Introduction

Gestational trophoblastic diseases (GTDs) are a rare group of diseases originating from placental tissues that occur in women of childbearing age. Many different diseases are included in this group: partial and complete hydatidiform mole, invasive and metastatic mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor. Among GTDs, PSTT is the least common and the most ambiguous, usually manifesting a benign behavior, although it actually is a malignant disease with a possibly fatal outcome and a high chemo-resistance. Presentation of PSTT may occur in the course of gestation or from 1 week to years after a normal or an abnormal pregnancy (mole, ectopic pregnancy, abortion) [1, 2]. PSTT consists of intermediate trophoblast cells, which are a distinct portion of the trophoblasts, predominantly found at the normal placental implantation site and arising from the cytotrophoblasts [3]. Normally, the first symptom is abnormal vaginal bleeding, followed by amenorrhea, but the onset of the disease can also occur with nephrotic syndrome and/or uterine perforation [4••]. Metastasis can occur many years after diagnosis and have been reported in the lung, liver, lymph nodes, and brain [4••]; only 10% of cases are metastatic at the time of the diagnosis [5]. The indicators of aggressive behavior for this tumor are not well established. The most important prognostic factors taken into account are usually the number of mitosis [6, 7], the clinical stage, maternal age over 35 years, human chorionic gonadotropin (hCG) levels, a long (> 24 months) interval between the last pregnancy, and the clinical presentation of the disease [8]. For the diagnosis of this rare tumor, a combination of serum marker concentration and diagnostic imaging is necessary. Usually, hCG serum levels are not as high as in other GTDs given to the lack of syncytiotrophoblast, whereas human placental lactogen (hPL) may be elevated, as it is produced by the intermediate trophoblasts [9]. Ultrasonographic features show a large variability: in most of the cases, a solid mass is reported, with or without cystic areas [10,11,12]. Magnetic resonance imaging (MRI) is often used to confirm ultrasonographic findings and to identify potential extra-uterine invasion, although CT can reveal the presence of distant metastasis. For uterine-confined disease, the safest therapeutic option is hysterectomy and pelvic lymph node sampling, followed by adjuvant chemotherapy. Nevertheless, for women of reproductive age, a conservative approach is often desired, but the risk of disease recurrence must be shared [13]. Due to the rarity of this disease, it is difficult to ascertain the risk of recurrence when a conservative approach is undertaken; therefore, we aimed to review the current literature, in order to identify risk factors and the best conservative management.

Materials and methods

We performed a systematic literature search of articles in English language, published from 1996 to 2017 and indexed in PubMed and Scopus. We searched the following Medical Subject Headings (MeSH): “Placental Site Trophoblastic tumor” and “Fertility Sparing Treatment.”

The initial database screening was performed by three authors (O.T., V.P., and F.C.), who were blinded to the aim of the study. Subsequently, other four authors (B.C, A.S.L., S.G.V., and G. S.) selected relevant information from the screened literature. We considered all original manuscripts (randomized, observational, and retrospective studies), case series, and case reports eligible. Furthermore, we extracted relevant information from the selected reviews.

Results

From our research, we considered nine papers eligible for the review [14,15,16,17,18,19,20,21,22]. Six were case reports [14, 15, 17, 18, 21, 22] and three were retrospective studies [16, 19, 20]. We extracted and organized data into three categories depending on the treatment used. All the data extracted from selected articles are summarized in Table 1.

Table 1 Summary of relevant information from selected studies
Full size table

Laparotomy

Laparotomy was the most commonly performed treatment in the reviewed studies to excise tumor with free myometrial margins and subsequent reconstruction of the uterine wall. Leiserowitz et al. [14] reported the first case of PSTT treated conservatively. The patient was 25 years old at diagnosis and presented irregular menstruation during breastfeeding of her child born 15 days earlier; serum levels of β-hCG and hPL were not particularly elevated (21 IU/L and 0.6 μg/mL, respectively). During surgery, a PSTT of 2 cm in diameter was removed from the anterior uterine wall. The patient had no recurrence in 4 years of follow-up.

Tsuju et al. [15] described a case of PSTT in a 26-year-old patient. She had spotting for 3 weeks and an episode of metrorrhagia after a spontaneous abortion occurred 4 months previously. Serum levels of β-hCG and hPL were 0.95 ng/mL and 0.37 μg/mL, respectively. Ultrasound and MRI showed a 3-cm uterine mass that was treated with two cycles of EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) chemotherapy and resection of the tumor. After 9 months, there was no evidence of disease (NED).

Machtinger et al. [16] reviewed their case series of PSTTs, in order to analyze clinical features. Among the 5 reported cases, only two were treated with a fertility sparing approach. One patient underwent excision of the tumor in a referring hospital; however, histological analysis showed invasion of vascular spaces, positive margins, and necrotic areas. After 6 weeks, computed tomography (CT) scan showed a suspicious uterine lesion; therefore, a total hysterectomy was recommended, although no residual tumor was found on the definitive specimen. After a follow-up of 33 months, the patient was alive with no evidence of recurrence.

Pfeffer et al. [17] published a case report of a 30-year-old woman with vaginal bleeding, following a complete molar pregnancy at 11 weeks gestation, treated with uterine evacuation. Because of the persistent elevated β-hCG serum levels and an ultrasound finding of a vascular solid lesion of the uterus, the patient underwent two chemotherapy lines: first line consisted of intramuscular methotrexate (50 mg on days 1, 3, 5, and 7) alternating with oral folinic acid (15 mg on days 2, 4, 6, and 8) repeated for 2 weeks; afterwards, she underwent combination chemotherapy with etoposide, methotrexate, and dactinomycin, alternating weekly with cyclophosphamide and vincristine. Despite chemotherapy, the uterine lesion of 2.5 cm persisted on positron emission tomography (PET), but considering the desire of the patient to maintain her fertility, a third-line chemotherapy was administered (gemcitabine twice a week and carboplatin AUC5 every 3 weeks). Despite these therapies, the tumor size increased to 3.5 cm; therefore, the patient underwent resection of the right uterine fundus and pelvic lymph node sampling. The surgical specimen revealed a 2-cm PSTT with negative margins and 5–7 mitotic count per 10 high-power field (HPF). During the adjuvant therapy with paclitaxel and etoposide alternating every 2 weeks with paclitaxel and cisplatin, β-hCG increased once again, despite negative MRI and CT/PET. For this reason, total abdominal hysterectomy with right salpingo-oophorectomy was performed, and the histological analysis found a microscopic aggregate of PSTT. After 2.5 years, the patient was alive with NED.

Liszka et al. [18] resected an intrauterine lesion during a cesarean section for a spontaneous twin pregnancy in a 29-year-old woman. Histological analysis found a 4 × 3 × 3-cm PSTT with a low mitotic index and negative margins. No adjuvant therapies were administrated. After 30 months of follow-up, the patients had NED.

Saso et al. [19] described a case series of four PSSTs and one epithelioid trophoblastic tumor treated with a modified Strassman procedure, consisting of a temporary devascularization of the uterus with a full thickness excision of the uterine lesion with 1 cm of free margins. Due to positive or unclear margins, in 4 cases, a total abdominal hysterectomy was performed. The only successful conservative treatment was performed in a 36-year-old nulliparous woman: at the last follow-up 1 year later, the patient had NED and her menstrual cycle was normal.

Shen et al. [20] described retrospectively the first case series of PSTTs successfully treated with conservative approaches. They described six patients with a mean age of 27.5 years. Two of these patients with a nodular lesion were treated with a laparotomy for tumor resection followed by systemic chemotherapy; the second also received intrauterine arterial chemotherapy. The intrauterine arterial chemotherapy regimen was floxuridine-based and was infused 8 h per day in 5 consecutive days of treatment. Both the patients were alive with NED after a mean follow-up of 41.5 months, and a successful spontaneous pregnancy was described in the second patient 22 months after treatment.

Minimally invasive treatments

The second case described by Macthinger et al. [17] occurred with vaginal bleeding and β-hCG levels 175 IU/L, 4 months after vaginal delivery. A 20×20-mm intrauterine mass was effectively treated with a hysteroscopic resection followed by three courses of EMA-CO. The patient was alive without evidence of disease 29 months after surgery.

Four patients described by Shen et al. [20] (three with a polypoid lesion and one with a nodular lesion) were treated with uterine evacuation, one case also with hysteroscopic resection, and another with combined hysteroscopic and laparoscopic resection. All of these patients received intrauterine arterial and systemic chemotherapy. All the patients were alive and free of disease with a mean follow-up of 49.75 months. Two of these patients were not planning a pregnancy yet, the patient that received hysteroscopic treatment failed to achieve pregnancy and underwent infertility management, and the last patient, treated with a combined laparotomic and hysteroscopic approach, opted for contraceptive therapy in consideration of a short interval since the disease (10 months).

Similarly, a recent case reported by Ashton et al. [21] occurred in a 28-year-old patient, with a history of uncomplicated term vaginal delivery, 2.5 years prior to presentation of the disease with irregular vaginal bleeding. Laboratory values revealed a serum hCG of 17 mIU and normal serum hPL. MRI of the pelvis showed a small fundal lesion with no evidence of myometrial invasion. Since the patient refused hysterectomy and lymph node sampling, she underwent a laparoscopic-guided hysteroscopic resection of the tumor. Nevertheless, the pathology of the resected specimen showed extensive myometrial invasion with residual PSTT and, for this reason, the patient ultimately agreed to hysterectomy with pelvic lymph node sampling and adjuvant treatment with paclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE). Three months after the surgery, β-hCG was below 5 mIU/mL and CT scan was negative.

Pharmacologic treatment only

The only case successfully treated with medical treatment exclusively was described by Numnum et al. [22]. They reported a case report of a 29-year-old nulliparous woman with vaginal bleeding and elevated β-hCG (130 IU/L), without radiological signs of disease, in which a diagnostic uterine curettage diagnosed PSTT. The patient was treated with a chemotherapy regimen consisting of etoposide, methotrexate, and actinomycin D on day 1 followed by etoposide and cisplatin on day 8 (EMA-EP). The patient responded well to the treatment and her hCG decreased from 130 IU/L to < 5 IU/L after three cycles of EMA-EP. She received three additional cycles after her hCG was < 5 IU/L. Two years after completion of the therapies, she was free of disease and had a successful singleton pregnancy.

Considerations

Based on our literature search, we identified 18 cases of PSTT treated with a fertility sparing approach [14,15,16,17,18,19,20,21,22]. Eleven patients underwent first-line open surgery that was effective in 6 cases [14, 15, 18,19,20]; in the remaining 5 cases, a total hysterectomy was necessary for suspected relapse or close/positive margins in the post-operative specimen [16, 17, 19].

Minimally invasive techniques are reported mostly for polypoid tumors, treated with operative hysteroscopy [16, 17, 21]. Laparoscopy was utilized in 2 cases in association with hysteroscopy [20, 21]. Only one patient was treated with exclusive chemotherapy [22].

Some authors used post-operative chemotherapy [16, 17, 21]; in other cases, systemic and intrauterine arterial chemotherapy were administrated preoperatively [20]; lastly in some cases, neither adjuvant nor neoadjuvant therapy were given [14,15,16, 18, 19].

Conclusion

Preservation of fertility in PSTT patients of reproductive age is a reasonable therapeutic option. Based on our review of the available literature, conservative treatments were effective in 72% of cases. However, because of the lack of well-defined prognostic factors and of the relative chemo-resistance of this disease, the current evidence does not allow to draw firm conclusions regarding the gold standard management for patients affected by PSTT who desire to preserve fertility [23].

As we recently highlighted [4••], each patient should be considered individually. Multidisciplinary assessment is necessary to evaluate risk factors, such as the mitotic count, ß-hCG level, the interval since the previous pregnancy, the stage of disease, the age of the patient, and desire to maintain fertility in order to propose a tailored treatment. According to a PSTT series from the UK, the most important prognostic factor identified on a multivariate analysis is the interval between the antecedent pregnancy and the clinical presentation of the disease, regardless of disease stage or ß-hCG levels [8]. Local uterine resection via laparotomy with the modified Strassman approach could be offered to patients with clinical stage-one disease who are motivated to retain fertility, informing the patient of risks and benefits related with this choice. Our analysis showed that minimally invasive approaches could be considered a feasible option in cases of polypoid intrauterine tumor.

In any case, revision surgery for a radical treatment is advised in case of positive or unclear margins and multifocal disease. In patients treated with chemotherapy, ovarian function may be affected, especially when multiple agents are administered; therefore, ovarian tissue cryopreservation is advised [24]. Larger cohorts and long-term follow-up are necessary to identify the best fertility sparing therapeutic approach for PSTT patients.