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.