Gestational Trophoblastic Neoplasia

Gestational Trophoblastic Neoplasia (GTN) refers to a group of malignant tumours that arise from abnormal trophoblastic cells, usually following molar pregnancy and may be seen on ultrasound as a heterogeneous mass in the uterine cavity with typical metastasis to the lung.

Description

Gestational Trophoblastic Neoplasia (GTN) is a spectrum of pregnancy-related disorders characterised by the proliferation of trophoblastic cells. These tumours include invasive moles, choriocarcinomas, placental-site trophoblastic tumours (PSTT), and epithelioid trophoblastic tumours (ETT). It can arise from any type of pregnancy but is most commonly associated with molar pregnancies.

Pathogenesis

GTN develops following abnormal fertilisation, resulting in anomalous proliferation of placental trophoblasts. The pathogenesis is strongly linked to molar pregnancies, specifically hydatidiform moles, which present an imbalance in parental genetic material. Complete moles occur due to fertilisation of an empty oocyte by a haploid sperm that duplicates its chromosomes, resulting in a 46, XX karyotype. Complete moles do not contain foetal parts. Partial moles arise when two sperm fertilise a normal oocyte, leading to a triploid karyotype (69, XXX or 69, XXY). Visualisation of foetal parts suggests partial moles.

Tumours arise from the atypical proliferation of trophoblastic cells (particularly in complete moles), which are the cells that form the outer layer of a blastocyst during embryogenesis and later become part of the placenta. These cells have the capacity for deep invasion into the myometrium and blood vessels, and for distant metastasis.

GTN can also develop without a preceding molar pregnancy, such as in cases of a normal pregnancy, ectopic pregnancy, miscarriage, or even a non-gestational tumour.

Subtypes

GTN is categorised into four subtypes:

• Invasive mole: This is the most common type of GTN and is characterised by the local invasion of trophoblastic tissue into the myometrium.
• Choriocarcinoma: This is a highly malignant form of GTN with a propensity for vascular invasion and distant metastases.
• Placental-site trophoblastic tumour (PSTT): This is a rare form of GTN that arises from the placental site and has a less aggressive course.
• Epithelioid trophoblastic tumour (ETT): This is the rarest type of GTN and is characterised by the proliferation of chorionic-type intermediate trophoblastic cells.

Epidemiology, Risk Factors & Associations

• GTN most commonly follows molar pregnancies (15-20% of complete moles and 1-5% of partial moles).
• Other risk factors include prior GTN, extremes of maternal age <20 years and > 40 years, and blood type A or AB in a woman carrying an O or B foetus.
• Known associations include prior spontaneous abortion, infertility, ectopic pregnancy, or normal-term pregnancy, diet deficient in carotene (vitamin A precursor) and animal fats, smoking.

Clinical Features

Clinical features of GTN can vary and may include:

• Irregular vaginal bleeding: This is the most common presenting symptom of GTN.
• High levels of human chorionic gonadotropin (hCG): This hormone is produced by trophoblastic cells and its levels in the blood and urine are typically elevated in GTN.
• Enlarged uterus: Due to the growth of the tumour, the uterus may be larger than expected for the duration of the pregnancy or may be irregularly enlarged in post-menopausal women.
• Symptoms related to metastases: Depending on the sites of metastases, patients may experience chest pain, hemoptysis, neurological symptoms, or abdominal pain.

Complications

Complications of GTN primarily revolve around the aggressive nature of these tumours and their propensity for metastasis. Most commonly, these include:

• 50% of choriocarcinoma cases arise from complete mole
• Metastasis: The lungs are the most frequent site of metastasis (80% of cases), followed by the vagina (30%), pelvis (20%), liver (10%), and brain (10%). These can cause organ-specific symptoms and further complicate management.
• Trophoblastic embolism: Tumour fragments can embolise to the lungs, leading to acute respiratory distress.
• Gestational hyperthyroidism: High levels of hCG can mimic thyroid-stimulating hormone, leading to hyperthyroidism in some cases.
• Early-onset pre-eclampsia or theca lutein cysts: Seen particularly in molar pregnancies, these conditions pose additional challenges to treatment.
• Resistance to chemotherapy: Some cases of GTN, particularly those with high initial hCG levels or metastatic disease, may be resistant to first-line chemotherapy agents.

Pathological Features

Histopathology

• Macroscopic: Depending on the subtype, GTN may appear as a honeycomb-like mass (invasive mole), a necrotic and haemorrhagic tumour (choriocarcinoma), or a well-circumscribed lesion (PSTT and ETT).
• Microscopic: Invasive moles show trophoblastic tissue invading the myometrium. Choriocarcinomas consist of both cytotrophoblasts and syncytiotrophoblasts with extensive haemorrhage and necrosis. PSTT and ETT show sheets of monomorphic trophoblastic cells without villi.

Serology

• Persistently high levels of hCG are seen in all types of GTN, typically > 100,000 IU.

Biochemistry

• No specific biochemical markers apart from hCG.

Radiological Features

General Features

• Characteristically demonstrates a heterogeneous mass in the uterine cavity, often with areas of haemorrhage and necrosis.
• Metastatic disease is common and can affect the lungs, liver, brain, and other sites.
• Theca lutein cysts in the ovaries may be seen, due to elevated β-hCG.

CT

• Non-contrast: May show a heterogeneous uterine mass with areas of high attenuation due to haemorrhage.
• Contrast-enhanced: Shows enhancement of the tumour. Metastases can also be identified.

MRI

• T1WI: The tumour is typically isointense to slightly hyperintense compared to the myometrium.
• T2WI: The tumour is typically heterogeneously hyperintense.
• T1 C+: Shows enhancement of the tumour and can help in identifying invasive disease.
• DWI/ADC: Can help in differentiating GTN from other types of uterine tumours.

US

• B-mode: Uterine enlargement with a classic heterogeneous and multicystic bunch of grapes appearance. Visualisation of foetal parts suggests a partial mole
• Colour:
  • Molar mass demonstrates internal vascularity
  • Abnormal blood flow within myometrium suggests an invasive mole.

NM

• PET FDG: Can help in identifying metastatic disease.

Grading and Staging

The FIGO/WHO system is used for the staging of GTN, with stages ranging from I (confined to the uterus) to IV (metastases to the brain or liver).

Diagnosis

The diagnosis of GTN is based on clinical features, high hCG levels, and characteristic imaging findings. Definitive diagnosis requires histopathological examination of the tumour.

Differential Diagnosis

• Molar pregnancy: This condition can also cause high hCG levels and abnormal uterine bleeding, but the characteristic ‘snowstorm’ appearance on ultrasound is not seen in GTN.
• Uterine fibroids: These are benign tumours that can cause an enlarged uterus and abnormal uterine bleeding, but they do not cause elevated hCG levels.
• Endometrial carcinoma: This malignancy can also present with postmenopausal bleeding and an enlarged uterus, but it is associated with normal hCG levels and different imaging findings.

Management

Management of GTN typically involves chemotherapy and/or surgical removal of the tumour, depending on the stage and subtype of the disease. The patient should be referred to a specialist in gynaecological oncology for further management. Close follow-up of serum hCG for 6 months.