Understanding and management of gestational trophoblastic disease

Hydatidiform mole

Hydatidiform mole is a benign trophoblastic tumor²⁷ and accounts for the majority of GTD; about 80% of GTDs are hydatidiform moles¹³. Hydatidiform mole is associated with abnormal gametogenesis and fertilization. The incidence varies around the world and is higher in Asia (~1 in 500) and the Middle East and Africa (~1 in 1000) than in Europe and North America (~1 in 1500)^14,28. Risk factors include extremes of age, ethnicity, genetic basis, spontaneous miscarriage, and nutrient restriction⁸. Women from 21 to 35 years of age have a lower risk of complete mole than women older than 35 years and younger than 21 years¹⁵. Women with a history of prior spontaneous miscarriage have a two- to three-fold risk of molar pregnancy in comparison with the general population²⁹. Women with a history of molar pregnancy have a 10- to 20-fold risk of repeat molar pregnancy, and about 20% of patients will develop malignant transformation after evacuation of the mole.

Hydatidiform moles are edematous immature placentas which are broken down into complete and partial moles. A complete mole occurs when an empty ovum is fertilized by a sperm, about 90% of complete hydatidiform moles are 46XX which originate from duplication of the chromosomes of a haploid sperm and the other 10% are 46XY (Figure 2)¹⁵, and the chromosomes are paternally derived. Complete hydatidiform moles take on the appearance of a “bunch of grapes” which undergo diffuse villous enlargement with hydropic changes. The trophoblast has varying degrees of atypia and villous capillaries are absent. Fetal tissue or the embryo is absent in complete moles. In complete hydatidiform moles, the uterus is typically significantly enlarged for gestational age, and patients always have an elevated human chorionic gonadotropin (hCG) level for gestational age. Often, there can be early onset of medical complications such as pregnancy-induced hypertension, hyperthyroid, and hyperemesis gravidarum^15,30. The most common presentation of molar pregnancy is abnormal vaginal bleeding during the first trimester and ovarian theca lutein cysts greater than 6 cm in diameter^8,31.

Figure 2. Schematic of the different karyotypes of complete and partial hydatidiform moles.

Schematic of the different karyotypes of complete and partial hydatidiform moles.

A partial mole occurs when an empty ovum is fertilized by two sperm, the normal karyotype being 69XXX, 69XXY, or 69XYY, although a diploid karyotype may also exist (Figure 2)¹⁵. In PHMs, placental villi have focal edema and denatured areas of varying size and shape and pathological trophoblast cell proliferation. Fetal tissue or a recognizable embryo will be present. Most often, the fetus is not living, although occasionally there will be a small living fetus. Rarely, a term infant will be born.

Choriocarcinoma

Choriocarcinomas are malignant trophoblastic tumors developing in the uterus from villous CTB cells^15,32. About 50% of all choriocarcinomas arise from a complete molar gestation, 25% following a normal pregnancy, and 25% after a spontaneous miscarriage or ectopic pregnancy³³. Choriocarcinoma occurs in about 1 in 20,000 to 40,000 pregnancies in the United States and three to nine per 40,000 pregnancies in Southeast Asia and Japan³⁴. However, in all populations, the incidence rates of choriocarcinoma have declined over the past 30 years, although the precise incidence of choriocarcinoma may be under-reported because hemorrhage with biopsy precludes tissue diagnosis^15,16.

Choriocarcinomas produce high levels of angiogenic growth factors and are able to remodel the uterine vasculature which can lead to hemorrhage³⁵. The clinical manifestation most often includes irregular vaginal bleeding, enlarged uterus, cough, hemoptysis, headache, and vomiting^17,36–40. Choriocarcinoma in the vagina can appear as purple/blue nodules and the uterus often becomes asymmetrically enlarged but not all women will present with all of these symptoms. In addition, intraperitoneal hemorrhage and high serum hCG levels exist^32,41.

There are many potential predictive factors for choriocarcinoma. Rodabaugh et al.¹⁸ found that a pretreatment hCG level of more than 100,000 mIU/mL, disease duration greater than 4 months from delivery, and the presence of liver or brain metastases were important predictors of outcome in patients with choriocarcinoma. The risk of choriocarcinoma is increased in women younger than 20 and in women older than 39¹⁴. Deep myometrial invasion, tumor size, tumor stage, and site of metastases also influence the outcome of patients with choriocarcinoma^15,32,41. Usually, choriocarcinoma occurs secondary to molar pregnancy, spontaneous miscarriage, or ectopic pregnancy but can also occur after full-term normal pregnancy⁸.

Standard treatment options

Standard treatment options for GTD differ depending on the type and stage of disease and include chemotherapy, dilatation and curettage (D&C), or hysterectomy or a combination of these. In general, D&C is used for molar pregnancy and where a woman wishes to retain her fertility; however, careful post-treatment monitoring is required to ensure no recurrence of disease. For more severe and chemoresistant disease and when fertility preservation is not a concern, hysterectomy is the more common option, particularly if there are no distant metastases. Some types of GTD respond well to chemotherapy, either single or combined therapy; however, chemotherapy is not effective for all types of disease. Common chemotherapeutic agents include methotrexate, actinomycin D, etoposide, cyclophosphamide, vincristine, and cisplatin. There is a high risk of metastatic spread of some types of GTD and therefore a combination treatment modality of hysterectomy and chemotherapy is often employed. Careful β-hCG or human placental lactogen testing or both are required to ensure efficacy of any treatment modality. The majority of GTDs are treatable with one of the above common options; however, some more novel and controversial treatment modalities have recently been introduced and will be discussed further here.

Prophylactic chemotherapy

One aspect of the treatment of GTD that is still controversial is whether to initiate prophylactic chemotherapy in a subpopulation of women with hydatidiform mole who are at high risk of persistence rather than following their hCG levels until they achieve the criteria for declaring no evidence of disease or meet the definition of persistent GTD. The idea is to reduce the need for more intense chemotherapy regimens in a smaller group of women by administering a more modest regimen to increase the chance of complete resolution. Several non-randomized trials demonstrated impressive reductions in the risk of recurrent/persistent disease. For example, in Korea, Kim et al. reported on 262 patients who were identified as having high-risk hydatidiform mole⁴⁵. Fifty (19%) received prophylactic chemotherapy and the remaining 216 patients served as controls. There were no cases of persistent GTD in the 59 patients who received prophylactic chemotherapy, but 59% of the control group developed persistent GTD⁴⁵.

In a randomized trial of a single dose of actinomycin D, 18% of the high-risk patients who received prophylactic chemotherapy and 34% of the high-risk patients who did not developed recurrent GTD (risk ratio [RR] = 0.54, 95% confidence interval [CI] = 0.35–0.82, number needed to treat = 7). Adverse events were similar in the two groups, and progression was not associated with increased disease severity in the chemotherapy group. Also, costs were lower with the prophylactic chemotherapy strategy⁴⁶.

A recent Cochrane review identified only three randomized trials, including the study of actinomycin D summarized above. The combined studies demonstrated a reduced risk of GTD (RR 0.37, 95% CI 0.24 to 0.57) but the Cochrane authors judged two of the three studies to be of low quality. The Cochrane authors concluded that prophylactic chemotherapy might reduce the risk of progression to GTD in women at high risk, but the strength of the conclusion is limited by the poor quality of the studies. Concerns about increased drug resistance, delays in treatment of GTD, and toxic side effects remain, so they conclude: “it is not possible to strongly recommend the practice”⁴⁷.

Second dilatation and curettage

Another area where there is some divergence of typical practice in the treatment of GTD is whether to perform a second uterine curettage when a patient’s hCG trend is non-reassuring after initial diagnosis and evacuation of a molar pregnancy. The classic teaching was that owing to the risk of life-threatening hemorrhage or uterine perforation (or both), a second D&C should not be performed.

However, in some centers with substantial experience in treating GTD, second uterine evacuation appears to prevent the development of persistent disease and reduce the requirement for chemotherapy⁴⁸. In the GOG 242 trial, 60 women with a first diagnosis of low-risk GTD underwent a second uterine curettage and 24 (40%) subsequently experienced complete resolution of disease without the need for chemotherapy. The study noted that no patient with an hCG level of greater than 100,000 mIU/mL was cured and no patient with an International Federation of Gynecology and Obstetrics/World Health Organization (FIGO/WHO) score of more than 4 was cured. Success rate also appeared to be lower in women younger than 19 and older than 40. No surgical complications were reported⁴⁹.

Selective uterine surgery

Women with chemoresistant disease typically are counseled to consider hysterectomy; however, many women in this position wish to retain their fertility. A review of the literature reports on women with PSTT who received fertility-saving treatment. Of 11 women who had laparotomy with uterine preservation, six patients had what was considered a successful procedure and the remaining five required total hysterectomy⁴³. Therefore, although this therapy may be effective in about 50% of cases, careful monitoring of excision margins and further disease progression are required. However, in the case of PSTT, hCG monitoring is not useful and a better marker of disease presence is human placental lactogen. In addition, studies on the effectiveness of these treatments for saving fertility have yet to be conducted.