Hydatidiform mole

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Hydatidiform mole
MOLE, HYDATIDIFORM, HYSTERECTOMY SPECIMEN. VARIABLY SIZED VESICLES, NO NORMAL PLACENTA, NO FETUS. Image courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

Classification

Gestational trophoblastic disease (GTD) may be classified as follows:

• Hydatidiform mole (HM)

• Complete HM
• Partial HM

Pathophysiology

A hydatidiform mole is characterized by a conceptus of hyperplastic trophoblastic tissue attached to the placenta. The conceptus does not contain the inner cell mass. 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 46, XY genotype may occur when 2 sperm (one 23, X and the other 23, Y) fertilize an empty egg. Their DNA is purely paternal in origin, and is diploid. Ninety percent are 46,XX, and 10% are 46,XY. In a complete mole, the fetus fails to develop.
• 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.

Genetics

• Invasive mole- diploid or aneuploid karyotype
• Choriocarcinomas- aneuploid karyotype

Gross Pathology

• Dark, shaggy, focally hemorrhagic & friable/necrotic-appearing
• Invasive border

Microscopic Pathology

Gestational trophoblastic neoplasia classification

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.

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.

Staging

According to the Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) cancer staging system, there are 4 stages of choriocarcinoma.

Stage	FIGO Anatomical Staging
I	Disease confined to the uterus
II	GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament)
III	GTN extends to the lungs, with or without known genital tract involvement
IV	All other metastatic sites

Symptoms

Early symptoms of gestational trophoblastic disease

• Vaginal bleeding
• Nausea and vomiting
• Passing of tissue resembling a “bunch of grapes” from the vagina
• Absent fetal movement during pregnancy
• Abdominal distention

Rare symptoms of gestational trophoblastic disease

• Headache
• Edema of the hands and feet
• Abdominal or pelvic pain
• Vaginal discharge
• Overactive thyroid gland (hyperthyroidism) that causes:

• Tachycardia
• Sweating
• Shaking
• Heat intolerance
• Fever

Laboratory Findings

Quantitative serum HCG

• Human chorionic gonadotropin (HCG or b-HCG) is the most common tumor marker test used to diagnose GTD
• HCG is a very sensitive test for diagnosing most gestational trophoblastic tumors. HCG is usually measured in the blood, but it can also be measured in the urine
• HCG levels are much higher in women with complete hydatidiform mole compared to HCG levels in women with a normal pregnancy
• With partial moles, the HCG level is higher than normal, but it is not as high as with other types of GTD
• An HCG test can help find GTD after pregnancy or miscarriage as this hormone should not be present in the blood or urine soon afterward

Complete blood count

• Complete blood count can check for anemia from long-term (chronic) vaginal bleeding.

Thyroid-stimulating hormone

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

Diagnostic Findings

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.

Snow storm ultrasound (hydatidiform mole)

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.

Images courtesy of RadsWiki

Complete mole

Complete mole

Complete mole

Complete mole

Complete mole

Pathology

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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. D&C is a treatment option for women diagnosed with complete or partial hydatidiform moles by human chorionic gonadotropin (HCG or b-HCG) testing or ultrasound. D&C will not be done if a gestational choriocarcinoma is suspected because this type of tumour bleeds very easily.

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. D&C is a treatment option for women diagnosed with complete or partial hydatidiform moles by human chorionic gonadotropin (HCG or b-HCG) testing or ultrasound. D&C will not be done if a gestational choriocarcinoma is suspected because this type of tumour bleeds very easily.

Carboprost medication may be used to contract the uterus. Treatment of hydatidiform mole (HM) is within the purview of the obstetrician/gynecologist and will not be discussed separately here. However, following the diagnosis and treatment of HM, patients should be monitored to rule out the possibility of metastatic gestational trophoblastic neoplasia. In almost all cases, this can be performed with routine monitoring of serum beta human chorionic gonadotropin (beta-hCG) to document its return to normal. An effective form of contraception is important during the follow-up period to avoid the confusion that can occur with a rising beta-hCG as a result of pregnancy.

Chemotherapy is necessary when there is the following:

• A rising beta-hCG titer for 2 weeks (3 titers)
• A tissue diagnosis of choriocarcinoma
• A plateau of the beta-hCG for 3 weeks
• Persistence of detectable beta-hCG 6 months after mole evacuation
• Metastatic disease
• An elevation in beta-hCG after a normal value
• Postevacuation hemorrhage not caused by retained tissues

Chemotherapy is ultimately required for persistence or neoplastic transformation in about 15% to 20% of patients after evacuation of a complete HM but for fewer than 5% of patients with partial HM. Chemotherapy is determined by the patient's modified World Health Organization score.

In women with complete HM, risk of persistence or neoplastic transformation is approximately doubled in the setting of certain characteristics, which include the following:

• Age older than 35 years or age younger than 20 years
• Pre-evacuation serum beta-hCG greater than 100,000 IU/L
• Large-for-date uterus
• Large uterine molar mass
• Large (>6 cm) ovarian cysts
• Pre-eclampsia
• Hyperthyroidism
• Hyperemesis of pregnancy
• Trophoblastic embolization
• Disseminated intravascular coagulation

Studies have shown that a single course of prophylactic dactinomycin or methotrexate can decrease the risk of a postmolar gestational trophoblastic disease (GTD). However, there is concern that chemoprophylaxis increases tumor resistance to standard therapy in the women who subsequently develop GTD. Therefore, this practice is generally limited to countries in which a large number of women do not return for follow-up.

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.

See also

• Gestational trophoblastic disease
• Echinococcosis