key: cord-0827995-uk1cddkm
authors: Ngu, Siew-Fei; Ngan, Hextan Y.S.
title: Surgery including fertility sparing treatment of GTD
date: 2020-10-10
journal: Best Pract Res Clin Obstet Gynaecol
DOI: 10.1016/j.bpobgyn.2020.10.005
sha: 8e4c9cda4e42543d59018e7f7123800ee7c5b781
doc_id: 827995
cord_uid: uk1cddkm

Gestational trophoblastic disease (GTD) consist of a spectrum of diseases, including hydatidiform moles, invasive mole, metastatic mole, choriocarcinoma, placental site trophoblastic tumour (PSTT) and epithelioid trophoblastic tumour (ETT). GTD are relatively uncommon disease occurring in women of reproductive age, with high cure rates. Primary treatment of hydatidiform moles includes uterine evacuation, followed by close monitoring of serial hCG levels to detect for post-molar gestational trophoblastic neoplasia (GTN). In patients with GTN, the main therapy consists of chemotherapy, although some surgical procedures are important in selected patients in order to achieve cure. Hysterectomy is the mainstay treatment for PSTT or ETT, and may be considered in selected patients for management of hydatidiform mole and malignant GTN especially in chemoresistant disease. Resection of metastatic lesions such as in the lung or brain can be considered in selected patients with isolated chemoresistant tumour. Surgical treatment of GTD will be discussed in this chapter.

hysterotomy for evacuation has been confined to case reports of coexistent mole and a live twin fetus, due to obstetric indications such as placenta previa, or prematurity and breech presentation, or HELLP Syndrome [18] [19] [20] .

Hysterectomy with salpingectomy may be considered as initial treatment for molar pregnancies in women who are older and do not wish to retain fertility [21] . It can be performed via laparotomy, laparoscopic or vaginal approach, depending on uterine size and the surgeon's expertise with the techniques. In addition to removing the molar pregnancy, hysterectomy allows permanent contraception and eliminates the possibility of local myometrial invasion as a source of persistent disease, hence reduces the need for subsequent chemotherapy. Previous two studies in USA of women aged 40 to 49 years [22] , and ≥50 years [23] with complete mole found that none of the women receiving primary hysterectomy develop GTN. In contrast, for those women who had dilatation and curettage, GTN developed in 53% and 60% of women aged 40 to 49 years, and ≥50 years respectively [22, 23] . Similarly, Zhao et al found that the incidence of post-molar GTN in women aged >40 years was significantly lower in patients who had hysterectomy compared to patients who had dilatation and curettage (11% vs 37%, P=0.004) for complete mole [24] . In contrast, Giorgione et al reported that in women with hydatidiform mole aged >40 years, primary hysterectomy does not reduce the incidence of port-molar GTN when compared with dilatation and curettage (58% vs 30% respectively, P=0.094) [25] . Moreover, they also found that hysterectomy does not reduce the amount of chemotherapy required to treat GTN, although 42% (5 out of 12) of their patients who had primary hysterectomy achieved complete remission after surgery. Nonetheless, after hysterectomy for hydatidiform mole, serial monitoring of hCG is important for all patients because hysterectomy does not eliminate the possibility of post-molar GTN completely.

Ovaries can be conserved, even if theca lutein cysts are present because these cysts usually regress over few months after uterine evacuation as hCG levels decrease [26] . However, in the presence of large and symptomatic ovarian theca lutein cysts, aspiration can be considered to reduce J o u r n a l P r e -p r o o f the volume and relief symptoms. Theca lutein cyst may cause cyst complications such as torsion or rupture, which can usually be managed laparoscopically. In majority of premenopausal women undergoing hysterectomy for GTD, ovaries can be conserved because GTN rarely metastasized to the ovaries, and these tumours are usually not influence by hormone [27] .

Following evacuation of molar pregnancy, monitoring of hCG levels postoperatively is mandatory to promptly identify and manage post-molar GTN regardless of whether fertility sparing surgery (e.g. suction curettage) or radical surgery (e.g. hysterectomy) is done. FIGO recommends hCG monitoring every 1-2 weeks until hCG normalised, and then monthly [1]. For partial mole, one additional confirmatory normal hCG measurement 1 months after first hCG normalisation is recommended. For complete mole, monthly hCG measurements are required for 6 months after hCG normalisation.

Routine second suction curettage is not indicated for management of molar pregnancies. In a recent cohort study including 173 patients with molar pregnancy, routine second curettage performed around 7 days after first evacuation in patients with sonographic evidence of residual uterine tissue, resulted in similar incidence of GTN compared to patients who did not have repeat curettage. However, the GTN risk score was found to be significantly lower in the group who had second curettage [28] .

Women who develop post-molar GTN commonly present with vaginal bleeding and finding of uterine enlargement. Second uterine evacuation has been utilised to remove residual trophoblastic tissue in the hope to allow spontaneous regression and avoid chemotherapy. Several retrospective series suggest that routine second uterine evacuation is unlikely to benefit the majority of patients with post-molar GTN [29] [30] [31] [32] . One study found that second curettage performed for suspected post-molar GTN had either no impact or only result in transient drop followed by a rise in hCG levels in majority of patients, with only 20% of patients had sustained drop in hCG levels and spontaneous remission [31] .

Similarly, other studies have reported that a second curettage led to change in management in only about 10% of patients, by either inducing remission or providing malignant GTN histology [29, 30] .

Furthermore, the reported incidence of uterine perforation during second curettage was up to 8% [31, 33 ].

An observational study performed over a period of 10 years in the United Kingdom (UK) including 544 women who had second uterine curettage for persistent GTD, found that 68% had no more evidence of disease or require chemotherapy after repeat evacuation [34] . However, chemotherapy was needed more frequently for women with a histologic confirmation of persistent GTD and for urinary hCG levels of more than 1500 IU/L at time of repeat curettage. Another retrospective cohort study conducted in the Netherlands involving 2122 patients observed that only 9.4% of patients who underwent second curettage for low-risk GTN avoided chemotherapy compared to 0% in patients who did not have a repeat curettage [35] . Although the proportion of patients who avoided chemotherapy is not high, the study noted a debulking effect of second curettage leading to a reduction of the number of chemotherapy cycles required, on average by one cycle. The apparently conflicting results in these 2 large studies is probably due to the differences in definition of post-molar GTN. In the UK study, persistent GTN was defined as failure of serum hCG to normalise within 4-6 weeks or a rising hCG at any time during post-molar follow-up, while the Netherland study used stricter criteria of 3 consecutive weeks of hCG plateau or rise with at least one measurement above Generally, routine second curettage is not recommended for management of post-molar GTN.

Instead, consultation or referral to the trophoblastic centre should be considered before second curettage. However, second curettage is an alternative to immediate chemotherapy for selected patients with nonmetastatic, low-risk GTN, particularly in patients with sonographic evidence of residual uterine tissue, significant vaginal bleeding, and opting for this procedure with the aim of avoiding chemotherapy.

Hysterectomy may be necessary in the event of uncontrolled uterine bleeding [42] . However, with the availability of uterine artery embolization nowadays, hysterectomy can often be avoided. [48, 49] . Thus, primary hysterectomy could be offered to women with localised disease or with minimal metastatic involvement if they have no wish to preserve fertility.

For patients with high-risk GTN, primary hysterectomy was not effective in reducing requirement for chemotherapy or improving cure rates [44] . Compared with patients with localised or low-risk metastatic disease, it is not surprising that hysterectomy would play much less role in the reduction of tumour burden because these patients often present with disseminated disease. Instead, control of extrauterine disease with multiagent chemotherapy is critical to the success of treatment for these patients.

Hysterectomy also has a role in the management of chemoresistant low-risk GTN. In patients with localised or low-risk metastatic GTN who failed to respond to primary chemotherapy, salvage hysterectomy can lead to complete remission in most of the patients, without needing multiagent chemotherapy [46, 48, 50, 51] . For high-risk GTN, salvage hysterectomy may be considered in selected patients with small volume of extrauterine tumour. In a review of 25 patients with chemoresistant disease and relapse after treatment, who were referred to Charring Cross Hospital in UK for surgical treatment, the reported overall survival was 88% [52] . Three deaths happened in patients with significant extrauterine disease and rising hCG levels after hysterectomy. Similarly, another case series of 14 patients who underwent hysterectomy for recurrent GTN resulted in sustained remission in 83% [53] . Consequently, in the management of chemoresistant GTN, salvage hysterectomy may be necessary in selected patients to achieve cure.

For patients with CNS metastasis, neurosurgery may be required to manage intracranial bleeding or raised intracranial pressure. Cerebral haemorrhage leading to acute neurological deterioration resulted in a significant proportion of early deaths before effective treatment can be started, or very early after initiation of treatment [71, 72] . The main aims of therapy involve prompt recognition of brain metastases, stabilisation of the patient's neurological condition, and initiation of treatment. When GTN is clinically diagnosed based on raised hCG levels and metastatic disease, tissue biopsy for histological confirmation is not indicated as this can be dangerous and has little impact on clinical care.

Other treatment modalities, such as craniotomy with surgical excision, whole brain irradiation and stereotactic radiosurgery may be used along with systemic combination chemotherapy. The cure rates of brain metastases are reported to range between 50% to 80%, depending on the patient's symptoms, and number, size and location of brain lesions [70] [71] [72] [73] [74] [75] . Savage at al reported on 27 GTN patients with brain metastases treated at the Charing Cross Hospital, UK from 1991 to 2013 with overall cure rate of 85% [70] . All patients were treated with high dose multiagent systemic and intrathecal chemotherapy, 5 patients required emergency craniotomy and 5 patients had stereotactic radiotherapy for residual lesions at the end of treatment. In their experience, whole brain radiotherapy is not part of their routine management. In contrast, Neubauer et al recommended an approach using whole brain irradiation combined with systemic multiagent chemotherapy to treat patients with brain metastases. They reported overall survival of 51% and noted that presence of symptoms was associated with worse survival. These studies emphasise the varied strategies used in the treatment of brain metastases in GTN. Craniotomy is mostly reserved for management of isolated lesion especially in chemoresistant disease and for acute decompression due to intracranial haemorrhage.

Selective angiographic embolization can be used to control haemorrhage due to GTN. For instance, uterine artery embolization (UAE) has been used to manage bleeding from the uterus [76, 77] , especially in patients who wish to retain their fertility potential. In a series including 8 patients, 

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