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(GTN): Clinical sciences

Clerkships ⓘ Obstetrics and gynecology Neoplasia Gestational trophoblastic disease (GTD) and neoplasia (GTN)
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Gestational trophoblastic
disease (GTD) and
neoplasia (GTN): Clinical
sciences
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Gestational trophoblastic disease

(GTD) and neoplasia (GTN)

Gestational trophoblastic

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Gestational trophoblastic disease
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Content Reviewers
Andrew Allen, MD, FACOG, Stefan Stoisavljevic, MD, Lisa Miklush, PhD, RNC, CNS, Antonella Melani, MD,
Anita Tamirisa, DO

Contributors
Kathleen Pombier, MD, Mike Cothren, Tina Collins, Ursula Florjanczyk, MScBMC

Gestational trophoblastic disease, or GTD, is a group of conditions where trophoblastic cells of

pregnancy grow improperly. The most common type of GTD is benign hydatidiform mole, which includes
complete molar pregnancies and partial molar pregnancies that arise from abnormal fertilization.

Diagnosis and treatment of GTD is important because early recognition and proper management reduces
the risk of gestational trophoblastic neoplasia, or GTN, which is a malignant type of GTD. While GTN can
arise from pregnancies that aren’t GTD, such as miscarriages or viable pregnancies, GTN is most common
after a molar pregnancy and therefore, close surveillance is warranted in all cases of GTD.

When a patient presents with a chief concern suggesting gestational trophoblastic disease, perform a
focused history and physical exam, order a quantitative human chorionic gonadotropin, or hCG, test, and
obtain a pelvic ultrasound. Your patient will usually report amenorrhea and present for care thinking they
are pregnant. But unlike a normal pregnancy, the patient might report pelvic pain or pressure from early
uterine enlargement, or vaginal bleeding with possible passage of “grape-like” vesicles. The patient may
also report symptoms specific to high hCG levels often seen with GTD, such as tremors or heat
intolerance which are due to hCG stimulation of the thyroid. Or the patient might experience hyperemesis
and weight loss. Risk factors for GTD include a prior molar pregnancy; extremes of maternal age
including those older than 40 years and those younger than 20 years; and individuals of Asian ancestry.

On examination, you might see signs of preeclampsia like new blood pressure elevations and protein in
the urine. You may also find that the uterus is larger or smaller than you would expect for the estimated
gestational age. You might also feel an adnexal mass on a bimanual exam because high hCG levels can
stimulate the formation of large theca lutein cysts. Finally, you may also note that the hCG level is higher
than you'd expect for the anticipated gestational age.

On pelvic ultrasound, you might see a heterogeneous intrauterine mass with diffuse anechoic spaces,
with a characteristic “bunch of grapes” or “snowstorm appearance” and peripheral vascularity that is
highly suggestive of a complete molar pregnancy. On the other hand, a partial molar pregnancy can look
very similar to a normal pregnancy or spontaneous abortion, so you might see an empty gestational sac
or even fetal tissue. If the placenta is identified, it might be enlarged and cystic. Make sure to also look at
the ovaries, which often reveal large theca lutein cysts.

Based on these findings, suspect a molar pregnancy, and proceed with a suction dilatation and curettage,
or D&C, which serves as both diagnosis and treatment.

Here’s a clinical pearl! There’s a high risk of hemorrhage at the time of D&C in cases of molar pregnancy.
Make sure to order a type and cross before going to the operating room in case a transfusion is needed,
and have medications readily available to treat uterine atony, such as methylergonovine, carboprost, or
oxytocin. Additionally, order CBC, CMP, and thyroid function tests preoperatively; and get a serum
quantitative hCG level to serve as a reference point against future values. Also, remember to get a chest
X-ray for future comparison since the lungs are the most common extrapelvic metastatic site for GTN.
Spread to the lungs may appear as discrete rounded opacities classically described as “cannonball”
metastases.

Now, some patients who have completed childbearing may request a hysterectomy rather than D&C.
While this isn’t common, it’s a reasonable choice. However, patients must be warned that they’ll require
postsurgical monitoring because a hysterectomy doesn’t exclude potential metastatic GTN developing in
the future.

Alright, back to our treatment. After D&C, send the products of conception for pathology and cytogenetic
analysis to confirm the diagnosis. If the analysis reveals focal villous edema with slight to moderate
proliferation and mild atypia of trophoblasts, fetal tissue, and a triploid karyotype on cytogenetics, most
frequently 69,XXY, then you can diagnose a partial molar pregnancy.

Now, while it’s accepted that hCG levels need to be monitored after a molar pregnancy, there’s no hard
and fast rule of how often to monitor. Many chose to do a quantitative hCG every 1 to 2 weeks until the
value is negative. Once a negative hCG is reached, a repeat is usually done one month later. As long as
the hCG remains negative twice over the span of a month, no additional testing is needed to rule out
GTN. But, because there is a higher chance of a subsequent molar pregnancy, you’ll want an early
ultrasound for all future pregnancies. Even if future pregnancies are normal, send the placenta for
examination after delivery and order a quantitative hCG 6 weeks postpartum, because there’s also an
elevated risk of GTN in the future. However, if at any point during monitoring after the D&C, the hCG
value plateaus or increases, you should diagnose GTN.

Here’s another clinical pearl! While your patient’s hCG levels are monitored, you should counsel them to
use reliable contraception to avoid pregnancy, since the rise in hCG from a new pregnancy can’t be
distinguished from an hCG rise caused by GTN.

Okay, let’s go back to pathology and cytogenetic analysis. If pathology identifies widespread villous
edema with moderate to severe proliferation and marked atypia of trophoblasts; absent fetal tissue, and
a diploid karyotype on cytogenetics, most commonly 46,XX, diagnose a complete molar pregnancy.

Similar to a partial mole, it’s important to trend quantitative hCG levels every 1 to 2 weeks until negative.
But, because complete moles are at higher risk for GTN, after the hCG reaches negative it should be
followed monthly for longer, usually 3 to 6 months, before you can be confident there is no GTN. In this
case, the patient will need additional monitoring in future pregnancies, which means obtaining an early
ultrasound, sending the placenta to pathology after delivery, and checking an hCG 6 weeks postpartum.

As with partial moles, if at any point during monitoring after a complete molar pregnancy the hCG value
plateaus or increases, you should diagnose GTN.

So, let’s talk about what to do when GTN develops. To begin, GTN is a malignancy, and while it most
commonly follows cases of benign GTD, specifically hydatidiform moles, GTN can also occur after any
miscarriage, ectopic pregnancy, or normal pregnancy.

Once GTN is diagnosed, it’s important to do a thorough pelvic exam, paying careful attention to
examining the vagina, which is the most common site of metastasis. Obtain a pelvic ultrasound to look for
tumors invading deeply into the uterus, and assess for spread to other pelvic organs outside the uterus.
Get a chest X-ray also because the lungs are the most common extrapelvic site of metastasis. A CT of the
abdomen and pelvis and an MRI of the brain are only needed if the patient is symptomatic, or if there is
evidence of metastatic disease on exam or chest X-ray.

Based on exam and imaging, assign a stage of GTN using the International Federation of Gynecology and
Obstetrics, or FIGO, anatomical staging. Additionally, you may apply a World Health Organization, or
WHO, risk score depending on the subtype of GTN. The two most common types of GTN are postmolar
GTN, also known as an invasive mole and choriocarcinoma. Both of these can follow benign hydatidiform
moles, and use WHO risk scores to guide management.

For invasive moles and choriocarcinoma, low-risk disease confined to the uterus generally responds well
to single-agent chemotherapy. If the disease is more extensive, or if there’s an elevated WHO risk score,
then multiagent chemotherapy is recommended. If the disease is FIGO stage 4 or if the WHO risk score is
very high, usually single-agent induction chemotherapy is used to decrease the tumor burden before
multiagent chemotherapy, due to the risk of tumor lysis syndrome.

There are less common forms of GTN called placental site trophoblastic tumor and epithelioid
trophoblastic tumor, and treatment for these two subtypes is based on FIGO anatomic staging alone. For
these conditions, hysterectomy is the mainstay of treatment, unless it’s a later stage or more than 4 years
from the preceding pregnancy, as these more complicated cases warrant multiagent chemotherapy.

Alright, as a quick recap… GTD refers to a group of disorders where the trophoblastic cells of pregnancy
grow incorrectly. Benign GTD includes partial and complete molar pregnancies, both of which are
managed with a D&C.

Following D&C, hCG levels must be monitored to ensure a malignant form of GTD, known as GTN, does
not develop. If hCG levels plateau or rise during postmolar surveillance, GTN is diagnosed. The most
common forms of GTN are treated with either single or multiagent chemotherapy depending on the
extensiveness of the disease, while the less common forms are usually treated with hysterectomy.

Sources

"Epidemiology, diagnosis, and treatment of gestational trophoblastic disease: A Society of Gynecol

Oncology evidenced-based review and recommendation. " Gynecol Oncol. (2021;163(3):605-613.)

"Gestational trophoblastic neoplasia, FIGO 2000 staging and classification [published correction
appears in Int J" Int J Gynaecol Obstet. (2021 Dec;155(3):563]. 2003;83 Suppl 1:175-177. )

"Update on the diagnosis and management of gestational trophoblastic disease. " Int J Gynaecol
Obstet. (2018;143 Suppl 2:79-85.)

"Gestational trophoblastic disease. " Obstet Gynecol. (2021;137(2):355-370. )

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