Gestational trophoblastic disease

Gestational trophoblastic disease
Patient Information
Overview
Causes
Classification Hydatidiform Mole Gestational trophoblastic neoplasia
Epidemiology
Risk factors
Clinical Features
Differential Diagnosis
Prognostic Factors and Survivorship

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Gestational trophoblastic disease
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Micrograph of intermediate trophoblast, decidua and a hydatidiform mole (bottom of image). H&E stain.

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List of terms related to Gestational trophoblastic disease

Synonyms and keywords: GTD, pregnancy-related tumors, trophoblastic diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Gestational trophoblastic disease (GTD) includes a spectrum of disease states affecting pregnant individuals and range from benign conditions such as complete and partial molar pregnancy, exaggerated placental site tumor (EPS), and placental-site nodule (PSN) to malignant disorders (gestational trophoblastic neoplasia) such as invasive mole, choriocarcinoma (CC), placenta-site trophoblastic tumor (PSTT), and epitheloid trophoblastic tumors (ETT). Hydatidiform moles are a benign entities which may be either complete or partial. These benign moles may occasionally transform into invasive moles, which are malignant and may even progress to choriocarcinoma. Gestational trophoblasts may invade uterine tissue. GTD may simulate pregnancy due to increased uterine size, however they contain abnormal fetal tissue and typically the uterus is inappropriately large for date. This tissue may grow at the same rate as a normal pregnancy, and produces beta human chorionic gonadotropin (beta-hCG), a hormone produced by the placenta, which is measured to monitor fetal well-being after implantation. While GTD overwhelmingly affects women of child-bearing age, it may rarely occur in postmenopausal women.

Classification

Gestational trophoblastic disease (GTD) may be classified as follows:

• Hydatidiform mole (HM).

• Complete HM
• Partial HM

• Gestational trophoblastic neoplasia:

• Invasive mole
• Choriocarcinoma
• Placental-site trophoblastic tumor (PSTT); (very rare)
• Epithelioid trophoblastic tumor (ETT); (extremely rare)

Epidemiology

The reported incidence of GTD varies widely worldwide, from a low of 23 per 100,000 pregnancies (Paraguay) to a high of 1,299 per 100,000 pregnancies (Indonesia). However, at least part of this variability is caused by differences in diagnostic criteria and reporting. The reported incidence in the United States is about 110 to 120 per 100,000 pregnancies. The prevalence rates of both hydatidiform mole and choriocarcinoma have declined over the past three decades in all groups, which may be due to better awareness of the condition leading to risk factor avoidance, dietary improvement and decreased overall birth rate.

Hydatidiform Mole

• The worldwide prevalence of molar pregnancy varies according to geographic region, ranging from 1200 per 100,000 pregnancies in Indonesia, India, and Turkey to 100-200 per 100,000 pregnancies in Japan and China and 50 to 100 per 100,000 pregnancies in North America and Europe.

Choriocarcinoma

• The reported incidence of choriocarcinoma, the most aggressive form of GTD, in the United States is about 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is about 0.18 per 100,000 women between the ages of 15 years and 49 years.
• The reported prevalence of choriocarcinoma varies widely according to the geographic region, and ranges from a low of 2 per 100,000 pregnancies in the United States to a high of 202 per 100,000 pregnancies in China.

Risk Factors

Risk factors for gestational trophoblastic disease include the following:

• Maternal age (younger than 20 and greater than 35 years of age- bimodal distribution, relative risk 1.1 to 11)
• History of hydatidiform mole (including positive family history- associated with a 1 % risk in subsequent pregnancies, 25 % with history of more than one prior hydatidiform mole)
• Low levels of carotene and vitamin A
• Blood groups A or AB
• Prior spontaneous abortions
• Multigravida women

Clinical Features

Gestational trophoblastic disease (GTD) may present with the following clinical features:

• Vaginal bleeding
• Rapidly enlarging uterus
• Elevated human chorionic gonadotropin (hCG) levels
• Pelvic pain or sensation of pressure
• Anemia
• Hyperemesis gravidarum
• Hyperthyroidism (secondary to the homology between the beta-subunits of hCG and thyroid-stimulating hormone (TSH), which causes hCG to have weak TSH-like activity)
• Preeclampsia early in pregnancy
• Neurological symptoms (in cases of brain metastasis from choriocarcinoma)
• Anxiety
• Weight loss
• Insomnia
• Abdominal swelling

The following table outlines the variation in clinical presentations of molar pregnancy (complete, partial and invasive), choriocarcinoma, placental-site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT):

Clinical Features	Complete Hydatidiform Mole	Partial Hydatidiform Mole	Invasive Molar Pregnancy	Choriocarcinoma	Placental-site trophoblastic tumor (PSTT) and Epithelioid trophoblastic tumor (ETT)
Presenting Complaints	Vaginal bleeding Inappropriately large for date uterine size Hyperemesis	Vaginal bleeding	Vaginal bleeding Elevated beta-hCG	Vaginal bleeding	Vaginal bleeding
Neoplastic Conversion	High rate of progression (15-20%)	< 5 % progression rate	Neoplastic	Neoplastic	Neoplastic
Beta Human Chorionic Gonadotropin (Beta-hCG) baseline levels	Extremely high levels ( > 100000 mIU/ml in half of the patients	Highly elevated ( > 100000 mIU/ml in one in ten patients)	High	High	Moderatley elevated (< 1000 mIU/ml in majority of patients)
History of Pregnancies	Not related	Not related	Consequence of molar pregnancy	Approximately half of the cases occur as a consequence of molar pregnancy Quarter of the cases follow abortion or tubal pregnancy Rest follow term or pre-term pregnancy	About 60% follow term pregnancy 40 % follow molar pregnancy or abortion
Metastatic Route	Benign	Benign	Hematogenous	Hematogenous	Lymphatic
Management	Dilation and curettage (suction)	Dilation and curettage (suction)	Chemotherapy (Methotrexate)	Chemotherapy (Methotrexate)	Hysterectomy

Differential Diagnosis

Gestational trophoblastic disease must be differentiated from other causes of hyperthyroidism such as Grave's disease and toxic nodular goiter. The following table differentiates these causes of hyperthyroidism:

Cause of thyrotoxicosis	TSH receptor antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	?	Diffuse uptake	Ophthalmopathy, dermopathy, acropathy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules on thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	?	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	?	-
Amiodarone induced thyroiditis-Type 1	-	Diffuse or nodular goiter	?/Normal/?	? but higher than in Type 2	High urinary iodine
Amiodarone induced thyroiditis-Type 2	-	Normal	Absent	?/absent	High urinary iodine
Central hyperthyroidism	-	Diffuse or nodular goiter	Normal/?	?	Inappropriately normal or high TSH
Trophoblastic disease	-	Diffuse or nodular goiter	Normal/?	?	-
Factitious thyrotoxicosis	-	Variable	Reduced/absent flow	?	Normal or decreased serum thyroglobulin
Struma ovarii	-	Variable	Reduced/absent flow	?	Increased abdominal RAIU

Disease		Findings
Thyroiditis	Direct chemical toxicity with inflammation	Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.
	Radiation thyroiditis	Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
	Drugs that interfere with the immune system	Interferon-alfa is a well-known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.
	Lithium	Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves' disease.
	Palpation thyroiditis	Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during the physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism	Factitious ingestion of thyroid hormone	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Acute hyperthyroidism from a levothyroxine overdose	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.
	Struma ovarii	Functioning thyroid tissue is present in an ovarian neoplasm.
	Functional thyroid cancer metastases	Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis		It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves' disease. It is then followed by the development of hypothyroidism due to the infiltration of the thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.
Toxic adenoma and toxic multinodular goiter		Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation. Findings of single or multiple nodules are seen on physical examination or thyroid scan.
Iodine-induced hyperthyroidism		It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors		Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.

Prognostic Factors and Survivorship

The prognosis for cure of patients with GTDs is good even when the disease has spread to distant organs, especially when only the lungs are involved. Therefore, the traditional TNM staging system has limited prognostic value. The probability of cure depends on the following:

• Histologic type (invasive mole or choriocarcinoma).
• Extent of spread of the disease/largest tumor size.
• Level of serum beta-hCG.
• Duration of disease from the initial pregnancy event to start of treatment.
• Number and specific sites of metastases.
• Nature of antecedent pregnancy.
• Extent of prior treatment.

Selection of treatment depends on these factors plus the patient’s desire for future pregnancies. The beta-hCG is a sensitive marker to indicate the presence or absence of disease before, during, and after treatment. Given the extremely good therapeutic outcomes of most of these tumors, an important goal is to distinguish patients who need less-intensive therapies from those who require more-intensive regimens to achieve a cure.