189Gestational Trophoblastic Disease

CHARACTERISTICS

•   Gestational trophoblastic disease (GTD) describes a group of tumors that arise from trophoblastic cells. This is usually the result of an abnormal fertilization event and includes molar pregnancy, choriocarcinoma, placental site trophoblastic tumor (PSTT) and epitheliod trophobblastic tumor (ETT).

•   Hydatidiform molar pregnancy occurs in approximately 1 out of 1,000 pregnancies in North America. Clinical features of a mole are vaginal bleeding in the first trimester or early second trimester; uterine size large for dates; ovarian theca-lutein cysts (seen in 46% of patients, 2% of which may torse); early preeclampsia less than 20 weeks (12%–17%); hyperthyroidism due to the similarity between the alpha subunit of both human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH) hormones; hyperemesis gravidarum (20%); passage of vesicles per vagina; and respiratory complaints due to tumor emboli or increased progesterone (27%).

•   Risk factors for a molar pregnancy include age (<20 years or >40 years of age), history of a prior mole, and Asian ethnicity.

•   WHO has classified GTD into two states: premalignant and malignant. The premalignant tumors are the complete and the partial moles. The malignant tumors are the invasive mole, gestational choriocarcinoma, ETT and PSTT. Within the malignant tumors are the categories of nonmetastatic and metastatic. Within the metastatic category are low-risk metastatic and high-risk metastatic disease.

•   There is an increased risk for a second mole after a first molar pregnancy. This is usually paternally related. The risk of another molar pregnancy increases from 1 out of 1,000 to 1 out of 100. There is a familial recurrent hydatidiform mole syndrome (FRHM). This is an autosomal recessive disorder with mutations in NLRP7 (in 70% of cases) or KHDC3L (5% of cases) that results in a diploid complete mole of biparental origin.

•   A mole and fetus have been diagnosed at a rate of 1 out of 100,000 pregnancies. There are data to suggest a 40% chance of a live birth. Persistent GTD is diagnosed in 55% of these patients, and 22.7% are found to have metastatic disease. There is an increased risk for hemorrhage, preeclampsia, and metastatic disease. The pregnancy should be terminated if these life-threatening complications occur.

•   Tumors from other primary sites can produce hCG. Genetic studies should be performed on patient’s tumors who are refractory to common first line and salvage therapies to rule out nongestational choriocarcinoma.

190HISTOLOGY

•   Complete and partial moles are usually diagnosed at the time of uterine evacuation. Histopathology is the main diagnostic method. Other abnormal pregnancies/fetuses can be mistaken for a partial mole. These include Turner’s, Beckwith-Wiedemann, and Edward’s syndromes.

•   A complete mole has no fetal components. Furthermore, the placental villi are hydropic (or edematous) with no identifiable vasculature. The origin of this mole is considered to arise from fertilization of an anuclear oocyte with either two sperm or one sperm that duplicates itself, thus all nuclear DNA is paternal (most commonly diploid with a 46XX karyotype) while the mitochondrial DNA is maternal. Fluorescence in situ hybridization (FISH) can confirm the diagnosis. The rate of persistent GTD after a complete mole is 15% to 20%.

•   The partial mole’s origin is thought to arise from the dual fertilization of an egg by two sperm, or duplication of a paternal chromosome resulting in triploidy with 2:1 paternal to maternal DNA content. Fetal components can be seen, along with fetal vasculature and hydropic villi. FISH can aid with the diagnosis if necessary, and immunohistochemistry can add information with positive staining for p57 KIP2. Cytogenetic techniques, to include chromosomal banding and restriction fragment length polymorphism (RFLP) analysis of DNA, have allowed chromosomal patterns for partial and complete molar pregnancies differentiation. The rate of persistent GTD after partial mole is 0.5% to 5% (Table 2.32).

•   Choriocarcinoma occurs in 1 of 20,000 pregnancies and is inherently a high-risk disease at diagnosis, regardless of metastasis. It should be treated aggressively. 50% of tumors follow a term gestation, 20% occur after molar gestations (both partial and complete), and 25% occur after a spontaneous or elective abortion. These tumors have diverse, nonspecific ploidies and are highly malignant. Both cytotrophoblasts and syncytiotrophoblasts are present, with syncytiotrophoblasts predominating, but there are no chorionic villi. Metastasis occurs frequently to the lung (80% with symptoms such as hemoptysis or dyspnea), vagina (30% with bleeding), brain (10% with focal neurologic deficits, headache, mass effect), and liver (10% pain, hemoperitoneum).

•   PSTT may follow a term gestation, a nonmolar abortion, a complete mole, and, in theory, a partial mole. These tumors are mostly diploid and produce very low amounts of beta hCG as well as serum human placental lactogen (HPL). This is due to the presence of intermediate cytotrophoblast cells. There is an increased proportion of free beta hCG. These tumors stain for HPL, B1-glycoprotein, and Ki-67. PSTT’s grows slowly and can be seen years after any type of pregnancy. It can produce a nephrotic syndrome or hematuria. The prognosis depends on the time until diagnosis; if it presents less than 4 years since a pregnancy, the prognosis is better than if later. FIGO scoring is not used to determine treatment of PSTT. These tumor present with lung metastases in 10-29% of cases and 10% of patients develop metastases during followup. Treatment is recommended with hysterectomy and LND—ovarian conservation does not adversely affect outcomes. Adjuvant chemotherapy is recommended for: metastatic disease (also surgically remove primary tumor site) and for adverse prognostic factors such as interval from last known pregnancy greater than 2 years, deep myometrial invasion, tumor necrosis, mitotic count greater than 6/10 HPF. Recommended chemotherapy regimens are: EMA-EP or paclitaxel/cisplatin-paclitaxel/etoposide doublet.

•   Quiescent GTD is the state of elevated beta hCG without documented hyperglycosylated hCG. There has never been a documented case of quiescent GTD with a beta hCG level that is higher than 230 mIU/mL. In this disease state, the residual mole lacks a cytotrophoblastic cell population. Therefore, there is no hyperglycosylated hCG production, and as a result, no invasion. Usually the residual mass of tissue dies after 6 months. In 10.4% of cases, however, quiescent GTD can activate and lead to persistent trophoblastic disease. Therefore, when a hyperglycosylated hCG is detected, the patient should be treated with chemotherapy. This is similar to a low malignant potential tumor. There are some data to suggest waiting to treat until a threshold beta hCG level of 3,000 mIU/mL is detected (1,2).

•   Epithelioid trophoblastic tumor (ETT) is an extremely rare subtype derived from chorionic type intermediate trophoblast cells. Treatment is best with hysterectomy and LN dissection. Chemotherapy is recommended in addition to surgery for metastatic disease (after removal of the primary tumor site), and for adverse prognostic factors such as interval from last known pregnancy greater than 2 years, deep myometrial invasion, tumor necrosis, mitotic count greater than 6/10 HPF. EMA-EP or the paclitaxel/cisplatin-paclitaxel/etoposide doublet are chemotherapy options.

DIAGNOSIS

•   Diagnosis of a mole is by ultrasound and serum beta hCG level. Invasive hydatidiform mole/GTD occurs usually after evacuation of a complete mole or partial mole.

•   The diagnosis of an invasive mole/GTN is made if there is: persistent beta hCG for 6 months after evacuation of a molar pregnancy, an elevating beta hCG (a 10% rise over three values in 2 weeks), a plateauing beta hCG (a plateau of 10% over four values in 3 weeks), or evidence of metastatic disease (mainly lung). In addition, some may consider the presence of an hCG value greater than 20,000 mIU/mL 4 weeks after evacuation, diagnostic for an invasive mole. It is imperative to perform dual serum and urine hCG testing to rule out phantom hCG, which is due to heterophilic/cross-reacting antibodies in the serum hCG test.

192PRE-TREATMENT WORKUP

•   The pre-treatment workup of GTD is a pelvic ultrasound (which can document the primary tumor as a uterine mass and give its dimensions) and a chest x-ray. If the chest x-ray is negative, a CT of the chest can be obtained. If the lungs show metastatic disease, it is then necessary to obtain an MRI of the abdomen and the brain. Alternatively, some practitioners routinely obtain a CT of the chest, abdomen, and pelvis for initial evaluation, but only the lesions seen on the CXR should be scored. A urine beta hCG and serum beta hCG both need to be performed to confirm beta hCG presence. Serum laboratories include a quantitative beta hCG and hyperglycosylated hCG, CBC, renal function tests, liver function tests, thyroid function tests, and a physical examination. A lumbar puncture can be considered if central neurologic symptoms are present and the brain MRI is negative. The plasma to CSF ratio of hCG can be less than 60 in cases with cerebral metastasis, but this ratio is not always reliable.

•   Repeat D&C is controversial. With a second D&C, the risk of needing chemotherapy is 21%; with a third D&C, the risk of needing chemotherapy more than doubles to 47%, possibly due to hematogenic metastasis induced by curettage (3).

SERUM BETA hCG

•   Serum beta hCG is a very sensitive and specific marker for trophoblastic tissue and thus a good tumor marker for this disease. The half-life of beta hCG is 24 to 36 hours. The amount of hCG correlates to the amount of viable tissue: 5 mIU/mL is approximately equal to 10,000 to 100,000 viable cells. However, it is also produced by many other carcinomas, including lung cancer, ovarian cancer, and colon cancer. Genetic testing should be performed on refractory tumors to ensure the primary is GTD and not otherwise.

STAGING

•   FIGO 2002 staging is clinical incorporating WHO risk factors to obtain a final modified FIGO/WHO risk score (Table 2.33 A–C).

Stay updated, free articles. Join our Telegram channel

Join