Gestational trophoblastic disease: Pathology

INTRODUCTION — Gestational trophoblastic disease (GTD) comprises a heterogeneous group of related lesions arising from abnormal proliferation of trophoblast of the placenta. The pathogenesis of GTD is unique, because the maternal lesions arise from fetal, not maternal, tissue.

The histopathology of GTD is discussed here. The epidemiology, clinical manifestations, diagnosis, and treatment of hydatidiform moles and malignant GTD are reviewed separately (see "Hydatidiform mole: Epidemiology, clinical features, and diagnosis" and "Hydatidiform mole: Treatment and follow-up" and "Initial management of low-risk gestational trophoblastic neoplasia"). Differential diagnosis on clinical grounds may be difficult in a patient with an elevated serum beta-human chorionic gonadotropin (hCG) with abnormal tissue in the uterus on ultrasonography and therefore, histology is necessary for definitive diagnosis.

TERMINOLOGY

●Gestational trophoblastic disease (GTD) – Lesions characterized by abnormal proliferation of trophoblast of the placenta. This category is comprised of benign, non-neoplastic lesions, including placental site nodule, exaggerated placental site, and hydatidiform mole.

●Gestational trophoblastic neoplasia (GTN) – Gestational neoplasms include: choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor, and invasive mole. In the absence of tissue for a definitive histopathologic diagnosis, disease diagnosed as a result of persistent elevation of human chorionic gonadotropin (hCG) after evacuation of a molar pregnancy is termed GTN.

OVERVIEW — Most, but not all, GTD produces the beta subunit of human chorionic gonadotropin (hCG). Chromosomal abnormalities are characteristic of some GTD subtypes such as molar pregnancies; assessment of DNA content enhances the diagnostic accuracy of histologic diagnosis [1,2]. (See 'Genetics' below.)

Types of GTD — There are various histologically distinct subtypes of GTD:

Benign, non-neoplastic trophoblastic lesions — These lesions are frequently diagnosed only as an incidental finding on an endometrial curettage or hysterectomy specimen.

●Exaggerated placental site

●Placental site nodule

Hydatidiform mole — Hydatidiform moles result from abnormalities in fertilization. They are essentially benign, but carry an increased risk of persistent or malignant gestational trophoblastic neoplasia (GTN).

●Complete hydatidiform mole

●Partial hydatidiform mole

●Invasive mole (chorioadenoma destruens)

Gestational trophoblastic neoplasia — True GTN comprises a group of tumors with the potential for local invasion and metastases [3]. In contrast to other more common malignancies, GTN is curable in 85 to 100 percent of cases, even in the presence of advanced disease [4].

●Choriocarcinoma

●Placental site trophoblastic tumor

●Epithelioid trophoblastic tumor

In addition, the recent World Health Organization (WHO) classification adds an additional category of "abnormal (nonmolar) villous lesions," which are considered to have histologic features simulating a partial hydatidiform mole [5]. These lesions have some features of partial moles such as hydropic villi and mild trophoblastic proliferation but insufficient for diagnosis of a partial mole. These lesions have a diverse origin and include hydropic abortus, chromosomal abnormalities, digynic triploid conceptions, and placental mesenchymal dysplasia. DNA genotyping may be necessary to distinguish these from partial moles and if unavailable, then patients may need to be followed as a partial mole.

Genetics — Molar pregnancies have an imbalance or excess of paternal genetic material versus maternal. Complete moles develop due to loss of genetic material from the oocyte, which is then fertilized by two sperm or one sperm that duplicates its chromosomes. Therefore, complete moles consist of only paternal DNA and are most commonly diploid with a 46XX karyotype (46XY also occurs). Partial moles develop due to fertilization of an oocyte by two sperm, resulting in triploidy with 2:1 paternal to maternal DNA content. GTN may have contributions from both paternal and maternal genomes. Choriocarcinoma may be either androgenetic or biparental, the latter often being associated with an intraplacental choriocarcinoma [6]. (See 'Choriocarcinoma' below.)

Pathogenesis — It is known that imprinting has a role in the development of molar pregnancies and GTD. Paternal genes have more control over placental growth, while maternal genes have more control over fetal growth. Thus, with excess paternal genes, there is excessive placental or trophoblastic proliferation. There is also a difference between the malignant potential of moles that are heterozygous (arising from two sperm) and homozygous (arising from a single sperm with duplication of DNA). This was illustrated in a study that detected Y chromatin in only 9 percent of hydatidiform moles, but 50 percent of invasive moles, and 74 percent of choriocarcinomas [7].

Several studies have described interesting molecular pathways that might contribute to the development of GTD [3]. Somatic point mutations and instability of mitochondrial DNA were found in samples of hydatidiform moles and choriocarcinoma [8]. Amplification and overexpression of various oncogene products, such as c-erbB-2, c-myc, c-fms, and mdm-2, have been shown to be associated with a higher proliferation index, more aggressive behavior, and development of malignancy in GTD [9,10]. Epidermal growth factor receptor (EGFR) is highly expressed in choriocarcinoma and complete hydatidiform moles, possibly presenting a therapeutic target [11]. Downregulation of tumor suppressor genes, including p53, p21, and Rb, has also been demonstrated in GTD [12,13]. Finally, telomerase activity and expression of cell-cell adhesion molecules, metalloproteinases, and tissue inhibitors of metalloproteinases have been suggested to have a role [13].

BENIGN, NON-NEOPLASTIC TROPHOBLASTIC LESIONS — Benign trophoblastic lesions are frequently diagnosed only as an incidental finding in a pathology specimen after uterine curettage or hysterectomy.

Exaggerated placental site — The exaggerated placental site (EPS) is characterized by an extensive infiltration of the endometrium and myometrium by implantation site intermediate (extravillous) trophoblastic cells that occur in clusters or as single cells [14]. There is no destruction of the normal endometrial glands and stroma, and it occurs in the presence of a current pregnancy (ie, chorionic villi). It likely represents an excessive physiologic process rather than a true lesion and therefore, the distinction between a normal placental site and an EPS is often subjective.

The EPS can occur in a normal pregnancy or after a first trimester abortion. The associated placenta is usually normal. However, EPS occurs with increased frequency in molar pregnancies and thus can give a clue to diagnosis of these lesions. The trophoblastic cells contain abundant amphophilic to eosinophilic cytoplasm with hyperchromatic, irregularly shaped nuclei, but fail to show mitotic activity. The lack of mitotic activity and association with chorionic villi is an important clue in diagnosis, particularly between EPS and placental site trophoblastic tumor. (See 'Gestational trophoblastic neoplasia' above.)

The protein expression pattern of the trophoblastic cells in the EPS by immunohistochemistry is comparable to the implantation site intermediate (extravillous) trophoblastic cells found in the normal placental site. Thus, they show strong expression for human placental lactogen (hPL) and Mel-CAM (CD146) with focal positivity for placental alkaline phosphatase (PLAP). This is the same profile as seen in placental site trophoblastic tumors [15]. (See 'Gestational trophoblastic neoplasia' above.)

Placental site nodule — Placental site nodules (PSN) are found in uterine curettages, cervical biopsies, or hysterectomy specimens most commonly in reproductive-age patients. In one series, 40 percent of PSNs were located in the endocervix, 56 percent were in the endometrium, and 4 percent were found in the fallopian tube [15]. The intermediate trophoblastic cells of PSNs are likely derived from the migratory intermediate (extravillous) trophoblasts of the placenta, similar to the trophoblast in the chorion laeve and chorionic plate rather than the invasive intermediate trophoblast of the implantation site. They represent the non-neoplastic counterpart of epithelioid trophoblastic tumors [15]. (See 'Gestational trophoblastic neoplasia' above.)

In approximately one-half of cases, PSNs are discovered as an incidental finding in curettage or hysterectomy specimens. They can occasionally arise in extrauterine sites like the fallopian tube, presumably developing after an ectopic pregnancy [16]. When grossly identifiable, they are characterized by a yellow or tan surface and range from 1 to 14 mm (average 2.1 mm) in size. They are occasionally found as multiple nodules or plaques. Histologically, the nodules are well circumscribed and surrounded by a thin rim of chronic inflammatory cells. Abundant hyalinized or fibrinoid extracellular matrix separates trophoblastic cells, which are small and monomorphic compared with implantation site trophoblast (picture 1). They tend to have vacuolated cytoplasm and a somewhat degenerated appearance. Mitotic figures are rare and usually absent. PSNs express the intermediate trophoblastic markers of migratory trophoblast, and therefore show strong diffuse staining for PLAP, but only focal staining for hPL and Mel-CAM (CD146) [14,15].

HYDATIDIFORM MOLE — The hydatidiform mole is the most common form of GTD, representing 80 percent of cases. Moles may be complete, partial, or invasive. Complete and partial hydatidiform moles are differentiated by their karyotype, gross morphology, histologic appearance, and clinical features; invasive moles act in an aggressive manner and are often treated similarly to choriocarcinomas.

The development of gestational trophoblastic neoplasia (GTN) is significantly increased after a complete mole, but only slightly increased after a partial mole. A review of 3000 partial moles (triploid and nontriploid) found that only 15 (0.5 percent) required chemotherapy for GTN, and only rarely, if ever, were followed by choriocarcinoma [17]. When strict criteria are used for the diagnosis of partial moles, including the presence of triploidy, no cases of choriocarcinoma have been reported to develop (0 out of 196 cases of triploid partial mole) [18]. (See "Hydatidiform mole: Treatment and follow-up".)

Genetics of molar pregnancy

Complete mole genetics — A complete mole most commonly has a 46,XX karyotype, with all chromosomes of paternal origin [19]. This results from fertilization of an "empty" egg (ie, absent or inactivated maternal chromosomes) by a haploid sperm that then duplicates (46,YY moles do not occur because this karyotype is lethal); a complete mole resulting from a spermatogonium (diploid) has also been described [20]. A small number (3 to 13 percent) of complete moles have a 46,XY chromosome complement; this is thought to occur when an empty ovum is fertilized by two sperm [19]. A few complete moles have a 46,XX karyotype but develop from fertilization of an empty ovum by two sperm. Because the nucleus is entirely paternal in origin, a complete mole is actually a paternal allograft in the mother. Aneuploidy can also occur, and rarely, tetraploid complete moles have been described.

Rarely, complete moles are biparental and are associated with an autosomal recessive condition predisposing to molar pregnancy. These patients often have recurrent hydatidiform moles. This defect is likely due to dysregulation of genomic imprinting, in some cases related to a mutation at the 1.1 MB region on chromosome 19q13.4 [21-23]. As an example, women with biparental complete mole have significant underexpression of p57(KIP2), which is the product of CDKN1C (an imprinted, maternally expressed gene) [22].

It is now recognized that some patients with recurrent complete mole have diploid biparental rather than androgenetic complete mole with mutations primarily in the NLRP7 gene, and in some cases, the KHDC3L gene [24,25]. One study found that maternal chromosomal 11 is retained in the rare case of complete mole exhibiting p57 staining and helps to explain the occurrence of familial recurrent complete hydatidiform moles of biparental, rather than the usual androgenetic origin [26].

Compared with women with androgenic complete moles, women with biparental complete moles have a very high risk of recurrence, and also an increased risk of persistent trophoblastic disease [21]. In one series of 152 pregnancies among 37 women with familial recurrent mole, complete mole and partial moles occurred in 74 and 4 percent of pregnancies, respectively [23]. A normal pregnancy developed in only 5 percent; the remainder were described as spontaneous abortions (17 percent). These women may require ovum donation to achieve a normal live birth.

Partial mole genetics — Partial moles are pathologically and karyotypically distinct from complete moles. They are usually (approximately 90 percent) triploid (69,XXX, 69,XXY, rarely 69,XYY) due to the fertilization of an ovum (one set of haploid maternal chromosomes) by two sperm (two sets of haploid paternal chromosomes). Flow cytometry studies have revealed a variety of other karyotypes in the remaining 10 percent [27], although the true existence of nontriploid partial mole has been challenged [28]. The fetal or embryonic tissue that is present with a partial mole will most commonly have a triploid karyotype.

Histology — Hydatidiform moles are characterized by a marked proliferation of villous trophoblast associated with hydropic swelling of the chorionic villi. A major difference between complete and partial molar pregnancy is that complete moles typically do not contain any fetal/embryonic tissue whereas partial moles contain fetal tissue admixed with hydropic villi [29]. The genetics of the two types of mole also differ. (See 'Genetics' above.)

Complete mole — The chorionic villi of a complete mole are diffusely hydropic and surrounded by hyperplastic, often atypical, trophoblast (picture 2 and table 1). Fetal tissue is not typically present. A twin pregnancy may be complicated by GTD, with a combination of a normal conceptus and a mole (complete or partial) or two moles. (See "Initial management of low-risk gestational trophoblastic neoplasia".)

The genetic differences between complete and partial moles allow for differentiation between these two types of GTD by immunohistochemistry. As noted in a preceding section, the p57(KIP2) protein is the product of a paternally imprinted, maternally expressed gene. Immunohistochemical staining for p57 is therefore absent in complete moles (paternal, but no maternal genome) and present in partial moles or nonmolar hydropic abortuses (both paternal and maternal genetic material) [30]. p57 is strongly imprinted in villous cytotrophoblasts; this imprinting does not occur in extravillous trophoblasts (intermediate trophoblasts). Therefore, extravillous trophoblasts will express p57 in both partial and complete moles, and extravillous trophoblasts and decidual tissue serve as good internal controls for this immunostain.

Early complete mole — With the advent of ultrasonography at earlier gestational ages, molar pregnancies are being detected increasingly early, often as early as eight or nine weeks of gestation. The histologic features so characteristic of traditional complete moles, large hydropic villi and extensive trophoblast hyperplasia, are not typically seen at these early stages of development. Here, the differential diagnosis is usually between a hydropic abortus and an early complete mole.

There are, however, distinctive histologic features seen in these "early complete moles" (often defined as a complete mole identified before 10 weeks gestational age). These include a cellular, myxoid-like villous stroma; markedly irregular villous contours (referred to as "toes and knuckles"); karyorrhectic debris visible in the villous stroma; and atypical trophoblasts (both villous and extravillous). Trophoblastic proliferation is not as marked as in more mature moles [31]. In difficult cases, the use of p57 immunohistochemistry can be very helpful in identifying early complete moles [30,32].

Partial mole — In contrast to complete mole, a partial mole often contains normal appearing chorionic villi and fetal tissue admixed with hydropic villi. The hydropic changes are focal and less prominent with less trophoblastic hyperplasia and atypia (picture 3). Marked scalloping of chorionic villi and trophoblastic stromal inclusions are also common.

Differentiation of a partial mole from a nonmolar hydropic abortus may be problematic. However, hydropic abortuses usually have a spectrum of villous sizes versus the two populations of villi in partial moles. Also, abortuses will have attenuated trophoblast over the surface of the hydropic villi, while partial moles show at least modest trophoblastic proliferation. The presence of hydropic villi alone is not diagnostic of a molar pregnancy as it is the trophoblastic proliferation that is the key diagnostic feature. Therefore, description of hydropic villi alone without mention of trophoblastic proliferation indicates that the conceptus is a hydropic abortus rather than a mole and does not require follow-up.

Invasive mole — An invasive mole is a hydatidiform mole characterized by the presence of enlarged hydropic villi invading into the myometrium, into vascular spaces, or into extrauterine sites. The abnormal villi penetrate deeply into the myometrium. These lesions may be differentiated from choriocarcinoma in that they contain hydropic villi along with the marked trophoblastic proliferation. Both invasive moles and choriocarcinoma may show invasion of the uterine vasculature and the production of secondary metastatic lesions, particularly involving the vagina and lungs. Invasive moles do not often resolve spontaneously. Histologic confirmation of the clinical diagnosis is usually not pursued. Invasion can be difficult to diagnose by curettage, as myometrium is often not present. Thus, it is usually only diagnosed histologically if a hysterectomy has been performed.

GESTATIONAL TROPHOBLASTIC NEOPLASIA — The group of true gestational trophoblastic neoplasia (GTN) includes choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). As noted in the preceding section, invasive mole that does not resolve spontaneously is also GTN. Each of these neoplasms can follow a normal pregnancy or a molar pregnancy. Choriocarcinoma follows a mole in 50 percent of cases, while PSTT and ETT follow a mole in only 8 percent of cases.

Data from protein expression studies and immunohistochemical profiles have shown the presence of a common trophoblast stem cell that subsequently develops along one of three possible lines of differentiation [33,34]. Choriocarcinoma is thought to be the most "undifferentiated" trophoblastic tumor compared with PSTT and ETT, as the latter two tumors show phenotypic characteristics of extravillous intermediate trophoblast cells either in an implantation site (PSTT) or the migratory intermediate trophoblast (ETT).

However, more convincing data have shown that the common trophoblastic stem cell develops along two lines of trophoblastic differentiation: villous and extravillous [35]. Molar pregnancies and choriocarcinoma are derived from villous trophoblast, and PSTT and ETT are derived from extravillous trophoblast. Further differentiation along the extravillous (intermediate) trophoblast line produces invasive trophoblast, which are involved in remodeling and invasive of the implantation site from which PSTT is derived and the migratory trophoblast that are present in other parts of the placenta like the chorionic plate, fetal membranes, cell islands and so on, from which ETT is derived.

GTN following molar pregnancy — After the evacuation of a molar pregnancy, trophoblastic tissue persists in approximately 20 percent of patients overall, but in a greater proportion of high-risk patients. Higher risk is associated with older age, longer interval from previous pregnancy, and higher beta-human chorionic gonadotropin (hCG) levels. Surveillance is essential after the evacuation of a molar pregnancy to exclude the presence of persistent disease. The diagnosis is usually based upon the finding of stable or serially rising serum beta-hCG concentrations rather than by examination of tissue. It is interesting to note that GTN (choriocarcinoma, PSTT, and ETT) may occur many years after the antecedent pregnancy and may even occur during menopause. (See "Hydatidiform mole: Treatment and follow-up".)

Molar pregnancy with a persistent hCG elevation is considered to be persistent or recurrent GTN. Often there is no histopathologic confirmation and patients are treated empirically. Histologically, 75 percent of cases of stable or serially rising serum hCG concentrations after a molar pregnancy represent invasive moles, and 25 percent are choriocarcinomas. PSTTs do not usually occur in this context.

The risk of choriocarcinoma is increased after a complete mole and has only rarely been reported after a partial mole [18] (see "Hydatidiform mole: Treatment and follow-up"). Therefore, a rise in serum hCG after a molar pregnancy signals the presence of persistent or recurrent GTD, which may be a recurrent mole, invasive mole, or choriocarcinoma. In contrast, persistent elevation of serum hCG following any nonmolar pregnancy (eg, miscarriage, ectopic, or preterm/term pregnancy) may be due to development of choriocarcinoma or PSTT (rare) rather than invasive mole [36].

Types of GTN

Choriocarcinoma — Choriocarcinoma is a highly malignant epithelial tumor. It can arise from any type of trophoblastic tissue (molar pregnancy, abortion, ectopic, preterm/term intrauterine pregnancy) but, as noted in the preceding section, occurs only rarely, if ever, after a partial mole [17,36].

Histologically, choriocarcinoma consists of sheets of anaplastic cytotrophoblasts and syncytiotrophoblasts without chorionic villi. While some trophoblasts, which are intermediate in appearance, may also be seen, the biphasic pattern of obviously malignant appearing mononuclear (cytotrophoblasts) and multinuclear cells (syncytiotrophoblasts) is essentially pathognomonic of choriocarcinoma (picture 4). Extensive necrosis, hemorrhage, and vascular invasion are common.

Immunohistochemical markers can confirm the histologic diagnosis with strong staining for hCG, inhibin, and cytokeratin in all trophoblast cells. Ki-67 is diffusely expressed in approximately half the cells [37].

Choriocarcinoma following a normal gestation is often comprised of biparental chromosomes identical to the fetus [38]. However, this is not always the case as some choriocarcinomas do not have the DNA complement of the previous pregnancy but rather the pregnancy preceding [39]. Postmolar choriocarcinoma is often comprised exclusively of paternal DNA or androgenetic; most choriocarcinomas that follow molar pregnancies are aneuploid [6,12]. Some choriocarcinomas appear to arise within a term placenta, referred to as an intraplacental choriocarcinoma. These are most often biparental in origin and do not necessarily arise after a molar pregnancy [6].

Most lesions begin in the uterus, although ectopic pregnancies provide extrauterine sites of origin. When choriocarcinoma metastasizes, the most common sites are lung, brain, liver, pelvis, vagina, spleen, intestine, and kidney.

Sometimes, when curettage is performed for an early pregnancy loss, gestational endometrium and implantation site without villi may be encountered. Histopathologic diagnosis of choriocarcinoma in the setting of an early pregnancy is often problematic. Although the presumptive diagnosis is a missed abortion, choriocarcinoma may have to be excluded by following quantitative serum hCG concentrations and performing a chest radiograph.

Placental site trophoblastic tumors — PSTT, initially described in 1981, is a rare, potentially malignant neoplasm originating from extravillous (intermediate) trophoblast cells [40]. Approximately 300 cases of PSTT had been reported [41,42]. They can occur months to years after a pregnancy. PSTTs most commonly develop after a term gestation, but also occur after a molar pregnancy in approximately 8 percent of cases; a PSTT can develop after any type of pregnancy. The majority of PSTTs, approximately 70 percent, act in a benign manner, while the remaining 30 percent can develop metastasis and even result in death. Interestingly, PSTTs are usually diploid and molecular genotyping has shown them to have a female predominance or 46XX [43]. (See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

On histologic examination, PSTT generally presents as a proliferation of extravillous or intermediate trophoblast in the myometrium or endomyometrium (picture 5). Chorionic villi are rarely found and the typical dimorphic pattern of choriocarcinoma is absent. Instead, there is a characteristic pattern consisting of a relatively monomorphic population of predominantly mononuclear trophoblastic cells infiltrating the myometrium and splitting apart the muscle fibers. Scattered multinucleated trophoblasts are also present as are multinucleated syncytiotrophoblastic-like cells. Nuclear atypia is quite variable as is the cytoplasm, which is most often amphophilic but can also be eosinophilic or clear. Spindling of tumor cells may be present. In addition, there is usually abundant fibrinoid material and prominent vascular invasion. A variable amount of inflammation and necrosis is identified but the marked hemorrhage and necrosis typical of choriocarcinoma is not present.

Immunohistochemical staining for human placental lactogen (hPL), CD146 (MEL-CAM), and placental alkaline phosphatase (PLAP) are additional diagnostic tests for PSTT that have a specificity of approximately 60 percent [15,44]. Mel-CAM and hPL are usually strongly positive, while PLAP is focally positive consistent with origin from implantation site trophoblast. In addition, high proliferative activity (as assessed by Ki-67 staining) and positive staining for alpha-inhibin and cytokeratin 8/18 and negative smooth muscle markers confirm the diagnosis of PSTT [15]. Most PSTTs are diploid, although a report of a tumor with triploid cells has been published [45].

Although the majority of PSTTs are considered benign, there is no specific clinical or pathologic feature on which one may rely to determine malignant behavior. However, there are a number of adverse prognostic factors which, when present, confer a greater likelihood of malignant behavior. These include advanced stage, older age, longer interval from previous pregnancy, previous term pregnancy, higher serum hCG level, higher mitotic rate, coagulative tumor necrosis, and clear cytoplasm [42,46]. When a PSTT is malignant, it is fairly resistant to chemotherapy. (See "Initial management of low-risk gestational trophoblastic neoplasia".)

Epithelioid trophoblastic tumor — ETT is a rare form of trophoblastic disease [47]. As of 2008, only 52 cases had been reported [48]. ETTs are clinically, pathologically, and prognostically similar to PSTTs. ETT primarily occurs in reproductive-age women up to 18 years following a prior gestation. The majority of ETT occur after a full-term pregnancy, but approximately one-third arise following a spontaneous abortion or hydatidiform mole [48].

Vaginal bleeding is the presenting symptom in two-thirds of patients; approximately one-third of patients present with metastatic disease. Serum hCG levels are elevated, but usually do not exceed 2500 milli-international units/mL.

Gross inspection of ETT shows a solid to cystic, fleshy, and well-defined mass in the uterine wall, lower uterine segment, or endocervix. Histologically, ETT is nodular, with proliferation of smaller, more monomorphic trophoblastic cells in comparison with PSTT. The cells display eosinophilic to clear cytoplasm forming numerous cell nests with surrounding necrosis (picture 6). The borders of nodular growth are usually well circumscribed, but focal invasion into the surrounding tissue is frequently found. The predominant cell type is the migratory type of extravillous or intermediate trophoblast, but occasional syncytiotrophoblast-type cells may be present [49]. Mitotic rate is variable, from 0 to 9 per 10 high-power fields.

Behavior and prognosis is similar to that of PSTT. A minority of ETTs act in a malignant manner and treatment is usually problematic in those cases. However, a significant percentage present with extrauterine disease at diagnosis [50].

Molecular markers expressed on ETT by immunohistochemistry include pancytokeratin, epithelial membrane antigen, cytokeratin 18, inhibin-a, hCG, human placental lactogen, placental alkaline phosphate, and Mel-CAM (CD146). P63 is expressed in ETT, placental site nodule, and choriocarcinoma, but not in PSTT [51]. Placental alkaline phosphatase staining is usually strong, while hPL, inhibin, and Mel-CAM staining is usually more weak and focal.

Epithelioid trophoblastic tumor can be confused with squamous cell carcinoma because of its frequent involvement of the lower uterine segment or endocervix, its epithelioid histologic appearance, and expression of p63 and cytokeratins.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gestational trophoblastic disease".)

SUMMARY

●Gestational trophoblastic disease (GTD) is characterized by abnormal trophoblastic proliferation. In GTD, the lesion arises from fetal, not maternal, tissue. (See 'Introduction' above.)

●GTD may be non-neoplastic or neoplastic. Non-neoplastic GTD includes exaggerated placental site, placental site nodule, and complete or partial hydatidiform mole. Gestational neoplasia includes invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), or epithelioid trophoblastic tumor (ETT). (See 'Terminology' above and 'Gestational trophoblastic neoplasia' above.)

●Hydatidiform moles, choriocarcinomas, and the majority of PSTTs and ETTs are identified by a marker, the beta subunit of human chorionic gonadotropin or by the marker for human placental lactogen. Moles have characteristic chromosomal abnormalities. (See 'Overview' above.)

●A complete mole usually has a 46,XX karyotype (rarely, a 46,XY karyotype), but both sets of chromosomes are of paternal origin. Partial moles are typically triploid due to the fertilization of an ovum by two sperm. (See 'Genetics' above.)

●After the evacuation of a molar pregnancy, trophoblastic tissue persists in approximately 20 percent of patients. Malignant GTD usually occurs after a complete mole, rather than a partial mole and consists of an invasive mole in 75 percent of cases and choriocarcinoma in 25 percent; other types of gestational trophoblastic neoplasia (GTN) are rare. (See 'Gestational trophoblastic neoplasia' above.)

●Persistent elevation of serum hCG following any nonmolar pregnancy (eg, miscarriage, ectopic, or preterm/term pregnancy) is more commonly due to choriocarcinoma rather than placental site trophoblastic tumor or invasive mole. (See 'Gestational trophoblastic neoplasia' above.)