Chapter 29: SONOGRAPHY OF TROPHOBLASTIC DISEASES

Gestational trophoblastic disease (GTD) represents a variety of diseases arising from the placenta. The most common is the hydatidiform mole. Gestational trophoblastic neoplasia (GTN) indicates processes that have the capacity for local invasion and/or metastasis, and include invasive moles, gestational choriocarcinomas, and placental site tumors.¹ The incidence of hydatiform moles in the United States is about one 1 in 1000 to 1200 pregnancies. Malignant sequelae after the evacuation of the mole occur in about 20%. Gestational choriocarcinoma occurs in about 1 in 20,000 to 40,000 pregnancies. Although these diseases are not particularly common, women with GTD are seen for pregnancy, or arrive at emergency centers with bleeding, and sonography is almost universally the first imaging test performed.¹

Gestational trophoblastic diseases are a group of disorders that are thought to originate through fertilization of the ovum by 1 or more spermatozoa in either a normal or abnormal manner. This is in contrast to the nongestational forms of choriocarcinoma that can arise in the ovary or testicle and do not involve fertilization or a prior gestational event. The trophoblastic neoplasms arise from the trophoblastic elements of the developing blastocyst, and therefore retain certain inherent characteristics, such as the ability to invade underlying tissues and the ability to synthesize human chorionic gonadotropin (hCG).

The principal role of sonography in gestational trophoblastic disease is in establishing the diagnosis of hydatidiform mole.² A characteristic sonographic appearance of hydropic villi occurs with most molar pregnancies. Sonography is also considered an important adjunctive test to serial β-hCG assays in malignant trophoblastic disease. With sonography, it is sometimes possible to demonstrate uterine invasion by trophoblastic tissue.³ It can also be used to monitor the response of the tumor to therapy, and the presence of other metastatic sites can be ascertained.⁴ Color Doppler sonography affords detection in areas of abnormal blood flow within the myometrium and can be used as a means to monitor the effectiveness of chemotherapy (Figure 29-1).⁵

Gestational trophoblastic disease has been classified in a variety of ways (Table 29-1). Initial attempts at classification were based on histopathologic criteria. Currently, with the use of hCG monitoring, patients have been classified according to a clinical staging system. The use of different classification systems has probably contributed to confusion among obstetricians and sonologists concerning the sonographic categorization of these diseases. In this chapter, the sonographic features of the various forms of GTD are presented relative to both the pathologic and clinical classifications.

Because the sonographic features of an invasive mole and choriocarcinoma are similar, they are presented under the same heading. Accordingly, the discussion portion of the chapter is divided into 2 major categories of GTD: molar pregnancies and malignant GTDs. Although it may be difficult to differentiate the various pathologic types of gestational trophoblastic disorders by their sonographic features alone, the combination of clinical, laboratory, and sonographic findings can usually specify the type and extent of trophoblastic disease that is present.

Histopathologic

This classification divides trophoblastic diseases into hydatidiform mole, invasive mole (chorioadenoma destruens), choriocarcinoma, and placenta site trophoblastic tumor based on histopathologic criteria.

Hydatidiform mole is characterized by marked edema and enlargement of the chorionic villi, producing vesicular structures. The vesicles are the characteristic that allows sonographic identification. These changes are accompanied by disappearance of the villus blood vessels and proliferation of the trophoblast (cytotrophoblast and syncytiotrophoblast) that line the villi (Figure 29-2). Although moles with an abundantly proliferative trophoblast may have a greater likelihood of being malignant, it is not possible to accurately predict the malignant potential of a given mole based on the histologic appearance. Approximately 20% of complete moles are followed by additional malignant sequelae of invasive mole or choriocarcinoma.⁶ Further classification of hydatidiform mole based on histopathologic criteria has not proven to be an accurate prognostic indication to select the 20% of patients with a molar pregnancy who will subsequently develop malignant disease.⁷

Invasive mole (chorioadenoma destruens) is the term used to describe trophoblastic disease where there has been invasion into the myometrium of the uterus. Grossly, a vesicular structure is preserved (Figure 29-3). Microscopic examination will reveal edematous villi invading the myometrium. There is often abundant trophoblastic proliferation of the remaining villi. Where the villi invade the underlying myometrium, some hemorrhage is produced. Necrosis, however, is absent. Hysterectomy is rarely used in the treatment of trophoblastic disease today. Therefore, the diagnosis of invasive mole is rarely made based on surgical pathology.

Choriocarcinoma is characterized by the lack of any remaining villus structure. Microscopic examination will reveal sheets of highly malignant trophoblast with proliferation of both cytotrophoblast and syncytial trophoblast (Figure 29-4). There is associated hemorrhage and necrosis, which is the other hallmark of choriocarcinoma. Choriocarcinoma accounts for approximately 5% of all GTDs.⁷ Local pelvic metastases and lung metastases are the most common, but liver, brain, kidney, and bowel metastases may occur as well.

Placental site trophoblastic tumors (PSTTs) are extremely rare and arise from the placental implanation site, resembling a form of syncytial endometritis. The myometrium is invaded by the trophoblastic cells, and vascular invasion is usually seen. Human chorionic gonadotropin levels are low, whereas human placental lactogen is secreted by the cells. Whereas the other forms of GTN respond to chemotherapy, PSTTs are not responsive to medical therapy, and are treated by hysterectomy.¹

Clinical Aspects

Careful follow-up of patients with hCG monitoring and the use of chemotherapy as the main mode of therapy rather than surgery has led to a replacement of the histopathologic classification by a more practical clinical classification of GTD. This clinical classification still recognizes hydatidiform moles, both the complete and partial types.

Any patient with a pathologic diagnosis of choriocarcinoma or invasive mole is considered to have malignant GTD, as are patients who develop plateauing or rising hCG levels, as defined by the 2000 FIGO staging. Patients are not classified as having malignant GTD solely by a pathologic diagnosis of hydatidiform mole; such patients may or may not follow a malignant clinical course.⁴ Patients with malignant GTD are further subdivided into nonmetastatic or metastatic groups. Clinical experience in treating patients with trophoblastic disease has further identified a group of patients with metastatic disease that is considered to be at high risk.^8,9 This includes patients with liver or brain metastasis, β-hCG levels above 40,000 mIU/mL before therapy, an interval of more than 4 months between pregnancy and initiation of therapy, failure of previous chemotherapy, and trophoblastic disease that develops after a full-term pregnancy.¹⁰ These high-risk patients require especially diligent radiologic and sonographic evaluation in their follow-up.

Pathogenesis

The pathogenesis of hydatidiform mole has remained a subject of considerable speculation for many years. The work of Kajii and Ohama,¹¹ however, demonstrated that hydatidiform mole results from the fertilization of an "empty egg," that is, an ovum without any active chromosomal material. The chromosomes of the sperm, finding no chromosomal complement from the ovum, reduplicate themselves, resulting in a 46,XX molar pregnancy. This has also been called a complete mole or classic mole. In complete mole, there is complete lack of fetal development, so there are no identifiable fetal parts or fetal membranes that can be seen in this situation. Complete moles are associated with different degrees of trophoblastic proliferation and may follow either a benign or malignant clinical course. Only about 20% of cases will eventually pursue a malignant course.⁶

Some cases of hydatidiform mole are found to contain a small complement of fetal structure, such as a placenta with membranes, or even a developed fetus. This is referred to as a partial mole. These cases usually involve some edema of the villi but relatively little trophoblastic proliferation. Hydropic degeneration is present, but with some elements associated with fetal structures, the designation partial mole has been made.¹² Although subsequent malignancy has been reported, partial moles are almost always benign.¹³ In a partial mole, the fetus usually has significant congenital anomalies and a triploid karyotype.¹⁴ Two sets of chromosomes are of paternal origin, and the third set is of maternal origin, usually leading to a karyotype of 69 XXY or 69 XXX.

A fetus with a coexisting molar pregnancy can occur. This is much less common than a partial molar pregnancy; however, it can grossly appear similar to the partial mole. This disorder is thought to result from a dizygotic pregnancy, with one fetus resulting from a normal fertilization and the other being a complete molar pregnancy.¹⁵ In these patients, a fetus and normal placenta can usually be identified, in contrast to a partial molar pregnancy where a normal placenta is not present.

Hydropic degeneration of the placenta may give a similar sonographic appearance to complete and partial mole, but, histologically, it is not associated with trophoblastic proliferation. The villi and hydropic degeneration of the placenta are swollen and edematous, and thus may resemble abnormal trophoblastic tissue. Microscopic examination will usually reveal the absence of cisternal formation; only hydropic swelling is seen. Hydropic degeneration may be seen in 20% to 40% of placentas from abortuses.⁶

Clinical Aspects

The most common presenting clinical sign of molar pregnancy is vaginal bleeding, which may be seen in 89% to 97% of cases; in approximately half of the cases, the bleeding may be severe enough to produce anemia.¹⁶ A uterus that is enlarged beyond what is expected based on gestational age is considered "classic" for molar pregnancy; however, this is only seen in 33% to 51% of cases.¹⁶ In approximately 50% of cases, patients will present with what is easily recognized as a molar pregnancy based on the passage of vesicular tissue via the vagina.¹⁷ If there has been significant expulsion of molar tissue before presentation, the uterus may appear normal for size or even small for dates, both clinically and sonographically.

Molar pregnancies should always be considered in the differential diagnosis of a patient presenting with severe preeclampsia before 24 weeks of gestation without underlying renal disease. Although this presentation is considered classic for hydatidiform mole, it is only seen in 6% to 12% of cases of molar pregnancy.¹⁶

Theca-lutein cysts are often encountered in patients with molar pregnancies. These are physiological cysts and not neoplasms due to the high hCG levels. The actual incidence of these cysts in association with molar pregnancy has been reported in various series to range from 18% to 37%.^18,19 Compared with clinical examination, sonography can more accurately assess the presence or absence of thecalutein cysts (Figures 29-5 and 29-6).²⁰ In one large series, theca-lutein cysts were detected clinically in 10% of patients with molar pregnancy, compared with 37% of patients when examined by sonography.¹⁹ The presence or absence of theca-lutein cysts does not seem to be an accurate predictor of later development of an invasive mole or choriocarcinoma.¹⁹ A review of a series at the University of Southern California has suggested, however, that patients with theca-lutein cysts have a 2-fold increase of malignant sequelae.²¹ In most patients who undergo spontaneous resolution of hCG levels, the cysts also regress spontaneously; however, they may occasionally undergo torsion, and therefore require surgical intervention.

The laboratory findings for molar gestation are usually diagnostic. Measurement of hCG, specifically the β subunit, is almost always abnormally elevated in molar gestations. The assay is not foolproof, because it can be spuriously elevated in twin gestations or may occasionally fail to show significant elevation in a molar pregnancy.²² In PSTT, the human placental lactogen level will be elevated.

As soon as the diagnosis of molar pregnancy is confirmed, the uterus should be evacuated. This typically involves suction curettage (dilation and evacuation, or D&E). Before evacuation, a chest x-ray should be obtained to exclude metastatic disease that might already be present. The patient should also be evaluated as to her pulmonary status, cardiac status, thyroid status, and to be sure that adequate coagulation factors are present.¹⁶ After D&E, serial β-hCGs are obtained weekly to assess the status of any remaining trophoblastic tissue. The level of this glycoprotein hormone should return to normal approximately 10 to 12 weeks after evacuation; however, it may occasionally take longer.²³ Recurrence of GTD is increased 10- to 15-fold; thus, patients should be instructed to seek medical attention, and early hCG testing and sonography should be exercised to assess future pregnancies. As previously mentioned, theca-lutein cysts will usually regress after successful treatment of molar pregnancy. Their presence or absence should not be taken as an absolute indication of the presence or activity of residual trophoblastic disease.²⁴

Sonography has an important role in evaluating those patients in whom the β-hCG subsequently rises. It can detect the presence or absence of intrauterine pregnancies that may occur after the initial evacuation. It can also detect the small number of patients with molar gestation who have a coexisting normal pregnancy.²⁵ It may also detect the presence of residual trophoblastic disease and can detect invasion of the myometrium by this residual trophoblastic tissue.³

Sonographic Features

The sonographic appearance of a hydatidiform mole is quite distinctive.^1–2 In most cases, a sonographic pattern arising from molar tissue consists of echogenic intrauterine tissue that is interspersed with numerous punctuate sonolucencies (see Figure 29-5). Irregular sonolucent areas may occur secondary to internal hemorrhage or an area of unoccupied uterine lumen.

The sonographic appearance of a hydatidiform mole differs according to its gestational duration and the size of the hydropic villi.²⁶ For instance, hydatidiform moles that occur from 8 to 12 weeks typically appear as homogeneously echogenic intraluminal tissue, because the villi at this stage have a maximum diameter of 2 mm (see Figure 29-6). As the hydatidiform mole matures to 18 to 20 weeks, the vesicles have a maximum diameter of 10 mm, which is readily delineated as cystic spaces on sonography (Figure 29-7).

Complete moles do not have fetal tissue; in contrast, partial molar pregnancy, hydatidiform mole coexistent with fetus, and hydropic degeneration of the placenta are associated with the presence of a fetus or fetal parts. Although it may be difficult to differentiate between a partial molar pregnancy and a complete mole with a coexistent fetus on the basis of sonography, these 2 entities can be differentiated from a complete mole when an identifiable fetus is present.^15,18 In addition, the complete mole with a coexistent fetus typically has a fetus with a separate normal placenta as well as the molar mass. This contrasts with a partial mole in which only a portion of the placenta is normal and most of it has a vesicular pattern.

Sonography can also delineate the theca-lutein cyst that enlarges under the influence of high levels of β-hCG elaborated by the trophoblasts. These cysts appear as multiloculated cystic masses that are usually located superior to the uterine fundus or, less commonly, in the cul-de-sac (see Figure 29-6). There are typically thin septa present.

Rarely, there can be massive enlargement of the ovaries with luteinization of several follicles in apparently normal pregnancies. This condition, which is termed hypereactio luteinalis, may be a result of hypersensitivity of the woman's ovary to high circulating levels of hCG (Figure 29-8).

Invasive trophoblastic disease can be diagnosed with color Doppler sonography by demonstration of enlarged vessels within the myometrium that usually exhibit low-impedance, high-diastolic flow (see Figure 29-1).⁵

Sonographic Differential Diagnosis

Hydropic degeneration of the placenta associated with incomplete or missed abortions is the most common condition that can simulate the appearance of a molar pregnancy (Figure 29-9). The hydropic areas may be focal or diffuse and appear as anechoic space within the placenta (see Figure 29-9). This is due to the sonographic similarity of a hydropic placenta with marked swelling of the villi to molar tissue. A fetus may or may not be present with hydropic degeneration of the placenta. Serum β-hCG levels are generally lower in hydropic degeneration than in partial or complete moles, probably due to the reduced number of functioning trophoblasts. Hydropic changes in the placenta can be associated with triploidy.²⁷

Technical factors that may be used to improve the ability to distinguish partial from complete moles or hydropic degeneration have been described.³ Specifically, detailed examination of the entire intrauterine contents with transducers that are optimally focused to a particular region within the uterus has been stressed. Transvaginal scanning may be helpful in some cases in which the molar tissue cannot be adequately delineated transabdominally. Using this technique, the typical vesicular texture arising from molar tissue can be correctly distinguished from tissue texture emanating from retained products of conception or leiomyomata.⁴

Pulsed and color Doppler sonography have been used to assess the presence of invasive trophoblastic disease.²⁸ This technique is discussed in greater detail in the section devoted to invasive trophoblastic diseases.

Occasionally, the sonographic appearance of a uterine leiomyoma may mimic that of a hydatidiform mole. However, as described in Chapter 33 uterine leiomyomata typically have a whorled internal consistency that is distinctly different from the vesicular pattern encountered in the hydatidiform mole. They may also contain areas of hyaline and myxomatous degeneration that can simulate the sonographic appearance of hemorrhage within a hydatidiform mole. We have also encountered some partially solid ovarian tumors that simulate the appearance of a hydatidiform mole. Patients with this type of mass can usually be distinguished from those with molar pregnancies by clinical and laboratory methods because the β-hCG is not elevated in nonpregnant conditions.

Finally, patients with retained products of conception with hemorrhage can simulate the sonographic appearance of molar pregnancies, due to the appearance of echogenic material within the uterus. One is usually not able to demonstrate a vesicular pattern of tissue associated with retained products, however. The hCG levels likewise would not typically be markedly elevated.

Although absolute distinction between the various trophoblastic disorders may not always be possible on the basis of sonography, the sonographic evaluation of these disorders plays a vital role of clinical importance. Specifically, it is known that the malignant potential of a complete mole is greater than that of a partial mole or hydropic degeneration. Thus, the sonographic findings can have a significant clinical impact on the treatment and management of these disorders.

Pathogenesis and Clinical Aspects

The majority of patients that develop malignant trophoblastic disease will have a history of an antecedent molar pregnancy. In a series of patients reported by Duke University, 86% of patients who developed malignant trophoblastic disease did so after a hydatidiform molar pregnancy.²⁶ Approximately 10% of patients had a history of a previous full-term pregnancy, and another 5% had an abortion or some other form of pregnancy event. In patients who presented with high-risk disease, there was a larger proportion of patients presenting after full-term pregnancy, abortions, and other types of pregnancy events. In other words, GTN that follows a term pregnancy is often aggressive.

Histologically, invasive moles differ from choriocarcinoma. A villous structure is maintained in invasive mole and is always absent in choriocarcinoma. Both disorders are associated with excessive trophoblastic proliferation and invasion of the myometrium. In general, choriocarcinoma is associated with a great deal of hemorrhage and necrosis.

Generally, an invasive mole is first suspected in a patient with a history of evacuation of a hydatidiform mole who subsequently presents with continued uterine bleeding, a persistently elevated hCG level, persistently enlarged theca-lutein cysts, or a combination of these. This clinical picture, however, can also be seen in patients who histologically are found to have choriocarcinoma. Because hysterectomy is rarely performed in the current management of trophoblastic diseases, these entities are not recognized separately in the clinical staging system. Patients with choriocarcinoma that extends outside the uterus can present for the first time with manifestations of metastatic spread to the lungs, liver, or brain. In the lungs, metastatic choriocarcinoma has a rather specific radiographic appearance of radiodense masses with hazy borders, due to the hemorrhage around the metastases. The metastases may undergo rapid regression after therapy has been instituted. Because these diseases are very responsive to chemotherapeutic agents, their early clinical and sonographic recognition is imperative for institution of appropriate therapy.

The sonographic appearance of invasive trophoblastic tissue is that of a focal irregular echogenic region within the uterine myometrium (see Figures 29-9 and 29-10). Irregular hypoechoic areas may surround the more echogenic trophoblastic tissue corresponding to areas of myometrial hemorrhage.

Ultrasound examination of PSTT usually reveals the appearance of a heterogeneous, hyperechoic mass with numerous cystic spaces within the myometrium of an enlarged uterus. These features alone do not allow distinction from other forms of GTN, though on Doppler both hypervascular and hypovascular forms of the disease have been reported. None of these findings is diagnostic of PSTT.²⁹

Because of its proximity to the uterus, myometrial implants may be best delineated with transvaginal scanning (see Figure 29-10). Pulsed Doppler sonography has been used to assess the presence and relative aggressiveness of myometrial implants by depicting increased and typically turbulent flow to these tumors through the uterine arteries.²⁷ Color Doppler sonography of invasive trophoblastic disease usually exhibits low-impedance, high-diastolic velocity flow within the myometrium (Figure 29-11).⁵

In addition to the echogenic intrauterine areas, sonography is helpful in the detection of theca-lutein cysts associated with trophoblastic disease. These cysts are typically bilateral, multiloculated cystic masses that characteristically measure between 4 and 8 cm in diameter. Sonography has been shown to be more sensitive than physical examination in the detection of these cysts, because it may be difficult to palpate a cyst that is displaced high in the pelvis by an enlarged uterus. Likewise, the practitioner is often reluctant to palpate due to the risk of rupture and hemorrhage of these cysts. The presence of theca-lutein cysts may be an indication of persistent trophoblastic activity because it has been shown that malignant trophoblastic disease develops more commonly in patients with persistent theca-lutein cysts.²¹ Because it can take several months, and rarely up to 12 months, for these cysts to regress after evacuation of a molar pregnancy, their presence or absence during the period of follow-up cannot be taken as an accurate indication of the presence or activity of remaining trophoblastic tissue.

Sonography and pulsed Doppler analysis of the uterus can be useful, when used in combination with serial β-hCG assays, in the evaluation of tumor response to chemotherapy.²⁵ Serial evaluation of tumor volume can be accomplished using sonography; reduced volume follows closely the diminution in β-hCG values in successfully treated patients. Preliminary reports also describe the sensitivity of pulsed Doppler techniques for detection of tumor growth or regression.²⁸ Transvaginal color Doppler sonography can demonstrate changes in blood flow, which correlate to a decrease in β-hCG in successfully treated choriocarcinoma or no change in nonresponders. The changes in flow seem to parallel changes in β-hCG in both responders and nonresponders.³⁰ The presence of tumor is implied when the Doppler waveforms obtained from the uterine arteries show increased systolic and diastolic flow with low resistance similar to that typically seen in third trimester pregnancy.

Sonography is also helpful in evaluation of the liver for metastatic disease in patients with malignant, metastatic trophoblastic disease.¹⁵ Typically, the metastases associated with choriocarcinoma appear as echogenic foci within the liver. The kidneys can also be evaluated for the presence of obstructive uropathy, which is important not only to rule out metastatic involvement but also because effective chemotherapy often requires adequate renal function. Computed tomography (CT) or magnetic resonance (MR) imaging are likely superior for localizing metastases in the liver or the brain.

Sonography is the single most important diagnostic examination in establishing the diagnosis of GTD. It has an important role in the evaluation of patients with benign and malignant GTD. The sonographic features of hydatidiform mole and its variants are usually diagnostic. Because of its rarity, it is incumbent on sonographers and sonologists to regularly study the sonographic characteristics of these conditions. If malignant trophoblastic disease is suspected clinically, sonography can be used to establish the presence and extent of disease, as well as in the serial evaluation of patients undergoing treatment.