Gestational Trophoblastic Disease – Diagnosis and work-up

1. What every clinician should know

Background

Molar pregnancy and gestational trophoblastic neoplasms (GTNs) comprise a group of interrelated diseases, including complete and partial molar pregnancy, invasive mole, choriocarcinoma, epithelioid trophoblastic tumor and placental site trophoblastic tumor, which have varying propensities for local invasion and metastasis. Although GTNs most commonly follow a molar pregnancy, they may develop after any gestation. Molar pregnancies are classified as either partial or complete on the basis of their cytogenetic, histopathological and morphological characteristics. The distinctive features of these two entities are outlined in Table I.

Table I.

Complete hydatidiform moles (CHMs) have a chromosomal complement totally derived from the paternal genome. There is no identifiable fetal or embryonic tissue. The 46XX genotype is most common, arising from an anuclear, empty ovum that has been fertilized by a haploid (23X) sperm which then duplicates its own chromosomes. The chromosomal make-up of CHM is therefore derived entirely from the father. Pathologic characteristics include diffuse trophoblastic hyperplasia, swollen villi, and atypia at the site of placental implantation.

Partial hydatidiform moles (PHMs) typically have a complement of 69 chromosomes derived from two paternal and one maternal haploid set of chromosomes. Triploid genotypes are derived from a haploid ovum which is fertilized by two sperm. Histopathologic features show mild trophoblastic atypia and focal trophoblastic hyperplasia, focal chorionic swelling, often with the presence of embryonic tissue. GTN occurs in about 1-4% of patients with partial molar pregnancies, in contrast with approximately 20% of patients with complete molar pregnancies.

Persistent gestational trophoblastic neoplasia (GTN) may occur following a partial or complete molar pregnancy. This is described pathologically by the invasion of molar villi into the myometrium. An invasive mole may metastasize and cause heavy uterine bleeding and infection. In contrast, gestational choriocarcinoma (CCA) is a pure epithelial neoplasm made up of both neoplastic syncytiotrophoblast and cytotrophoblast without chorionic villi. Approximately 50% of CCA develop after molar pregnancies and the remaining occur after term deliveries (25%) or other gestations (25%). Placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) are uncommon variants of trophoblastic disease, consisting of mononuclear intermediate trophoblasts without chorionic villi that arise from the placental implantation site and chorion respectively.

Presenting Signs and Symptoms

Complete Molar Pregnancy

The clinical presentation of complete hydatidiform mole (CHM) has changed dramatically in the last 30 years. Prior to the routine availability and use of ultrasonography, complete molar pregnancy was usually diagnosed in the second trimester. Classic signs included high levels of hCG (usually greater than 100,000 mIU/ml), uterus larger than dates, pre-eclampsia, heavy bleeding and anemia, hyperemesis, theca lutein ovarian cysts, hyperthyroidism, and, rarely, trophoblastic embolization.

With the routine use of first trimester ultrasonography and widespread availability of serum hCG testing, most women are diagnosed in the first trimester, before these classic symptoms of complete molar gestation become manifest. In fact, almost 20% of women with complete molar pregnancies are asymptomatic and diagnosed by routine first-trimester ultrasonography. For women who are symptomatic, vaginal bleeding remains the most common presenting complaint.

Molar chorionic villi may disrupt maternal vessels by separating from the decidua and may result in distention of the endometrial cavity by large volumes of retained blood. Vaginal bleeding was the presenting symptom in 84% of our current patients at the New England Trophoblastic Disease Center (NETDC), and ranged from low-volume spotting to life-threatening hemorrhage. Less than 10% of current patients were anemic (Hgb less than 10g/dL) when diagnosed. Other traditional symptoms of complete molar pregnancy, including uterine enlargement, preeclampsia, hyperthyroidism, theca lutein ovarian cysts and hyperemesis are seen much less frequently now that earlier detection of complete molar pregnancies has become commonplace.

When theca lutein ovarian cysts are detected, it is almost exclusively in patients with very high serum hCG levels. Circulating hCG causes hyperstimulation and hypertrophy of the ovarian stroma. Theca lutein cysts generally resolve over an interval of 8-12 weeks and rarely require surgical decompression. Torsion is infrequent but has been reported. Like theca lutein cysts, hyperthyroidism was seen primarily in patients with very high hCG values. It is believed that highly purified hCG may have intrinsic thyroid-stimulating activity. It is important to recognize when this occurs, as patients with poorly controlled or untreated hyperthyroidism may develop thyroid storm at the time of anesthesia induction for evacuation.

Partial molar pregnancy

Patients with partial molar pregnancies typically present with signs and symptoms more consistent with a missed abortion. Vaginal bleeding is common, but uterine enlargement, preeclampsia and the other classic signs of a complete molar pregnancy are rarely seen. Partial molar pregnancies are now also most commonly diagnosed in the first trimester but presenting symptoms have not changed appreciably.

Gestational Trophoblastic Neoplasia

Patients with CHM are categorized as being either high-risk or low-risk based on their risk of developing postmolar GTN. Patients classified as high risk are those who present with signs and symptoms of marked trophoblastic overgrowth, such as markedly elevated hCG levels above 100,000 mIU/ml and /or excessive uterine enlargement greater than dates. These patients are at an increased risk (40%) of developing GTN, whereas patients with low-risk CHM are at a 4% risk.

The diagnosis of post-molar GTN is dependent on the careful monitoring of post-evacuation hCG levels. The Cancer Committee of the International Federation of Gynecology and Obstetrics (FIGO) has established the following guidelines for the diagnosis of postmolar GTN: (1) four or more hCG values that have plateaued over at least 3 weeks; (2) a rise in hCG greater than 10% for three or more values over at least 2 weeks; (3) the presence of histological choriocarcinoma; and (4) persistence of hCG six months after molar evacuation.

Locally invasive mole develops in approximately 15% of patients after evacuation of CHM and infrequently after PHM. Untreated invasive trophoblastic tumor may perforate through the myometrium, producing intraperitoneal bleeding, or erode into uterine vessels, causing vaginal hemorrhage. A bulky necrotic tumor may also serve as a nidus for infection. GTN is always associated with persistently elevated hCG levels. Presenting signs may include irregular vaginal bleeding, theca lutein cysts, uterine subinvolution, endometritis and persistently elevated hCG levels. Metastases occur in approximately 4% of patients with CHM.

GTN following a non-molar pregnancy is often diagnosed when a patient presents following a miscarriage, elective termination or term delivery with persistent vaginal bleeding. This complaint should prompt an evaluation of the serum hCG level. If elevated, a dilation and curettage is the routine next step, as this procedure is both diagnostic and potentially therapeutic. Following a molar pregnancy, persistent GTN may have the histologic pattern of either molar tissue or choriocarcinoma. After a term pregnancy or miscarriage, GTN characteristically has only the histologic features of CCA or its variant PSTT or ETT.

Gestational choriocarcinoma tends to metastasize early via the hematogenous route to the lungs, vagina, brain, liver, kidneys, gastro-intestinal tract and other distant organs. Pulmonary involvement occurs in 80% of patients with metastatic GTN. Because trophoblastic tumors are perfused by fragile vessels, metastases are hemorrhagic. Patients may present with symptoms related to the presence of metastatic disease. Patients with lung metastases can exhibit dyspnea, cough, hemoptysis and chest pain.

Trophoblastic emboli may cause pulmonary arterial occlusion and subsequent right-heart strain. Patients may have such significant pulmonary symptoms that they may be thought to have a primary pulmonary disease. Vaginal metastases can cause significant hemorrhage, particularly if biopsied. Patients with brain metastases are frequently symptomatic, presenting with vomiting, seizures, headache or focal neurologic deficits. In contrast, liver metastases are less commonly symptomatic. The diagnosis of GTN should be considered in any woman in the reproductive age group who presents with unexplained pulmonary or systemic symptoms.

2. Diagnosis and Differential Diagnosis

Work-up of Molar Pregnancy

Laboratory studies

When a diagnosis of complete or partial molar pregnancy is suspected, the patient should be evaluated for the presence of medical complications, including anemia, preeclampsia and hyperthyroidism. All patients should have a baseline serum hCG level and thyroid function tests performed in addition to a complete blood count with platelets, blood type and antigen screen. Patients who are Rh negative should receive Rh immunoglobulin at the time of molar evacuation because RhD factor is expressed on trophoblast. Patients should also have renal and hepatic function tests in anticipation of possible future chemotherapy.

hCG

Patients with CHM commonly have markedly elevated hCG levels in excess of 100,000 mIU/ml. hCG is produced by the hyperplastic syncytiotrophoblastic cells characteristic of molar pregnancy. Genest et al reviewed the clinical and pathological characteristics of 153 cases of complete mole managed at the NETDC between 1980 and 1990. Pre-evacuation hCG levels were greater than 100,000 mIU/ml in 46% of the patients. Similarly, Menczer et al reported that 30 (41%) of 74 patients with molar pregnancy had pre-evacuation hCG values greater than 100 000 mIU/ml. The measurement of high hCG levels in excess of 100,000 mIU/mL suggests the diagnosis of a complete molar pregnancy, particularly when associated with vaginal bleeding, uterine enlargement and abnormal ultrasound findings.

In contrast, partial hydatidiform mole (PHM) is less commonly associated with markedly elevated hCG values, which is attributed to the relative lack of trophoblastic hyperplasia when compared with complete moles. Only two (6%) of 30 patients with partial mole at our center had pre-evacuation hCG levels greater than 100,000 mIU/ml.

Sonography

The widespread use of ultrasonography during the first trimester of pregnancy has expedited the diagnosis of molar pregnancies. Complete molar pregnancies produce a characteristic vesicular pattern due to generalized swelling of the chorionic villi. Most first trimester complete moles have a typical ultrasound appearance characterized by a complex, echogenic intrauterine mass containing many small cystic spaces.

Among 24 cases of first trimester complete moles (mean gestational age 8.7 weeks), the initial sonographic interpretation was a complete mole in 17 (71%) cases. Those that were not correctly identified were classified as missed abortions. The specificity of the sonographic findings in a complete molar pregnancy may be increased by correlation with the serum human chorionic gonadotropin level.

Although the diagnosis of partial molar pregnancy by sonography is generally less reliable, unique ultrasonographic characteristics of PHMs have also been described, including focal cystic changes in the placenta and a ratio of the transverse to anteroposterior dimension of the gestational sac greater than 1.5. When both of these findings were present, the positive predictive value for partial mole was 87%. Fetal tissue may also be identified in partial moles.

Pathology

Diagnosis is confirmed once the pathology specimen is obtained, either from curettage of the uterine cavity or from hysterectomy. Because of earlier diagnosis and evacuation, the pathologic interpretation of the curettage material has been made more difficult. The pathology of early complete moles can be difficult to distinguish from both a partial mole and a hydropic abortion. Early CHM have smaller villi and less prominent trophoblastic hyperplasia and swelling of chorionic villi than second trimester cases.

Distinguishing early CHM from PHM and hydropic abortion may be facilitated by the use of flow cytometry to differentiate from diploid from triploid and the use of immunostaining for maternally expressed gene products. P57 is a protein from a gene that is only maternally expressed, therefore complete moles have absent villous stromal and cytotrophoblastic nuclear activity for p57. Other gestations, including partial moles, show nuclear reactivity of p57 in at least 25% of nuclei.

Chest radiography

A simple plain film may be helpful as part the work-up, primarily to identify preexisting lung disease that may later be misinterpreted as metastases.

Work-Up of GTN

Laboratory Studies

Patients being evaluated for GTN should undergo laboratory testing identical to what is described above for molar pregnancies. The use of chemotherapy in these patients is anticipated, so the addition of a differential blood count is helpful.

hCG

Serum hCG levels are used as a marker for diagnosis, monitoring response to treatment and follow-up. Occasionally, patients will have an elevated hCG that is unrelated to pregnancy or GTD. Evaluation of patients with elevated hCG of unclear etiology is aided by the intrinsic properties of hCG produced by GTN. The hCG produced by GTN is more heterogeneous than that produced by normal placental tissue. Trophoblastic disease samples contain higher amounts of free β-hCG, nicked hCG and β- core fragment. Clinicians following patients for GTN should use assays that detect intact hCG, as well as its metabolites and fragments.

False Positive hCG (Phantom hCG)

False elevations in hCG can also be seen with a phenomenon known as “phantom hCG.” Phantom hCG results from the presence of heterophilic antibody that causes low, false persistent elevations in hCG, often without a clear antecedent pregnancy. Serial serum values that remain mildly elevated, rather than rising or normalizing, support this diagnosis. Phantom hCG is not detected in the urine, and the diagnosis of heterophilic antibodies can be made by obtaining a negative urine pregnancy test in parallel with serum testing confirming the presence of heterophilic antibodies.

False positive hCG levels can also be caused by elevated cross-reacting LH levels in perimenopausal or menopausal women. These false elevations can be suppressed with estrogen replacement. Furthermore, low hCG levels in menopausal women can be due to pituitary hCG which can also be suppressed by estrogen. Furthermore, low hCG levels in menopausal women can be due to pituatary hCG which can also be suppressed by estrogen.

Quiescent GTD

Quiescent GTD is occasionally seen in women being treated for GTN. These patients have had a molar pregnancy or other type of GTN with appropriate treatment and subsequent regression of hCG levels. The hCG fails to normalize, however, and remains persistently elevated at a low level. While the hCG is real, it is predominantly non-hyperglycosylated. Exhaustive work-ups fail to reveal sites of recurrent or persistent disease and chemotherapy is ineffective in this setting. The source of the hCG is presumably dormant though viable trophoblastic tissue that is resistant to chemotherapy.

In most of these patients, the hCG level ultimately becomes undetectable spontaneously. However, it is recommended that these patients continue to be followed closely because 10-20% will develop active tumors requiring additional chemotherapy. When active disease recurs, hCG levels are higher and hyperglycosylated, which supports the need for chemotherapy in this setting.

A further cause of low level real hCG is the presence of hCG in PSTT and ETT. Intermediate trophoblastic tissue tends to produce lower levels of hCG than choriocarcinoma or invasive moles. These patients have been reported to have high levels of free beta, which strongly supports the diagnosis of PSTT. Cole et al reported that when hCG-free beta-subunit was greater than 35% it accurately distinguished PSTT from both CCA and quiescent GTD.

It is also important to note that low levels of real hCG can be measured in normal healthy menopausal women. The source of this hCG is the pituitary gland and it can be suppressed with estrogen replacement therapy.

Sonography

Pelvic ultrasonography can be used to identify extensive uterine involvement by trophoblastic tumor as well as the presence of chemotherapy-resistant disease within the uterine cavity. It has been described as a particularly useful tool in identifying patients who may benefit from hysterectomy for treatment of persistent GTN. As such, ultrasonography should be considered in the assessment of any patient with persistent or recurrent disease.

Hammond et al examined the role of hysterectomy in the management of GTN. In their retrospective cohort of 246 patients, hysterectomy, performed coincident with the institution of systemic chemotherapy, was shown to significantly reduce the amount of chemotherapy needed to achieve remission, regardless of whether or not metastases were present. Eysbouts et al. recently confirmed that hysterectomy reduced the need for chemotherapy in non-metastatic GTN.

Role of Chest Imaging Including Chest Computed Tomography

Choriocarcinoma has a propensity for early vascular invasion and subsequent widespread metastases. The presence of metastases impacts the stage, prognosis and treatment course (see Table II and Table III). The most common metastatic sites are the lung (80%), vagina (30%), brain (10%) and liver (10%).

Table II.

Table III.

Chest radiography is often adequate for detecting metastatic disease. Several studies have shown that chest CT will demonstrate micro metastases in about 40% of patients with a negative chest x-ray. However, micrometastases on chest CT has generally not been shown to influence the response to chemotherapy and clinical outcome. In addition, micro metastases on chest CT should not be used in defining stage of GTD.

Patients with a negative chest CT infrequently need additional imaging unless they have symptoms suggesting involvement of other metastatic sites. A case series from Duke University evaluated patients for features that might predict the presence of high-risk metastases (i.e. metastatic disease outside of the lungs, pelvis and vagina). All patients with metastatic disease in the liver or brain also had disease in the lungs or vagina. Many also had other high-risk features, such as markedly elevated hCG (above 40,000 mIU/mL) or an interval greater than 4 months since the antecedent pregnancy. The majority of patients in this series (15/18) had symptoms related to their metastatic disease. Patients who are asymptomatic with a normal pelvic examination and negative chest CT are unlikely to have liver or brain metastases.

Evaluation for cerebral involvement

Patients with brain metastases commonly present with symptoms consistent with increased intracranial pressure or focal hemorrhage, such as vomiting, seizures, headache, hemiparesis and visual disturbances. Bakri et al reported the presence of neurologic symptoms in 20 out of 23 (87%) patients with brain involvement. Athanassiou et al reported 66 of 69 patients (96%) as being symptomatic. Patients who have any neurologic symptoms or lung involvement should undergo CT or MRI of the brain.

If CT and MRI of the brain are negative, but the patient has symptoms consistent with brain metastases, it is reasonable to obtain a CSF sample in order to compare the plasma/CSF ratio of hCG. Bagshawe and Harland examined the plasma/spinal fluid ration in 73 patients with gestational choriocarcinoma. The mean plasma/CSF ratio was 286 in this cohort. However, in the 33 patients with documented brain metastases, 29 had a ratio less than 60.37

Although the widespread availability of brain MRI in most tertiary health care centers obviates the need for routine CSF testing in patients with GTN, it can be a useful adjunct when imaging is equivocal. Additionally, following the plasma/CSF ratio of hCG is a means of observing response to chemotherapy. It is important to recognize that a single plasma/CSF ratio can be misleading, as these values may fluctuate widely. While serum hCG levels may rapidly change, CSF hCG levels require more time to equilibrate. Serial measurements may provide more reliable information.

Patients with GTN and acute neurologic symptoms may not have metastatic disease. For example, there have been case reports of cerebral venous sinus thrombosis mimicking brain metastases in patients with choriocarcinoma.

Evaluation for liver metastases

Unlike patients with brain involvement, patients with liver metastases are infrequently symptomatic. Bakri et al. noted that only 5 (26%) of 19 patients with liver metastases presented with jaundice, intra-abdominal bleeding, or epigastic pain. Patients with metastases to the lungs or vagina should undergo imaging to evaluate liver involvement.

Role of PET scans in GTN

PET CT has a role in detecting the viability of persistent disease in patients undergoing treatment for GTN. It is often used before consideration of surgical resection to confirm the presence of isolated disease recurrence. In the series by Dhillon et al, seven patients underwent 18FDG-PET scans which correctly confirmed the presence (4 of 7 cases) or absence (3 of 7 cases) of disease sites defined by other imaging investigations.

Not only is PET scan important in identifying metastatic resistant disease, it may be valuable in identifying viable resistant disease confined to the uterus to facilitate local resection. Roja-Espaillat et al published a case report describing the use of PET scan to identify an isolated focus of active drug-resistant disease within the uterus. The patient strongly desired fertility sparing treatment. The lesion was removed surgically with preservation of the uterus and the patient was subsequently cured after two further courses of multiagent chemotherapy. As this case illustrates, PET scan can prove useful in detecting persistent viable disease in a myometrial sanctuary in patients with resistant, nonmetastatic GTN. Conservative surgical excision with uterine preservation is possible and can be of value in achieving remission.

There is currently no data supporting the use of PET CT for the routine staging of GTN, but it has an evolving role in identifying viable tumors, particularly in patients who may be candidates for surgical resection of drug-resistant disease.

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