Gestational trophoblastic disease: Pathology and genetics

INTRODUCTION — Gestational trophoblastic disease (GTD) and gestational trophoblastic neoplasia (GTN) comprise a heterogeneous group of related lesions arising from abnormal cellular proliferation of placental trophoblasts. Most, but not all, of these lesions produce human chorionic gonadotropin (hCG) at some level. The pathogenesis of GTD/GTN is unique because maternal lesions arise from fetal, not maternal, tissue, making them genetically distinct from the maternal host, and distinguishing them from other tumorous processes. Consequently, understanding the histomorphology, immunohistochemistry, and genetics of GTD/GTN is central to their diagnosis, prognosis, and clinical management [1,2].

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".)

●(See "Hydatidiform mole: Treatment and follow-up".)

●(See "Initial management of low-risk gestational trophoblastic neoplasia".)

●(See "Initial management of high-risk gestational trophoblastic neoplasia".)

●(See "Management of resistant or recurrent gestational trophoblastic neoplasia".)

TERMINOLOGY

●Gestational trophoblastic disease (GTD) – Lesions characterized by abnormal proliferations of placental trophoblasts, including exaggerated or involuting placental implantation site, placental site nodule (PSN), and hydatidiform moles. Although usually benign, some GTD has premalignant potential.

●Gestational trophoblastic neoplasia (GTN) – Gestational neoplasms includes choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). GTN is typically diagnosed after pregnancy (any type; molar or nonmolar) in which human chorionic gonadotropin (hCG) levels are persistently elevated.

The distinction between GTD and GTN, while convenient for conceptual discussion, may be somewhat misleading. For example, some GTD has the biological potential to evolve into GTN (ie, some molar pregnancies may metastasize as choriocarcinoma, and some atypical PSNs may transform into ETT). In addition, the overlapping pathobiological and clinical features of GTD and GTN tend to promote synonymous usage of these terms, especially in the absence of a definitive histopathologic diagnosis (eg, when abnormal gestational trophoblast proliferation is diagnosed by persistent elevation of hCG after evacuation of a molar pregnancy). Generalization or imprecise use of terminology, however, should not cause confusion when a specific histologically defined entity (and its biologic potential) is known (table 1 and table 2).

GESTATIONAL TROPHOBLASTIC DISEASE

Tumor-like lesions — Benign trophoblastic lesions are frequently diagnosed as incidental findings in pathology specimens after uterine curettage or hysterectomy. These tumor-like lesions may present months to years after the antecedent pregnancy and represent an abnormal type of retained products of conception lacking chorionic villi. Most of these lesions are composed of extravillous, predominantly mononuclear trophoblasts, termed intermediate trophoblasts. These trophoblasts can be further subdivided based on their histological and immunophenotypic resemblance to normal trophoblast populations forming either the placental membranes or implantation site. Some atypical lesions carry an increased risk of malignancy [3].

Exaggerated placental site — Exaggerated placental site (EPS) is characterized by an exuberant infiltrate of implantation site extravillous (intermediate) trophoblast cells involving the endometrium and superficial myometrium [4]. Implantation site trophoblasts are arranged as single cells, or in small clusters and irregular ribbons. Some cells may have multiple nuclei. Confluent or sheet-like trophoblast proliferation is present only near the plane where chorionic villi anchor, defining the maternal side of the placental disk. The trophoblastic cells contain abundant amphophilic to eosinophilic cytoplasm with hyperchromatic, irregularly shaped nuclei, and show little or no mitotic activity. Though extensive, the implantation site trophoblasts in EPS do not destroy normal endometrial glands and stroma. The associated placenta is usually normal.

EPS is most often observed in conjunction with a normal first-trimester pregnancy or missed abortion and likely represents nothing more than a physiologic process rather than a true lesion. As such, the distinction between normal placental site and EPS is subjective. EPS, however, must be distinguished from more serious trophoblastic proliferations, such as placental site trophoblastic tumor (PSTT), choriocarcinoma, molar implantation site, and atypical implantation site. Lack of mitotic activity and association with chorionic villi are important clues, particularly in distinguishing between EPS and PSTT. Minimal or absent trophoblast atypia (beyond that seen in normal placental implantation) distinguishes it from molar implantation site (especially in complete hydatidiform moles). (See 'Placental site trophoblastic tumors' below and 'Hydatidiform mole' below.)

The protein expression pattern of the trophoblastic cells in EPS determined by immunohistochemistry is comparable to implantation site intermediate (extravillous) trophoblastic cells found in normal placental implantation 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 PSTT [5]. (See 'Placental site trophoblastic tumors' below.)

Old or involuted implantation site — Hyalinized histologic variants of implantation site with or without sclerotic chorionic villi may also be found in the endometrium after term pregnancy. Such retained products of conception may persist many months or years after the antecedent pregnancy. Though most often found as an incidental finding in curettings, old implantation site may cause abnormal uterine bleeding because of its infiltrative association with maternal spiral arterioles in the endometrium. For pathologists, retained old implantation site can be most problematic when it is found in the background of decidualized endometrium, giving a false indication of intrauterine pregnancy when the current pregnancy is actually ectopic. In such uncommon concurrences, recognition of the hyalinized stroma, limited abundance of trophoblast cells, and lack of placental villi are keys to arriving at the correct diagnosis.

As with placental site nodule (PSN) (see 'Placental site nodule or plaque' below), old implantation site is composed of extravillous (intermediate-type) trophoblasts in hyalinized extracellular matrix within the endometrium. The trophoblast cell density is typically lower than that found in the implantation site of an ongoing pregnancy, and the cytology lacks atypia, often giving the impression that the cells are quiescent. Mitotic activity in trophoblasts should be very low or absent (<5 percent of trophoblasts stain for the Ki-67 antigen using the MIB-1 antibody). In addition to the less squamoid cytology and lack of nested architecture, it can be distinguished from membranous intermediate-type trophoblasts by its immunophenotype. Like active implantation site trophoblasts, cells in retained implantation site express CD146 (Mel-CAM), but generally lack p63.

Atypical placental implantation site — Atypical implantation site has, as its name suggests, increased cytologic or nuclear atypia. These atypical trophoblasts may be arranged in sheets, and often associate with or infiltrate endometrial spiral arterioles. Like its counterpart, atypical PSN, trophoblasts have proliferation rates between normal (exaggerated or involuted) implantation site and PSTT (ie, >5 and <10 percent positive for the proliferation marker Ki-67 in cytokeratin- or CD146-positive lesional cells) [6,7]. (See 'Atypical placental site nodule' below and 'Placental site trophoblastic tumors' below.)

Atypical placental implantation may have the potential to transform into or occur with malignant PSTT, but the frequency is estimated to be low (<10 percent). Atypical placental implantation site is also associated with complete hydatidiform moles. Finally, atypical placental implantation site must be distinguished from syncytiotrophoblast-poor forms of choriocarcinoma, and profiling by immunohistochemical markers (CD146 [Mel-CAM]-positive, negative or minimal SALL4, and p63 and beta-human chorionic gonadotropin [hCG] staining) is often helpful.

Placental site nodule or plaque — PSNs are found most commonly in reproductive-age patients. In approximately one-half of cases, PSNs are discovered as an incidental finding in curettage, cervical biopsy, or hysterectomy specimens. They can occasionally arise in extrauterine sites like the fallopian tube, presumably developing after an ectopic pregnancy [8]. In one series evaluating PSNs, 40 percent were located in the endocervix, 56 percent were in the endometrium, and 4 percent were found in the fallopian tube [5].

Based on cytologic and immunophenotypic features, the intermediate trophoblast cells of PSNs appear to be derived from membranous intermediate (extravillous) trophoblasts that are similar to those in the chorion laeve and chorionic plate and not like the normal tissue-infiltrating extravillous trophoblast of implantation site. Thus, they likely represent the nonneoplastic counterpart of epithelioid trophoblastic tumors (ETT) [5]. (See 'Epithelioid trophoblastic tumor' below.)

When grossly identifiable, they are characterized by yellow or tan mucosal surface lesions and range from 1 to 14 mm (average 2.1 mm) in size. As their name suggests, PSNs are occasionally found as multiple nodules or plaques. Histologically, the nodules or flat plaques are well circumscribed and surrounded by a thin rim of chronic inflammatory cells, including lymphocytes and plasma cells (picture 1). Abundant hyalinized or fibrinoid extracellular matrix separates trophoblastic cells, which are small and monomorphic compared with implantation site trophoblast. They typically have either moderately abundant eosinophilic or vacuolated cytoplasm. Mitotic figures are usually absent or, at most, rare (<5 percent of trophoblasts stain for the Ki-67 antigen using the MIB-1 antibody). PSNs express markers of membranous intermediate trophoblastic differentiation and therefore show strong diffuse staining for p63, PLAP, but only focal staining for hPL and CD146 (Mel-CAM) [4,5].

Atypical placental site nodule — Although distinction of PSN from old implantation site is usually not clinically significant, PSN must be distinguished from atypical PSN (aPSN), ETT, and when found in the cervix, neoplastic squamous proliferations. Atypical PSNs are defined by presence of both cytologic and nuclear atypia. In addition, atypical PSN have proliferation rates between normal PSN and ETT (>5 and <10 percent positive for the proliferation marker Ki-67 [MIB-1] in cytokeratin [AE1/AE3]-positive lesional cells) [9]. It has been estimated that 5 to 15 percent of atypical PSN occur with or later transform to malignant ETT, but there is some uncertainty with this estimate given both the rarity and diagnostic ambiguity associated with these lesions [3].

Abnormal (nonmolar) villous lesions — "Abnormal (nonmolar) villous lesions" is a term adopted by gynecologic pathologists to describe a number of entities with histologic features simulating hydatidiform moles [10].

Such lesions may have enlarged, irregularly or edematous villi and mild trophoblastic proliferation but their histomorphology overall is insufficient for diagnosis of mole. Furthermore, these lesions have a diverse origin and include hydropic abortus, chromosomal abnormalities (eg, trisomy 11, trisomy 13, and to a lesser extent trisomy 18 or trisomy 21) created by maternal nondisjunction events, digynic triploid conceptions, and placental mesenchymal dysplasia. In part, such lesions have gene dosage abnormalities with less effect than that of a full haploid excess of paternal deoxyribonucleic acid (DNA).

Detection of the various genetic abnormalities may refine diagnostic classification once complete mole has been excluded. Furthermore, chromosome testing or DNA genotyping may be necessary to distinguish these diagnostic possibilities from partial moles. In histologically challenging cases, follow-up management as if partial mole has been diagnosed may be appropriate. (See 'Partial mole' below.)

Hydatidiform mole — Hydatidiform moles are the most common (approximately 80 percent) form of GTD. Moles may be complete, partial, or invasive and occur when the expression of imprinted genes is aberrant, most often because of abnormalities in fertilization.

Hydatidiform moles are characterized by a marked proliferation of villous trophoblast associated with hydropic swelling of chorionic villi, but the phenotypic penetrance of complete moles (picture 2) is greater than that for partial moles (picture 3). Complete and partial hydatidiform moles are also differentiated by their karyotype, gross morphology (eg, complete moles typically do not contain embryonic or fetal tissue whereas partial moles often do), histologic appearance, and clinical features (table 1).

While they may be considered benign proliferations, molar pregnancies carry an increased risk of persistent GTD or malignant GTN. (See 'Persistent GTD' below and 'Gestational trophoblastic neoplasia' below.)

Complete mole — Three mechanistic categories that cause hydatidiform moles, in decreasing order of frequency, are: sporadic errors in fertilization, heritable errors in genetic imprinting, and complex errors that appear to involve chimerization or mosaicism of the early embryo.

Pathogenesis and imprinting — Genetic imprinting has an important role in the development of molar pregnancies. This epigenetic phenomenon causes some genes to be silenced depending upon whether the gene was inherited from the mother or father. Early development depends on balanced gene dosage of imprinted genes from both biological parents. For such imprinted genes, paternal gene expression seems to have more control over placental growth, whereas maternal gene expression has more control over fetal growth. One interesting region of imprinted genes, including H19, IGF2, and cyclin-dependent kinase inhibitor 1C (CDKN1C1; p57/Kip2), is located at band 15.5 on chromosome 11. Modulation of imprinting in this region controls placental development. Hypomethylation of this region in Silver Russell Syndrome 1 [11] has a phenotype notable for dwarfism, growth restriction, and placental hypoplasia [12]; by contrast, hypermethylation of the imprinted region in Beckwith-Weideman Syndrome has a phenotype including somatic and placental overgrowth with dysmorphic chorionic villi resembling the histomorphology of partial mole [13,14]. In molar gestations, with excess paternal genomic material, there is excessive placental or trophoblastic proliferation. Excess maternal genomic material suppresses placental development in digynic triploid (3n) gestations, whereas its absence yields anembryonic ("empty") gestational sacs in diandric diploid (2n) complete moles.

Genetic mechanisms — There are a variety of genetic mechanisms by which a molar conceptus may be generated, with errors occurring during fertilization representing the primary pathologic process.

●Diandric diploidy – A complete mole most commonly has a 46,XX karyotype, with all chromosomes of paternal origin [15]. This results from fertilization of an "empty" egg (ie, absent or inactivated maternal chromosomes) by a haploid sperm that then duplicates. Such gestations have genome-wide absence of heterozygosity. Complete moles with a 46,YY karyotype do not occur, presumably because they are nonviable. A small number (3 to 13 percent) of complete moles have a 46,XY chromosome complement [15]. This is thought to occur when an empty ovum is fertilized by two sperm, one of which carries the Y chromosome. Less commonly, an empty ovum is fertilized by two different sperm, each contributing an X chromosome and nonidentical haploids (1n). This latter mechanism can be identified by detecting genetic heterozygosity, and such genome-wide heterozygosity in complete moles may confer a substantial homozygous: 11.6 percent; heterozygous: 37 percent) risk for persistent GTD/GTN [16]. Complete moles resulting from a diploid spermatogonium [17] and tetraploid complete moles have also been described. In all these errors of fertilization, the nuclear genetic material is entirely of paternal origin. In a sense, such androgenetic complete molar gestations may be regarded as a paternal allograft in the mother. Importantly, diandric diploidy results in a situation in which imprinted genes like CDKN1C1 cannot be expressed because maternally derived copies are not present.

●Biparental diploidy – A second, rarer, and genetically distinct mechanism accounts for a subset of complete moles having biparental inheritance (meaning that haploid genomes of both maternal and paternal origin are present). Such moles have a high risk of recurrence in subsequent pregnancies and an increased risk of persistent trophoblastic disease [18]; the predisposition for producing biparental complete moles is heritable in a Mendelian autosomal recessive pattern [19]. In one series including 37 patients with familial recurrent mole, complete and partial moles occurred in 74 and 4 percent of pregnancies, respectively [20]. A normal pregnancy developed in only 5 percent of patients; the remainder resulted in spontaneous abortion. Thus, for patients in whom the diagnosis of biparental mole is suspected, a familial history with genetic counseling referral is often appropriate. Such patients will likely require ovum donation to achieve a normal live birth.

In the most studied kindreds with recurrent or familial diploid biparental complete moles, the defective locus maps to a 1.1 MB region on chromosome 19 [18,20,21]. Subsequent studies have identified germline maternal mutations of NRLP7 (at 19q13.4), KHDC3L (C6ORF221; also known as Embryonic Stem Cell-Associated Transcript 1, at 6q13), and PADI6 in affected families and a number of sporadic cases [22,23]. NLRP7 is expressed at high levels in oocytes and early embryos and plays a role in DNA methylation as well as inflammation and trophoblast differentiation [24]. KHDC3L accumulates in oocytes as a part of the subcortical maternal complex and colocalizes with NLRP7 [25]. Their related cell biological functions and nuclear colocalization suggests that biparental moles share a common pathobiological mechanism.

The genetic defect predisposing mothers to biparental molar pregnancy is likely due to dysregulation of genomic imprinting. In support of this hypothesis, females with biparental complete mole have underexpression of p57 (formerly known as KIP2), which is the product of CDKN1C, an imprinted, maternally expressed gene located at 11p15 [21]. Interestingly, other genetic abnormalities of CDKN1C, including maternal gene rearrangement and uniparental disomy, are associated with Beckwith-Wiedemann syndrome (BWS) [26]. Moreover, BWS usually has a placental phenotype that grossly and microscopically overlaps with partial mole (see 'Partial mole' below). However, the molecular mechanism explaining how such maternal-effect genes result in defective oocyte maturation or zygote development is not fully understood [23,27,28].

Histology — The chorionic villi of a "classic" (ie, fully developed) complete mole are diffusely enlarged and surrounded by hyperplastic, often atypical, trophoblasts. Many villi have internal cavities filled with watery fluid, and shearing during collection frequently bursts larger swollen villi. Embryonic and yolk sac (hematopoietic) development are usually absent. Presence of embryonic or fetal tissue or abundant nucleated red blood cells should prompt consideration of another diagnosis (eg, normal or aneuploid gestation, partial mole, molar twin gestion). Histologic grading based on the presence of atypia, proliferative rate, or necrosis is of no prognostic value.

Uncommonly, dizygotic twin pregnancies may be a combination of normal and molar (complete or partial) gestations (see "Hydatidiform mole: Epidemiology, clinical features, and diagnosis", section on 'Multiple gestation'). The boundary between normal and molar chorionic villi is grossly well demarcated in intact molar twin placentas, but when such a molar twin gestation is evacuated (and mixed) by curettage, the biphasic morphology of chorionic villi may be mistaken for a partial mole histologically. Fortunately, this pitfall can be recognized by evaluating a putative "partial mole" for dichotomous p57 staining [29].

Intraplacental choriocarcinoma may confound the diagnosis of complete mole. Intraplacental choriocarcinoma occurs in a normal term placenta (picture 4), missed abortions, and partial moles. Presumably, they also arise from complete moles, but there are no widely established criteria for judging when the trophoblastic atypia and proliferation of a complete mole has crossed the threshold to frank neoplasia, and consultation with an expert team of gynecologic pathologists and oncologists is prudent for such uncommon cases.

Immunohistochemistry — Immunohistochemistry, particularly staining for p57, is a key tool for improving diagnostic accuracy and differentiating complete moles from partial moles and other mimics (table 1) [30-32].

The p57 protein is a product of the maternally expressed allele, but not of the paternally silenced allele. Thus, immunohistochemical staining for p57 is absent (or nearly so) in androgenetic and biparental complete moles because of the lack of an actively transcribed allele (picture 2) [21]. Of note, p57 imprinting is strong in villous cytotrophoblasts and stromal cells, but "relaxed" (does not occur) in extravillous (intermediate) trophoblasts. Therefore, extravillous trophoblasts will express p57 in both partial and complete moles, and extravillous trophoblasts and maternal decidual tissue serve as positive internal controls for this immunostain. Given the consistent loss of p57 immunostaining in complete moles, its application should be performed in all but the most histologically obvious cases of "classic" complete hydatidiform mole.

Anomalous (discordant) p57 staining patterns have been noted in some patients with clinical features of complete mole [33,34]. In these cases, the chorionic villi have some histological features of complete mole as well as loss of p57 staining confined to either villous cytotrophoblast or stromal cells of those chorionic villi. Although the etiologic mechanism remains to be fully elucidated, the observations are compatible with generation of mixed androgenetic/biparental conceptuses due to early chimerism of or mosaicism arising in the embryo. Finally, rare diandric triploid partial moles have been reported to be p57 negative because of loss of the maternally inherited copy of chromosome 11 [35]. These other subgroups represent pitfalls for an unsuspecting histopathologist relying on p57 immunohistochemistry for diagnosis of difficult cases.

Early complete mole — As ultrasonography at earlier gestational ages has become more widely used, molar pregnancies are being detected at increasingly early gestational ages, often as early as eight to nine weeks of gestation. The histologic features characteristic of "classic" complete moles (ie, large hydropic villi, extensive trophoblast hyperplasia) are not typically seen at these early gestational ages and it can be difficult to distinguish an early complete mole from a hydropic abortus or a very early normal gestation.

Microscopic features that are distinctive of early complete moles include a cellular, myxoid-like (blue/basophilic) villous stroma; empty primitive or poorly formed villous stromal blood vessels; markedly irregular villous contours (colloquially known as "toes and knuckles" or "popcorn"); karyorrhectic debris visible in the villous stroma; and atypical trophoblasts (both villous and extravillous) (picture 2) [36]. Trophoblastic proliferation is not as marked as in more mature moles and overlaps with that found in very early normal gestation. As chorionic villous stromal and endothelial cells degenerate, small irregularly shaped voids in the villous stroma form and fill with fluid, but additional time is required for the nascent cisterns to fill with enough volume to become the swollen grape-like villi of "classic" complete moles (picture 5).

In many cases, p57 immunohistochemistry can be helpful in accurately identifying early complete moles [30,37]. The staining pattern (eg, p57 loss in chorionic villous cytotrophoblasts and stromal cells), however, is the same observed in "classic" complete moles, reflecting their shared underlying pathobiology. (See 'Immunohistochemistry' above.)

Partial mole — Partial moles are pathologically and cytogenetically distinct from complete moles (table 1).

Genetic mechanisms — Approximately 90 percent of partial moles are diandric triploid gestations (69,XXX, 69,XXY, rarely 69,XYY) resulting from the fertilization of an ovum (with one set of haploid maternal chromosomes) by two sperm (with two sets of haploid paternal chromosomes). Other aneuploid states (eg, a tetraploid gestation with three paternal and one maternal genomes) occur in the remaining 10 percent of cases [38,39]. The majority (99 percent) of diandric triploid partial moles are a consequence of fertilization by two sperm (rather than endoreduplication of a single sperm) [31,40]. By contrast, digynic triploid gestations (two maternal and one paternal haploid genomes) are nonmolar (though they also may be histologically abnormal) [41,42]. Such examples reinforce that the genotypic key to partial moles is an excess of paternally silenced genomic material combined with expression from imprinted genes like p57 from at least one maternal haploid genome.

The fetal or embryonic tissue that is present with a partial mole will most commonly have the same karyotype as the placental tissue.

Histology — In contrast to complete mole, a partial mole is comprised of two populations of chorionic villi: one population is histologically normal whereas the second population is enlarged, irregularly shaped, and infrequently cavitated (cystic). Consequently, the ultrasonographic or gross physical appearance may be more subtle than "classic" complete moles with less cavitation, trophoblastic hyperplasia, and atypia when compared with complete moles. Marked scalloping of chorionic villi and trophoblastic inclusions (defined as deep, narrow invaginations of the surface trophoblasts deep into the villous stroma, often seen only as two-dimensional cross-sections) are common and often prominent (picture 6). In further contrast to complete mole, fetal capillaries are typically well filled with nucleated red blood cells, and fetal tissue or an intact fetus are often found macroscopically or microscopically. Such diandric triploid fetuses may have multiple congenital abnormalities, with digital syndactyly (especially between the third and fourth digits in the hands) being the most distinctive (picture 3) [43].

Histological differentiation of a partial mole from nonmolar hydropic abortus may be more difficult. However, hydropic abortuses usually have a greater spectrum of villous sizes and more round villous contours compared with the bimodal distribution of villi in partial moles. Abortuses may also have stunted villous proliferation, yielding an attenuated trophoblast layer over the surface of the hydropic villi, whereas partial moles show at least modest trophoblastic proliferation. Certain types of nonmolar aneuploid gestations can present histological features so akin to those of partial moles that they may be exceedingly difficult to distinguish. Trisomies involving chromosomes 11, 13, 18, and sometimes 21 may histologically mimic partial mole. Of note, the gene for p57 (CDKN1C) resides in key region regulated by canonical imprinting located at 11p15, and thus trisomy 11 might result in a gene dosage effect due to an extra silenced paternal allele, like partial mole.

While cases having most, but not all, histologic features found in partial mole, may not always be entirely persuasive for pathologic diagnosis, effective ancillary diagnostic tools (eg, p57 immunohistochemistry; genetic detection of triploidy by flow cytometry, karyotype, microsatellite polymorphism polymerase chain reaction ["DNA fingerprinting"], single nucleotide polymorphisms detection by microarray or sequencing) are limited and cannot rigorously determine parent of origin (ie, digyny versus diandry) without parental reference data. Such additional testing can also be costly and burdensome. Thus, an abnormal histologic appearance suspicious for partial mole combined with knowledge of triploidy (without knowing parental origin) may be sufficient and, as the risk for serious GTD or GTN following partial mole and any of its histological mimics is at least an order of magnitude lower than the risk following complete mole, a precise genetic diagnosis is not needed in most cases [31,44].

Immunohistochemistry — Partial moles (and nonmolar hydropic abortuses) have both paternal and maternal genetic material present and therefore retain p57 immunostaining because they have at least one active allele of maternal origin [30]. In rare instances of partial mole and Beckwith-Weideman syndrome (a histologic mimic of partial mole in the placenta), loss of p57 immunostaining may be encountered and lead to incorrect classification as a complete mole [35]. (See 'Immunohistochemistry' above.)

Invasive mole — An invasive mole, also known as chorioadenoma destruens in older literature, is a hydatidiform mole characterized by the presence of enlarged hydropic villi invading into myometrium, vascular spaces, or extrauterine sites (picture 7). This entity can be regarded as the phenotypic cross between molar pregnancy and placenta increta, but the pathobiological mechanism is not well understood. The villous histology is typically that of complete moles, but rare invasive partial moles have been reported [31,45]. In either case, abnormal villi penetrate deeply into the myometrium. These lesions may be differentiated from choriocarcinoma by their hydropic villi with marked trophoblastic proliferation. Both invasive moles and choriocarcinoma may show invasion of the uterine vasculature and have secondary metastatic lesions, particularly involving the vagina and lungs [46].

Invasive moles do not often resolve spontaneously and can be difficult to diagnose by curettage, as myometrial infiltration often cannot be documented. Thus, definitive diagnosis and treatment often require hysterectomy. (See "Hydatidiform mole: Treatment and follow-up", section on 'Choice of procedure for removal of molar tissue'.)

Persistent GTD — After evacuation of a molar pregnancy, trophoblastic tissue can persist in up to 20 percent of patients; this risk is greater in those with complete compared with partial moles (20 versus 2 to 4 percent) [47]. In addition to histologic diagnosis, molar pregnancies associated with extremes of age, longer interval from previous pregnancy, and higher initial hCG levels are at greater risk of persistent disease.

Diagnosis of persistent gestational trophoblastic disease (GTD) is usually based on a stable or serially rising serum hCG concentration rather than histologic examination of tissue. Thus, surveillance of serum hCG levels to undetectable is essential after evacuation of a molar pregnancy.

The risk of malignant GTD is typically stratified based on the nature of antecedent pregnancy; thus, the stratification of risk for post-gestational neoplasia and rationale for treating persistent GTD are highly dependent on accurate histopathologic and pathogenetic distinction between partial and complete hydatidiform mole:

●Following complete molar pregnancy, persistent hCG elevation is often associated with invasive mole or, less often, choriocarcinoma [48].

●By contrast, following partial mole, persistent hCG elevation is most frequently associated with sclerotic chorionic villi, resembling normal retained products of conception, albeit with some architectural abnormalities [44]. Nevertheless, care must be taken to exclude rare choriocarcinoma, ETT, or PSTT in such patients [44].

In one retrospective study of 3000 patients with histologically diagnosed partial moles, 15 patients (0.5 percent) had persistent GTD of whom only three patients were diagnosed with choriocarcinoma [49]. In a subsequent series of 196 cases of triploid partial mole (using strict criteria for diagnosis), no cases of choriocarcinoma were reported [50]. However, at least one case of metastatic choriocarcinoma following intraplacental choriocarcinoma arising in a triploid partial mole has been documented [51,52]. Similar studies of one to two hundred well-annotated partial moles found that the risk for adverse outcomes was no higher than 1.3 percent [16,31,44].

●Following any nonmolar pregnancy (eg, miscarriage, ectopic, preterm/term pregnancy resulting in a live birth), persistent hCG elevation is usually due to retained products of conception; rarely hCG elevations in such patients are due to the development of choriocarcinoma or PSTT and not invasive mole [47]. Observation of intraplacental choriocarcinoma in an otherwise benign nonmolar gestion, however, changes the risk calculus.

There is also a difference in the malignant potential of complete moles depending on whether they are heterozygous (arising from two sperm) or homozygous (arising from a single sperm with duplication of DNA) [16]. In one study, Y chromosomal DNA (indicating heterozygosity) was detected in only nine percent of hydatidiform moles but enriched to 50 and 74 percent of invasive moles and choriocarcinomas, respectively [53].

Frequency of GTN and monitoring of hCG following evacuation of molar pregnancy are discussed in more detail separately. (See "Hydatidiform mole: Treatment and follow-up", section on 'Protocol for serial hCG measurements' and "Hydatidiform mole: Treatment and follow-up", section on 'Frequency of gestational trophoblastic neoplasia after molar pregnancy'.)

GESTATIONAL TROPHOBLASTIC NEOPLASIA — GTN comprises a group of tumors with the potential for local invasion and metastases [54]; such tumors include choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT).

As noted above (see 'Invasive mole' above), invasive moles that do not resolve are also regarded as GTN. Choriocarcinoma, ETT, and PSTT can follow either nonmolar or molar pregnancies and may occur years after the antecedent pregnancy, even during menopause.

Rarely, PSTT or ETT coexisting with choriocarcinoma has been described, suggesting that not all trophoblastic can be cleanly classified [55,56]. Such mixed tumors often metastasize as choriocarcinoma.

Following molar and nonmolar pregnancies — Data from proteomic and immunohistochemical profiling suggest the presence of a common trophoblast stem cell that subsequently develops along one of three lines of differentiation [57,58]. Choriocarcinoma is thought to be the most "undifferentiated" trophoblastic tumor while PSTT and ETT show phenotypic characteristics of more differentiated trophoblast cells.

Another model for understanding GTN is based on the distinction between villous and extravillous trophoblasts [59]. Molar pregnancies and choriocarcinoma are derived from villous trophoblasts, while PSTT and ETT are derived from extravillous trophoblasts. Further differentiation along the extravillous (intermediate) trophoblast line produces invasive trophoblasts, which are involved in remodeling and invasive of the implantation site (from which PSTT is derived) and the membranous (chorion laeve) trophoblasts (from which ETT is derived). While this model may be overly simplistic (eg, it ignores atypical placental implantation site in complete moles), it provides a useful nosological framework and correlates with the principal genetic mechanisms.

Genetic mechanisms — In contrast to hydatidiform moles and their mimics, GTN may have equal contributions from both paternal and maternal genomes. For example, diploid choriocarcinoma may be either androgenetic or biparental. Of note, intraplacental choriocarcinoma is biparental and genetically related to the accompanying normal placenta [60] (see 'Choriocarcinoma' below). By contrast, the two other nonvillous GTN types (ie, PSTT and ETT), which have cellular phenotypes corresponding to extravillous intermediate trophoblasts, tend to be diploid biparental females (46,XX). The pathogenetic basis of skewed sex in PSTT and ETT, however, is not fully understood [61]. Possible genetic mechanisms include lyonization of X-linked genes and imprinting. Importantly, the presence of paternal alleles in PSTT and ETT [62] has important implications for therapy [63]. By contrast, genome-wide imprinting does not seem to play a role in the pathogenesis of PSTT and ETT, but their female predominance raises the possibility that X chromosome-specific silencing might be relevant [64].

Types —  (table 2)

Choriocarcinoma — Choriocarcinoma is a highly malignant epithelial tumor.

●Pathogenesis – Choriocarcinoma can arise from any type of trophoblastic tissue (molar pregnancy, abortion, ectopic, or preterm/term intrauterine pregnancy). The most frequent antecedent pregnancy is a complete mole but it can also occur after a partial mole [31,44,47,49-51]. (See "Hydatidiform mole: Treatment and follow-up", section on 'Frequency of gestational trophoblastic neoplasia after molar pregnancy'.)

Choriocarcinoma following a normal gestation usually features biparental disomy, identical to the fetus [60,65,66]. However, this is not always uniformly so as some choriocarcinomas have the DNA complement from a pregnancy preceding the current or recent one [67]. As one might predict, postmolar choriocarcinoma is comprised exclusively of DNA of paternal origin (ie, it is androgenetic); most choriocarcinomas following molar pregnancies are also frequently aneuploid [60,68].

When choriocarcinoma metastasizes, the most common sites are lung, brain, liver, pelvis, vagina, spleen, intestine, and kidney. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification", section on 'Metastatic sites'.)

Finally, it is important to note that choriocarcinoma can arise from gonadal and extragonadal germ cells, independent of gestational or placental tissue. Germ cell-derived choriocarcinoma differs in genetics, including absence of DNA of paternal origin (ie, the patient's partner). Importantly, germ cell derived-choriocarcinoma is considerably more refractory to chemotherapy.

●Histopathology – Histologically, choriocarcinoma consists of sheets of anaplastic mononuclear cytotrophoblasts and multinuclear syncytiotrophoblasts, usually without chorionic villi (picture 8). Extensive necrosis, hemorrhage, and vascular invasion are common. Unusual cases having microscopic foci of biphasic and anaplastic trophoblasts proliferating profusely around often dysplastic stromal cores in the context of otherwise normal-appearing chorionic villi represent in situ lesions and are diagnosed as intraplacental choriocarcinoma. Of note, prominent hemorrhage clinically or pathologically is a common feature of choriocarcinoma, and intraplacental choriocarcinoma sometimes presents as fetomaternal hemorrhage [69].

Infrequently, when curettage is performed for an early pregnancy loss, gestational endometrium and implantation site without chorionic villi may be encountered. Histopathologic distinction from choriocarcinoma is often problematic in the setting of an early pregnancy, when more florid cytomorphology and high proliferation are expected. In most cases, the relatively limited volume of trophoblastic tissue provides an indication of benignity. Although the presumptive diagnosis may be missed abortion, greater atypia than expected can prompt consideration of choriocarcinoma, necessitating follow-up recommendation for quantitative serum hCG testing and performance of chest radiograph to fully exclude a diagnosis of choriocarcinoma.

●Immunohistochemistry – Immunohistochemical markers can confirm the histologic diagnosis of gestational trophoblastic proliferations. The typical immunoprofile for choriocarcinoma includes strong staining for beta-hCG (in syncytiotrophoblasts), inhibin, cytokeratins, and GATA3 (in all neoplastic trophoblast cells). Ki-67 is diffusely expressed in approximately half the cells, indicating excessive and unregulated growth [70]. Distinction of choriocarcinoma from PSTT can be facilitated by observing SALL4 (a germ cell marker) in 10 to 70 percent of neoplastic cytotrophoblasts [71] and absence of CD145 (Mel-CAM).

Placental site trophoblastic tumors — Relative to choriocarcinoma and complete mole, PSTT is uncommon [64,72].

●Pathogenesis – PSTT is a potentially malignant neoplasm originating from extravillous (intermediate) trophoblast cells [73]. Although PSTTs can develop after any type of pregnancy, they most commonly develop after a term gestation. Only a fraction (approximately 8 percent) of cases occur after a molar pregnancy.

Most PSTTs are female and diploid [61], although triploid PSTT has been described [74]. The pathobiological significance of female predominance is not well understood.

Roughly two-thirds of PSTTs act indolently, while the remaining 30 to 40 percent can develop metastasis and even result in death [64,75].

●Histopathology – PSTT is a mass-forming tumor and may not always be diagnosable by endometrial biopsy or curettage.

On histologic examination, PSTT generally presents as a sheet-like proliferation of extravillous or intermediate trophoblast in the myometrium or endomyometrium (picture 9). 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, destructively splitting apart or effacing muscle fibers. Scattered multinucleated trophoblasts are also present as are occasional multinucleated beta-hCG-positive syncytiotrophoblast-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 are not commonly present.

●Immunohistochemistry – Immunohistochemical staining for human placental lactogen (hPL), CD146 (Mel-CAM), and placental alkaline phosphatase (PLAP) are additional diagnostic tests for PSTT [5,76]. CD146 (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 >10 percent in CD146-positive cells [6,7]), positive staining for alpha-inhibin and cytokeratin 8/18, and negative smooth muscle markers provide further support for the diagnosis of PSTT [5].

Expression of paternal (nonhost) antigens by PSTT cells may allow for immunoregulatory therapies in selected patients with resistant or recurrent disease. (See "Management of resistant or recurrent gestational trophoblastic neoplasia", section on 'Investigational therapies'.)

Epithelioid trophoblastic tumor — ETT is a rare form of trophoblastic disease [77,78] that is genetically, clinically, pathologically, and prognostically similar to PSTT (see 'Placental site trophoblastic tumors' above). Key differences are the specific subtype of intermediate trophoblasts (corresponding to membranous/chorion laeve trophoblasts) undergoing transformation and its proclivity for cervical involvement, where it can be misinterpreted as a neoplastic squamous cell proliferation.

●Pathogenesis – The majority of ETTs occur after a full-term pregnancy, but approximately one-third arise following a spontaneous abortion or hydatidiform mole [78].

RNA sequence analysis of a small cohort of intermediate trophoblast lesions uncovered recurrent fusion of telomerase (TERT) and lysophosphatidylcholine acyltransferase 1 (LPCAT1) in ETT but not in other lesions [79]. A small interstitial deletion near the terminus of chromosome 5's short arm (5p15.33) results in utilization of the LPCAT1 promotor, thus driving expression of a fusion transcript that lacks the TEN and RNA binding domains from N-terminus of TERT but preserves the reverse transcriptase and C-terminal domains. In an in vitro model, this LPCAT1-TERT fusion localizes to the nucleus and promotes cell viability and metabolism. The fusion is found in 16 to 67 percent of ETTs; however, TERT upregulation is also found in ETT without the gene fusion [79,80], suggesting that inappropriate TERT expression regardless of the mechanism is an important pathogenetic mechanism for ETT. Furthermore, transcriptional analysis of 760 genes involved in tumorigenesis segregates ETT from typical and atypical placental site nodules (aPSNs), suggesting that the latter represents transitional stage(s) between benign retained chorionic membrane and ETT [80].

●Macroscopic inspection – Macroscopic inspection of ETT shows a solitary, solid to cystic, fleshy, and well-defined mass in the uterine wall, lower uterine segment, or endocervix (picture 10).

●Histology – Histologically, ETT is nodular, with proliferation of smaller, more monomorphic trophoblastic cells in comparison with PSTT. The ETT cells display eosinophilic to clear or vacuolated cytoplasm forming numerous cell nests with surrounding necrosis (picture 10), resembling the trophoblast layer found in the placental membranes (chorion laeve); this histologic (and immunophenotypic) resemblance is the basis for segregating ETT from PSTT. The central necrosis often undergoes dystrophic calcification, providing a valuable clue to as to its identity. The borders of nodular growth are usually well circumscribed, but focal invasion into the surrounding tissue is frequently found. Although the predominant cell type is an extravillous intermediate trophoblast, occasional syncytiotrophoblast-type cells also may be present [81], accounting for the low hCG levels often found in patients at presentation. The mitotic rate may be variable, but generally elevated across the entirety of the tumor. When present in the cervix or lower uterine segment, the nested architecture, central keratinized-like necrosis and squamoid cytology may mislead an unsuspecting pathologist to incorrectly diagnose a squamous cell neoplasm.

●Immunohistochemistry – Immunohistochemistry is an important adjunct to histopathology for correct classification of avillous trophoblastic tumors having intermediate differentiation. p63 is expressed in ETT, PSN, and choriocarcinoma, but not in PSTT [82]. In addition to p63, PLAP, and GATA3 staining are usually strong, while placental lactogen (hPL), inhibin, and CD140 (Mel-CAM) staining are usually weak and focal in ETT. Contrasts drawn by employing a panel of markers are usually sufficient to distinguish between ETT and PSTT. For delineation from atypical PSN and benign PSN, documentation of high proliferative activity (as assessed by Ki-67 staining >10 percent in CD146-positive cells) supports diagnosis of trophoblastic malignancy [9].

As previously stated, ETT 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. In contrast to cervical squamous cell carcinomas, however, ETTs stain for GATA3 by immunohistochemistry and their pathobiology does not involve human papilloma virus infection. Poorly differentiated carcinomas also may resemble ETT, but DNA studies can prove their somatic, nongestational origin [83].

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

●Clinical significance – Gestational trophoblastic disease (GTD) and gestational trophoblastic neoplasia (GTN) comprise a heterogeneous group of related lesions arising from abnormal cellular proliferation of placental trophoblasts. The pathogenesis of GTD/GTN is unique because the maternal lesions arise from fetal, not maternal, tissue, distinguishing them from other tumorous processes. (See 'Introduction' above.)

●Gestational trophoblastic disease – GTD is characterized by abnormal proliferations of placental trophoblasts, including exaggerated placental site (EPS), old or involuted implantation site, atypical placental implantation site, placental site nodule (PSN) or plaque, and hydatidiform moles. Although usually benign, some GTD has premalignant potential. (See 'Gestational trophoblastic disease' above.)

•Benign trophoblastic lesions are frequently diagnosed as incidental findings in pathology specimens after uterine curettage or hysterectomy and represent an abnormal type of retained products of conception lacking chorionic villi. These trophoblasts can be further subdivided based on their histological and immunophenotypic resemblance to normal trophoblast populations forming either the placental membranes or implantation site. Some atypical lesions carry an increased risk of malignancy. (See 'Tumor-like lesions' above.)

•Hydatidiform moles are the most common form of GTD. Moles may be complete, partial, or invasive and occur when the expression of imprinted genes is aberrant, most often because of abnormalities in fertilization. (See 'Hydatidiform mole' above.)

•Complete and partial hydatidiform moles are differentiated by their karyotype, gross morphology (eg, complete moles typically do not contain embryonic or fetal tissue whereas partial moles often do), histologic appearance, and clinical features (table 1). (See 'Hydatidiform mole' above.)

●Gestational trophoblastic neoplasia – GTN comprises a group of tumors with the potential for local invasion and metastases and includes choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT) (table 2). Invasive moles that do not resolve are also regarded as GTN. (See 'Gestational trophoblastic neoplasia' above.)

•Choriocarcinoma is a highly malignant epithelial tumor that can arise from any type of trophoblastic tissue (molar pregnancy, abortion, ectopic, or preterm/term intrauterine pregnancy). The most frequent antecedent pregnancy is complete mole. (See 'Choriocarcinoma' above.)

•PSTT is less common than choriocarcinoma and although it can develop after any type of pregnancy, it most commonly develops after a term gestation. Roughly two-thirds of PSTTs act indolently, while the remaining lesions can develop metastasis. (See 'Placental site trophoblastic tumors' above.)

•ETT is a rare form of trophoblastic disease that is genetically, clinically, pathologically, and prognostically similar to PSTT. Key differences are the specific subtype of intermediate trophoblasts undergoing transformation, and its proclivity for cervical involvement, where it can be misinterpreted as a neoplastic squamous cell proliferation. (See 'Epithelioid trophoblastic tumor' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Rebecca Baergen, MD, who contributed to earlier versions of this topic review.