Hydatidiform mole

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Overview
Hydatidiform mole (or mola hydatidiforma) is a common complication of pregnancy, occurring once in every 1000 pregnancies in the US, with much higher rates in Asia (e.g. up to one in 100 pregnancies in Indonesia). It consists of a nonviable embryo which implants and proliferates within the uterus. The term is derived from hydatidiform ("like a bunch of grapes") and mole (from Latin mola = millstone).

Most moles present with painless vaginal bleeding during the second trimester of pregnancy. They are diagnosed by ultrasound imaging. Extremely high levels of human chorionic gonadotropin (HCG) are suggestive, but not diagnostic, of molar pregnancy. Today moles are surgically removed by curettage, in order to avoid the risks of choriocarcinoma.

Natural history
A hydatidiform mole is a pregnancy/conceptus in which the placenta contains grapelike vesicles that are usually visible with the naked eye. The vesicles arise by distention of the chorionic villi by fluid. When inspected in the microscope, hyperplasia of the trophoblastic tissue is noted. If left untreated, a hydatidiform mole will almost always end as a spontaneous abortion.

Based on morphology, hydatidiform moles can be divided into two types: In complete moles, all the chorionic villi are vesicular, and no sign of embryonic or fetal development is present. In partial moles some villi are vesicular, whereas others appear more normal, and embryonic/fetal development may be seen but the fetus is always malformed and is never viable.

Hydatidiform moles are a common complication of pregnancy, occurring once in every 1000 pregnancies in the US, with much higher rates in Asia (e.g. up to one in 100 pregnancies in Indonesia).

In rare cases a hydatidiform mole co-exists in the uterus with a normal, viable fetus. These cases are due to twinning. The uterus contains two conceptuses: one with an abnormal placenta and no viable fetus (the mole), and one with a normal placenta and a viable fetus. Under careful surveillance it is often possible for the woman to give birth to the normal child and to be cured of the mole.

The etiology of this condition is not completely understood. Potential risk factors may include defects in the egg, abnormalities within the uterus, or nutritional deficiencies. Women under 20 or over 40 years of age have a higher risk. Other risk factors include diets low in protein, folic acid, and carotene. The diploid set of sperm-only DNA means that all chromosomes have sperm-patterned methylation suppression of genes. This leads to overgrowth of the syncytiotrophoblast whereas dual egg-patterned methylation leads to a devotion of resources to the embryo, with an underdeveloped syncytiotrophoblast. This is considered to be the result of evolutionary competition with male genes driving for high investment into the fetus versus female genes driving for resource restriction to maximise the number of children.

Parental origin
In most hydatidiform moles, the parental origin of the genes in the cellular nucleus is abnormal.

In most complete moles, all nuclear genes are inherited from the father, only (androgenesis). In approximately 80% of these androgenetic moles, the most probable mechanism is that an empty egg is fertilized by a single sperm, followed by a duplication of all chromosomes/genes (a process called "endoreduplication"). In approximately 20% of complete moles the most probable mechanism is that an empty egg is fertilised by two sperms. In both cases, the moles are diploid (i.e. there are two copies of every chromosome). In all these cases, the mitochondrial genes are inherited from the mother, as usual.

Most partial moles are triploid (three chromosome sets). The most probable mechanism is that a normal haploid egg is fertilized by two sperms. Thus the nucleus contains one maternal set of genes and two paternal sets.

In rare cases, hydatidiform moles are tetraploid (four chromosome sets) or have other chromosome abnormalities.

A small percentage of hydatidiform moles have biparental diploid genomes, as in normal living persons; they have two sets of chromosomes, one inherited from each biological parent. Some of these moles occur in women who carry mutations in the gene NLRP7, predisposing them towards molar pregnancy. These rare variants of hydatidiform mole may be complete or partial.

Pathophysiology
A mole is characterized by a conceptus of hyperplastic trophoblastic tissue attached to the placenta. The conceptus does not contain the inner cell mass (the mass of cells inside the primordial embryo that will eventually give rise to the fetus).

The hydatidiform mole can be of two types: a complete mole, in which the abnormal embryonic tissue is derived from the father only; and a partial mole, in which the abnormal tissue is derived from both parents.


 * Complete moles usually occur when an empty ovum is fertilized by a sperm that then duplicates its own DNA (a process called androgenesis). This explains why most complete moles are of the 46,XX genotype. A 46, XY genotype may occur when 2 sperm (one 23, X and the other 23, Y) fertilize an empty egg. They grossly resemble a bunch of grapes ("cluster of grapes" or "honeycombed uterus" or "snow-storm" ). Their DNA is purely paternal in origin (since all chromosomes are derived from the sperm), and is diploid (i.e. there are two copies of every chromosome). Ninety percent are 46,XX, and 10% are 46,XY. In a complete mole, the fetus fails to develop, thus on gross examination there are no signs of fetal tissue. All of the chorionic villi are enlarged. The main complication of the complete mole is a 2% chance of progression to a cancer called choriocarcinoma.
 * Partial moles can occur if a normal haploid ovum is fertilized by two sperm, or, if fertilized by one sperm, if the paternal chromosomes become duplicated. Thus their DNA is both maternal and paternal in origin. They can be triploid (e.g. 69 XXX, 69 XXY) or even tetraploid. Fetal parts are often seen on gross examination. There is also an increased risk of choriocarcinoma, but the risk is lower than with the complete mole.

Etiology
The etiology of this condition is not completely understood. Potential risk factors may include defects in the egg, abnormalities within the uterus, or nutritional deficiencies. Women under 20 or over 40 years of age have a higher risk. Other risk factors include diets low in protein, folic acid, and carotene.

Diagnosis
Molar pregnancies usually present with painless vaginal bleeding in the fourth to fifth month of pregnancy. The uterus may be larger than expected, or the ovaries may be enlarged. There may also be more vomiting than would be expected (hyperemesis). Sometimes there is an increase in blood pressure along with protein in the urine. Blood tests will show very high levels of human chorionic gonadotropin (hCG).

The diagnosis is strongly suggested by ultrasound (sonogram), but definitive diagnosis requires histopathological examination.

Sometimes symptoms of hyperthyroidism are seen, due to the extremely high levels of hCG, which can mimic the normal Thyroid-stimulating hormone (TSH).

Ultrasonography

 * Complete hydatidiform mole has a classic sonographic appearance of a solid collection of echoes with numerous anechoic spaces (snowstorm appearance).
 * In partial moles, the placenta is enlarged and contains areas of multiple, diffuse anechoic lesions.



CT
A CT scan usually demonstrates a normal-sized uterus with areas of low attenuation, an enlarged inhomogeneous uterus with a central area of low attenuation, or hypoattenuating foci surrounded by highly enhanced areas in the myometrium.

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Pathology


Treatment
Hydatidiform moles should be treated by evacuating the uterus by uterine suction or by surgical curettage as soon as possible after diagnosis, in order to avoid the risks of choriocarcinoma. Patients are followed up until their serum human chorionic gonadotrophin (hCG) level has fallen to an undetectable level. Invasive or metastatic moles (cancer) may require chemotherapy and often respond well to methotrexate. The response to treatment is nearly 100%.

Patients are advised not to conceive for one year after a molar pregnancy. The chances of having another molar pregnancy are approximately 1%.

Management is more complicated when the mole occurs together with one or more normal fetuses.

Carboprost medication may be used to contract the uterus.

Prognosis
More than 80% of hydatidiform moles are benign. The outcome after treatment is usually excellent. Close follow-up is essential. Highly effective means of contraception are recommended to avoid pregnancy for at least 6 to 12 months.

In 10 to 15% of cases, hydatidiform moles may develop into invasive moles. These may intrude so far into the uterine wall that hemorrhage or other complications develop. It is for this reason that a post-operative full abdominal and chest x-ray will often be requested.

In 2 to 3% of cases, hydatidiform moles may develop into choriocarcinoma, which is a malignant, rapidly-growing, and metastatic (spreading) form of cancer. Despite these factors which normally indicate a poor prognosis, the rate of cure after treatment with chemotherapy is high.

Over 90% of women with malignant, non-spreading cancer are able to survive and retain their ability to have children. In those with metastatic (spreading) cancer, remission remains at 75 to 85%, although the ability to have children is usually lost.