Answers

Short answers

1. The diagnosis is a gestational trophoblastic neoplasia, most likely a choriocarcinoma.

2. Prognostic factors include age; type of pregnancy; time interval from the pregnancy; pre-treatment hCG concentration; tumour size, sites, and number of metastases; and previous chemotherapy.

3. High risk patients (those with a FIGO (International Federation of Gynaecology and Obstetrics score of 7 or more) should be treated with multiple agent chemotherapy.

Long answers
1. Raised hCG in the absence of a normal pregnancy in a woman of childbearing age is likely to be due to a gestational trophoblastic disease. Gestational trophoblastic diseases comprise the premalignant conditions of complete and partial hydatidiform moles along with the malignant invasive mole, choriocarcinoma, and the rare placental site trophoblastic tumour (PSTT).¹ The latter three conditions are collectively known as gestational trophoblastic tumours or neoplasia (GTN). Although both complete and partial moles can transform into any of the three malignant forms of GTN, choriocarcinoma and PSTT can also occur after any other type of pregnancy. The incidence of GTN after a complete mole is about 20% and after a partial mole 0.5% to 5%.^{2 3 4}

In the case presented here, after a term delivery the two most likely potential diagnoses are either a choriocarcinoma or a PSTT. Choriocarcinoma is estimated to occur in one pregnancy in 50 000, and PSTT is much less common.^{5 6} The two diseases differ in their biological and clinical behaviour: choriocarcinoma tends to grow and metastasise more rapidly, producing more hCG and responding better to chemotherapy. This case best fits a gestational choriocarcinoma because no obvious disease is visible for the amount of hCG. Occult distant metastases are likely, given the negative pelvic investigations. Vaginal bleeding or amenorrhoea is a common presenting symptom, but signs of metastatic disease such as dyspnoea or abnormal neurological presentation can occur.

Alternative diagnoses in a woman with a high serum hCG may be a pregnancy or a non-gestational trophoblastic neoplasia. A normal or molar intrauterine pregnancy can readily be excluded here, given the high serum hCG and normal ultrasound scan. Miscarriage is excluded too, given the absence of vaginal bleeding and evolution of hCG. An ectopic pregnancy (tubal, ovarian, or abdominal) is also reasonably ruled out after normal laparoscopy and radiological investigations.

Non-gestational trophoblastic neoplasias associated with raised serum hCG include ovarian or extragonadal germ cell tumours containing trophoblastic components and many non-gynaecological tumours, such as lung, bladder, liver, pancreas, and stomach. These tumours are generally associated with low serum hCG, although concentrations up to 750 000 IU/l have been reported.⁷ These diagnoses were reasonably excluded here, as no abnormalities were observed at laparoscopy and radiological investigations.

Uncommon diagnoses associated with a slightly raised serum hCG may indicate a false positive result due to interference by non-hCG substances (heterophile antibodies or luteinising hormone); a quiescent gestational trophoblastic disease; hCG derived from the pituitary, occurring at menopause or with premature ovarian failure; and normal concentration in an individual whose hCG is above the normal distribution for the population.^{8 9 10}

2. The FIGO scoring system is used in an attempt to subcategorise risk factors and permits the designation of a prognostic score (table).¹ The score is then used in managing chemotherapy. Our patient was scored 7 because she was post-term pregnancy (2) and had a four month interval between end of pregnancy and diagnosis (1) and a serum hCG concentration of more than 100 000 IU/l (4).

View this table: [in this window] [in a new window]   Modified WHO prognostic scoring system as adapted by FIGO1

 
Systematic search for metastasis is required, including a clinical examination, chest and abdomen computed tomography, brain and pelvis magnetic resonance imaging, and Doppler ultrasound of the pelvis.⁹ Positron emission tomography scanning can occasionally add information, and ultrasound of the abdomen may define liver lesions seen on computed tomography. Computed tomography is more sensitive than radiography in detecting pulmonary metastases; these may include micrometastasis, which do not affect prognosis, so chest x ray remains the best tool for scoring the disease.¹¹ Distant metastases are reported in 31-64% of patients with a GTN after a term pregnancy.^{12 13}

Histopathological confirmation is not mandatory for the diagnosis of GTN. It is a rare example of cancer where it is acceptable to start chemotherapy in the absence of a histopathological diagnosis. Biopsy of suspicious lesions should be undertaken with great care since choriocarcinomas are highly vascular and biopsy can cause life threatening haemorrhage. Therefore, biopsy should be performed only in locations where vascular control is possible.

3. A score of 6 or less represents low risk disease treatable by single agent chemotherapy. A score of 7 or more represents high risk disease that is more likely to be resistant to single agent chemotherapy and should be treated initially with combination chemotherapy. Chemotherapy regimens for the high risk group include etoposide, methotrexate, and actinomycin plus cyclophosphamide and vincristine (EMA-CO).¹⁴ The efficacy of these combinations has been reported in different studies, but the risks, benefits, and cure rates need to be evaluated through randomised controlled trial.

Cite this as: BMJ 2008;337:a2107