Gestational trophoblastic disease (GTD) is a heterogeneous group of interrelated lesions and is biologically unique for several reasons:

Several histologically distinct entities make up GTD:

Complete and partial moles are abnormal pregnancies and are considered benign. The last three entities (CCA, PSTT, and ETT) are called gestational trophoblastic neoplasia (GTN) and are considered malignant because of their potential for local invasion and metastases. GTN is one of the rare human malignancies that can be cured even in the presence of widespread metastases. The term GTN is used instead of the more specific morphologic entity because treatment is frequently undertaken without knowledge of the precise histology.

When GTN develops after evacuation of a hydatidiform mole, the resulting tumor morphologically is either an invasive mole (IM), CCA, or, on rare occasion, PSTT or ETT. The tumor that develops after a term pregnancy or miscarriage histologically is CCA, PSTT, or ETT because there is no molar tissue in these gestations. When GTN develops after an ectopic pregnancy, the tumor morphology can be molar, CCA, PSTT, or ETT.

Incidence and Epidemiology

The incidence and etiologic risk factors that contribute to the development of GTD have been difficult to characterize because of problems in accumulating reliable data, bias, and interpretation and differing methods of expressing incidence in terms of hospital-based versus population-based data. Despite these problems, there are sufficient data to indicate that there are wide regional variations in the incidence of CHM. Estimates from North America, Australia, New Zealand and Europe have shown the incidence of CHM to range from 0.57 to 1.1 per 1000 pregnancies, whereas studies from Southeast Asia and Japan report an incidence approaching 2.0 per 1000 pregnancies.8–12 The incidence of hydatidiform mole in Taiwan is reported to be one in 125 pregnancies.⁹ In Ireland, the incidence of CHM and PHM has been determined to be 1 in 1945 and 1 in 695 pregnancies, respectively.¹³ In the United States, molar pregnancy is encountered in 1 in 600 therapeutic abortions and in 1 in 1000 pregnancies. There are data that show an increased incidence of CHM among American Indians, Eskimos, Hispanics, and African Americans.^14,15 There is no conclusive evidence that genetic traits, cultural factors, or differences in reporting account for this increase. The etiologic factors that have been linked to the development of CHM are advanced maternal age (>40 years) and prior molar pregnancy.^16,17 Familial clusters of biparental CHM have been associated with the NLRP7 gene mutation on chromosome 19q.¹⁸ In addition, well-documented nutritional studies have shown an inverse relationship between beta-carotene and animal dietary fat intake and the incidence of CHM.^19,20 In this regard, it is of interest that the documented decrease in the incidence of CHM in South Korea has been associated with a gradual Westernization of the Korean diet.²¹

The epidemiological features of CHM and PHM differ markedly. Parazzini and coworkers¹⁶ reported that the risk for partial mole was not associated with maternal age. Additionally, the risk for partial mole has been reported to be associated with the use of oral contraceptives and a history of irregular menstruation but not with dietary factors.²² Therefore, the risk of partial mole appears to be associated with reproductive history rather than dietary factors.²³

The overall incidence of invasive mole (IM) has been estimated at 1 in 15,000 pregnancies. Approximately 15% to 29% of hydatidiform moles will result in invasive mole.⁹ Determining the incidence rate of CCA is even more problematic because of the rarity of this condition and the difficulty in clinically distinguishing postmolar CCA from metastatic mole. In Europe and North America, CCA affects approximately 1 per 40,000 pregnancies, whereas in Southeast Asia and Japan the rates of CCA are 9.2 and 3.3 per 40,000 pregnancies, respectively.²⁴ The gradual decline in the incidence of both CHM and CCA in developing countries over the past 40 years presumably is due in part to improved socioeconomic conditions, earlier completion of childbearing, and improved nutrition.

Risk factors of CCA include prior CHM, ethnicity, and advanced maternal age. CCA is 1000 times more likely to occur after CHM than after another type of pregnancy. The risk is also increased in women of Asian, American Indian, and African descent.²⁴

Etiology and Pathogenesis

Studies over the past few years have substantially increased our understanding of the etiology and pathogenesis of hydatidiform mole and GTN. We now know that hydatidiform mole develops because of abnormal gametogenesis and fertilization. Recent studies have defined two different forms of hydatidiform mole: partial and complete. They are distinct cytogenetic processes with characteristic clinical and histopathological findings and do not represent a transition from normal to molar gestation.

PHM are characterized by a triploid karyotype (69 chromosomes) derived from two paternal and one maternal haploid sets of chromosomes.27–27 Most have a 69,XXX or 69,XXY genotype derived from a haploid ovum with dispermic fertilization. The fetus present in a PHM generally exhibits the stigmata of triploidy, including growth retardation and multiple congenital anomalies such as syndactyly, hydrocephaly, omphalocele, and hare lip.

CHM, in contrast, usually have a 46,XX genotype totally derived from duplication of the haploid genome of one sperm. A small percentage of CHM have 46,XY karyotype, consistent with dispermic fertilization. It appears that molar disease, both partial and complete, is associated with excess male genetic composition due to an abnormality of the egg, which is either devoid of maternal chromosomal material or allows for dispermy.²⁸

Several growth factors and oncogenes have been studied in molar tissues and CCA. Increased expression of p53 and c-fms has been observed in CHM, and increased ras and c-myc RNAs have been measured in CCA.31–31 Fulop and associates^32,33 have investigated the expression of various growth factors and oncogenes in normal placenta, complete and partial mole, and CCA. CHM and CCA were characterized by overexpression of c-myc, c-erbB-2, and bcl-2, and these oncoproteins could be important in the pathogenesis of GTN. Expression of c-fms protein did not differ between normal placenta and GTN. CHM and CCA were also characterized by increased expression of p53, p21, Rb, and MdM2. The p53 gene was studied to detect any mutation in 22 complete moles and 11 CCAs that had increased expression of p53. Because only one nonsense mutation in p53 was detected by polymerase chain reaction analysis, it is likely that the overexpressed p53 protein was the wild type. Although studies have identified increased expression of several growth factors in GTN, the precise molecular pathogenesis has not been determined. It was observed that the level of expression of epidermal growth factor receptor (EGFR) in CCA and the syncytiotrophoblast and cytotrophoblast of complete mole was significantly greater than the expression of EGFR in syncytiotrophoblast and cytotrophoblast of placenta and partial mole.²⁹ This observation was consistent in both immunohistochemical and in situ hybridization studies. In complete mole, strong expression of EGFR and c-erbB-3 in the extravillous trophoblasts was significantly associated with the development of postmolar tumor. The EGFR-related family of oncogenes might be important in the pathogenesis of GTN.

Extracellular proteinases such as matrix metalloproteinases (MMPs) are thought to be important in modulating both cell-matrix interactions and the degradation of the basement membrane necessary for invasion and metastases. CCA exhibits significantly stronger expression of MMP-1 and MMP-2 and decreased expression of tissue inhibitor of MMP-1 (TIMP-1) than are seen in the syncytiotrophoblast of complete and partial mole and normal placenta.³⁴ The increased expression of MMP-1 and MMP-2 and decreased expression of TIMP-1 in CCA could contribute to the invasiveness of CCA cells.

Certain genes are expressed normally on either the maternal or paternal allele, and this occurrence is described as parental imprinting. Modification of parental imprinting has been associated with tumor formation; both complete moles and CCA have relaxation of parental imprinting.³⁵ Relaxation of parental imprinting could be important in the pathogenesis of GTN.

Pathology

Hydatidiform moles can be categorized as either complete or partial on the basis of gross morphology, histopathology, and karyotype (Table 90-1).

Complete Hydatidiform Mole

CHM is characterized by the following pathological features:

• Vesicular swelling of placental villi.

• Proliferation of trophoblastic cells (both cytotrophoblasts and syncytiotrophoblasts) with varying degrees of hyperplasia and dysplasia (Figure 90-1).

• Fluid-filled and distended chorionic villi with scant or absent blood vessels.

• Absence of a fetus.

However, the pathological features of CHM have changed significantly over the past two decades owing to earlier diagnosis.³⁶ Whereas cavitation and circumferential trophoblastic proliferation were present in three quarters of complete moles in the past, these findings are now present in fewer than half the cases. Mosher and coworkers³⁷ compared pathological findings of 23 current complete moles (1994 to 1997; mean gestational age: 8.5 weeks) with 20 past complete moles (1969 to 1975; mean gestational age: 17 weeks). Histologically, complete moles that are now encountered have smaller mean maximal villous diameter (5.7 vs. 8.2 mm), less circumferential trophoblastic hyperplasia (39% vs. 75%), more primitive villous stroma (70% vs. 10%), and less global necrosis (22% vs. 54%). Keep and coworkers³⁸ observed that early complete moles were characterized by focal trophoblastic hyperplasia, minimal villous cavitation, and hypercellular primitive stroma. Complete moles are now often characterized by subtle morphologic alterations that could result in their misclassification as partial moles or nonmolar hydropic abortions. DNA ploidy studies or karyotyping are useful adjuncts in these circumstances.^26,27 Immunohistochemical tests for maternally expressed genes can also differentiate complete mole from partial mole and hydropic abortion.^39,40

Partial Hydatidiform Mole

PHM is characterized by the following pathological features:

• Varying-sized chorionic villi with focal swelling and focal trophoblastic cell hyperplasia

• Focal, mild atypia of implantation-site trophoblast

• Marked villous scalloping and prominent stromal trophoblastic inclusions

• Identifiable fetal or embryonic tissues (Figure 90-2)

Invasive Mole

IM is a tumor arising from a molar pregnancy that invades the myometrium by direct extension or by venous channels. Metastases to distant sites occur in about 15% of cases, most commonly to the lungs and vagina.²⁸ The tumor is characterized by swollen placental villi and accompanying hyperplastic trophoblastic tissue, which is usually dysplastic when located in sites outside the uterine cavity (Figure 90-3).

Choriocarcinoma

CCA is a highly malignant tumor characterized by abnormal trophoblastic cell hyperplasia and anaplasia, absence of chorionic villi, hemorrhage, and necrosis that invades the uterine wall directly or metastasizes hematogenously to distant sites, most commonly the lungs, vagina, brain, liver, spleen, kidneys, and intestines (Figure 90-4).

Placental Site and Epithelioid Trophoblastic Tumors

PSTT and ETT are extremely rare, monocellular tumors that arise from the intermediate trophoblast of the implantation site. In the case of PSTT, tumor cells infiltrate the myometrium and grow between smooth muscle cells with vascular invasion (Figure 90-5). ETT characteristically tends to form nodular masses that invade the myometrium. Hemorrhage and necrosis are less evident. Placental villi are absent in both of these tumors. With the use of immunoperoxidase stains, human placental lactogen can be identified prominently in PSTT, whereas hCG is present only sparsely. In both these tumors, serum hCG levels are low, but relatively high levels of free beta subunit of hCG are detectable in patients with PSTT compared with other forms of GTN.⁴¹ There appears to be a direct correlation between the mitotic activity of PSTT and outcome.⁴²

Immunobiology

The remarkable curability of GTN might be attributable partly to a host immunologic response to paternal antigens expressed on trophoblastic cells.⁴³ The prognosis of patients with gestational CCA has been related to the intensity of lymphocytic and monocytic infiltration at the tumor-host interface.⁴⁴ Because the lymphocytes and macrophages that infiltrate gestational CCA are probably exposed to paternal antigens and oncoproteins, the immune cells could become activated. Immunologically active cells might promote the regression of GTN through their release of cytokines. Cytokines have been reported to inhibit the proliferation of CCA cells in vitro and to increase the human leukocyte antigen (HLA) expression of CCA cells in vitro, thereby increasing immunogenicity.⁴⁵

It has been theorized that the development and progression of GTN could be favored by histocompatibility between the patient and her partner. If the patient and her partner are histocompatible, the trophoblastic tumor that bears paternal antigens might not be immunogenic in the maternal host. The intensity of the host’s immunologic response might depend on the immunogenicity of the trophoblastic tumor. On the other hand, histocompatibility between the patient and her partner does not appear to be a prerequisite for the development of persistent GTN.⁴⁶ HLA systems could, however, influence the clinical course of rapidly progressive and fatal GTN. Tomoda and colleagues⁴⁷ reported that drug-resistant CCA was associated with increased histocompatibility between the patient and her partner. Similarly, Morgenson and coworkers observed that histocompatibility between patients and partners was associated with a greater risk of metastatic disease.⁴⁸ Because all chromosomes in a CHM are paternal in origin, a CHM is a complete allograft and could stimulate a vigorous immune response by the maternal host. There is evidence for both a cellular and a humoral response to CHM. When compared with normal placentas, molar implantation sites have fivefold increased infiltration by helper T cells.⁴⁹ Circulating immune complexes have also been measured in patients with CHM and have been noted to increase as the patient entered remission.⁵⁰

Circulating immune complexes in patients with CHM have been demonstrated to contain paternal HLA antigens.⁵¹ The maternal host with a CHM is therefore sensitized to paternal HLA antigens. The distribution of HLA antigens in molar chorionic villi has been determined by immunofluorescent assays.⁵² HLA A, B, and C antigens were detected on the stromal cells of molar chorionic villi but not on the villous trophoblast; however, the molar villous fluid that bathes the stromal cells does not contain soluble HLA antigen.⁴³ The maternal host could therefore be sensitized to paternal HLA antigen when the villous trophoblastic layer is disrupted and HLA-positive villous stromal cells are released into the circulation.

The clinical presentation of CHM has changed dramatically over the past two decades in the wake of the widespread use of ultrasound and improved methods for hCG measurement. Prior to 1980 CHM was usually diagnosed in the second trimester, whereas the diagnosis is now usually made in the first trimester, before the classic clinical signs and symptoms appear. Table 90-2 summarizes the signs and symptoms of classic CHM and PHM. When patients with CHM present with these classic signs and symptoms, they are at higher risk of developing GTN. Soto-Wright and associates³⁶ compared the clinical presentation and outcome of patients with CHM at the New England Trophoblastic Disease Center (NETDC) between 1988 and 1993 with those of patients between 1965 and 1975 and noted that despite the change in presentation, there was no change in the incidence of GTN.

Gestational Trophoblastic Neoplasia

GTN is the term used when there is clinical, radiologic, pathological, and/or hormonal evidence of persistent GTD, which can follow any type of antecedent pregnancy. Rarely, the antecedent pregnancy cannot be determined. GTN comprises two distinct disease entities—nonmetastatic or metastatic—based on whether there is evidence of disease beyond the uterus. Guidelines for the diagnosis of postmolar GTN recommended by the Cancer Committee of the International Federation of Gynecologists and Obstetricians (FIGO) are as follows:

• A plateau in the level of hCG over more than 3 consecutive weeks

• 10% or greater rise in hCG for 3 or more values over at least 2 weeks

• Persistence of hCG 6 months after molar evacuation

• Histologic evidence of IM, CCA, PSTT, or ETT

Nonmetastatic Gestational Trophoblastic Neoplasia

Nonmetastatic or locally invasive GTN (NMGTN) develops in about 15% of patients after evacuation of CHM, 1% to 6% after PHM, and infrequently following other pregnancies.22,28,56 Patients with NMGTN present with irregular vaginal bleeding, ovarian theca lutein cysts if hCG levels are markedly elevated, and uterine subinvolution or asymmetrical enlargement due to the presence of tumor. Invasive tumor can erode through the uterine vessels causing vaginal bleeding, or perforate through the myometrium causing intraperitoneal hemorrhage. The presence of bulky necrotic tumor, characteristic of CCA, can serve as a nidus for sepsis, particularly Clostridium welchii. The presence of deep myometrial invasion can be confirmed by ultrasound or imaging studies such as magnetic resonance imaging (MRI).

Metastatic Gestational Trophoblastic Neoplasia

Metastatic GTN (MGTN) occurs in approximately 5% of patients after molar evacuation and infrequently after other gestations. Although IM infrequently metastasizes to distant sites, most MGTN is due to CCA, which characteristically disseminates widely hematogenously. Because trophoblastic tumors are highly vascular, metastatic lesions often present with signs and symptoms of spontaneous bleeding. The most common metastatic sites are the lung (80%), vagina (30%), brain (10%), and liver (10%).⁹ As a general rule, cerebral and hepatic metastases are uncommon unless there is concurrent involvement of the lungs and/or vagina.

Pulmonary Metastasis

The pulmonary parenchyma is the most common site of metastasis. Eighty percent of patients with metastatic disease have lung involvement that presents with cough, chest pain, hemoptysis, and/or dyspnea, or as an asymptomatic lesion on chest x-ray. Respiratory symptoms can be acute or chronic depending on the extent of disease. Pulmonary involvement produces four principal radiologic patterns:

1. Solitary or multiple discrete rounded densities

2. “Snowstorm” or alveolar pattern

3. Embolic pattern resulting from pulmonary artery occlusion

4. Pleural effusion

Patients can develop pulmonary hypertension in the absence of substantial parenchymal involvement because of vascular obstruction with tumor. Because the respiratory symptoms and radiographic findings can be striking, patients may be thought to have a primary pulmonary disease, thus delaying the diagnosis. Therefore, it is important to obtain an hCG level in any woman of reproductive age who presents with evidence of metastatic disease without a known primary. Gynecologic symptoms may be minimal or absent in patients with extensive pulmonary involvement. In fact, the reproductive organs are frequently free of disease in patients with widespread metastases. Early respiratory failure requiring mechanical ventilation can develop in patients with extensive pulmonary involvement and can cause death before effective chemotherapy can be started.59–59 Risk factors for early respiratory failure within 1 month of presentation include greater than 50% lung opacification, dyspnea, anemia, cyanosis, and pulmonary hypertension. With chemotherapy, patients could develop bleeding into metastatic sites and potentially worsen pulmonary symptoms and radiologic findings. Kelly and associates⁵⁷ observed that reducing the initial dose of chemotherapy did not protect against early respiratory failure and recommended administering intensive chemotherapy at the outset.

Vaginal Metastases

Thirty percent of patients with MGTN have vaginal involvement. Vaginal metastases are most commonly located in the suburethral area or fornices and are due to venous embolization of either IM or CCA. They usually present with either a purulent discharge or irregular bleeding (Figure 90-6). Surgical excision of a vaginal metastasis should be avoided (except in unusual circumstances) because the hemorrhage that results is frequently difficult to control. After chemotherapy is instituted, and tumor shrinkage has occurred, the vaginal lesion can be excised with less risk, if necessary. However, the optimal treatment for bleeding from a vaginal metastasis is arterial embolization.⁶⁰

Hepatic Metastases

CCA metastasizes to the liver in 10% of patients with MGTN, usually in postterm disease in which delay in diagnosis is more likely to occur. Hepatic lesions can present with symptoms of intraperitoneal bleeding, but in most patients hepatic involvement is asymptomatic.⁶¹

Brain Metastases

Cerebral lesions also occur in approximately 10% of patients with MGTN. Similar to hepatic metastases, cerebral involvement is usually seen in postterm patients with advanced disease due to delayed diagnosis. Involvement of the central nervous system (CNS) is usually associated with headache, vomiting, seizures, and focal neurologic signs such as slurred speech, hemiparesis, visual disturbances, or signs of a spinal cord lesion. Neurologic symptoms usually result from increased intracranial pressure or bleeding.64–64

Bagshawe and Harland⁶⁵ reported that the plasma-to-CSF hCG ratio was <60 in patients with CNS disease. However, a single plasma-to-CSF hCG ratio can be misleading because rapid changes in serum hCG levels due to the effects of treatment on the tumor output of hCG might not be reflected promptly in the CSF.⁶⁶ Occult asymptomatic CNS metastases are now being detected because of improved imaging techniques (particularly MRI), which allows for earlier therapeutic intervention before neurologic sequelae develop.

Other Metastatic Sites

Gastrointestinal, renal, and splenic metastases usually occur in patients with advanced disease in which the diagnosis has been delayed. Abdominal computed tomography (CT) scanning is the best imaging technique for detecting these metastatic sites, although the use of whole-body ¹⁸F FDG-PET scanning is being used more commonly.⁶⁷

Placental Site and Epithelioid Trophoblastic Tumors

PSTT and ETT are rare tumors that are derived from intermediate implantation site cytotrophoblasts. They can develop from any antecedent pregnancy, but most commonly arise from a term pregnancy or miscarriage and generally present months to years after the antecedent pregnancy with irregular vaginal bleeding or amenorrhea, enlarged uterus, and, rarely, nephrotic syndrome. The serum hCG level is relatively low in relation to tumor volume in comparison to other types of GTN. More than 30% of patients already have metastases at diagnosis.68,69

Laboratory and Imaging Studies

The optimal management of GTN requires a thorough evaluation of the extent of the disease prior to treatment. All patients with persistent disease should undergo a thorough pretreatment evaluation, including a complete history and physical examination, baseline levels of peripheral blood and platelet counts, baseline hCG titer, hepatic, thyroid, and renal function tests, and stool guaiac tests. A pelvic sonogram is helpful in detecting adnexal involvement, the presence of residual tissue in the uterine cavity, or the presence of deep myometrial invasion. Patients with evidence of chest metastases on chest x-ray should undergo a metastatic workup including CT scan of the pelvis and abdomen, and an MRI of the brain to facilitate staging.

Ultrasound

Ultrasound examination of the first-trimester uterus, particularly when combined with transvaginal color Doppler flow, has made possible the detection of abnormalities of early pregnancy. The diagnosis of CHM is nearly always made by ultrasound, except in very early pregnancy when the findings are frequently thought to resemble a missed abortion. Similarly, early ultrasound diagnosis of PHM is problematic. The indications for ultrasound when molar disease or GTN is suspected include the following:

• First-trimester bleeding

• The appearance of signs and symptoms of molar pregnancy

• Unusually high hCG levels

The ultrasound appearance of CHM does not vary considerably between the first and second trimesters. At either stage, complex, echogenic masses with multiple small cystic spaces are visible within the uterus, and no fetus is identifiable (Figure 90-7). Two sonographic features have been described that are characteristic of PHM: focal cystic changes in the placenta and a ratio of the transverse-to-anteroposterior dimension of the gestational sac greater than 1.5.⁷⁶ Changes in the shape of the gestational sac could be part of the embryopathy of triploidy. On rare occasions, particularly when PHM has progressed into the late first or early second trimester, the sonogram will show the presence of a fetus with multiple congenital abnormalities, focal hydropic changes in the placenta, oligohydramnios, and abnormal placental Doppler flow pattern. These changes might not be visible in the first trimester.

Ultrasound is also useful after molar evacuation when there is abnormal bleeding or a plateau or rise in the hCG level, to determine whether there is sufficient residual tissue in the uterine cavity to justify another evacuation, or whether invasive disease or adnexal involvement is present. Ultrasonography can also be used to help the clinician select patients who will benefit from hysterectomy because it can help assess the degree of uterine involvement with tumor. Ultrasound is also useful in monitoring the progress of theca lutein cyst regression and guide in the decompression of ovarian cysts when symptomatic.

Staging and Prognostic Scoring System

Table 90-3 summarizes the anatomic staging system and prognostic scoring system adopted by the FIGO Cancer Committee in 2002 that is now widely used both as a basis for comparison of treatment outcomes among treatment centers and as a guide for clinicians in the selection of optimal treatment regimens. A patient’s stage and total risk score are described by Roman and Arabic numerals, respectively, separated by a colon (e.g., III:8). The Prognostic Scoring System has proved to be particularly useful in predicting which patients are likely to become drug resistant and require modifications in their treatment regimens to optimize outcome.

The variables included in the prognostic score include tumor volume (hCG measurement, size, and number of metastases), site of involvement, prior chemotherapy exposure, and duration of disease. Each of these factors is considered an independent variable and is assumed to be additive.⁷⁹ Patients with prognostic scores of 6 or lower are considered to be at low risk for drug resistance, and are treated initially with single agents. When the prognostic score is >7, multiagent regimens are required to optimize outcome. In general, patients with stage I tumors have low-risk scores, and patients with stage IV tumors have high-risk scores. Therefore, the prognostic scoring system is best applied to patients with stages II and III by identifying those patients who initially require more intensive therapy to reduce the likelihood that they will become drug-resistant CCA after term pregnancy, which is one of the variables associated with poor prognosis.

We reviewed the experience with postterm CCA at the NETDC from 1964 to 1996.⁸⁰ Seven of 44 patients (16%) presented with clinical evidence of maternal–fetal bleeding that resulted in severe fetal anemia and nonimmune hydrops or third trimester bleeding. Although none of the infants had evidence of metastatic CCA, rare cases of fetal involvement by CCA have been reported and usually have resulted in either fetal or neonatal death. Other risk factors, including the time interval from delivery to diagnosis, sites of metastases, and pretreatment hCG level, were all significant in predicting outcome. All 31 of our patients with a prognostic score <8 survived, whereas 6 of 13 patients (46%) with a score >8 succumbed to their disease.

The primary management of molar pregnancy is surgical evacuation. Before proceeding with evacuation, the patient should be thoroughly evaluated to identify and stabilize medical complications, such as preeclampsia, electrolyte imbalance due to hyperemesis, hyperthyroidism, and/or anemia. After evacuation, conscientious hCG follow-up to detect GTN is mandatory.

Methotrexate With Folinic Acid Rescue

In 1964 Bagshawe and Wilde⁸⁹ described administering MTX with folinic acid (FA) to reduce chemotherapeutic toxicity. This regimen remains the initial treatment protocol for nonmetastatic and low-risk metastatic GTN at the Charing Cross Trophoblastic Disease Center as well as at our institution. Although MTX/FA is highly effective, its use is associated with a 20% rate of resistance. At the NETDC, complete remission was achieved in 147 of 163 patients (90%) with stage I and in 15 of 22 patients (68%) with low-risk stage II and III GTN.⁹⁰ Among the 23 patients who were resistant to MTX/FA, 14 (61%) subsequently achieved remission with ActD, and 9 required multiagent chemotherapy. Thrombocytopenia, granulocytopenia, and hepatotoxicity occurred in only 11 (6%), 3 (2%), and 26 (14%) patients, respectively. One patient required platelet transfusion and developed sepsis due to myelosuppression. No patient developed alopecia. The effectiveness of this protocol is thought to be due to the prolonged exposure to MTX because when MTX is administered at a higher dose (300 mg/m²) and short duration (over 12 hours), the remission rate declines to 69%.⁹¹

Multiagent Chemotherapy

Multiagent protocols are the treatment of choice for patients with high-risk GTN (prognostic scores >6) or as salvage therapy for patients with low-risk GTN who experience resistance to single-agents.

Other Multiagent Regimens

Regimens containing ifosfamide and paclitaxel have met with some success103,104 as has autologous bone marrow transplantation or stem cell support concurrent with high-dose chemotherapy although its role in GTN has yet to be defined.^105,106

Osborne and colleagues described a novel three-drug doublet regimen consisting of paclitaxel, etoposide, and cisplatin (TE/TP) that induced remission in two drug-resistant patients.¹⁰⁷

Experience with these multiagent protocols is limited; thus studies to clarify their role are ongoing, as are attempts to identify new agents to treat drug-resistant patients.

Method of Administration

At the NETDC, hCG levels are measured weekly after each course of chemotherapy and serves as the primary basis for determining the need for additional treatment. Courses of chemotherapy are usually administered at 2- to 3-week intervals until the hCG level becomes undetectable. One or two courses of consolidation therapy are administered to patients with stage I GTN who are resistant to their initial drug and require sequential or multiagent therapy, and all patients with low-risk stage II or III MGTN after gonadotropin remission is achieved (defined as 3 consecutive weekly undetectable hCG tests). We have not found it necessary to administer consolidation therapy to patients with stage I GTN who respond completely to the initial single-agent regimen. In select patients with stage I GTN and low FIGO scores (<4), it is our practice to closely monitor the hCG level after the first treatment, and administer additional therapy only if the hCG level plateaus for more than 2 consecutive weeks or reelevates, or hCG levels do not decline by 1 log (tenfold) within 18 days after completing the first treatment. If a second course of MTX/FA is necessary, the dosage of MTX remains unaltered if the patient’s response to the first treatment has been adequate. An adequate response is defined as a fall in the hCG level by 1 log (tenfold) after each course. When the response to the first treatment is inadequate, the dose of methotrexate is increased by 50%. If the response to two consecutive courses is inadequate, the patient is considered to be resistant to MTX and ActD is instituted. If a patient fails to respond to sequential MTX/ActD, then either MAC or EMACO is administered.

Patients who require multiagent chemotherapy should be treated intensively to maximize outcome. We administer multiagent chemotherapy as frequently as toxicity permits (usually at 2- to 3-week intervals) until the patient attains three consecutive weekly undetectable hCG values. After the patient achieves normal hCG levels, three or four additional courses of chemotherapy are administered to reduce the risk of relapse. Relapse occurs because of the presence of undetectable resistant foci of disease that produces amounts of hCG below the threshold of assay systems in use.

Table 90-9 summarizes treatment protocols used for the management of stage I GTN.

Treatment is either surgical or medical, depending on the patient’s desire to preserve fertility. Primary hysterectomy as initial treatment in patients who desire sterilization reduces the number of courses of chemotherapy required to achieve remission or avoids chemotherapy altogether.¹⁰⁸ We advocate the use of a single dose of adjuvant chemotherapy (usually ActD 1.25 µg/m²) at the time of surgery to eradicate any occult metastases. In our experience, its use has not been associated with increased postoperative morbidity.

Table 90-10 summarizes the results achieved at the NETDC with stage I GTN. Between July 1965 and December 2011, 600 patients were treated. Complete sustained remission was achieved in 514 patients (85.6%), of whom 468 received sequential MTX/ActD and 45 underwent surgery. The 34 patients who underwent hysterectomy as initial therapy sought sterilization. The one patient who was treated primarily with a multiagent regimen had a prognostic score of 6, which is high for low-risk patients and appears to be associated with a higher risk of resistance to single agents. The remaining 86 patients (14.4%) who were resistant to their initial therapy subsequently were cured with either multiagent chemotherapy or surgical intervention.

Management of Cerebral Metastases

Craniotomy should be reserved for patients who develop progressive neurologic deterioration, indicating the need for acute decompression or for control of bleeding. In rare instances, cerebral metastases that are resistant to chemotherapy may be treated with local resection, particularly if located at the periphery. Most patients with cerebral metastases who achieve remission have little or no residual neurologic deficits unless there has been an acute hemorrhagic episode.

Management of Hepatic Metastases

The management of liver metastases may be difficult. If a patient is resistant to systemic chemotherapy, hepatic arterial infusion might be effectively used in selected cases. Hepatic resection might be necessary to control acute hepatic bleeding or to remove localized areas of resistant tumor. Grumbine and associates¹¹⁴ reported the use of selective occlusion of the hepatic arteries and concurrent combination chemotherapy in a patient with bleeding liver metastases who ultimately attained remission. Wong and colleagues¹¹⁵ also noted that 9 out of 10 patients with hepatic involvement achieved complete remission with primary intensive multiagent chemotherapy without hepatic irradiation. Bakri and colleagues⁶¹ similarly reported that 5 of 8 patients (63%) with liver metastases treated with multiagent chemotherapy alone attained remission.

Table 90-15 summarizes the results obtained in patients with stage IV GTN at the NETDC. Prior to 1975, before the routine use of multiagent protocols for stage IV disease was initiated, only 6 of 20 patients (30%) achieved remission. After 1975, 16 of 19 patients (84%) were cured. This dramatic improvement in survival is a result of recognizing the importance of risk factors, using a multimodal approach to the management of these critically ill patients and the use of support systems for the management of complications both from their disease and treatment.

Management of Relapsed and Chemoresistant GTN

When a tumor becomes drug resistant or relapses after treatment with either primary and secondary chemotherapy as manifested either by a plateau or reelevation of the hCG level, it is necessary to reevaluate her status and look for occult metastases. Mutch and colleagues¹¹⁶ reported that recurrences occur after initial remission in 2% of patients with nonmetastatic GTN, 4% of patients with good-prognosis (low-risk) metastatic disease, and 13% of patients with poor-prognosis (high-risk) disease. Relapses developed within 3 and 18 months in 50% and 85% of patients, respectively. At the NETDC, we have observed relapses in 3% of patients with stage I, 8% with stage II, 4% with stage III, and 9% with stage IV disease.¹¹⁷ The mean time to recurrence from the last undetectable hCG level was 6 months, and this rate did not differ among the four FIGO stages. All patients with stage I, II, and III GTN who relapsed were subsequently cured, whereas both of the stage IV patients with recurrent disease succumbed. In contrast to patients with GTN, relapse is rare in patients with molar pregnancy once the hCG level becomes undetectable.^118,119

Management of PSTT and ETT

Patients diagnosed with PSTT and ETT are managed similarly. Hysterectomy rather than chemotherapy is the first-line treatment in patients even when metastases are present. At surgery, lymph node sampling should be carried out when there is deep myometrial invasion because, in contrast to CCA, these tumors can spread via lymphatics. The survival rate for patients with nonmetastatic disease is 100%. Patients with metastases may achieve remission if treated with multiagent chemotherapy, particularly if they are diagnosed within 4 years of the antecedent pregnancy.120–123 Risk factors for metastatic disease in patients with PSTT include interval from the previous pregnancy of longer than 2 years, deep myometrial invasion, the presence of tumor necrosis, and mitotic count of more than 6 per high-power field. At present, platinum-containing regimens such as EMAEP are the treatment of choice. Survival rates approach 50% to 60%. In the largest series reported to date, the group from Charing Cross has reported that all 31 patients treated by primary hysterectomy and adjuvant chemotherapy achieved complete remission with no additional therapy.¹²⁴

After evacuation of a molar pregnancy, all patients should be followed with weekly quantitative hCG tests until the levels are undetectable for 3 consecutive weeks. Although the current guidelines of the American College of Obstetricians and Gynecologists recommend monthly testing for 6 months before pregnancy is advised, recent reports from the NETDC and other centers indicated that the risk of relapse after achieving undetectable hCG levels is negligible.118,119 We now discontinue testing and allow for pregnancy after 3 consecutive weeks and 3 consecutive months of undetectable hCG tests.

Patients should be counseled to use effective contraception during the entire interval of follow-up. We do not encourage the insertion of intrauterine devices until the patient achieves undetectable hCG levels because of the risk of infection or perforation if residual tumor is present. Unless the patient desires surgical sterilization, her options are either hormonal or barrier methods. Although the incidence of postmolar tumor has been reported to be increased in patients who start oral contraceptives before the hCG level becomes undetectable,¹²⁵ data from the NETDC and other centers indicate that oral contraceptives do not appear to increase the risk of postmolar GTN.^9,126

After completion of the prescribed follow-up period, pregnancy may be undertaken. Patients should be counseled that they are at increased risk of another molar pregnancy in any subsequent gestation. For that reason, we highly recommend that a pelvic ultrasound be performed at 10 weeks of gestation, at which time it should be possible to rule out a recurrent molar gestation. There is also anecdotal evidence that patients who have been treated for GTN have a higher incidence of another trophoblastic event after any subsequent pregnancy. Therefore, all patients with a history of molar pregnancy or GTN should undergo hCG testing at the 6-week postpartum or postabortal visit.

Psychosocial Consequences of Gestational Trophoblastic Neoplasia

Women who develop GTN can experience significant mood disturbance, marital and sexual problems, and concerns over future fertility.¹³¹ Because GTN is a consequence of pregnancy, patients and their partners must confront the loss of a pregnancy at the same time that they face concerns regarding malignancy. Patients can experience clinically significant levels of anxiety, fatigue, anger, confusion, sexual problems, and concern for future pregnancy that last for protracted periods of time. Patients with metastatic disease and active disease are particularly at risk of serious psychological disturbances.

Psychosocial assessments and interventions should be provided to patients with GTN and their partners; these assessments should be targeted particularly to patients in the metastatic and active disease groups. The psychological and social stresses related to persistent GTN can last for many years beyond achieving remission.

Issues for the Future

Survival in GTN has improved dramatically over the past three decades because of the introduction of sensitive and specific hCG assays for diagnosis, treatment, and follow-up and because of the introduction of effective chemotherapy regimens based on patients’ risk profiles. Further advances in the treatment of GTN can be achieved through earlier detection and intervention and through the introduction of effective chemotherapeutic protocols for resistant disease.

It is well recognized that the treatment of patients, particularly those with high-risk GTN, by physicians who are experienced in the management of this disease achieves optimal results. Therefore, prompt referral to or consultation with treatment centers is always in the best interest of the patient.