Practice Essentials
Gestational trophoblastic neoplasia (GTN) represents a spectrum of premalignant and malignant diseases that occur after abnormal fertilization. GTN includes complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), invasive mole, choriocarcinoma, placental-site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). [1] CHM and PHM together account for 80% of all cases of GTN. [2, 3, 4, 5]
Clinical features of hydatidiform mole in patients 40 years of age or older may differ from those in younger patients. For example, older patients may have vaginal bleeding, increased uterine volume, and heremesis. [6] Patients are often asymptomatic, but vaginal bleeding continues to be the most common presenting symptom. Other symptoms can develop in the case of metastatic disease.
Hydatidiform moles are the most common type of GTN. Internationally, the incidence of hydatidiform moles is 1-2:1000 pregnancies. [7]
Hydatidiform moles should be regarded as premalignant lesions because 15-20% of CHMs and 1% of PHMs undergo malignant transformation into invasive moles, choriocarcinomas, or, in rare cases, PSTTs. [2, 8, 9] Maternal symptoms, fetal anomalies, beta-human chorionic gonadotropin (β-hCG) level, and placental growth pattern on imaging may help differentiate between complete hydatidiform mole and coexistent fetus and placental mesenchymal dysplasia. [10]
Imaging modalities
Ultrasonography is the imaging investigation of choice (see the images below) to confirm the diagnosis of hydatidiform mole. An experienced operator should perform transabdominal and transvaginal imaging using transducers with the highest frequency possible. [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21] Clinical examination and β-hCG determinations are the recommended initial tests for hydatidiform mole.
In some cases, sonographic examination may be limited because of inadequate equipment or inadequate operator experience. The sonographic appearance of a first-trimester hydatidiform mole can be indistinguishable from that of an anembryonic gestation, specifically blighted ovum. Second-trimester CHM can be confused with retained products of conception. Ultrasound, serum hCG, and sometimes additional imaging such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) can confirm the diagnosis and the stage of disease. Familiarity with the pathogenesis, classification, imaging features, and treatment of GTN facilitates diagnosis and appropriate management. [22]
In a multicenter study, many proven cases of hydatidiform mole were not clinically or sonographically evident. Of 155 cases of hydatidiform mole, only 53 (34%) were correctly diagnosed as hydatidiform mole with ultrasonography. [15]
Magnified transverse sonogram shows a complete hydatidiform mole (CHM) at 7 weeks of menstrual age with a small anembryonic gestational sac. This appearance is often sonographically and pathologically indistinguishable from that of an anembryonic gestation (specifically a blighted ovum).
Sagittal endovaginal sonogram of a complete hydatidiform mole (CHM) at 12 weeks of menstrual age demonstrates an enlarged endometrium containing an anembryonic gestational sac with adjacent hyperechoic material containing tiny anechoic spaces.
Transverse endovaginal sonogram of a second-trimester complete hydatidiform mole (CHM) demonstrates a distended endometrial cavity containing innumerable, variably sized anechoic cysts with intervening hyperechoic material.
Transverse endovaginal sonogram of a second-trimester complete hydatidiform mole (CHM). Note that retained products of conception may mimic a hydatidiform mole.
Transverse transpelvic sonogram of a partial hydatidiform mole (PHM) at 16 weeks of menstrual age. The major imaging feature distinguishing PHM from complete hydatidiform mole (CHM) is the presence of fetal tissue on the left side of the image (mother's right side). Note the normal-appearing placental tissue along the posterior wall of the uterus in the midline and the many small cysts that replace the placental tissue on the right side (mother's left side). This finding has a distribution more focal than that typically found in CHM.
Because approximately a third of CHMs and two thirds of PHMs are not diagnosed on ultrasound in cases of missed miscarriage, histopathologic examination of all products of conception in case of early pregnancy failure is essential to detect molar changes. This is particularly important for management of CHM in women who are at higher risk of developing GTN. [23]
MRI has no established role in the initial diagnosis of hydatidiform moles. It is useful in malignant forms of GTN to characterize the degree of myometrial and/or parametrial invasion and to assess the treatment response.
No reliable plain radiographic findings are reported for hydatidiform mole. Associated risks of ionizing radiation disfavor the use of radiography in pregnant women.
No angiographic studies are clinically useful for assessing hydatidiform mole. Performed by an interventional radiologist, selective embolization of the uterine artery is reported as a well-tolerated and effective treatment option for managing severe bleeding from residual uterine vascular malformations in patients with gestational trophoblastic tumors that have been treated. [24, 25]
Computed Tomography
Computed tomography (CT) presents risk of ionizing radiation, and it has no role in the diagnosis of hydatidiform mole. However, if CT is performed, it may show an enlarged uterus with focal areas of hypoattenuation and unilateral or bilateral ovarian enlargement.
In malignant forms of GTN, CT scanning of the head, chest, abdomen, and pelvis is recommended for detecting metastatic disease.
Hong et al found that although chest radiography is ineffective in diagnosing pulmonary micrometastases in patients with hydatidiform mole, the use of chest CT should be considered for initial evaluation of hydatidiform mole. Of 14 patients who underwent chest CT on initial evaluation, 57% were found to have pulmonary micrometastases. [26]
Magnetic Resonance Imaging
MRI currently plays no role in the diagnosis of hydatidiform mole. MRI is indicated in patients with malignant forms of GTN for assessment of tumor vascularity and of myometrial and parametrial extension.
MRI findings may include the following [27, 28, 29, 30] :
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Heterogeneous endometrial enlargement with several hyperintense foci that represent hydropic villi on T2-weighted imaging
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Focal tumor masses in the endometrium and/or the myometrium
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Loss of uterine zonal anatomy (indistinctness of the endometrial-myometrial border)
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Pathologic myometrial, endometrial, and parametrial vasculature characterized by dilated and tortuous vessels
In a series of 13 patients with various histologic types of GTN, Preidler et al found the pathologic uterine vasculature to be the most reliable MRI finding for diagnosing hydatidiform mole. [31] They noted that there was no correlation between the severity of MRI findings and serum β-hCG levels or specific histologic types of GTN.
Ultrasonography
Ultrasonography (US) is the imaging investigation of choice for hydatidiform mole. Established roles for sonography include the following [16, 32, 33, 34]
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Initial diagnosis
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Assessment of treatment responses
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Determination of invasion in malignant forms of GTN
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Determination of recurrent disease in malignant forms of GTN
US should include transabdominal and transvaginal real-time gray-scale imaging. The role of grayscale US and spectral and power/color Doppler techniques has become pivotal in the diagnosis, staging, and management of GTN. [35]
The development of a complete hydatidiform mole follows a well-defined pattern, starting with a macroscopically normal gestational sac at 4 weeks, which transforms into a polypoid mass between 5 and 7 weeks of gestation. Hydropic changes in villous tissue are progressive and are rarely visible in utero on US before 8 weeks of gestation. These findings should allow earlier diagnosis and should assist in management counseling for women with CHM. [36]
Complete hydatidiform mole
With modern equipment, the typical sonographic appearance of CHM in the second and third trimesters is an enlarged uterine endometrial cavity containing innumerable anechoic cysts sized 1-30 mm (see the images below). On pathologic examination, these cysts represent grossly swollen (hydropic) chorionic villi that have a bunch-of-grapes appearance. [20]
Transverse endovaginal sonogram of a second-trimester complete hydatidiform mole (CHM) demonstrates a distended endometrial cavity containing innumerable, variably sized anechoic cysts with intervening hyperechoic material.
Transverse endovaginal sonogram of a second-trimester complete hydatidiform mole (CHM). Note that retained products of conception may mimic a hydatidiform mole.
Durinn the first trimester, the sonographic appearance of CHM is relatively nonspecific. The classic finding of multiple, tiny, anechoic cystic spaces is rarely seen. The most common sonographic appearance of CHM in the first trimester is a homogeneously hyperechoic endometrial mass. An anembryonic gestation (empty gestational sac) may be the only sonographic finding (see the images below); if it is, its distinction from blighted ovum is difficult or impossible.
Magnified transverse sonogram shows a complete hydatidiform mole (CHM) at 7 weeks of menstrual age with a small anembryonic gestational sac. This appearance is often sonographically and pathologically indistinguishable from that of an anembryonic gestation (specifically a blighted ovum).
Sagittal endovaginal sonogram of a complete hydatidiform mole (CHM) at 12 weeks of menstrual age demonstrates an enlarged endometrium containing an anembryonic gestational sac with adjacent hyperechoic material containing tiny anechoic spaces.
Partial hydatidiform mole
Sonograms of PHM may show cystic changes similar to those of CHM but in a more focal distribution. The major distinguishing feature of PHM is embryonic tissue (see the image below). In practice, PHM can be difficult to distinguish from CHM on sonograms; this distinction is usually made pathologically. This limitation is insignificant because management approaches are similar for CHM and for PHM. [37]
Transverse transpelvic sonogram of a partial hydatidiform mole (PHM) at 16 weeks of menstrual age. The major imaging feature distinguishing PHM from complete hydatidiform mole (CHM) is the presence of fetal tissue on the left side of the image (mother's right side). Note the normal-appearing placental tissue along the posterior wall of the uterus in the midline and the many small cysts that replace the placental tissue on the right side (mother's left side). This finding has a distribution more focal than that typically found in CHM.
Theca lutein ovarian cysts
Theca lutein ovarian cysts are present in 50% of hydatidiform moles. They result from ovarian hyperstimulation secondary to high circulating levels of β-hCG. On sonograms, theca lutein cysts appear as large, septate cystic ovarian lesions. They may be unilateral or bilateral, and they may be extremely large. If the lesions are large, transabdominal scanning is needed to completely visualize them. The presence of bilateral and/or large theca luteins is well correlated with serum β-hCG levels greater than 100,000 mIU/mL.
Theca lutein cysts usually resolve within 8-12 weeks after hydatidiform moles are evacuated. [38] Cysts that persist after β-hCG levels return to normal should prompt further workup to exclude a neoplastic process. In rare cases, theca lutein cysts rupture, hemorrhage, or cause ovarian torsion.
When theca lutein cysts are present, the radiologist must recommend appropriate imaging follow-up to exclude the small possibility of a preexisting or concomitant cystic ovarian neoplasm. This follow-up should include sonographic evaluation after serum β-hCG levels are normalized. In most patients, theca lutein cysts regress within 8-12 weeks after the hydatidiform mole is evacuated.
Doppler
Doppler US has no clearly defined role in the evaluation of hydatidiform mole. However, it is useful in diagnosing invasive forms of GTN, in which cystic vascular spaces with high-velocity, low-impedance flow are almost always demonstrated. Doppler US also plays a role in monitoring the response of the disease after chemotherapy. Regression of cystic vascular masses is observed after successful treatment. [16, 19, 39, 40]
After uterine evacuation, serial β-hCG levels are evaluated for early detection of GTN. Once GTN is suspected, Doppler US is the primary tool to confirm the diagnosis; however, MRI can help in selected cases. Metastatic disease workup can involve various modalities, including US, radiography, CT, MRI, and PET/CT. [41]
β-hCG normalization
According to Kerkmeijer et al, earlier serum β-hCG regression in patients with complete hydatidiform moles is likely the result of first-trimester US that leads to detection and evacuation of complete moles at younger gestational ages, resulting in lower β-hCG levels at the time of evacuation. Investigators found that 99% of a recent cohort achieved hCG normalization within 19 weeks after uterine evacuation, as compared to 25 weeks in a historic group. [17]
Degree of confidence
Sebire et al reviewed findings in 155 women with histologically proven CHMs or PHMs who had previous sonograms. [15] In only 34% was a molar pregnancy diagnosed. In the remainder, the condition was misdiagnosed as a miscarriage. [42] Accuracy was greater with CHMs (37 [58%] of 64 patients) than with PHMs (16 [18%] of 91 patients).
In a single-center study of first-trimester CHM, initial sonographic diagnoses were made in 17 (71%) of 24 cases. [18] Early pregnancy failure was the most common alternative diagnosis in cases that were missed.
In a Swedish study, US predicted a molar diagnosis in 73% of cases of CHM but in only 35% of cases of PHM. [43]
False positives/negatives
The radiologist must recognize that a first-trimester hydatidiform mole can be pathologically and sonographically indistinguishable from an early pregnancy failure. [3] Sonograms may simply show an empty gestational sac without other findings to suggest a hydatidiform mole. In a study of first-trimester CHM by Benson et al, an initial sonographic diagnosis was made in 71% of 24 cases, [18] with early pregnancy failure being the most common alternative diagnosis in missed cases.
The radiologist must maintain a high index of suspicion for hydatidiform mole during the first trimester, even when it is not suspected based on clinical findings. The serum β-hCG level may be normal, and clinical findings may be absent or minimal. The classic clinical findings of vaginal bleeding, anemia, hyperemesis gravidarum, preeclampsia, and hyperthyroidism are usually absent until the second trimester.
Nuclear Imaging
No nuclear medicine studies are clinically useful for evaluating hydatidiform mole. PET and PET-CT show promise as problem-solving tools in malignant forms of GTN. Selected case reports and case series have demonstrated the usefulness of PET for identifying lesions in patients with GTN and with negative or equivocal US, CT, and MRI findings. [44, 45]
Data regarding the effectiveness of PET in evaluating GTN are limited. Grisaru et al reported that PET-CT had a sensitivity of 97% and a specificity of 94% for gynecologic malignancy. [44] However, in 53 patients, only 1 had GTN; the remainder had various other types of cancer, including ovarian, uterine, vaginal, and cervical cancers.
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Magnified transverse sonogram shows a complete hydatidiform mole (CHM) at 7 weeks of menstrual age with a small anembryonic gestational sac. This appearance is often sonographically and pathologically indistinguishable from that of an anembryonic gestation (specifically a blighted ovum).
-
Sagittal endovaginal sonogram of a complete hydatidiform mole (CHM) at 12 weeks of menstrual age demonstrates an enlarged endometrium containing an anembryonic gestational sac with adjacent hyperechoic material containing tiny anechoic spaces.
-
Transverse endovaginal sonogram of a second-trimester complete hydatidiform mole (CHM) demonstrates a distended endometrial cavity containing innumerable, variably sized anechoic cysts with intervening hyperechoic material.
-
Transverse endovaginal sonogram of a second-trimester complete hydatidiform mole (CHM). Note that retained products of conception may mimic a hydatidiform mole.
-
Transverse transpelvic sonogram of a partial hydatidiform mole (PHM) at 16 weeks of menstrual age. The major imaging feature distinguishing PHM from complete hydatidiform mole (CHM) is the presence of fetal tissue on the left side of the image (mother's right side). Note the normal-appearing placental tissue along the posterior wall of the uterus in the midline and the many small cysts that replace the placental tissue on the right side (mother's left side). This finding has a distribution more focal than that typically found in CHM.
