Gestational trophoblastic disease

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. Hydatidiform moles are benign in most cases, but sometimes may develop into invasive moles, or, in rare cases, into choriocarcinoma, which is likely to spread quickly,[1][2] but which is very sensitive to chemotherapy, and has a very good prognosis. Gestational trophoblasts are of particular interest to cell biologists because, like cancer, these cells invade tissue (the uterus), but unlike cancer, they sometimes "know" when to stop.[citation needed]

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.[3]

While GTD overwhelmingly affects women of child-bearing age, it may rarely occur in postmenopausal women.
Commonly used synonyms
Gestational trophoblastic disease (GTD) may also be called gestational trophoblastic tumour (GTT).

Hydatidiform mole (one type of GTD) may also be called molar pregnancy.

Persistent disease; persistent GTD: If there is any evidence of persistence of GTD, usually defined as persistent elevation of beta hCG (see «Diagnosis» below), the condition may also be referred to as gestational trophoblastic neoplasia (GTN).
Types
GTD is the common name for five closely related tumours (one benign tumour, and four malignant tumours):[6]

The benign tumour
Hydatidiform mole
Here, first 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.
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.[7][8][9]

Although molar pregnancies affect women of all ages, women under 16 years of age have a six times higher risk of developing a molar pregnancy than those aged 16–40 years, and women 50 years of age or older have a one in three chance of having a molar pregnancy.[10]

Being from Asia/of Asian ethnicity is an important risk factor.[11]

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.[12][13][14]

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.

The four malignant tumours
Invasive mole
Choriocarcinoma
Placental site trophoblastic tumour
Epithelioid trophoblastic tumour
All five closely related tumours develop in the placenta. All five tumours arise from trophoblastic cells. The trophoblast is the membrane that forms the wall of the blastocyst in the early development of the fetus. In a normal pregnancy, trophoblastic cells aid the implantation of the fertilised egg into the uterine wall. But in GTD, they develop into tumour cells.
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.[15] 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.[16] 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.
Treatment

The treatment for hydatidiform mole consists of the evacuation of pregnancy.[17][18][19][20][21] 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.[22]

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.[23][24][25][26] Only a few women with GTD suffer from 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.[27]

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 1 year, and by 3 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.[28][29]

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 and staging
Women with a hydatidiform mole have an excellent prognosis. Women with a malignant form of GTD usually have a very good prognosis.[citation needed]

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[30] 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.[31] 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.

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