High-intensity focused ultrasound as a pretreatment combined with hysteroscopic resection for gestational trophoblastic neoplasia with chemotherapy intolerance: a case report

Abstract Background Due to resistance and intolerance to chemotherapy, localized lesion resection may be required in some patients with Gestational trophoblastic neoplasia (GTN), which may lead to massive bleeding. In this case report, we describe the successful use of high-intensity focused ultrasound (HIFU) as an effective pretreatment method for surgical procedure in a patient with GTN to reduce the perioperative risk and the impact on fertility. Case presentation A 26-year-old woman was diagnosed with high-risk GTN (FIGO Stage III: 12 prognostic scores) after a hydatidiform mole. The fifth chemotherapy cycle was interrupted due to severe chemotherapy toxicity. However, the uterine lesion was still present and the beta-human chorionic gonadotropin (β-hCG) level was not restored to normal. Therefore, ultrasound-guided HIFU was performed as a pretreatment method to shrink the lesion and prevent massive bleeding during localized lesion resection. The effectiveness of ablation was evaluated immediately using contrast-enhanced ultrasound and Color Flow Doppler ultrasonography. One month after HIFU treatment, the uterine lesion was completely resected under hysteroscopic surgery. During the surgery, HIFU was found to have shrunk the lesion and there was minimal bleeding (5 mL). The uterine cavity morphology and menstruation returned to normal after surgery. The patient has showed no signs of recurrence as of one-year follow-up. Conclusion Ultrasound-guided HIFU ablation may be a new choice for high-risk GTN patients with chemoresistance or chemo-intolerance. As a noninvasive pretreatment method, HIFU can shrink the uterine lesion, and reduce the risk of bleeding with no obvious effect on fertility.


Background
Gestational trophoblastic neoplasia (GTN) is a disease characterized by abnormal proliferation of human placental trophoblastic cells with varying degrees of increase in serum beta-human chorionic gonadotropin (b-hCG) level.The condition often occurs secondary to hydatidiform mole [1].Chemotherapy is the recommended first-choice treatment for GTN [2].However, adjuvant surgery may be required in high-risk patients because of chemoresistance and/or unsuitability for chemotherapy [3].Extensive vascularity of GTN lesions may lead to uncontrollable intraoperative bleeding which may necessitate hysterectomy [4].
Ultrasound-guided high-intensity focused ultrasound (HIFU) can achieve lesion ablation through thermal effect and cavitation effect.It has been shown to be a safe and effective noninvasive treatment in oncology [5].Moreover, it has minimal potential for impact on fertility [6].HIFU has been successfully used as an adjuvant noninvasive surgery to shrink the lesion and reduce chemotherapy cycles in GTN with chemoresistance or recurrence [7].Although HIFU has not been used as a pretreatment for localized lesion resection, shrinkage of the uterine and disappearance of the vascular signal indicates the potential possibility.
We present this case to illustrate the potential value of HIFU pretreatment of GTN lesion for reducing the perioperative risk and preserving fertility.

Case presentation
The patient was a 26-year-old woman (gravida 3 para 1) with an obstetric history of two induced abortions followed by one full-term cesarean section delivery in 2017.She presented with chief complaints of cessation of menstruation for 45 days and irregular vaginal bleeding.The b-hCG level was more than 500,000 IU/L.Initial uterine evacuation had been performed at a local hospital and the pathological diagnosis was partial hydatidiform mole.In the subsequent two weeks, because of persistent vaginal bleeding and the progressive increase in b-hCG level, repeat uterine evacuation was performed.One month later, she was referred to our hospital as a case of GTN with increase in b-hCG level by !10% on 3 successive measurements performed over a period of 2 weeks (from 16 February 2021 to 26 February 2021).Her uterine size was equivalent to 8 weeks gestation, and no visible lesion was seen in the lower genital tract.She had no history of dizziness, nausea, headache, cough, hemoptysis, or abdominal pain since the onset of the disease.Her serum b-hCG level was 86,357 IU/L and the hemoglobin was 108 g/L.Transvaginal ultrasound showed an enlarged uterus and a heterogeneous mass located in the uterine fundus and the left horn, which showed a rich blood flow signal.Pelvic magnetic resonance imaging (MRI) showed a heterogeneous solid mass in the posterior wall and left horn of the uterus, consistent with the results of ultrasound.The maximum diameter of the uterine lesion was 5.1 cm.Chest computed tomography revealed multiple nodules scattered throughout both lungs, ranging from 0.4 cm to 1.0 cm (Figure 1(A and B)).Based on these findings, a diagnosis of high-risk GTN (FIGO Stage III: 12 prognostic scores) was established.
The patient was treated with EP (etoposide, cisplatin) every 3 weeks for 3 cycles.Because of chemotherapy-induced bone marrow depression and nasopharyngeal ulcer, the fourth chemotherapy cycle was delayed and the fifth chemotherapy cycle was interrupted.Nevertheless, the uterine lesion was persisting (size of the residual uterine lesion: 3.6 cm) (Figure 2(A)).The young patient was desirous of preserving fertility, but at the same time, the severe postchemotherapy reactions were a hindrance to completion of treatment; therefore, combining adjuvant treatment modalities was necessary.Considering the abundant perilesional blood flow (Figure 2(B)) and the potential risk of perioperative bleeding, pretreatment to prevent massive hemorrhage was needed.Given the potential effect of uterine artery embolization (UAE) on fertility, HIFU ablation surgery was conducted as a pretreatment before hysteroscopic resection using the JC200 Focused Ultrasound Tumor Therapeutic System (Chongqing HIFU Technology, Chongqing, China).
The patient was placed in a prone position on the HIFU table with the abdominal fully in contact with degassed water.A degassed water balloon was used to push the bowel away from the acoustic pathway.The sonication time was 102 s and a total of 40,800 J energy was delivered.In the process of HIFU radiation, overall grayscale changes in the lesion were observed on ultrasonographic imaging (Figure 3(A)).The ablation effectiveness was assessed using Color Flow Doppler ultrasonography and contrast-enhanced ultrasound (CEUS).Color Doppler ultrasonography showed disappearance of the vascular signal and CEUS showed no perfusion in the lesion (Figure 3 performed using a rigid hysteroscope under intravenous anesthesia.Intraoperatively, the left uterine horn and the uterine fundus were found covered by the neoplastic tissue with no clear delineation of the border with the uterine muscle layer (Figure 4(A)).The uterine cavity was distended using normal saline solution, and a bipolar resection system was used to excise the lesion.The total surgical time was 33 min, and the total intraoperative blood loss was 5 mL.The uterine lesion was completely resected (Figure 4(B)).Her menstrual cycle resumed 48 days after HIFU.One month

Discussion
GTN is a group of malignant lesions which arise from abnormal proliferation of placental trophoblasts.The FIGO prognostic scoring system defines high-risk GTN as prognosis score of !7 [8].Currently, multidrug combination chemotherapy is the most frequently used initial treatment for high-risk GTN.Nevertheless, 30-40% patients with high-risk GTN show relapse or develop chemotherapy resistance after the completion of initial therapy [9].Surgery is an appropriate adjuvant treatment for patients with chemotherapy resistance or those who are unable to tolerate chemotherapy.In a 50-patient high-risk GTN case series, 48% (24/50) patients underwent a surgical procedure and 87.5% (21/24) patients were cured [10].In a study by Wan et al. 80% of GTN patients were able to conceive after uterine-sparing lesion resection [11].Machtinger et al. reported a 26-year-old patient with GTN who was treated with chemotherapy after hysteroscopic resection, and who showed no signs of recurrence at 29-month follow-up.They suggested that a combination of chemotherapy and surgical hysteroscopic may achieve a good prognosis [12].
In the present case, although the patient was chemosensitive, the chemotherapy had to be discontinued due to severe adverse reactions.We opted for hysteroscopic resection of the lesion considering the young patient's strong desire for fertility.Owing to extensive vascular proliferation induced by GTN, chemotherapy-induced necrosis of lesions may destroy the vessel wall and even cause uncontrolled bleeding [4,13].Therefore, using an efficient pretreatment to shrink the lesion and reduce the potential bleeding was a key imperative.
Compared with traditional surgeries (including abdominal hysterectomy or uterine artery ligation), UAE has shown good results in the management of pelvic abdominal surgical bleeding [14,15].Nevertheless, the effect of UAE on fertility is still uncertain.UAE may impair the ovarian reserve and cause uterine adhesion and postpartum complications [16][17][18][19].The current guidelines do not recommend UAE for patients who wish to preserve fertility [20].HIFU treatment has been shown to have no obvious effect on ovarian function or on the risks and complications associated with pregnancy [6,[21][22][23].
HIFU as a noninvasive treatment has been widely applied to treat solid tumors, and several clinical trials have confirmed its safety and efficacy [5,24].In the study by She et al.HIFU was found to be a useful adjuvant method for salvage treatment of high-risk GTN patients who underwent chemotherapy with a willingness to preserve uterus [7].However, the previous report emphasized the role of chemotherapy combined with HIFU, while the focus of the current case report was on the HIFU combined with hysteroscopic resection of the localized lesion.By concentrating energy on the lesion, HIFU causes coagulative necrosis of the tissue and damages the blood vessels of the lesion, to achieve the purpose of treating GTN and reducing bleeding.Thus, it is regarded as an efficient pretreatment method.The effect of HIFU was assessed immediately based on the overall grayscale changes and absence of perfusion of uterine lesion during the treatment process.If the HIFU pretreatment is ineffective, other procedure can be selected.After one month of HIFU, hysteroscopic resection was performed successfully and the uterine lesion was resected completely.The shrinkage of the uterine lesion reduced the difficulty and surgery time of hysteroscopic resection.In addition, the disappearance of blood flow in the uterine lesion avoided the potential risk of massive bleeding.In the absence of pretreatment, active bleeding may occur during hysteroscopy in women with GTN.In a previous study, tumor bleeding was controlled by intravenous administration of hemostatic drugs and insertion of an inflated Foley balloon into the uterine cavity [25].Even with UAE pretreatment, the bleeding volume of hysteroscopic resection of the GTN lesion can reach up to 50 mL or more [26].After surgery, there was rapid restoration of menstruation and hysteroscopic examination showed normal uterine cavity with no adhesion.There were no signs of recurrence at 1-year follow up.To our knowledge, this is the first study to report the pretreatment of HIFU for GTN.A combination of HIFU and hysteroscopic resection may be an effective strategy for treatment of GTN, which can help reduce drug toxicity by shortening the duration of chemotherapy and maximize the chances of fertility preservation.
HIFU offers a new choice for GTN patients with chemoresistance or those who are unable to tolerate chemotherapy.In addition to being a noninvasive method for lesion ablation, HIFU could help shorten the duration of chemotherapy, avoid potential bleeding, and help preserve fertility.

Figure 1 .
Figure1.Pulmonary metastatic nodules on CT.CT images of the lung before chemotherapy, the largest pulmonary nodule is located in the left lung, with a diameter of 1.0 cm (A) and multiple nodules were seen (B).Shrinkage in the size of the pulmonary lesion pre-HIFU (C), the diameter of the lesion was 0.3 cm.Disappearance of the pulmonary nodules post-HIFU (D).CT, computed tomography; HIFU, high-intensity focused ultrasound.

Figure 2 .
Figure 2. MRI of the uterine lesion pre-HIFU (A and B) and post-HIFU (C and D) treatment.Sagittal T2 image showing the uterine lesion of GTN located in the posterior wall and left horn of the uterus.The size was 3.6 cm.Flow void effect was seen (arrow pointing in Figure A) (A).Sagittal contrast-enhanced image showing the rich blood flow signal of the lesion (B).Sagittal contrast-enhanced imaging performed one day after the surgery showed no perfusion of uterine lesion (C).Sagittal contrast-enhanced image showing the shrinkage of the uterine lesion 22 days after HIFU treatment (size: 2.6 cm) (D).MRI, magnetic resonance imaging; HIFU, high-intensity focused ultrasound; GTN, gestational trophoblastic neoplasia.

Figure 3 .
Figure 3. Ultrasound-guided HIFU treatment.Overall gray-scale change was seen during the surgery (A), while the vascular flow disappeared and the contrastenhanced ultrasound showed no perfusion of uterine lesion immediately after the surgery (B).HIFU, high-intensity focused ultrasound.

Figure 4 .
Figure 4. Hysteroscopic features after HIFU (A) and after hysteroscopic resection (B).White neoplastic tissue in the left horn of the uterus with no visual vascularity (A).The uterine lesion was completely resected under hysteroscopy (B).HIFU, high-intensity focused ultrasound; GTN, gestational trophoblastic neoplasia.