Continuing Education Activity

Gestational trophoblastic disease (GTD) involves both benign and malignant entities that include hydatidiform mole (complete and partial), choriocarcinoma, invasive mole, epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT). The latter four, known as gestational trophoblastic neoplasia (GTN), can metastasize and be fatal if not treated. This activity reviews the etiology and pathophysiology of GTN in the clinical setting. Participants will gain insights into evidence-based diagnostic approaches, including histopathological evaluation and imaging modalities, to facilitate accurate and timely diagnosis. Clinicians will delve into the multidisciplinary management of GTN, including surgical techniques, chemotherapy regimens, and emerging targeted therapies.

The activity addresses challenges in treatment, including considerations for fertility preservation, managing complications, and follow-up surveillance. It emphasizes patient-centered care and shared decision-making and highlights the need for effective communication and collaboration among the interprofessional team to achieve optimal, comprehensive care for patients with GTN. 

Objectives:

• Implement appropriate screening measures, such as evaluating persistent or rising human chorionic gonadotropin levels and identifying clinical signs and symptoms suggestive of gestational trophoblastic neoplasia (GTN).

• Differentiate the pathophysiology and distinguishing features of various GTN subtypes, including invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor.

• Assess the current evidence-based treatment strategies for managing GTN, including surgical interventions, chemotherapy regimens, and targeted therapies.

• Apply interprofessional team strategies for improving clinical coordination to ensure comprehensive and individualized care for patients with GTN.

Introduction

The first description of gestational trophoblastic disease (GTD) was by Hippocrates around 400 BC. However, it wasn't until 1895 that Felix Marchand discovered the association between pregnancy and GTD: when healthy trophoblastic tissue penetrates the endometrium, it creates the placenta, a rich uterine vasculature connecting the fetus and mother; with malignant tissue, invasion is characteristic. 

Although the malignant behavior of a healthy trophoblast is well-controlled, in GTD, the regulatory mechanisms can become dysfunctional, resulting in highly invasive vascular and metastatic tumors. Gestational trophoblastic neoplasia (GTN) involves the malignant entities of GTD, including choriocarcinoma, invasive mole, epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT), all of which can metastasize and be fatal if not treated in a timely and effective manner.[1]

Etiology

Trophoblasts, the first cells to differentiate from the fertilized ovum, supply the embryo with nutrients and eventually form the fetal portion of the placenta. These placental trophoblasts are the origin of molar pregnancies and GTN and are comprised of cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblasts. Specifically, the cytotrophoblasts and syncytiotrophoblasts create hydatidiform moles and choriocarcinomas; PSTTs and ETTs arise from intermediate trophoblasts.[1]  

Epidemiology

The true incidence of GTN is difficult to definitively quantify, as data concerning the total number of pregnancies and trophoblastic disease vary. Approximately 50% of GTN cases arise after a molar pregnancy, whereas 25% may develop after miscarriage, termination, or ectopic pregnancy; the remaining 25% may result after a preterm or term pregnancy.

When GTN develops after a molar pregnancy, it is usually an invasive mole or choriocarcinoma, rarely a PSTT or an ETT. After a complete molar pregnancy, approximately 15% of patients will have persistent local disease with invasion, and 5% may develop metastatic disease. GTN after nonmolar pregnancy occurs in about 2 to 200 per 100,000 pregnancies (depending on global reporting) and is typically a choriocarcinoma. GTN after pregnancy loss occurs in 1 in 15,000 cases; GTN after term pregnancy occurs in 1 in 150,000 cases.[2][3]

Following a molar pregnancy, the risk of a repeat mole rises to 1% to 2%. Following two molar gestations, the risk of having a third mole is 15% to 20%. The prevalence of choriocarcinomas, PSTTs, and ETTs is unclear, as these diseases can emerge following pregnancy.[1][4][5]

Pathophysiology

All types of GTN originate from the placenta. Hydatidiform moles (HMs) and choriocarcinomas emerge from villous trophoblasts, whereas PSTTs and ETTs arise from intermediate trophoblasts. First-trimester complete HMs show aberrant budding, villous structures with trophoblastic hyperplasia, crumpled villous blood vessels, and stromal karyorrhectic debris. In contrast, early partial HMs show patchy villous hydrops, dispersed abnormally shaped erratic villi, patchy trophoblastic hyperplasia, and trophoblastic pseudo-inclusions.

Morphological differentiation of nonmolar miscarriage from a partial HM can be complicated, as villous dysmorphism can present without the characteristic trophoblastic hyperplasia of the partial mole. Furthermore, ploidy analysis demonstrated by in situ hybridization or flow cytometry can differentiate diploid from triploid conceptions. Still, it cannot distinguish between a complete mole and a diploid nonmolar miscarriage or molar and nonmolar triploid. In these instances, molecular investigations are necessary.

Infrequently, a molar pregnancy can coexist with a normal pregnancy. The diagnosis is usually made by ultrasound. Despite the high risk of spontaneous abortion, 40% to 60% of cases result in live births. The risk of GTN in a coexisting molar and normal pregnancy is 27% to 46%; in a singleton molar pregnancy, the risk is 15% to 20%. Pregnancy can proceed if there are no complications, negative genetic studies, and normal ultrasound findings.[6]

Choriocarcinomas are malignant human chorionic gonadotropin (hCG)-releasing epithelial tumors with central necrosis and a characteristic biphasic structure. Intraplacental choriocarcinomas can also occur and are likely responsible for metastatic disease after term pregnancies. The majority of neonatal choriocarcinomas are a result of metastatic spread from intraplacental choriocarcinomas.

PSTTs are malignant tumors formed from uterine lesions with less hemorrhage, necrosis, and lower hCG concentrations than choriocarcinomas.[1] Human placental lactogen (hPL), expressed by syncytiotrophoblasts, is highly expressed in the trophoblasts of PSTTs.[7]

ETTs, the rarest of GTN types, demonstrate nests of tumor cells made of fairly uniform mononucleate intermediate trophoblasts. These nests are interspersed between necrotic debris and hyaline degeneration. ETTs may appear as discrete hemorrhagic, solid, or cystic lesions.[8][9]

Extremely rare cases of mixed GTN tumors have been reported. Choriocarcinoma may coexist with PSTT and/or ETT. Diagnosis and treatment of these neoplasms is challenging due to limited data.[10]

Histopathology

Histological features of GTN types:

Complete HM

Karyotype: 46,XX (majority); 46,XY; no fetus/embryo, diffuse swelling of villi, and expanded trophoblastic hyperplasia.

Partial HM

Karyotype: triploid (69,XXY; 69,XYY; 69,XXX); abnormal fetus/embryo, central swelling of villi, and central trophoblastic hyperplasia.

Gestational Choriocarcinoma

Diffusely penetrative growth involving the endomyometrium. Tumor cells recapitulate chorionic villous trophoblasts of different types and are arranged in biphasic to triphasic growth arrangements. Sheets or cords of mononuclear tumor cells are surrounded by layers of multinuclear syncytiotrophoblasts. Lymphovascular tumor thrombi are usually present.

PSTT

Tumor cells invade the myometrium with vascular/lymphatic invasion. Focal hemorrhage and necrosis are seen in nearly one-half of cases, whereas transmural myometrial invasion is seen in 10% of cases. Perforation can occur.

ETT

The tumor usually creates discrete nodules or cystic hemorrhagic masses that deeply invade the surrounding tissues. Hemorrhage, necrosis, ulceration, and fistulas can be seen. Characteristically, ETT demonstrates nodular, expandable growth of uniform, medium-sized tumor cells organized in nests, cords, or large sheets.[11][12]

History and Physical

Due to the routine use of ultrasonography and quantitative beta-hCG testing, patients with complete HMs are commonly diagnosed early in gestation. Common clinical presentations include vaginal bleeding, usually taking place at 6 to 16 gestational weeks (46% of cases), large-for-dates uterine size (24% of cases), and hyperemesis (14% of cases). Patients may also be asymptomatic at the time of diagnosis.[13]

Patients with partial HMs are typically not diagnosed before surgical uterine evacuation. Histological examination of curettage specimens after incomplete or missed abortion is required for the diagnosis. As with complete HMs, most patients with partial HMs (75%) report vaginal bleeding, and they generally present later than those with complete HMs. Complete HMs are typically associated with a considerably elevated hCG level. Nearly one-half of patients with complete HMs have pre-evacuation hCG levels greater than 100,000 mIU/mL. Such elevated levels occur in less than 10% of patients with partial HM.[1]  

Evaluation

Ultrasound is the primary diagnostic tool for GTN.[14] Ultrasound of a complete mole characteristically shows a uterus filled with a heterogeneous mass (called the "snowstorm" sign), with the absence of fetal development and the presence of theca lutein ovarian cysts. Unfortunately, these findings are not detectable in the first trimester.

Due to high false-negative and false-positive rates with ultrasound, specifically in the case of partial HMs, histological examination is necessary to reach the final diagnosis. As histological examination may not be practical after every termination, testing the hCG level 3 to 4 weeks posttermination to verify a negative result is highly recommended.[1]

Patients with postmolar GTN often present without symptoms or characteristic ultrasound findings; therefore, a correlation between hCG levels and tumor burden is necessary to reach the diagnosis. MRI is typically unnecessary in the routine evaluation of GTN, except in cases with atypical presentations, recurrence, ETT, or PSTT.[14]

Treatment / Management

Different treatment modalities are available for GTN, depending on the type and stage. 

Standard Treatments

These include dilation and curettage (D&C), chemotherapy, hysterectomy, or a combination of these modalities.[15]

D&C

More commonly performed in molar pregnancy where fertility is desired, monitoring after D&C is essential to ensure no disease recurrence.

Chemotherapy

Certain types of GTN can be treated by single or combination chemotherapy. Some chemotherapeutic agents used include methotrexate, etoposide, actinomycin D, cyclophosphamide, cisplatin, and vincristine. 

Hysterectomy

A hysterectomy is the most common treatment option in cases of chemoresistance, severe disease, or lack of desire for future fertility.[16]

Initial management of nonmetastatic PSTT or ETT is hysterectomy and salpingectomy, with or without lymph node sampling. In metastatic PSTT or ETT cases, if feasible, hysterectomy, salpingectomy, and resection of metastatic disease are followed by platinum-based chemotherapy. [NCCN Guidelines 2022]

Controversial Treatments

Prophylactic chemotherapy

Prophylactic chemotherapy has been proposed in place of monitoring hCG levels until disease clearance criteria are met. The treatment has been reported to decrease intense chemotherapy regimens and boost the chance of complete healing.[16][17] However, a recent Cochrane Review discourages this practice.[17]

Second D&C

A second D&C may be performed after a molar pregnancy evacuation if the hCG level remains nonreassuring. However, if there is a high risk of uterine perforation or hemorrhage, a second D&C must not be performed.[16] A prospective, multicenter study was conducted in Canada in 2016 to evaluate the efficacy and safety of this procedure in 64 patients with low-risk, nonmetastatic GTN, using the World Health Organization (WHO) prognostic score. The study concluded that a second D&C cured 40% of the patients without complications when used as an initial treatment for low-risk, nonmetastatic GTN.[18]

Drug-resistant GTN

Approximately 0.5% to 5% of women experience drug-resistant GTN and may die. Pembrolizumab is one of the drugs studied for use in this situation, and the results show that it represents a valuable new approach for treating drug-resistant GTN.[19] Other more complex regimens have been proposed, yet were found to be associated with additional adverse effects. Future randomized controlled trials must be conducted to assess alternate regimens and their efficacy.[20]

Differential Diagnosis

The differential diagnosis will largely depend on whether metastasis has occurred and, if so, to which organs. The differential diagnosis for GTN includes[21]:

• Incomplete abortion                                                                                                                    
• Ectopic pregnancy                                                                                                                       
• Cornual pregnancy                                                                                                                           
• Pregnancy in the rudimentary uterine horn                                                                        
• hCG-secreting germ-cell tumors                                                                                       
• Biliary obstruction                                                                                                              
• Bladder cancer

Medical Oncology

In patients with postmolar GTN, evaluation involves a detailed history, physical exam including a pelvic exam, pelvic ultrasound, and imaging including a chest x-ray and/or chest, abdominal, and pelvic computed tomography (CT) scans. If no extrauterine disease is present, single-agent therapy is appropriate. With extrauterine disease, the Federation of Gynecology and Obstetrics (FIGO) stage and prognostic score should be determined to assess if the patient is at a low or high risk for persistent or recurrent disease. Studies have reported a 2.9% recurrence rate in patients with nonmetastatic disease and up to a 9.1% recurrence rate in patients with metastatic disease.[21] Single-agent therapy for nonmetastatic disease is generally methotrexate or dactinomycin.

Scoring for metastatic disease is used to determine treatment. In low-risk metastatic disease (prognostic score <7), single-agent methotrexate or dactinomycin is appropriate. Between 10% and 30% of patients with low-risk GTN will develop resistance after single-agent chemotherapy, whereas up to 50% of patients with high-risk metastatic disease will develop resistance. Patients who develop resistance to the initial single-agent usually will respond to an alternative single agent, and only 5% to 10% of patients will require multiagent therapy.[22][23][24] Multiagent chemotherapy is indicated in high-risk metastatic disease (prognostic score ≥7), and guidelines recommend etoposide, methotrexate, and actinomycin D alternating with cyclophosphamide and vincristine (EMA/CO). However, up to 40% of patients with high-risk metastatic GTN may not respond or may have a relapse. There are no evidence-based guidelines for second-line treatment, although platinum-based regimens are generally used.[25] 

Staging

GTN staging is based on tumor location and extent as follows:[26]

• Stage I disease is confined to the uterus
• Stage II disease involves direct extension or metastasis to other genital structures
• Stage III disease is identified by lung metastasis
• Stage IV disease includes nonpulmonary distant metastasis

There are three primary systems used to stage and score GTD:

1. The Clinical Classification System by the National Institute of Health (NIH) 
2. The WHO Prognostic Scoring System
3. The FIGO Staging and Risk Factor Scoring System, which was revised and edited in 2000

The Clinical Classification System is widely used in the United States. This approach originated from the analyses of patients with metastatic GTN treated at the NIH. The system differentiates patients based on the presence or absence of metastatic disease, as all patients with nonmetastatic disease can be cured with initial single-agent chemotherapy.

Patients with metastatic disease are further subdivided according to the presence or absence of factors associated with response to initial single-agent chemotherapy. Patients with no high-risk clinical factors will likely benefit from initial single-agent therapy and are labeled as having good-prognosis metastatic GTD; conversely, patients with a single high-risk clinical factor are labeled as having poor-prognosis metastatic GTD. These patients with poor prognosis are at increased risk of failing single-agent chemotherapy and dying if treated with single-agent therapy followed by multiagent regimens.

The WHO Prognostic Scoring System offers precise information regarding disease prognosis. A 97% correlation of risk categorization was shown between the original WHO (1983) and FIGO 2000 systems.[27] The current FIGO prognostic scoring system was adapted from the WHO classification. FIGO prognostic scoring is based on individual risk factors that have been shown to predict GTN resistance to single-agent chemotherapy (see Table. FIGO Prognostic Scoring System).

 Table. FIGO Prognostic Scoring System

[Modified from NCCN guidelines Gestational Trophoblastic disease 2022]

The patient’s diagnosis is assigned to a stage group represented by a Roman numeral: I, II, III, and IV. Next, the sum of the individual prognostic scores is noted after a colon. For example, stage II:4 or stage IV:9. Each patient with GTD will be given a stage and score.

For patients with PSTT or ETT, only the stage will be given. A risk factor score is not applicable in these cases.

Low-risk GTD has a total prognostic score of less than 7. 

High-risk GTD has a total prognostic score of 7 or more.[26][28][29]

Prognosis

Low-Risk Disease

About 95% of patients diagnosed with an HM who develop neoplasia have a low risk of persistence. For most patients, single-agent chemotherapy with methotrexate or dactinomycin is the treatment of choice. If first-line therapy fails, usually due to resistance, it can easily be followed with second-line or, occasionally, third-line chemotherapy, making the overall survival rate almost 100%.[1]

High-Risk Disease

Most high-risk GTN patients present with metastases months or years following the causative pregnancy. Signs and symptoms differ according to the disease's location. For example, patients with brain metastases may present with headaches, seizures, or hemiparesis. In contrast, patients with lung metastasis can present with shortness of breath, hemoptysis, or pleuritic chest pain. Since menstrual irregularity is not always present, the diagnosis can be missed. Recommended imaging studies are whole-body CT scans, MRI of the brain and pelvis, and Doppler ultrasonography. If the brain scan is negative, a lumbar puncture should be done to assess the ratio of cerebrospinal fluid to serum hCG.[1]

Complications

Commonly reported complications of a molar pregnancy include hyperemesis, hyperthyroidism, vaginal hemorrhage, anemia, preeclampsia, and respiratory distress.[1] Pulmonary complications occur less commonly yet are life-threatening. These complications include pulmonary edema, pulmonary embolism, pleural effusion, and trophoblastic embolization.[30]

Deterrence and Patient Education

All patients with HMs should have hCG surveillance and monitoring. Surveillance protocols differ from one country to another, but the principles are identical. In the United Kingdom, serum and urine hCG levels are measured every 2 weeks until the values reach the negative range, then urine hCG levels are checked monthly. Patients who achieve negative hCG values within 56 days of uterine evacuation have a low risk of developing malignant disease and are further monitored monthly for 6 months from the evacuation date. 

During the hCG follow-up period, patients are advised to use reliable contraception (ideally, a combination of methods). Following hCG monitoring, serum or urine hCG concentrations should be measured 6 and 10 weeks after every pregnancy to ensure no reactivation of previous molar disease.[1]

After evacuation of a molar pregnancy, follow-up monitoring is critical to detect trophoblastic sequelae (invasive mole or choriocarcinoma), which occur in nearly 15% to 20% of patients with complete HMs and 1% to 5% of patients with partial HMs.[12]

Enhancing Healthcare Team Outcomes

Management of GTN requires the collaboration of laboratory personnel, ultrasonographers, nurses, advanced practice practitioners, radiologists, pathologists, gynecologists, medical oncologists, and gynecologic oncologists. Healthcare professionals must work together to schedule and coordinate diagnostic tests, such as hCG measurements, imaging studies, and histopathological evaluations, to accurately diagnose GTN and determine disease staging. Subsequently, the interdisciplinary team develops individualized treatment plans based on the specific subtype and stage of GTN. In certain complex situations, referral to centers for trophoblastic disease may be necessary. Regular communication and collaboration are essential to ensure ongoing assessment of patients' treatment responses. Adjustments to treatment plans are made based on multidisciplinary discussions and patients' individual needs, allowing for coordinated and shared decision-making. Comprehensive patient education on GTN and the critical hCG follow-up requirements are best addressed across medical disciplines. By setting interprofessional goals and standards, healthcare professionals can work together effectively to provide comprehensive, patient-centered care for individuals with GTN, optimizing treatment outcomes and improving the overall patient experience.[13][29]