This chapter should be cited as follows:
Ngu S-F, Ngan HYS, et al., Glob Libr Women's Med
ISSN: 1756-2228; DOI 10.3843/GLOWM.422063

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 13

Gynecological cancer

Volume Editors: Professor Hextan Ngan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong
Professor Karen Chan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong

Chapter

Management of Gestational Trophoblastic Disease and Neoplasia

First published: June 2026

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Responsibility for authorship: S.-F.N. and H.Y.S.N. were principal authors of the sections on GTD and Diagnosis, Investigation and Staging, whilst E.G., F.C. and M.S. wrote the section on Treatment of GTN.

INTRODUCTION

Gestational trophoblastic disease (GTD) is a group of uncommon pregnancy associated tumors that involve abnormal growth of trophoblastic cells. GTD comprises a spectrum of conditions. The premalignant forms include complete and partial hydatidiform mole, while the malignant forms include invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). Atypical placental site nodule (APSN) is considered part of the GTD spectrum, as 10–15% of cases coexist with or may progress to PSTT/ETT.^1,2 Altogether, the malignant forms are known as gestational trophoblastic neoplasia (GTN). In keeping with their trophoblastic origin, the majority of GTDs produce human chorionic gonadotropin (hCG), a hormone primarily associated with pregnancy. PSTT, ETT and APSN tend to produce more variable, often lower levels of this hormone. Nonetheless, hCG is an ideal biomarker in the management of GTD, particularly in monitoring of disease progression, treatment response and disease recurrence. In fact, measuring hCG levels plays an important role in monitoring the progression of hydatidiform mole to GTN, which occurs in 13–20% of cases of complete mole and 0.5–5% of partial mole.³ Nowadays, women diagnosed with GTN often have an excellent prognosis due to the availability of both a reliable biomarker (hCG) and effective treatment options.

The reported incidence of hydatidiform mole varies widely across the world, and ranges from < 1 per 1000 pregnancies to 13 per 1000 pregnancies, with higher rates observed in Asia and the Middle East compared to Europe, North America and Oceania.⁴ Risk factors for complete mole include previous history of molar pregnancy and pregnancy at extremes of reproductive age. The incidence of choriocarcinoma varies between 1 in 100 000 pregnancies in Europe and North America, and 10 per 100 000 pregnancies in Asia.⁴

HYDATIDIFORM MOLE

Diagnosis

Clinical assessment

A comprehensive medical history and physical examination are essential to identify potential symptoms and risk factors for GTD. Women with molar pregnancy often present with vaginal bleeding in the first trimester of pregnancy.⁵ On clinical examination, the uterus may be greater than dates. In the event of passage of tissue mass vaginally, vesicles may be seen on the products of gestation. Nonetheless, with the widespread availability of ultrasound, complete mole is diagnosed earlier and typical complications, including excessive uterine enlargement, hyperemesis gravidarum, hyperthyroidism, pre-eclampsia and theca lutein ovarian cysts, are now rarely encountered. In contrast, patients with partial molar pregnancy typically do not present with classical features of complete mole, and are often misdiagnosed as having a missed or incomplete miscarriage before uterine evacuation.⁶ Histological examination after evacuation for presumed missed or incomplete miscarriage can improve the detection of molar pregnancy.

Human chorionic gonadotropin

Women presenting with vaginal bleeding in early pregnancy commonly undergo ultrasound and hCG measurement, which may lead to the diagnosis of abnormal pregnancy requiring uterine evacuation. At presentation, around 50% of molar pregnancies have hCG levels of greater than 100,000 mIU/mL, however a single hCG result is not reliable in differentiating molar pregnancy from other types of pregnancy. Nonetheless, a baseline hCG measurement prior to uterine evacuation may be useful for subsequent surveillance for postmolar GTN.

Ultrasound scan

Pelvic ultrasound scan is commonly used in the initial assessment of suspected GTD. With greater availability of ultrasound scanning, diagnosis of complete mole is often made in the first trimester, particularly when there is absence of a fetus and amniotic fluid, together with a cystic appearance of the placenta. The characteristic intrauterine ‘snowstorm’ appearance on ultrasound is less common, especially in the first trimester. Ovarian theca lutein cysts may also be seen on ultrasound. Since fetal and amniotic tissue can be present in partial mole, it is often diagnosed incorrectly as missed or incomplete miscarriage.

Histopathology and genetics

Tissue specimens collected after evacuation for suspected molar pregnancy or miscarriage should undergo histopathological examination to confirm the diagnosis and classify the type of GTD. Macroscopically, complete mole consists of enlarged hydropic villi and semi-transparent vesicles of various sizes and an absence of fetal parts. However, early complete mole may exhibit minimal or no abnormal villi. Microscopically, complete mole shows trophoblastic proliferation, florid cistern formation, and no fetal tissues. There may be cytological atypia and mitotic figures. In first-trimester complete molar pregnancy, enlargement of villi may not be apparent. However, a characteristic polypoid appearance with abnormal villous stromal changes and trophoblastic hyperplasia may be present. In partial mole, these histologic findings are less distinct, and fetal parts may be seen. The appearance of a partial mole may resemble that of hydropic spontaneous miscarriage. When considering the diagnosis of a complete mole, the differential diagnoses should include partial mole, hydropic miscarriage and early non-molar pregnancy with florid trophoblastic hyperplasia.

Immunohistochemistry for p57 is useful in differentiating a complete mole from a partial mole. It is a cyclin-dependent kinase inhibitor protein that is encoded by paternally imprinted, maternally expressed gene, and thus is absent in the villous cytotrophoblasts and stromal cells of complete moles, in which the maternal genome is lacking. Conversely, partial mole and non-molar abnormal gestations have strong nuclear p57 expression as maternal genome is present. Although p57 can differentiate partial mole from complete mole, it cannot differentiate partial mole from non-molar gestations.

Advances in molecular genetics have given valuable insights into the pathogenesis of GTD. Complete mole, partial mole and hydropic spontaneous miscarriage have distinct cytogenetics. Typically, complete mole involves a diploid karyotype (46 chromosomes) that is entirely paternal in origin, while partial mole is triploid with an additional paternal set of chromosomes (diandric triploidy). Accurate diagnosis of complete and partial mole can be achieved using microsatellite short tandem repeat (STR) genotyping, which demonstrates absence of maternal genetic contribution in complete mole and diandric triploidy in partial mole.⁷

Treatment

Suction evacuation

The preferred treatment for molar pregnancy is suction evacuation, which is ideally performed using a large suction cannula under ultrasound guidance to reduce the chance of incomplete evacuation. Intravenous oxytocin infusion may be given once the suction evacuation has been initiated, which can be continued postoperatively to promote uterine contraction and control blood loss. Preoperative type and screen should be made available in case there is hemorrhage requiring blood transfusion, particularly if the uterus is larger than 16 weeks’ gravid size. Rh status should be checked and anti-D immunoglobulin should be administered to Rh-negative women after molar evacuation. A second uterine evacuation is usually not required, unless there is persistent bleeding due to retained products of gestation.³

Hysterectomy

An alternative option, especially in women of advanced maternal age who not desire future fertility, is hysterectomy. Apart from providing permanent contraception, it reduces the chance of requiring chemotherapy by preventing persistent disease due to myometrial invasion.⁸ Medical evacuation and hysterotomy are not recommended as they are associated with higher maternal morbidity and increased risk of postmolar GTN.

Prophylactic chemotherapy

Prophylactic chemotherapy with methotrexate or actinomycin-D soon after evacuation of molar pregnancy has resulted in a reduction of postmolar GTN.^9,10 However, it should be considered only in selected women who have higher than normal risk of developing GTN or are unable to have regular hCG monitoring. Risk factors for developing GTN include high initial serum hCG of more than 100 000 mIU/mL, uterine size larger than gestational age, presence of theca lutein cysts of more than 6 cm and maternal age over 40 years.⁹

Surveillance after uterine evacuation

Following uterine evacuation, hCG monitoring every 1–2 weeks is recommended for prompt diagnosis and treatment of postmolar GTN. After spontaneous normalization of hCG, the risk of developing postmolar GTN is low, therefore, a shortened follow-up period is considered safe.^11,12 After initial hCG normalization in partial mole, a repeat hCG measurement at 1 month is recommended to confirm sustained remission. For complete mole, monthly hCG measurement for 6 months after hCG normalization is recommended. Ideally, monitoring should be done in a specialized center with multidisciplinary team involvement to ensure consistent management and optimal outcomes.

If unplanned pregnancy occurs during the surveillance period after normalization of hCG, continuation of pregnancy is considered acceptable. Evidence suggests that oral contraceptives are safe after molar pregnancy.¹³ The risk of recurrence after one molar pregnancy is low at around 1%, but is higher after successive molar pregnancies.¹⁴ Familial biparental recurrent mole is associated with NLRP7 and KHDC3 L gene mutations and has been described in women with recurrent molar pregnancies and familial clustering.⁷

Molar pregnancy with coexistent fetus

Rarely, molar pregnancy may coexist with a normal pregnancy. Almost half of these pregnancies are terminated electively due to maternal complications or patient preference. Women who opt to continue the pregnancy carry a high risk of spontaneous miscarriage (~33%). However, around 40–60% progress to a live birth.¹⁵ If the fetal karyotype and ultrasound findings are normal, continuation of pregnancy can be considered provided the pregnancy is uncomplicated. The risk of GTN in pregnancies with a coexisting mole and normal fetus is increased (26–43%) compared with singleton molar pregnancy.¹⁵

GESTATIONAL TROPHOBLASTIC NEOPLASIA

Diagnosis

Clinical assessment

Around 75% of GTN arises after molar pregnancy, most cases of which are diagnosed based on serum hCG levels.³ Thus, post-molar GTN commonly has minimal symptoms or signs. However, it can also occur after any pregnancy, including spontaneous miscarriage, ectopic pregnancy or term pregnancy. A common presenting symptom is abnormal vaginal bleeding. In the presence of vaginal metastasis, irregular bleeding and a bluish mass may be seen in the vagina. Biopsy of these bluish masses should be avoided due to the possibility of hemorrhage, particularly as diagnosis can often be made with serum hCG and history.

Rarely, patients can present with symptoms and signs due to metastatic disease. Hemorrhage from the metastatic tumor can occur in the brain, lung, liver, spleen or intestines. Pulmonary metastases are common in GTN, although most patients are asymptomatic. If there is extensive lung metastasis, patients may present with respiratory distress, hemoptysis or chest pain. Patients may also present with neurological symptoms and signs such as paraplegia due to brain or spinal metastasis. Therefore, in patients presenting with unusual symptoms or signs, GTN should be included in the differential diagnosis and serum hCG level should be checked as part of the investigation.

Human chorionic gonadotropin

GTN that develops from molar pregnancy is often asymptomatic and is diagnosed during monitoring of serum hCG levels after evacuation of uterus. In 2000, the Gynecology Oncology Committee of the International Federation of Gynecology and Obstetrics (FIGO) established the definition of postmolar GTN based on the trend of hCG levels, histology and specific investigations, as follows.¹⁶

• When hCG level plateaus for four measurements over a period of 3 or more weeks; i.e. Day 1, 7, 14, 21
• When there is a rise in hCG for three consecutive weekly measurements over at least a period of 2 or more weeks; i.e. Day 1, 7, 14.
• Histological diagnosis of choriocarcinoma

Plateauing or rising hCG levels after a molar pregnancy or, less commonly, after other types of pregnancy such as term pregnancy or miscarriage, may indicate the presence of GTN.

Ideally, when monitoring for GTN, a hCG test that can identify all forms of hCG (beta-hCG, core hCG, C-terminal hCG, nicked-free beta, beta core and, if possible, hyperglycosylated forms) should be used. The commercially available pregnancy test devices usually measure total hCG only and thus are unsuitable for GTN monitoring as they can lead to false-negative results, misdiagnosis and delay in treatment. Women with persistently low levels of hCG should be monitored continuously, as rising hCG levels may indicate progression to GTN. When a false-positive result due to the presence of heterophilic antibodies in the serum is suspected, retesting with another hCG assay by serial dilutional assay or testing of urine hCG may be considered. In the absence of GTN, ‘phantom hCG’ may occur when the serum hCG levels are persistently raised, while the urine hCG is negative. Finally, it is important that the same hCG assay is used consistently for longitudinal monitoring as different assays may produce different results for the same serum sample.

Imaging

When GTN is suspected, imaging studies such as ultrasound, chest X-ray (CXR), computed tomography (CT) or magnetic resonance imaging (MRI) may be performed to assess the extent of disease and stage the GTN. When staging postmolar GTN, pelvic ultrasound is often performed to assess for uterine lesions and adnexal involvement. CXR is commonly used to assess for pulmonary metastases including to count the number and measure the size of metastases, which is vital in calculating the risk score. Chest CT is not mandatory in the risk score assessment but is commonly done to further delineate the extent of disease. Although around 40% of patients have pulmonary micrometastasis at presentation, replacing CXR with CT has not improved treatment outcomes, as small metastases often resolve spontaneously.^17,18 If a chest CT is done, only lesions that are more than 1 cm should be included in the risk score assessment.³

Abdominal ultrasound, CT or MRI can be used to assess for liver metastases, although MRI is better at delineating suspicious liver metastases. CT or MRI of the brain may be performed to assess for brain involvement, which is important especially in the presence of neurological symptoms or other metastases. In the presence of pulmonary metastases that are more than 1 cm, or when diagnosis of choriocarcinoma, PSTT or ETT are being considered, whole body imaging, including CT of the chest, and MRI of the brain, pelvis and abdomen (or CT of abdomen) should be performed to assess the extent of disease and guide treatment.

Histopathology

Choriocarcinoma

Choriocarcinoma usually arises in the uterus but can also occur in the ovaries and Fallopian tubes, and metastasize to the liver, spleen, kidneys, bowel, lung and brain. Macroscopically, the tumor appears as a bulky dark red mass and exhibits extensive hemorrhage and variable degrees of necrosis. Microscopically, choriocarcinoma is characterized by a predominantly biphasic proliferation of malignant cytotrophoblasts and syncytiotrophoblasts, with absence of chorionic villi and extensive hemorrhage and necrosis; intermediate trophoblast may also be present. To differentiate gestational choriocarcinoma from non-gestational choriocarcinoma of germ cell origin, genotyping to identify distinct paternal alleles can be performed.

Placental site trophoblastic tumor

PSTT often arises from the endomyometrium with around 50% of cases demonstrating deep myometrial invasion. The tumor has white-tan-to-yellow appearance and a size range of 1–10 cm. Microscopically, PSTT originates from the intermediate trophoblast cells of the placenta at the site of pregnancy implantation. The tumor cells exhibit hyperchromatic nuclei, abundant eosinophilic or amphophilic cytoplasm and irregular nuclear membranes. The tumor lacks chorionic villi and the mitotic count tends to be low. Immunohistochemically, it is characterized by diffuse expression of human placental lactogen (hPL), MUC-4, HSD3B1, HLA-G and Mel-CAM (CD146), and focal expression of hCG and inhibin. Typically, the proliferation index is raised with around 10–30% of cells expressing Ki67, which is higher than in benign exaggerated placental site reaction.¹⁹

Epithelioid trophoblastic tumor

Macroscopically, ETT comprises of solid and cystic nodules that are white or tan in appearance, with hemorrhagic lesions and deep infiltration into surrounding areas. Almost 50% of cases originate in the cervix or lower uterine segment, and some in the uterine fundus or broad ligament. Microscopically, ETT resembles chorionic-type intermediate trophoblast forming relatively uniform islands with round nuclei and moderate amount of eosinophilic to clear cytoplasm. It is often rimmed by extensive necrosis and associated with a hyaline-like matrix. There may be other coexisting trophoblastic neoplasms with ETT. Differential diagnosis of ETT includes choriocarcinoma particularly following chemotherapy, PSTT and cervical squamous cell carcinoma.

(Atypical) placental site nodule

Placental site nodule (PSN) and APSN are often found incidentally in endometrial curettage specimens obtained for abnormal uterine bleeding. PSN/APSN occurs mostly in the endometrium, lower uterine segment and cervix. PSN is a benign condition that resembles intermediate trophoblast of the chorion laeve type. Generally, the lesion is not visible macroscopically, although small lesions of 4–10 mm may be seen which have yellow or tan appearance. Microscopically, PSN comprises of discrete nodules with central hyalinization, and the proliferation index is commonly low (< 5%). APSN is an entity with histopathological features intermediate between those of typical PSN and PSTT/ETT. Although specific diagnostic criteria for APSN have not been established, APSN is generally more than 5 mm in size, and has significant nuclear atypia, increased mitotic activity and Ki-67 proliferative index of > 5%.¹⁹

Staging and scoring

The FIGO staging system is commonly used to stage GTN, which is important for determining the appropriate treatment strategy and predicting prognosis.²⁰ It comprises anatomical staging (Table 1) and the modified World Health Organization (WHO) prognostic scoring system (Table 2).^16,21 The FIGO system classifies GTN into four stages based on the extent of disease: Stage I (confined to the uterus), Stage II (involvement of genital structures), Stage III (lung metastases) and Stage IV (metastases to other organs). The FIGO scoring system is used for risk assessment which includes factors such as age, antecedent pregnancy, interval from antecedent pregnancy, pretreatment hCG levels, largest tumor size, site and number of metastases, and previous failed chemotherapy. The scoring system is used specifically for post-molar GTN and choriocarcinoma to assess the risk of such patients having disease that becomes resistant to single agent chemotherapy. Those with a FIGO score of 0–6 are considered low risk for developing resistance whilst those scoring ≥ 7 have high-risk disease and are best treated with multi-agent chemotherapy.²⁰ More recently, a further category has been identified in which women with a score ≥ 13 are at risk of death either early (within 4 weeks of starting treatment) or later due to multidrug-resistant disease. This new group is termed ultra-high risk.²² Each patient with GTN is assigned a stage using a Roman numeral (I, II, III or IV), which is separated by a colon and then a total of all risk scores using Arabic numerals (e.g. Stage II:4).³ FIGO scoring is not used for PSTT or ETT as these types of GTN are less sensitive to single and multi-agent chemotherapy.²³ However, the staging is still relevant.²⁴

The current FIGO staging and scoring system was last updated in the year 2000, and a revision is expected to be published in 2026.

Investigation of suspected GTN

Most cases of GTN develop after molar pregnancy and are detected early because these patients should be on regular hCG monitoring. Those meeting the criteria for GTN then need further investigation to assess the disease extent in order to complete the FIGO scoring and staging discussed above (Tables 1 and 2). For GTN following a molar pregnancy, routine blood tests should include an updated serum hCG measurement together with pelvic ultrasound and CXR. However, if the CXR is suspicious for metastasis then contrast enhanced CT of the chest and abdomen should be performed. Only lung lesions of ≥ 1 cm are counted in the FIGO/WHO scoring system. Patients with confirmed lung metastasis are at risk of disease spread to the brain and should have head MRI with contrast.^25,26 If this is negative, then a lumbar puncture should be considered to assess the cerebrospinal fluid-to-serum hCG ratio, which is < 1 : 60 in the absence of brain involvement.²⁰ Scoring should be done based on data obtained preferably within 48 hours of starting subsequent treatment as these tumors can be very fast growing.²⁷

Patients presenting with suspected choriocarcinoma after any other type of pregnancy need more extensive investigation as they are very likely to have high-risk disease. In addition to routine blood tests, including an updated serum hCG, contrast-enhanced MRI of the head and pelvis, and CT of the chest and abdomen should be performed.²⁰ Pelvic ultrasound can provide additional information and is always useful to exclude a pregnancy as the cause of elevated hCG before exposing patients to radiation. Similar investigations are required for patients with suspected PSTT or ETT. FDG-PET-CT is rarely needed except in occasional cases of unexplained elevated hCG in which all other imaging is negative.²⁸

Treatment

Low-risk GTN

About two-thirds of low-risk patients will respond well to relatively non-toxic single-agent chemotherapy using either methotrexate (MTX) or actinomycin D (ActD).²⁴ Whilst a variety of different regimens have been described, the most commonly used MTX regimen involves administering MTX either as a fixed dose of 50 mg or 1 mg/kg intramuscularly on days 1, 3, 5 and 7. This is alternated with oral folinic acid (MTX/FA), given at a fixed dose of 15 mg or 0.1 mg/kg on days 2, 4, 6 and 8 (24–30 h after each MTX injection). The cycle is repeated every 2 weeks.²⁴ The most frequent ActD regimen currently used is 1.25 mg/m² IV once every 2 weeks.²⁵ A recent randomized trial comparing MTX/FA with ActD in FIGO score 0–4 patients showed that, whilst ActD had a higher primary cure rate, it was also more toxic in terms of hair loss and nausea and vomiting.²⁹ Importantly, patients who fail one single agent are usually cured with the alternative, and nearly all are ultimately expected to be cured. The trial showed no difference in overall time to cure. Consequently, the choice of which single agent to employ first is largely dependent on local healthcare providers and their patients. The chance of remission with one single agent falls with a rising FIGO score but even when the score is 5–6, one or two sequential single agents will induce remission in 60% of patients.³⁰ That said, in patients with a FIGO score of 5–6, there are three situations in which combination chemotherapy should be used as first-line therapy, as single-agent regimens are unlikely to be effective: 1) those with metastatic choriocarcinoma; 2) those with post-molar metastatic disease and an hCG ≥ 150,000 IU/L; 3) those with non-metastatic post-molar GTN or choriocarcinoma with an hCG ≥ 410,000 IU/L.³⁰ Treatment efficacy is monitored by measuring the hCG at least every 1–2 weeks. As long as the hCG is falling by at least 10% every 2 weeks then treatment continues. Change of treatment is typically needed because of disease resistance but in some is due to toxicity. Resistance to therapy is determined by either a plateau over at least three consecutive hCG values or a rise over two values. The choice of the next line of therapy (employing the second single agent vs using combination agent therapy) is often determined by the hCG level at the point of needing to change therapy.²¹ However, some centers will use the second single agent regardless of this level. Once the serum hCG is normal, consolidation treatment continues for two to three cycles to reduce the risk of relapse.²⁴

There are two surgical alternatives to chemotherapy for those patients with low-risk GTN without metastatic disease.³¹ These include a second uterine evacuation for post-molar disease.³² This approach has about a 40% chance of preventing the need for subsequent chemotherapy but carries a small risk of triggering serious hemorrhage, infection and uterine perforation. For those women who have completed their families, a hysterectomy is also an acceptable intervention but does not completely eliminate the need for chemotherapy, so continued hCG monitoring is needed. The duration and frequency of hCG monitoring after any of these treatments varies widely globally but should be for at least 1 year as most recurrences will occur during this time. Indeed, the overall risk of recurrence is 4%, and 75% of these occur in the first year.³³ Careful imaging in cases of suspected recurrence is needed to determine whether surgical resection might achieve a cure, as opposed to the need for multi-agent chemotherapy. The overall cure rate for low-risk GTN is approaching 100%. More details on the management of low-risk disease can be found in the recently published international GCIG/ESGO/ISSTD/EOTTD guidelines.²⁰

High-risk GTN

Patients who have post-molar GTN or choriocarcinoma with a FIGO score ≥ 7 require aggressive multi-agent chemotherapy from the outset.³⁴ This frequently comprises etoposide, MTX and ActD alternating weekly with cyclophosphamide and vincristine (EMA/CO). Whilst this is safe for those scoring 7–12, individuals whose score is ≥ 13 and with very advanced disease require initial gentle induction chemotherapy using 100 mg/m² low-dose etoposide and 20 mg/m² cisplatin on days 1 and 2, repeated weekly for one to three cycles. The latter avoids causing early deaths from massive tumor collapse with associated life-threatening hemorrhage and metabolic upset.³⁴ Once the acute period is passed (generally 1–3 weeks) then standard treatment can resume. Further adaptation of treatment is required for patients with brain metastases whereby the MTX dose in the EMA regimen is increased from 300 mg/m² to 1000 mg/m², with or without the addition of intrathecal MTX after each CO. Moreover, the presence of liver metastases, with or without brain metastases, is associated with subsequent drug-resistant disease and poor prognosis. In such cases, consideration should be given to replacing EMA/CO with a platinum-based combination chemotherapy regimen (etoposide and cisplatin), alternating weekly with EMA. To maintain treatment intensity, patients need G-CSF support for 3–5 days each week. In China, the FAEV regimen is a well-recognized alternative to EMA/CO.³⁵ Further details of these treatments can be found in the recently published international guidelines.²⁰

As in low-risk GTN, the response to chemotherapy can be assessed effectively with serial serum hCG measurements at least once every 1–2 weeks. Whilst about 80% of high-risk patients will enter a sustained remission with their first-line therapy, the remainder will either develop resistance during first-line treatment or relapse after completing consolidation therapy and so need salvage management.³⁶ The duration of consolidation treatment for patients with a FIGO score of 7–12 and ≥ 13 is typically between 2–4 and 3–4 cycles, respectively. Patients who develop resistance or relapse require careful re-imaging. If there is no evidence of disease on CT or MRI, or if there are multiple sites of disease, FDG-PET-CT can be helpful in identifying a focus for potential surgical resection. Where this is not feasible, further chemotherapy with an alternative regimen, such as paclitaxel and etoposide alternating every 2 weeks with paclitaxel and cisplatin (TE/TP), may be effective. Should this fail then use of an anti-PD1 targeting checkpoint immunotherapy agent, such as pembrolizumab, appears to induce sustained remission in about 75% of patients.³⁷ This is far superior to the previously used high dose chemotherapy (HDCT) with stem cell support that resulted in only a 20–40% sustained remission rate and with a 5–10% risk of death from the procedure itself.³⁸ Consequently, this toxic therapy is now employed only after immunotherapy failure and provided the disease is still sensitive to standard doses of platinum and etoposide, the two main agents used in HDCT. The overall cure rate for high-risk disease is currently > 96%.³⁴

Placental site and epithelioid trophoblastic tumors

PSTT and ETT appear to behave in a clinically similar fashion. Unlike choriocarcinoma, PSTT/ETT are often slow growing, metastasize late, secrete less hCG for the volume of disease present, involve lymph nodes a little more often and are less sensitive to chemotherapy agents, so single-agent treatment is not an option. Consequently, the WHO/FIGO scoring system should not be used to determine treatment. Two key independent prognostic factors for disease outcome have been identified. The first is the interval between the end of the causative pregnancy (usually the most recent) and the diagnosis. If this is less than 4 years, the prognosis is usually excellent with nearly all patients achieving long-term remission.³⁹ However, patients presenting more than 4 years after the end of the causative pregnancy have a poorer prognosis, even if they have Stage-I disease confined to the uterus.⁴⁰ Staging is important and, indeed, Stage-IV disease is an independent adverse prognostic factor. Consequently, any patient with biopsy-proven PSTT/ETT needs extensive imaging, as previously outlined for suspected choriocarcinomas, to provide accurate staging together with genetic microsatellite polymorphism analysis to ensure that the tumor is gestational and to establish the causative pregnancy time interval. This enables stage/risk-adapted therapy. Thus, for Stage-I disease confined to the uterus, the standard of care is a hysterectomy with ovarian conservation in premenopausal patients unless there is a family history of ovarian/breast cancer. No further treatment is required if the disease is caught within 4 years. However, those beyond 4 years from the causative/antecedent pregnancy should be offered a platinum-based combination chemotherapy, such as EP/EMA, for 12–16 weeks.⁴¹ As this alone is unlikely to be sufficient to prevent recurrence, additional treatment should be offered, the least toxic of which is immunotherapy with an anti-PD1 targeting agent such as pembrolizumab for 6 months. If this is not available, then high-dose chemotherapy or, alternatively, an experimental therapy could be considered. Those with Stage-II–III disease within 4 years will also need EP/EMA chemotherapy either before or after hysterectomy and any residual disease sites should be resected to ensure no active cancer is left. This differs from the management of post-molar GTN or choriocarcinoma in which resection of residual disease sites after chemotherapy is not required. Individuals presenting with Stage-II–III disease beyond 4 years from the causative pregnancy will need additional pembrolizumab, as for long-interval Stage-I patients. Those with Stage-IV PSTT/ETT, regardless of interval, require EP/EMA followed by pembrolizumab.²⁰

Fertility conservation is clearly an important issue in patients who have no children and a new diagnosis of PSTT/ETT. Given the activity of immunotherapy in this disease, it is tempting to speculate that pembrolizumab alone or following or in combination with EP/EMA might be sufficient to eliminate the disease and enable avoidance of hysterectomy.³⁷ Alternatively, focal resection of disease within the uterus might be possible in good-prognosis cases. These approaches are being tested on an experimental basis but currently are not yet ready for adoption as standard of care. Further information on the management of PSTT/ETT can be found in the GCIG/ESGO/ISSTD/EOTTD guidelines for GTD.²⁰

Management of atypical placental site nodule

This relatively new member of the GTD spectrum carries a 15% risk of association with or development into ETT or PSTT.¹ Given this malignant potential, thorough evaluation is warranted at diagnosis. Baseline assessment should include comprehensive imaging to detect both localized and metastatic disease, typically comprising pelvic ultrasound, MRI of the brain, abdomen and pelvis, and CT of the thorax.

Definitive management is with hysterectomy, but this represents overtreatment in the majority of cases. Since fertility preservation is an important consideration for most patients diagnosed with APSN, surveillance is an attractive option. This strategy involves close follow-up with hCG monitoring and regular imaging with pelvic MRI.² Patients should be counseled carefully regarding the limitations of surveillance and the potential for malignant transformation, particularly as prognosis for PSTT and ETT appears less favorable when the diagnosis is made more than 4 years after the antecedent pregnancy.

Fertility-sparing surgical approaches, including hysteroscopic focal resection of the lesion, have been reported.⁴² However, these techniques do not reliably ensure complete excision, as residual premalignant or malignant trophoblastic cells may persist at a microscopic level beyond the visible lesion. Consequently, such approaches should be undertaken with caution and only within the context of meticulous follow-up.

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