Which of the following statements is true about a hydatidiform molar pregnancy?

Chronic Rx & Disposition

If pathology results are consistent with complete or partial mole, patients must be followed to evaluate for trophoblastic neoplasia. 15% to 20% of complete moles and 1% to 5% of partial moles can develop into trophoblastic neoplasia. Quantitative beta hCG should be followed weekly until three consecutive results show normal levels. After that, check quantitative beta hCG every month for a total of 6 mo. Patients should remain on reliable contraception during this time to prevent confusion from a rising beta hCG in the case of a new pregnancy.

Specific criteria by beta hCG have been established by International Federation of Gynecology and Obstetrics (FIGO) for diagnosis of postmolar gestational trophoblastic disease (seeTables E5, E6, andE7).

TABLE E5. The 2002 Criteria for the Diagnosis of Post Hydatidiform Mole Trophoblastic Neoplasia

hCG, Human chorionic gonadotropin.

TABLE E6. International Federation of Gynecology and Obstetrics Staging of Gestational Trophoblastic Neoplasia

GTN, Gestational trophoblastic neoplasia.

From Kohorn EI: The new FIGO 2000 staging and risk factor scoring system for gestational trophoblastic disease: description and critical assessment.Int J Gynecol Cancer 11:73-77, 2001.

TABLE E7. The World Health Organization (WHO) Prognostic Scoring System Is Used for the Medical Management of Patients with Partial, Complete Moles, and Choriocarcinomas

FIGO, International Federation of Gynecology and Obstetrics;hCG, human chorionic gonadotropin.

Abstract

Hydatidiform moles (HMs) are genetically abnormal conceptions characterized by abnormal chorionic villi, trophoblastic hyperplasia, poor fetal development, and an increased risk of malignant disease development. Approximately 15% of women with a complete hydatidiform mole (CHM) and 0.5% with a partial hydatidiform mole (PHM) will subsequently require chemotherapy for persistent gestational trophoblastic neoplasia. CHMs are predominantly androgenetic diploid conceptions, while PHMs are predominantly dispermic triploid conceptions. Unusual variants are also reported including pregnancies in which a HM coexists with a normal twin, mosaics in which the placenta is partly molar, and diploid biparental complete hydatidiform moles (BiCHMs) that are associated with a familial predisposition to molar pregnancies. Both PHM and CHM are characterized by the presence of two paternal chromosome complements and overexpression of paternally derived genes. Following both PHM and CHM, there is an increased risk of further HM in subsequent pregnancies: around 2% after a single HM rising significantly to around 15% after two molar pregnancies. This group includes a small number of women who have an autosomal recessive condition, familial recurrent hydatidiform mole (FRHM) that predisposes to molar pregnancies. In most women with FRHM, mutations in NLRP7 give rise to recurrent BiCHM with pathology and imprinting defects similar to the common androgenetic CHM.

Molar Pregnancy

Molar pregnancy, also known as a hydatidiform mole, comprises a spectrum of diseases characterized by disordered proliferation of chorionic villi. In the absence of fetal tissue, the pregnancy is termed acomplete hydatidiform mole. Complete moles are caused by the fertilization of an ovum without maternal DNA and the subsequent duplication of the haploid genome. The termincomplete mole refers to a mole that is caused by the fertilization of a normal ovum by two sperm. The duplication of the triploid karyotype causes some fetal tissue to be present, along with focal trophoblastic hyperplasia. In approximately 19% of molar pregnancies, neoplastic gestational disease develops, with persistence of molar tissue after the pregnancy has been evacuated.30 Metastatic disease can develop, requiring chemotherapy and intensive oncologic management.

Early molar pregnancy is usually not clinically apparent. The most well-described risk factor for the development of a molar pregnancy is extreme maternal age.31 Many patients present with abdominal pain, nausea and vomiting, or vaginal bleeding, and it may be difficult to differentiate these patients from those with threatened miscarriage or ectopic pregnancy by historical features alone. Patients sometimes seek treatment for apparent persistent hyperemesis gravidarum from high circulating levels of hCG, bleeding or intermittent bloody discharge, or respiratory distress; failure to hear fetal heart tones during the second trimester is the usual initial clue to diagnosis. If molar pregnancy spontaneously aborts, it is usually in the second trimester (before 20 weeks), and the patient or physician may note the passage of grapelike hydatid vesicles. Uterine size is larger than expected by date (by >4 weeks) in approximately 30% to 40% of patients. Theca lutein cysts may be present on the ovaries as a result of excessive hormonal stimulation, and torsion of affected ovaries can be seen.

The characteristic sonographic appearance of hydropic vesicles within the uterus, described as a snowstorm appearance, is highly suggestive of a diagnosis of molar pregnancy (Fig. 178.7). Alternatively, cystic changes are seen in partial molar pregnancies. In some cases, a partial molar pregnancy is detected only on pathologic examination of abortion specimens. Complications of molar pregnancy include preeclampsia or eclampsia, which can develop before 24 weeks of gestation, respiratory failure or distress from pulmonary embolization of trophoblastic cells, hyperemesis gravidarum, and significant uterine bleeding, acute or chronic. Ultrasonography usually provides the diagnosis of a complete molar pregnancy in the second-trimester patient who has “threatened miscarriage” or during sonographic assessment for fetal well-being and size. However, ultrasonography is only 58% sensitive, and diagnosis of a partial mole is made in 17% of cases.31 Up to two-thirds of molar pregnancies are diagnosed by pathologic specimens after miscarriage.

Partial Hydatidiform Mole

A partial hydatidiform mole is a completely independent ailment to complete hydatidiform mole. Partial hydatidiform mole presents to the physician as a mixture of normal villous placental trophoblastic tissue, hygromatous balls or cysts, and some fetal fragments, without an intact fetus. Figure 6.5.4 illustrates a partial hydatidiform mole as seen after hysterectomy.

A partial hydatidiform mole is a triploid pregnancy with 69 instead of 46 chromosomes and another strange complication of the reproductive process. Fertilization is an intricate process. Part of this process is the cortical granule action (see Chapter 3.10). As illustrated in Figure 6.5.5, upon a single sperm penetration of the zona pellucida or egg shell, the cortical granules enter the perivitelline space and secrete enzymes that cross-link the zona pellucida, making it impenetrable by further sperm. This limits the ovum to penetration by only one sperm.

Partial hydatidiform mole appears to be the result of what happens when this cortical granule process fails and an egg can be penetrated by multiple sperm (Figure 6.5.5). Classically a partial hydatidiform mole is triploid. It could be said that a complete hydatidiform mole is a consequence of an anucleate ovum, and a partial hydatidiform mole is the consequence of failure of the cortical granules to prevent dispermic penetration.

Partial hydatidiform mole can be indicated by ultrasound showing placenta tissue, some hygromatous cysts, and some fetal oddments but no clear fetal structure. Ultrasound, however, is strictly an indicator. After spontaneous abortion or dilation and curettage tissue needs to be examined by pathology and cytogenetics determined. If a triploid karyotype is determined, 69,XXX, 69XXY, or 69 XYY, a partial mole can then be confirmed.

Unlike the complete hydatidiform mole, where morula differentiation to a chorion and amnion fails, a partial hydatidiform mole has clear fetal elements. As speculated under complete hydatidiform mole, the presence of the maternal X chromosome in the triploid set may be the signal that limits differentiation. In a partial hydatidiform mole, this maternal X signal is present. However, development of a complete fetus does not happen, suggesting later problems with proper fetal differentiation. We have dissected a few partial hydatidiform mole masses. It can be quite disquieting. One can dissect one’s way through cystic and placenta tissues to suddenly come across an intact fully formed finger or an oddball eye.

Partial hydatidiform moles can very occasionally become invasive, developing persistent gestational trophoblastic disease like a complete hydatidiform mole. Research suggests that just 0.5% of partial mole cases become persistent or malignant disease.

Very often, partial hydatidiform moles cause miscarriage of pregnancy or spontaneous abortions. In some countries, dilation and curettage is not carried out when a partial hydatidiform mole is indicated. The partial mole is allowed to remain until the person has a miscarriage.

It is important to always fully differentiate a complete and partial hydatidiform mole properly using cytogenetics. A complete mole is almost always diploid while a partial mole is triploid. A complete hydatidiform mole must be distinguished from a partial hydatidiform mole because of the invasive or persistent nature of the complete hydatidiform mole and not the partial hydatidiform mole.

Hydatidiform Molar Pregnancy

Hydatidiform molar pregnancy is the most common and benign form of gestational trophoblastic disease, with an incidence of 1 in 1000 pregnancies in North America.134 The incidence is much higher in the Asian population. There is an increased risk in teenagers, in women older than 35 years of age, and in women with a previous molar pregnancy. The risk also increases with the number of previous spontaneous abortions.135 Molar pregnancy is characterized histologically by cystic (hydatidiform) degeneration of chorionic villi, with absent or inadequate vascularization and abnormal trophoblastic proliferation. Embryos or fetuses are either absent or abnormal.

The most frequent presenting symptom isvaginal bleeding, which occurs in more than 90% of cases. Passage of vesicles (hydropic villi) through the vagina occurs frequently and is considered specific for the diagnosis of molar pregnancy.136 The uterus may be enlarged for dates, and there may also be rapid uterine enlargement. Medical complications include pregnancy-induced hypertension, hyperemesis gravidarum, preeclampsia, and hyperthyroidism. The routine use of ultrasound for any woman with bleeding in pregnancy allows for early diagnosis, and few women in current practice show the classic features of hyperemesis and preeclampsia.137

Serum β-hCG levels in molar pregnancy are abnormally elevated, usually greater than 100,000 mIU/mL. The ovaries may be greatly enlarged in complete molar pregnancy by multiple, bilateral theca lutein cysts. These are large, usually multilocular, and may undergo hemorrhage or torsion and can be a source of pelvic pain. Theca lutein cysts are most marked when trophoblastic proliferation is severe, and when hCG is elevated. They are seen much less often in the first trimester.138,139

Molar pregnancy is treated by uterine evacuation, which is adequate in most patients. Approximately 80% of complete moles and 95% of partial moles will subsequently follow a benign course.136,140 However, accurate diagnosis and classification of molar pregnancy are important because of the risk of persistent trophoblastic neoplasia (PTN). The American College of Obstetrics and Gynecology currently recommends follow-up testing for hCG for 6 months after levels become undetectable.141

Hydatidiform molar pregnancy is classified as either complete molar pregnancy or partial molar pregnancy on the basis of cytogenetic and pathologic features.

Partial Hydatidiform Mole (PHM)

PHM is more common than CHM. Morphologically, partial moles differ from that of a complete mole in three principle respects:

An embryo/fetus is usually present.

Microcystic pattern may be diffuse or focal and is not as prominent as in a complete mole and trophoblastic hyperplasia is both less prominent and strikingly focal.

Genetically partial hydatidiform moles are usually triploid with two paternal and one maternal haploid complements (Hall, 1990). They result from fertilization of a normal ovum either by a diploid sperm or by two different haploid sperm. Occasionally, tetraploidy, arising as a result of abnormal fertilization of a haploid ovum by sperm representing three paternal chromosome sets, is detected. A few trisomic conceptuses with partial mole-like morphology have been described.

The gross specimen in PHM shows hydropic villi like those seen in CHM mixed with nonmolar placental tissue. Evidence of an embryo or an amnion is usually present; stromal vasculature and vessels may contain fetal nucleated erythrocytes. Microscopic and differential features between CHM and PHM are summarized in Table 1. However, the only conclusive means for the differential diagnosis is by cytogenetics or more practically flow cytometry (Lage et al., 1992). It is important to distinguish between partial and complete moles, as the malignant transformation rate in partial hydatidiform mole is the same as in any nonmolar pregnancy.

The parental origin of the extra haploid set in triploidy has been shown to have a detectable effect on fetal phenotype in the second and third trimester. Two fetal phenotypes have been delineated: type I fetus with paternal sets dominance, associated with a large cystic placenta, has relatively normal fetal growth and microcephaly; type II fetus with maternal sets dominance, associated with a small noncystic placenta, is markedly growth retarded, and has a disproportionately large head (McFadden and Kalousek, 1991).

Abstract

Hydatidiform moles (HM) are genetically abnormal conceptions characterized by hydropic chorionic villi, trophoblastic hyperplasia, poor fetal development and an increased risk of progressing to malignant disease. Most HM can be classified as complete hydatidiform moles (CHM), predominantly androgenetic diploid conceptions or partial hydatidiform moles, usually dispermic triploid conceptions. Unusual variants are also reported including pregnancies in which a HM co-exists with a normal twin and mosaic conceptions in which the placenta is partly molar. A small number of CHM are diploid but biparental. These are associated with a familial predisposition to recurrent molar pregnancies and mutations in NLRP7 or KHDC3L.

IMMUNOHISTOCHEMISTRY

The immunohistochemical phenotype of hydatidiform moles is similar to that of normal placenta with distinctive expression patterns of markers in different trophoblastic cell types. Cytotrophoblast is typically positive for keratins and CD10, but negative for hCG, inhibin, and HPL, while syncytiotrophoblast cells are strongly positive for hCG, placental lactogen alkaline phosphatase (PLAP), inhibin, and CD10, but weakly positive for hPL. p57 is a paternally imprinted, maternally expressed gene for which immunohistochemistry has recently become available. As CHM are androgenetic in origin, this paternally derived gene is not expressed in stromal villous cells and cytotrophoblast, in contrast to positive staining in cytotrophoblast and stromal cells of PHM. Thus, p57 can serve as a reliable marker for the diagnosis of CHM.

HYDATIDIFORM MOLES – PATHOLOGIC FEATURES

33.2 Partial hydatidiform mole

Partial hydatidiform mole appears to be an ailment separate from complete hydatidiform mole. Partial hydatidiform mole presents as a mixture of villous tissue, hygromatous balls or cysts, and some fetal tissues (no intact fetus). Figure 33.4 illustrates a partial hydatidiform mole at hysterectomy.

A partial hydatidiform mole is a triploid pregnancy and another oddball complication of the reproductive process. Fertilization is an intricate process. Part of this process is the cortical granule action. As illustrated in Figure 33.5 on single sperm penetration of the zona pellucida. The cortical granules enter the periviteline space and secrete enzymes that cross-link the zona pellucida, making it impenetrable to further sperm. This limits the ovum to penetration by one sperm.

Partial hydatidiform mole is the direct result of what happens when this cortical granule process fails, and an egg can be penetrated by multiple sperm (Figure 33.5). Classically, a partial hydatidiform mole is triploid. It could be said that a complete hydatidiform mole is a consequence of an anucleate ovum, and a partial hydatidiform mole is the consequence of failure of the cortical granules to prevent dispermic penetration.

Partial hydatidiform mole can be identified by ultrasound showing placenta tissue, some hygromatous cysts, some fetal oddities, but no clear fetus structure. Ultrasound is strictly an indicator. After spontaneous abortion or dilation and curettage, tissue needs to be examined by pathology and cytogenetics needs to be determined. If a triploid karyotype is determined as 69, XXX, 69XXY, or 69 XYY [6], then a partial mole can be confirmed.

Unlike the complete hydatidiform mole, where morula differentiation to a chorion and amnion fails, a partial hydatidiform mole has some fetal elements. As speculated with complete hydatidiform mole, the presence of the maternal X chromosome may signal the differentiation. In a partial hydatidiform mole, this signal may be present.

However, development of a complete fetus does not happen, suggesting later problems with fetal differentiation. I have personally dissected a few partial hydatidiform mole masses. It can be quite squeamish. One can dissect one’s way through cystic and placenta tissues to suddenly come across an intact fully formed finger or an odd eye. It is haunting.

Partial hydatidiform mole rarely becomes invasive, developing persistent gestational trophoblastic disease like complete partial moles. A large study by Seckl indicates that 0.5% of partial mole cases become persistent gestational trophoblastic disease [28].

Very commonly, partial hydatidiform moles cause miscarriage of pregnancy. In some countries, dilation and curettage is not performed when a partial hydatidiform mole is indicated by ultrasound. The mole is allowed to remain until the person has a miscarriage; however, problems can arise if this is done and the mole can become persistent disease.

It is important to differentiate a complete and partial hydatidiform mole correctly using cytogenetics on the dilation and curettage or spontaneous abortion results. A complete mole is traditionally diploid, whereas a partial mole is triploid. A complete hydatidiform mole must be distinguished from a partial hydatidiform mole because of the invasive nature of the complete mole. In cases of both complete and partial moles, weekly placental hCG measurements are suggested until the concentration reaches <1 mIU/ml. At that point, placental hCG should be measured for up to 3 months to ensure that recurrence or persistence is not a possibility.

Hydatidiform Moles

Hydatidiform moles are associated with specific genetic abnormalities in pregnancy. Complete hydatidiform moles are usually diploid, with both chromosomes of paternal origin. The most common scenario is thought to be a single sperm fertilizing an empty egg and then splitting, resulting in a 46XX gestation of paternal origin. Alternatively, fertilization of an empty egg by two sperm can occur and result in a 46XY or 46XX gestation of paternal origin (Figure 5). Tetraploid moles exist as well. Rarely, complete moles may be biparental, in a recurring condition called familial or sporadic recurrent biparental hydatidiform mole, depending on family history. Studies on families affected by this condition show NLRP7 region mutations on 19q13.3–13.4. Partial hydatidiform moles are usually triploid, containing one maternal and two paternal sets of chromosomes, most commonly due to dispermic fertilization of an egg (Figure 6). Only diandric triploidy results in partial mole. Digynic triploidy, with two maternal chromosomes and one paternal, results in an abnormal triploid fetus, but not a molar pregnancy. Recent advances in genotyping these gestations by short tandem repeat PCR have allowed more conclusive diagnoses to be made, when the modality is available, as well as distinguishing GTD from non-GTD.

Hydatidiform moles vary in incidence by geography, with the greatest incidence in Asian countries. Risk is greater in both younger and older mothers (< 16 and >45 years). Prior history of mole increases the risk of a recurrent mole in a subsequent pregnancy to about 2% for both complete and partial moles.