disease and taking a biopsy of lesions are extremely risky. Histological confirmation is not essential before commencing chemotherapy.
However, it may be useful to confirm diagnosis and obtain genetic analysis. Genotyping will be helpful to determine the causative pregnancy in patients with multiple pregnancies and to distinguish GTN from non gestational tumor [5]. The ßhCG measurement is essential for diagnosis and management of GTD. Some assays can lead to false negative or false positive results because hCG can exist in different forms in patients with GTN. It's essential that the hCG assay can measure all forms of hCG [3]. Since 2002, the management of GTN is guided by the FIGO prognostic scoring. Patients with high risk disease had 0% chance to be cured with a single-agent chemotherapy. One recent study re-evaluated all prognostic risk factors involved in the FIGO scoring system in 813 patients with GTN and proposed a simplified alternative using only five factors [6]. GTN most frequently spreads to the lung. In our study, vaginal metastases were present in 13%. In reported series vaginal metastases are present in 4-30% in GTN [7,8] [9].
Retrospective reviews of patients with low-risk GTN treated with single-agent chemotherapy showed significantly higher primary remission rate with Dactinomycin than with Methotrexate regimen [10,11]. Due to decreased cost and the good tolerance of Methotrexate, especially for not inducing hair loss, Methotrexate was preferred as first line treatment. However a recent study suggest that women with hCG >400,000 UI/l are unlikely to be cured by singleagent chemotherapy and should be treated by multi-agent chemotherapy as first line treatment [12]. Among the patients with high-risk GTN, our data supports the effectiveness of the combination chemotherapy. The preferred regimen in our study was the actinomycin, cisplatin and etoposide French regimen. The complete response rate with this regimen was 94.7% and the five-year OS 97%.
This regimen is highly active as first-line and as treatment for persistent/recurrent GTN [13]. Several regimens were developed.
EMACO is used worldwide and is the optimal primary treatment because of short term toxicity and effectiveness [14]. A Korean study demonstrated a higher remission rate (90.6%) with EMACO when compared with others regimens [15]. Patients with advanced disease may benefit from initial low dose chemotherapy to reduce early deaths [16]. Our study confirms the lower outcomes in patients with advanced-stage disease, metastatic disease and high-risk prognostic score [11,17]. The overall worldwide survival rate of low-risk GTN group is 100%, and 80-90% for high-risk GTN group [11]. The overall survival rate for patients with GTN treated at our institute was 85%.
The reproductive success rates and gestational complications have become a concern for women treated for GTD. EMACO regimen may induce menopause three years earlier but fertility is not affected and 83% of women became pregnant after Methotrexate or EMACO [3].
The number of studies in the literature regarding this theme is small.
The studies highlight that there is no change in fertility [18]. Under close monitoring, patients may conceive six months after achieving complete response [19]. One study demonstrated a slight increase in stillbirth after GTN treatment [20]. In our study, conception occurred resulting in no molar pregnancy, miscarriage and full-term pregnancy.

What this study adds
• Report a Tunisian experience with gestational trophoblastic neoplasia; • The results of this study can help to encourage a specialized multi-disciplinary environment for the management of