Gestational trophoblastic disease (GTD) is a term used for a group of pregnancy-related tumours. These tumours are rare, and they appear when cells in the womb start to proliferate uncontrollably. The cells that form gestational trophoblastic tumours are called trophoblasts and come from tissue that grows to form the placenta during pregnancy.
There are several different types of GTD. A hydatidiform mole also known as a molar pregnancy, is the most common and is usually benign. Sometimes it may develop into an invasive mole, or, more rarely into a choriocarcinoma. A choriocarcinoma is likely to spread quickly, but is very sensitive to chemotherapy, and has a very good prognosis. Trophoblasts are of particular interest to cell biologists because, like cancer, they can invade tissue (the uterus).
GTD can simulate pregnancy, because the uterus may contain fetal tissue, albeit abnormal. This tissue may grow at the same rate as a normal pregnancy, and produces chorionic gonadotropin, a hormone which is measured to monitor fetal well-being.Gestational trophoblastic disease: Epidemiology, clinical manifestations and diagnosis. Chiang JW, Berek JS. In: UpToDate [Textbook of Medicine]. Basow, DS (Ed). Massachusetts Medical Society, Waltham, Massachusetts, USA, and Wolters Kluwer Publishers, Amsterdam, the Netherlands. 2010.
While GTD overwhelmingly affects women of child-bearing age, it may rarely occur in postmenopausal women.
Types GTD is the common name for five closely related tumours (one benign tumour, and four malignant tumours).Gestational trophoblastic disease: Pathology. Kindelberger DW, Baergen RN. In: UpToDate [Textbook of Medicine]. Basow, DS (Ed). Massachusetts Medical Society, Waltham, Massachusetts, USA, and Wolters Kluwer Publishers, Amsterdam, the Netherlands. 2010. All five closely related tumours develop in the placenta. All five tumours arise from trophoblast cells that form the outer layer of the blastocyst in the early development of the fetus. In a normal pregnancy, trophoblasts aid the implantation of the fertilised egg into the uterine wall. However, in GTD, they develop into tumour cells.
Benign tumour The benign form of GTD is a hydatidiform mole. Here, a fertilised egg implants into the uterus, but some cells around the fetus (the chorionic villi) do not develop properly. The pregnancy is not viable, and the normal pregnancy process turns into a benign tumour. There are two subtypes of hydatidiform mole: complete hydatidiform mole, and partial hydatidiform mole.
Malignant tumours Invasive mole Choriocarcinoma Placental site trophoblastic tumour Epithelioid trophoblastic tumour
Cause Two main risk factors increase the likelihood for the development of GTD: 1) The woman being under 20 years of age, or over 35 years of age, and 2) previous GTD. Although molar pregnancies affect women of all ages, women under 16 and over 45 years of age have an increased risk of developing a molar pregnancy.
Hydatidiform moles are abnormal conceptions with excessive placental development. Conception takes place, but placental tissue grows very fast, rather than supporting the growth of a fetus.
Complete hydatidiform moles have no fetal tissue and no maternal DNA, as a result of a maternal ovum with no functional DNA. Most commonly, a single spermatozoon duplicates and fertilises an empty ovum. Less commonly, two separate spermatozoa fertilise an empty ovum (dispermic fertilisation). Partial hydatidiform moles have a fetus or fetal cells. They are triploid in origin, containing one set of maternal haploid genes and two sets of paternal haploid genes. They almost always occur following dispermic fertilisation of a normal ovum. Malignant forms of GTD are very rare. About 50% of malignant forms of GTD develop from a hydatidiform mole.
Diagnosis Cases of GTD can be diagnosed through routine tests given during pregnancy, such as blood tests and ultrasound, or through tests done after miscarriage or abortion. Vaginal bleeding, enlarged uterus, pelvic pain or discomfort, and vomiting too much (hyperemesis) are the most common symptoms of GTD. But GTD also leads to elevated serum hCG (human chorionic gonadotropin hormone). Since pregnancy is by far the most common cause of elevated serum hCG, clinicians generally first suspect a pregnancy with a complication. However, in GTD, the beta subunit of hCG (beta hCG) is also always elevated. Therefore, if GTD is clinically suspected, serum beta hCG is also measured.
The initial clinical diagnosis of GTD should be confirmed histologically, which can be done after the evacuation of pregnancy (see Treatment below) in women with hydatidiform mole. However, malignant GTD is highly vascular. If malignant GTD is suspected clinically, biopsy is contraindicated, because biopsy may cause life-threatening haemorrhage.
Women with persistent abnormal vaginal bleeding after any pregnancy, and women developing acute respiratory or neurological symptoms after any pregnancy, should also undergo hCG testing, because these may be signs of a hitherto undiagnosed GTD.
There might be some signs and symptoms of hyperthyroidism as well as an increase in the levels of thyroid hormones in some patients. The proposed mechanism is attaching hCG to TSH receptors and acting like TSH weakly.
Differential diagnosis These are not GTD, and they are not tumours Exaggerated placental site Placental site nodule
Both are composed of intermediate trophoblast, but their morphological features and clinical presentation can differ significantly.
Exaggerated placental site is a benign, non cancerous lesion with an increased number of implantation site intermediate trophoblastic cells that infiltrate the endometrium and the underlying myometrium. An exaggerated placental site may occur with normal pregnancy, or after an abortion. No specific treatment or follow up is necessary.
Placental site nodules are lesions of chorionic type intermediate trophoblast, usually small. 40–50% of placental site nodules are found in the cervix. They almost always are incidental findings after a surgical procedure. No specific treatment or follow up is necessary.
Treatment Treatment is always necessary.
The treatment for hydatidiform mole consists of the evacuation of pregnancy.Gestational trophoblastic disease: Management of hydatidiform mole. Garner EIO. In: UpToDate [Textbook of Medicine]. Basow, DS (Ed). Massachusetts Medical Society, Waltham, Massachusetts, USA, and Wolters Kluwer Publishers, Amsterdam, the Netherlands. 2010. Evacuation will lead to the relief of symptoms, and also prevent later complications. Suction curettage is the preferred method of evacuation. Hysterectomy is an alternative if no further pregnancies are wished for by the female patient. Hydatidiform mole also has successfully been treated with systemic (intravenous) methotrexate.
The treatment for invasive mole or choriocarcinoma generally is the same. Both are usually treated with chemotherapy. Methotrexate and dactinomycin are among the chemotherapy drugs used in GTD.Malignant gestational trophoblastic disease: Staging and treatment. Garner EIO. In: UpToDate [Textbook of Medicine]. Basow, DS (Ed). Massachusetts Medical Society, Waltham, Massachusetts, USA, and Wolters Kluwer Publishers, Amsterdam, the Netherlands. 2010. In women with low risk gestational trophoblastic neoplasia, a review has found that Actinomycin D is probably more effective as a treatment and more likely to achieve a cure in the first instance than methotrexate. Only a few women with GTD have poor prognosis metastatic gestational trophoblastic disease. Their treatment usually includes chemotherapy. Radiotherapy can also be given to places where the cancer has spread, e.g. the brain.
Women who undergo chemotherapy are advised not to conceive for one year after completion of treatment. These women also are likely to have an earlier menopause. It has been estimated by the Royal College of Obstetricians and Gynaecologists that the age at menopause for women who receive single agent chemotherapy is advanced by one year, and by three years for women who receive multi agent chemotherapy.
Follow up Follow up is necessary in all women with gestational trophoblastic disease, because of the possibility of persistent disease, or because of the risk of developing malignant uterine invasion or malignant metastatic disease even after treatment in some women with certain risk factors.
The use of a reliable contraception method is very important during the entire follow up period, as patients are strongly advised against pregnancy at that time. If a reliable contraception method is not used during the follow-up, it could be initially unclear to clinicians as to whether a rising hCG level is caused by the patient becoming pregnant again, or by the continued presence of GTD.
In women who have a malignant form of GTD, hCG concentrations stay the same (plateau) or they rise. Persistent elevation of serum hCG levels after a non molar pregnancy (i.e., normal pregnancy [term pregnancy], or preterm pregnancy, or ectopic pregnancy [pregnancy taking place in the wrong place, usually in the fallopian tube], or abortion) always indicate persistent GTD (very frequently due to choriocarcinoma or placental site trophoblastic tumour), but this is not common, because treatment mostly is successful.
In rare cases, a previous GTD may be reactivated after a subsequent pregnancy, even after several years. Therefore, the hCG tests should be performed also after any subsequent pregnancy in all women who had had a previous GTD (6 and 10 weeks after the end of any subsequent pregnancy).
Prognosis Women with a hydatidiform mole have an excellent prognosis. Women with a malignant form of GTD usually have a very good prognosis.
Choriocarcinoma, for example, is an uncommon, yet almost always curable cancer. Although choriocarcinoma is a highly malignant tumour and a life-threatening disease, it is very sensitive to chemotherapy. Virtually all women with non-metastatic disease are cured and retain their fertility; the prognosis is also very good for those with metastatic (spreading) cancer, in the early stages, but fertility may be lost. Hysterectomy (surgical removal of the uterus) can also be offered to patients > 40 years of age or those for whom sterilisation is not an obstacle. Only a few women with GTD have a poor prognosis, e.g. some forms of stage IV GTN. The FIGO staging system is used. The risk can be estimated by scoring systems such as the Modified WHO Prognostic Scoring System, wherein scores between 1 and 4 from various parameters are summed together: in turn citing:
+Modified WHO Prognostic Scoring System 0 1 2 4 Age <40 ≥40 – – Antecedent pregnancy mole abortion term – Interval months from index pregnancy <4 4–6 7–12 >12 Pretreatment serum hCG (IU/L) <103 103–104 104–105 >105 Largest tumor size (including uterus) <3 3–4 cm ≥5 cm – Site of metastases lung spleen, kidney gastrointestinal liver, brain Number of metastases – 1–4 5–8 >8 Previous failed chemotherapy – – single drug ≥2 drugs
In this scoring system, women with a score of 7 or greater are considered at high risk.
It is very important for malignant forms of GTD to be discovered in time. In Western countries, women with molar pregnancies are followed carefully; for instance, in the UK, all women who have had a molar pregnancy are registered at the National Trophoblastic Screening Centre. There are efforts in this direction in the developing countries too, and there have been improvements in these countries in the early detection of choriocarcinoma, thereby significantly reducing the mortality rate also in developing countries.
Becoming pregnant again