Management of Gestational Trophoblastic Diseases

Introduction

Gestational trophoblastic diseases (GTD) are a rare group of disorders that sometimes require a multi- disciplinary approach, principally the medical oncologist, for the best outcome. Though some are malignant, the outcome remains excellent if the correct treatment is given at the correct time. This guideline aims to achieve uniformity in how these patients receive care in the gynaecological clinical setting, with evidence-based recommendations and expert opinion.

Diagnosis, definitions and classifications

Gestational trophoblastic diseases (GTD) are a heterogeneous group of pregnancy-related diseases that include premalignant diseases (complete hydatidiform mole, partial hydatidiform mole) as well as malignant counterparts (invasive mole, gestational choriocarcinoma, placental site trophoblastic tumour, epithelioid trophoblast tumour). The malignant potential of atypical placental site nodules (PSNs) remains unclear.

Molar pregnancy

This represents the premalignant members of GTD, i.e., complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM). These are diagnosed histologically. It is well-recognized that molar pregnancies are formed due to an imbalance between the maternal and paternal haploid chromosomes.

Gestational trophoblastic neoplasia (GTN)

It is the presence of any evidence of persistence of GTD after primary treatment, most commonly defined as a persistent elevation of human chorionic gonadotrophin (hCG). The diagnosis of GTN doesn’t always require histological confirmation, and it represents the malignant subgroup of the spectrum of disease. High persistent hCG after evacuating hydatidiform mole is known as post-molar GTN. Invariably, all the subtypes would have high persistent hCG. The subtypes of GTN are as follows:

Postmolar GTN

It is diagnosed by the persistence of hCG following primary treatment of CHM and PHM. Usually, it is a biochemical diagnosis (See below). Postmolar GTN occurs in around 15-20% after CHM and in 1-5% after PHM1.

Invasive mole

This is a histological diagnosis with invasion into uterine muscle and blood vessels. It occurs only following molar pregnancies. Even though it is considered a locally invasive disease, 15% of Invasive moles can metastasise to the lungs and vagina.

Choriocarcinoma

This is a histological diagnosis which can occur following any type of pregnancy (Normal/Ectopic/ Molar). It has a high incidence of metastasis.

Placental site trophoblastic tumour (PSTT)/ Epithelioid trophoblastic tumour (ETT)

This is a histological diagnosis and can occur following any type of pregnancy (Normal/Ectopic/ Molar). Usually, there is a long interval from the last known pregnancy, and they often show varied production of hCG. Up to 50% of patients can have distant metastases at the time of diagnosis (commonly to the lungs). Unlike other malignant counterparts, lymphatic spread is also seen in these subtypes.

Investigations

At the Initial presentation of a possible molar pregnancy

• Ultrasound scan

This remains the primary method of preoperative diagnosis. Due to the widespread availability of ultrasound scanning, molar pregnancies rarely go unnoticed beyond the 1st trimester. The classical ultrasound features, such as a snowstorm or honey- comb appearance, may not be seen in the early ultrasound scans. The cystic appearance of the placenta without an identifiable gestational sac may indicate early CHM, while an empty gestational sac or missed miscarriage with cystic/enlarged placenta can suggest PHM.

Serum hCG level

Serum hCG is elevated in all types of GTD. It is an excellent biomarker of disease progression, response, and subsequent post-treatment surveillance. Therefore, all patients should have a baseline serum hCG level before surgical evacuation. If a patient has to undergo an emergency surgical evacuation before the hCG level can be done, a blood sample should be drawn before the surgery for hCG assay. An hCG assay that detects all hCG forms (beta-hCG, core hCG, C-terminal hCG, nicked-free beta, beta core) is preferred. However, the availability of such comprehensive assays is limited in Sri Lanka.

3.1.3 Chest X-ray

The lungs are the most common site of metastasis in GTN. Therefore, all patients should have a chest X- ray before uterine evacuation.

In choriocarcinoma/ PSTT/ ETT or suspected metastasis

These conditions are known to be associated with a high incidence of distant metastasis. Therefore, further imaging is required to stage the disease before planning further treatment.

CT head, thorax, abdomen and pelvis in all patients

MRI head if choriocarcinoma or pulmonary metastases are present or in the presence of neurological symptoms.

Management

Primary management of molar pregnancy

• Surgical evacuation

Suction curettage is the treatment of choice. This should be done under ultrasound guidance where facilities are available2. Priming of the cervix with prostaglandins immediately before surgical evacuation can be performed safely3.

All specimens should be sent for histological assessment. In addition, retained products of conception (RPOC) of all miscarriages where no fetal parts are identified at any stage of the pregnancy should also undergo histological evaluation. All Rh-negative patients undergoing evacuation due to suspected molar pregnancies should receive Anti D prophylaxis.

Place of hysterectomy

For women of reproductive age with CHM/PHM, a hysterectomy is not the first line of treatment. Women who are at least 40 years old and do not intend to become pregnant in the future, with probable molar pregnancy based on ultrasound characteristics and increased hCG, may be offered a total hysterectomy as a first option rather than uterine evacuation4.

However, before suggesting a hysterectomy as the first line of treatment, one should take into account the excellent results following chemotherapy in cases where GTN occurs. Women should always be given uterine evacuation and follow-up as their first option in the management of molar pregnancy.

Repeat surgical evacuation

Repeat evacuation is not encouraged, especially in situations where hCG is > 5000 and/or high-risk disease (WHO > 6) or non-CHM/PHM histology5. Patients with the above risk factors should have an early referral to a medical oncologist since it is more in favour of GTN. Repeat evacuation should be considered only in situations with life-threatening bleeding in the background of significant retained products.

4.1.4 Surveillance for postmolar GTN

All patients should undergo weekly serum hCG measurements until it returns to normal levels. Subsequently,

• In cases of CHM where hCG normalises within 8 weeks of evacuation, monthly serum hCG assessments should be performed for 6 months from uterine evacuation.
• In cases of CHM where hCG normalises after 8 weeks of evacuation, monthly serum hCG assessments should be performed for 6 more months from the date of hCG normalisation. These women have a higher risk of having postmolar GTN.
• In cases of PHM, serum hCG should be checked in 1 month. If negative, surveillance can be stopped.

4.1.5. Contraception during follow-up

It is very important that women should not get pregnant while on surveillance following a molar pregnancy. While traditionally, only barrier methods were recommended, hormonal contraception such as combined oral contraceptive pills and progesterone-only contraceptives are safe following surgical evacuation6,7,8. The use of intrauterine devices should be avoided.

• Management of GTN
• Postmolar GTN
• Diagnosis of postmolar GTN

This is often a biochemical diagnosis. The FIGO criteria for the diagnosis of postmolar GTN are as follows.

Treatment of postmolar GTN

If any of the FIGO diagnostic criteria for postmolar GTN are present, these patients should be referred to a medical oncologist for chemotherapy. Chemotherapy for GTN should only be provided by a specialist medical oncologist.

Once GTN is diagnosed, patients are further triaged into risk groups. According to the FIGO 2000 scoring system, a score of 6 and below is classified as Low risk and a score above 6 is considered high risk9. (Annex 1) low-risk patients are treated with single-agent chemotherapy (methotrexate or actinomycin D), while high-risk patients are treated with more complex multi-agent chemotherapy.

Invasive mole

This is a histological diagnosis. If diagnosed from a post-hysterectomy specimen on histology, the patient must be referred to the oncologist for chemotherapy.

Choriocarcinoma

This is a histological diagnosis. These patients need urgent referral to the oncologist for chemotherapy. They would also require further imaging to stage the disease.

PSTT/ETT

This is usually not responsive to chemotherapy. Surgical resection is the primary modality of treatment. However, due to the high incidence of metastasis, a staging CT scan should be performed prior to surgical planning. Hysterectomy and pelvic lymphadenectomy would be the standard treatment. Excision of the metastatic deposits should be carried out if this can be achieved with acceptable risks. All patients need a referral to the oncologist.

All patients with GTN should undergo monthly serial serum hCG surveillance for 12 months after completing chemotherapy and should be strictly advised not to conceive during the surveillance period.

Special considerations

Medical management of ectopic pregnancy and management of pregnancy of unknown location (PUL)

The above should not be mixed up with GTN management. In all 3 instances, methotrexate is used. However, methotrexate used in postmolar GTN is complex and extended and should be done by a medical oncologist. It should be worth noting that GTN with non-molar index pregnancy (miscarriage, ectopic, normal pregnancy) can present as PUL. We advise being mindful of this fact when managing PUL.

GTN patients with features of severe pre- eclampsia

GTN patients may complain of severe headaches, blurred vision, and vomiting. These patients must be checked for hypertension, exaggerated reflexes/clonus and proteinuria. They may need ICU care, stabilising blood pressure, intravenous magnesium sulphate and fluid management as per pre-eclampsia protocol. Permanent treatment would be an expedited suction evacuation or hysterectomy after initial stabilisation.

GTN patients with severe vaginal bleeding

To stop bleeding, either urgent suction evacuation or hysterectomy +/- internal iliac artery ligation may be required.

GTN patients on chemotherapy presenting with hypovolemic shock due to uterine rupture

Urgent exploratory laparotomy, evacuation of products, repair of the uterus/hysterectomy, and internal iliac artery ligation may be required to save the life of the woman.

Prophylactic chemotherapy at the time of uterine evacuation

Administration of methotrexate or dactinomycin at the time of or after evacuation has been shown to reduce the incidence of postmolar GTN by 3 - 8%. However, this should only be considered in high-risk patients such as women >40 years, hCG >100,000 mIU/ml, with excessive uterine enlargement or theca lutein cyst > 6cm. Long-term data on toxicity and drug resistance are still lacking11,12. Therefore, this decision should only be undertaken after a multi-disciplinary discussion and case-by-case consideration.

References

• Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 2010; 203: 531-9.
• Tidy JA, Gillespie AM, Bright N, Radstone CR, Coleman RE, Hancock BW. Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy. Gynecol Oncol 2000; 78: 309-12.
• Flam F, Lundstreom V, Pettersson F. Medical induction prior to surgical evacuation of hydatidiform mole: is there a greater risk of persistent trophoblastic disease? Eur J Obstet Gynecol Reprod Biol 1991; 42: 57-60.
• Zhao P, Lu Y, Huang W, Tong B, Lu W. Total hysterectomy versus uterine evacuation for preventing post-molar gestational trophoblastic neoplasia in patients who are at least 40 years old: a systematic review and meta-analysis. BMC Cancer. 2019; 19(1): 13.
• Management of Gestational Trophoblastic Disease: Green-top Guideline No. 38 - June 2020. BJOG. 2021; 128(3): e1-e27.

FSRH Guideline Contraception After Pregnancy. Faculty of Sexual and Reproductive Health care. January 2017 (Amended October 2020).

• Costa HL, Doyle P. Influence of oral contraceptives in the development of post-molar trophoblastic neoplasia-a systematic review. Gynecol Oncol. 2006; 100: 579-85.
• Dantas PRS, Maesta I, Filho JR, Junior JA, Elias KM, Howoritz N, Braga A, Berkowitz RS. Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after

controlling for risk factors? Gynecol Oncol. 2017; 147(2): 364-70.

• Ngan HYS, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, Lurain JR, Massuger L. Diagnosis and management of gestational trophoblastic disease: 2021 update. Int J Gynaecol Obstet. 2021; 155 Suppl 1(Suppl 1): 86-93.
• Diagnosis and Management of Ectopic Pregnancy: Green-top Guideline No. 21. BJOG. 2016; 123(13): e15-e55.
• Wang Q, Fu J, Hu L, Fang F, Xie L, Chen H, He F, Wu T, Lawrie TA. Prophylactic chemotherapy for hydatidiform mole to prevent gestational trophoblastic neoplasia. Cochrane Database Syst Rev. 2017; 9(9): CD007289.
• Abu-Rustum NR, Yashar CM, Bean S, Bradley K, Campos SM, Chon HS, et al. Gestational Trophoblastic Neoplasia, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019; 17(11): 1374-91.

Annexe: FIGO Scoring system