Curr Obstet Gynecol Rep (2014) 3:44–54 DOI 10.1007/s13669-013-0075-2

MANAGEMENT OF GESTATIONAL TROPHOBLASTIC DISEASES (A CHEUNG, SECTION EDITOR)

Classification and Morphology of Gestational Trophoblastic Disease Lars-Christian Horn & Jens Einenkel & Anne Kathrin Hoehn

Published online: 11 January 2014 # Springer Science+Business Media New York 2014

Abstract Gestational trophoblastic disease (GTD) is a clinically and morphologically very heterogeneous group of interrelated lesions, characterised by abnormal growth of the different types of trophoblastic cells, sometimes associated with villous dysmaturity. The management and follow up of the patients and risk calculation for persistent GTD is mainly based on histopathologic diagnosis. The morphologic and differential diagnostic criteria of the villous forms of GTD (complete, partial and invasive hydatidiform moles) are summarised in the paper as well as ancillary techniques for correct diagnoses. Exaggerated placental sites (EPS) and placental site nodules (PSN) represent benign lesions, derived from the intermediate trophoblast and their characteristics are given. The concept of atypical PSN as a recently defined lesion is discussed. Gestational choriocarcinoma (CC), placental site trophoblastic tumor (PSTT) and the epitheloid trophoblastic tumor (ETT) represent tumorous forms of GTD, also termed as gestational trophoblastic tumors (GTT). Their morphologic criteria and clues for differential diagnosis are given, including the discussion about the transition from one lesion into another.

Keywords Gestational trophoblastic disease (GTD) . Hydatidiform mole . Exaggerated placental site . Placental site nodule . Choriocarcinoma . Placental site trophoblastic tumor . Epitheloid trophoblastic tumor L.
Introduction Gestational trophoblastic disease (GTD) represents a clinically and histopathologically heterogeneous group of disease and is a rare complication of pregnancy. GTDs are characterised by abnormal growth of different cell types of the placental trophoblast, in some entities associated with villous dysmaturity. According to the WHO-classification [1] and more recent findings [2, 3•] GTDs are categorised into: & & & & & & & & &

complete (CHM) and partial (PHM) hydatidiform mole, invasive hydatidiform mole (IHM) gestational choriocarcinoma (CC), placental site trophoblastic nodule (PSN), exaggerated placental site (EPS), placental-site trophoblastic tumor (PSTT), epithelioid trophoblastic tumor (ETT) and mixed or unclassified trophoblastic lesions (see Table 1).

Because of the presence and alterations of placental villi, PHM, CHM and IHM are summarised as villous and all other types as non-villous forms of GTD.

Classification of Normal Trophoblastic Epithelium For a better understanding of the various forms of GTD and their correct morphologic diagnosis, some knowledge of the normal placental development is helpful. In the normal, especially first trimester placenta, three different types of trophoblastic cell populations are described, according to their functional and morphologic features [4]. Cytotrophoblastic cells (CT) are the most immature cells and responsible for proliferation, while the syncytiotrophoblast (ST) is the most differentiated population, responsible for hormonal

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Table 1 Classification of gestational trophoblastic disease (GTD) 1) villous GTD Partial hydatidiform mole (PHM) Complete hydatidiform mole (CHM) Invasive mole (IM) 2) non-villous GTD Chorioncarcinoma (CC) placental site trophoblastic tumor (PSTT) epitheloid trophoblastic tumor (ETT) placental site nodule (PSN) exaggerated placental site (EPS)

ICD-O: 9103/0 ICD-O: 9100/0 ICD-O: 9100/1 ICD-O: 9100/3 ICD-O: 9104/1

SNOMED 79420

production, especially the b-HCG. The intermediate trophoblastic cells stand in between CT and ST with some overlapping morphologic and functional features. The trophoblastic population, which grows along the chorionic villi (villous trophoblast) is mainly composed by CT and ST, intermixed with small amount of IT, whereas the extravillous trophoblast, which infiltrates the decidua, the myometrium and spiral arteries is mainly composed of IT. Based on its location and immunophenotype, the extravillous IT can be subcategorised by implantation site (located at the Chorion frondosum) and chorionic type IT (located at the Chorion laeve). These different trophoblastic cell populations can be found in the different forms of GTD and its composition and morphologic features represent the basis for morphologic categorisation and differential diagnosis.

Partial Hydatidiform Mole (PHM) The majority of PHM is triploid in origin [5, 6, 7•]. Patients with partial mole are less likely to have symptoms and signs similar to those seen in complete mole, especially in first trimester pregnancy. PHMs usually appear to have a missed abortion.

the chorionic villi is often irregular and scalloping, representing a “fjord-like” appearance. Within the villous stroma, trophoblastic inclusions are present and very useful for the diagnosis of PHM [1]. But, its presence is not specific for PHM and is also seen in abortions caused by other genetic aberrations, e.g., trisomic abortions [8]. The variable pattern of trophoblastic hyperplasia may help to distinguish PHM from hydropic abortion. In the latter, the villous trophoblasts often show focal, multifocal, or circumferential proliferation while polar or lateral proliferation is seen in first trimester abortions [9•]. As evidence of embryonal/fetal development, blood vessels containing fetal red blood cells may be present and embryonal/fetal tissue can be seen within the examined tissue. As in CHM, an early-PHM may occur. In that form the villi are enlarged with some hydropic stromal alterations but, without cystic transformation, trophoblastic inclusions may be present and the trophoblastic hyperplasia is not well developed (Fig. 1b,c). Immunohistochemistry Immunohistochemically, p57-staining is present in PHM (see below). The main differential diagnoses in PHM is CHM (see below) and mesenchymal dysplasia of the placenta [10].

Complete Hydatidiform Mole (CHM) CHM is in the majority of cases androgenetic in origin with a diploid karyotype containing paternal chromosomal and maternal mitochondrial DNA [7•]. Patients with CHM have more likely symptoms and the diagnosis is suspected by the clinicians because of the ultrasound finding of a complex intrauterine mass containing multiple small cystic spaces and elevated b-HCG-values. Macroscopy

Macroscopy Macroscopically, the evacuated material during D&C may be voluminous. If PHM occurs in second or rarely third trimester, the placenta may be enlarged and some cystic transformed and enlarged villi may be present at visual inspection and announced by the clinician because of ultrasound findings. In a serious number of cases, a fetus or fetal tissue can be identified.

More typically, D&C-evacuations show a voluminous appearance, and in serious cases, grossly cystic changed villies can be seen. Indeed, the name hydatidiform mole is derived from this ‘bunch of grapes’ appearance. But, in cases of early-CHM (see below) the evacuated tissue lacks any suspicious findings on visual inspection. Microscopy

Microscopy Microscopically, PHM contains a mixture of enlarged and normal sized villi (Fig. 1a). The former shows a variable degree of hydropic swelling with some central cistern formation, which is not so pronounced as in CHM. The outline of

Microscopically, in their typical appearances, the chorionic villi are markedly distended by the accumulation of stromal fluid with central cistern formation (Fig. 1d). The cysts are surrounded by a rim of loose connective tissue representing a variable degree of regressive change. In some cases,

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Fig. 1 Molar gestations, representing villous forms of gestational trophoblastic disease: a partial hydatidiform mole representing a mixture of enlarged and normal sized villies with some hydropic alterations and irregular, “fjord-like” outline and intravillous trophoblastic inclusions (arrows), b and c) early partial hydatidiform mole with more uniform hydropic enlarged villi, some of them with intravillous trophoblastic

inclusions, d complete hydatidiform mole with enlarged hydropic villies with central cisterns (stars) and apolar trophoblastic proliferation (arrows), e early complete hydatidiform mole with phylloid-like apearance of the villi with some hydropic changes of the villous stroma containing some thin walled blood vessels (arrows) and apolar trophoblastic proliferation

angioblastic proliferations may be seen representing abortive vessels without forming a vascular lumen. A variable degree of trophoblastic proliferation is present. The predominant cell types within that proliferation are CT and ST, intermingled by a variable number of IT. In the majority of cases, there will be an apolar trophoblastic proliferation at the villous surface with some intracellular vacuoles. Usually, the CHM will be diagnosed around the 11th week of gestation with vaginal bleeding and uterine enlargement. But, during the last years based on technologic advances and routine ultrasound examination in early weeks of gestation, CHM are evacuated quite earlier, around the 8th week [11, 12]. In those cases, the aforementioned histologic features are not well developed and cases of early-CHM may provoke some diagnostic difficulties [13•]. The villies of e-CHM are smaller in size but

representing a phylloides-like configuration (Fig. 1e). The central cistern formation is absent or inconspicuous. The villous stroma is typically hypercellular and myxoid and represents some cellular debris of villous stromal cells on higher magnification. In a serious number of cases ,stromal blood vessels may be seen with luminal formation, sometimes containing nucleated embryonal erythrocytes. The trophoblastic hyperproliferation may be present or can be missed, which may cause diagnostic problems with hydropic abortions. Although, CHM can occur in ectopic gestation [14], trophoblastic hyper-proliferation should be interpreted with care in tubal pregnancy [15]. Because of its special microenvironment, the villies of tubal pregnancy may accompanied by marked trophoblastic proliferation especially in early gestational age, which is not indicative for GTD and causes no elevation of HCG-levels in the woman.

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Immunohistochemistry

Invasive Hydatidiform Mole (IHM)

Immunhistochemically, p57-staining may be helpful. As mentioned above, the genome of CHM is androgenetic in origin and paternally derived. Consecutively, maternally expressed genes, as p57, are missed. Ideally, nuclear p57-staining of villous stromal cells and CT is negative in CHM [16, 17]. For diagnostic purposes, up to 10 % of villous stromal cells and/or cytotrophoblastic cells may be positive for p57 to meet the diagnosis of CHM [18•]. Positive stained nuclei of the extravillous trophoblast and decidual cells can be used as an internal positive control for p57-immunohistochemistry. Early and non-early CHM may be accompanied by an exaggerated placental site (see below). Especially early CHM may be seen with a placental implantation site. Physiologic invasive (intermediate) trophoblastic cells, invading decidual tissue, myometrium and spiral arteries may be present, representing a normal finding. Invasive trophoblastic cells, also with vascular invasion, in that context are not indicative for the diagnosis of invasive mole. In rare cases, when the molar villies are intermingled with normal appearing villi, the possibility of twin/multiple pregnancy (one with normal placenta and one with molar) should be considered [19]. In those cases clinical information and p57-immunostsining or even molecular analyses [17, 20•] may be diagnostic. The main differential diagnoses in CHM are the PHM (see above) and the mesenchymal dysplasia of the placenta [10]. As discussed above, p57-immunostaining is helpful in the diagnosis or exclusion of CHM but p57-staining pattern cannot distinguish PHM from non-molar abortions with hydropic change and mesenchymal dysplasia as all these lesions express p57 because of the presence of maternal DNA.

In the majority of cases, there is a CHM in the patient history [17].

Ancillary Techniques Sometimes, flow cytometry was used to determine the ploidy of conceptual products [21]. But this technique sometimes requires fresh tissue for optimal results and may be time consuming and is only available at institutions still using this method. Additionally, flow cytometry allows only the distinctions between triploidy (in PHM) and diploidy. Because of its chromosomal composition, the discrimination between CHM, hydropic abortion (with and without trisomy) and placental mesenchymal dysplasia is not possible. Molecular techniques may be helpful in that setting. Short tandem repeat genotyping (as it is used in forensic identity testing) can determine the parental source of polymorphic alleles and can aid the above mentioned differential diagnoses by discerning androgenic diploidy, diandric triploidy and biparental diploidy [20•, 22, 23].

Macroscopy Macroscopically, hysterectomy specimens contain some hemorrhagic areas within the myometrium from where the paraffin blocks should be obtained. Microscopy IHM is characterised by the presence of molar villies within the myometrium, its vascular spaces, or at distant sites, e.g., at the vagina or lung [24•]. Thus, only hysterectomy specimens or representative biopsies from distant sites allow the diagnosis of IHM (Fig. 2). The presence of infiltrative growing trophoblastic cells at the implantation site of a CHM is not indicative for the diagnosis of IHM. Histologic diagnosis on curettage material is possible only if fragments of myometrium containing invasive molar villies are present but this is a “once in a lifetime diagnosis”. The villi of IHM shares morphologic features with CHM, but their size is often smaller and the trophoblastic proliferation may be not so pronounced. Especially after previous chemotherapy of CHM, the villi undergo regressive change and sometimes only molar ghost villi are present histologically.

Gestational Choriocarcinoma (CC) CC is a rare but highly invasive and aggressive trophoblastic tumor and may develop during or after any type of pregnancy. The majority of patients have a history of CHM [24•]. But CC can occur in ectopic pregnancy [25] or concurrent with a nearterm or term pregnancy [26]. Macroscopy Macroscopically, both, uterine or metastatic CC typically forms hemorrhagic masses with a variable amount of necroses and ill-defined borders [27]. So, in specimens suspicious for CC paraffin blocks should be obtained from the transition zone between the hemorrhagic/necrotic mass and its surrounding tissue using extensive sampling. If CC is associated with a third-trimester placenta, it is frequently interpreted as placental infarction in an unusual site for an infarct (often central). Macroscopy The classic histologic pattern is biphasic representing an alternating mixture of multinucleated ST and mononucleated CT, arranged in a hazardous pattern. The cells represent a variable

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Fig. 2 Invasive hydatidiform mole: a Macroscopic view of a hysterectomy specimen representing a haemorrhagic nodule within the left uterine wall (LM=leiomyoma), b Molar villies (asterix) surrounded by marked trophoblastic proliferation within the myometrium of the uterus

degree of nuclear and cellular atypia. The number of IT in CC is variable but low. With respect to previous chemotherapy, the number of apoptotic cells may be abundant as its proliferative activity is highlighted by Ki-67 immunohistochemistry. The Ki67 labeling-index (60–80 % in CC) might be of some value in the differential diagnosis for PSTT and ETT (see below). Vascular invasion is a striking feature of CC. In contrast to other malignant epithelial tumors, CC lacks tumor-associated angiogenesis. CC realise their blood supply via extensive invasion and destruction of pre-existing vessels with secondary formation of hemorrhagic blood lakes, which are very characteristic features. In the majority of cases in uterine and all metastatic CC, chorionic villi are not seen in CC, beside the CC which develops in the context of CHM (intramolar CC; Fig. 3) [28] and within a term or near-term placenta (intraplacental CC) [26, 29]. On the other hand, the presence of trophoblastic cell clusters in small

curettage samples should be interpreted with caution. In the majority of cases, the clusters represent parts of “normal”, non-GTD associated trophoblastic tissue from the placental site within an abortion specimen. In an actual case, additional tissue should be embedded and examined, if possible. The clinician should be interviewed if there are clinical signs of GTD and HCG-values should be evaluated. In any doubtful cases, a serial HCG-measurement should be recommended and the cavum of the uterus should be evacuated completely, guided by ultrasound.

Fig. 3 Intramolar choriocarcinoma: a villies of a complete hydatidiform mole surrounded by marked trophoblastic proliferation, b apolar trophoblastic proliferation with an admixture mainly of zytotrophoblastic and syncytiotrophoblastic cells, intermingled by some intermediate

trophoblastic cells, c classical histologic appearance of choriocarcinoma representing an alternating mixture of multinucleated syncytiotrophoblastic and mononucleated zytotrophoblastic cells

Placental Site Trophoblastic Tumor (PSTT) PSTT is a neoplastic lesion of the implantation site by intermediate trophoblastic cells [3•]. In contrast to CC, which is

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preferentially associated with CHM or IHM, PSTT occurs mainly after normal pregnancy or non-molar abortion, sometimes with a long latency period of several years. In the majority of cases, tumoral lesion is clinically evident. Macroscopy Macroscopic findings are very variable with well circumscribed to ill-defined lesions of different size with a reported average of 5 cm [40•, 41]. The cutting surface may be soft, tan to yellow. In contrast to CC, striking hemorrhage is not evident. If hemorrhage, necroses and deep infiltrative growth occur, it may indicate malignant behavior (see below). Microscopy Microscopically, the cellular composition is similar to normal placental site reaction and EPS. Within the tumor itself, the intermediate trophoblastic cells are closely packed with a variable but generally low number of intermediate type trophoblastic giant cells. The cytoplasm of the cells is amphophilic and eosinophilic, and sometimes clear. At the periphery of the lesion, a characteristic pattern of infiltrative growth is evident. The cells infiltrate the myometrium singly or in small groups in a dissecting pattern preserving muscle fibers, which may be highly compressed (Fig. 6a). But cases with a destructive type of infiltration may occur. There is a distinctive vascular invasion, which is characterised by replacing the walls of the spiral arteries by monocleated IT cells and fibrinoid eosinophilic material forming “pale eosinophilic rings” maintaining a central lumen (Fig. 6b). The pale rings may be better visible at low or intermediate power. In several cases, these pale rings are incomplete (as seen in Figure 6b) and in other cases the vessels wall is complete replaced by intermediate trophoblastic cells. Within the lumen of the vessels within PSTT, groups of IT may be present recalling the pattern of normal placental site. The pattern of invasion may be highlighted with CK 18 and the muscle fibers by SMA or vimentin.

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extension beyond the uterus, infiltration of the myometrium >50 %, older age (>35 years), presence of tumor necroses, occurrence of mononucleated cells with clear rather than amphophilic eosinophilic cytoplasm, marked nuclear and cellular atypia, increased mitotic frequency (>5/10 HPF), and Ki67 labeling-index >50 % [40•, 41–43]. Differential Diagnoses Differential diagnoses include poorly differentiated carcinoma [26], malignant melanoma, sarcomas (especially epithelioid leiomyosarcomas), choriocarcinoma and EPS. As discussed above, the distinction between EPS and PSTT may be problematic. Features favoring PSTT are: presence of a tumor by visual inspection, high cellularity with a small number of giant cells of the intermediate trophoblastic type, destructive growth, no chorionic villi (in questionable cases go back to the bench for additional tissue embedding!), presence of mitoses, and high Ki-67 labeling-index (>5 – 10 %).

Epitheloid Trophoblastic Tumor (ETT) ETT is rarest type of GTD and has been described as an own entity several years before [44]. ETT represents a neoplastic proliferation of intermediate trophoblastic cells thought to be related to chorion leave (fetal membranes) [3•, 45]. There are some pathogenetic aspects to be addressed. It is thought that the majority of cases develop de novo from retained intermediate trophoblastic cells after pregnancy [30, 44]. As discussed below, some ETT may develop from atypical PSN [30, 36]. A third pathway may exist in cases where a CC was (heavily) pre-treated by polychemotherapy and the chemotherapeutically sensible trophoblastic cells were eradicated whereas the resistant cell clones may persist morphologically as ETT [31, 45]. This aspect might be supported by the fact that CC is a proliferative active tumor with a Ki-67 labeling-index of about 60 – 80 % (but not 100 %) and the ETT represent a low proliferative lesion. Additionally, ETT within the lung has been reported following (chemotherapeutically treated) CHM and IHM [46, 47].

Immunohistochemistry Macroscopy Immunohistochemically, the tumor cells are strong and diffuse positive for CK 18, EMA, inhibin, HPL, HLA-G and CD 146 but rarely for b-HCG and p63 is negative in almost all cases. Prognosis It is generally difficult to predict the clinical behaviour with certainty on morphology. Factors reported to be associated with malignant behaviour are: advanced tumor stage,

Macroscopically, there is a tumoral lesion in the majority of cases with variable size, which may be located in the corpus, isthmus or cervix uteri, sometimes outside the genitalia, e.g., the lung [40•, 46]. The appearance at the cut surface is variable mostly tan to brown solid, sometimes with pseudocystic degeneration and areas of hemorrhage and geographic necroses and sometimes calcification occurs.

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Fig. 4 placental site trophoblastic nodule (PSN) a and b) “classic” PSN representing a nodular lesion with a well circumscribed border nearby fragments of cycling endometrium, containing isolated and groups of hyperchromatic cells, embedded in an eosinophilic matrix, c and d

atypical PSN representing a nodular shaped lesion with pushing border, containing a large number of trophoblastic cells with sometimes vesiculated nuclei and some eosinophilic, geographic necroses (asterix)

Microscopy

cell borders. Mitoses may be seen and range between 0-9/10 HPF and the Ki-67 labeling-index is between 10–25 % [36].

Microscopically, the ETT represents a pushing border, but sometimes an infiltrative growth may occur [48]. The ETT is composed of a relatively uniform population of mononucleate cells of the IT, which grow in sheets or nodules. Two key features of the ETT are the presence of well-developed vessels, which are surrounded by the IT cells representing wellpreserved walls without vascular invasion and the occurrence of hyalinised necrotic eosinophilic material between these nodules, forming a geographic pattern (Fig. 6c, d). The hyalinised necrotic material may be misinterpreted as keratinised material (especially when it is sparsely present within tumor cell groups) and may represent calcifications. The IT cells have round uniform nuclei sometimes with prominent nucleoli and well-defined nucleolar membranes. The cytoplasm is pale, esinophilic, sometimes clear with variable

Immunohistochemistry Immunohistochemically, the ETT is positive for cytokeratines, CK 18, HLA-G, p63 and inhibin. In contrast to implantation site IT (and PSTT), HPL, b-HCG and CD 146 are only focally expressed or negative. The p16 is negative as well. The pushing border, geographic hyalinised necroses, the nodular pattern and the well- preserved walls of intratumoral vessels distinguishes the ETT from CC (infiltrative growth, hemorrhagic necroses, brisk vascular invasion) and PSTT (infiltrative growth, no/some dirty necroses, remodelling of vessels wall).

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Fig. 5 exaggerated placental site (EPS) a extensive proliferation of intermediate trophoblastic cells with infiltration of the decidua without destructive growth and replacing of the vessels wall of spiral arteries, b infiltration of myometrial cells by intermediate trophoblast without destructive growth, mimicking the patterns of normal placenta site but representing a high cellularity and an increased number of giant cells of intermediate trophoblastic type

Unclassified GTD and Intermediate Trophoblastic Tumor (ITT)

Macroscopy Almost all cases are macroscopically not visible.

As discussed above there is an overlapping immunohistochemical profile in EPS and PSTT as well as in PSN and ETT [35•, 49]. Furthermore, staining of HLA-G has been demonstrated in CC, PSTT and ETT [50, 51•] as well as stem cell features have been reported in different GTD [52]. The transition from one entity in another has been documented for atypical PSN into ETT and for CC into ETT after pretreatment with poylchemotherapy [30, 36]. More recently, trophoblastic lesions with mixed morphologic features of CC, PSTT and ETT in one single lesion were seen and the diagnostic term of intermediate trophoblastic tumor (ITT) was discussed [51•, 53].

Placental Site Nodule (PSN) The PSN represents a benign non-neoplastic lesion caused by the retention of intermediate trophoblastic cells after any type of pregnancy. The retained IT-cells are thought to present a chorionic type of IT [30, 31]. Other authors [32] have questioned this idea. Typically, PSN is an incidental finding in uterine curettings, endocervical biopsies or hysterectomies in a variety of clinical settings. About two thirds of the lesions have been reported to occur at the lower uterine segment [33, 34], sometimes associated with irregular/dysfunctional bleeding.

Microscopy Microscopically, PSNs are well circumscribed with a pushing border. They contain a variable number of isolated or small groups of almost mono-nuclear hyperchromatic and sometimes polymorphic IT-cells (Fig. 4a,b). These cells are embedded in an abundant eosinophilic matrix, which may contain hemosiderin. The trophoblastic cells may be very scanty but may be highlighted by immunohistochemistry using cytokeratin 18, pan-cytokeratines, EMA, and p63. Inhibin-a and HLA-G have been reported to be positive [36]. The Ki-67 labeling index is usually low (<5 %). The main differential diagnoses are eosinophilic CINlesions (p16 + ve) and decidual cells (−ve for cytokeratines but + ve for vimentin). More recently, the term of atypical PSN has been introduced (Fig. 4 c,d) [3•, 36]. These lesions are characterised by larger size (>0.4 cm), higher cellularity and a higher Ki-67 labeling index and sometimes with irregular borders. Atypical PSN were discussed to represent a lesion in transition between PSN and ETT (see above).

Exaggerated Placental Site (EPS) EPS represents a lesion with exuberant non-neoplastic proliferation of the intermediate trophoblast at the

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Fig. 6 Gestational trophoblastic tumors, derived from intermediate trophoblast: a PSTT: closely packed intermediate trophoblastic cells with a variable number of intermediate trophoblastic giant cells infiltrating the myometrium singly and in small groups with a dissecting but, not destructive pattern, preserving the muscle fibers, b PSTT: distinctive vascular invasion with replacement of vessels wall by fibrinoid eosino-

philic material and intermediate trophoblastic cells, c ETT: proliferation of intermediate trophoblastic cells separated by hyalinised necrotic material in a geographic pattern, d ETT: relatively uniform round intermediate trophoblastic cells with prominent nucleoli and well-defined nucleolar membranes and pale, esinophilic cytoplasm, intratumoral vessels are surrounded by these cells with preserving vessels wall without invasion

implantation site. The WHO-classification defines that lesion as an exaggeration of the normal implantation process [1]. In the past, it was termed by Felix Marchand in 1895 as syncytial endometritis, a term which is no longer used. EPS can be found in association with normal pregnancy, abortion and complete hydatidiform moles and is seen mostly in the first trimester. Very rare cases have been seen by the authors in association with PHM. EPS is the most poorly defined GTD [37] because no clear-cut criteria exist to differentiate EPS form placental site reaction in normal developed first or second trimester pregnancy. In some cases, the differential to PSTT may be challenging.

Macroscopy As in PSN, the diagnosis is microscopic and incidental. Microscopy Microscopically, EPS is characterised by an extensive trophoblastic infiltration of the decidua and the underlying myometrium without destructive growth, mimicking the patterns of a normal placental site. The endometrial glands are surrounded by the infiltrative growing intermediate trophoblastic cells and the cells infiltrate between smooth muscle fibers of the myometrium, which are sometimes heavily compressed but not destroyed, representing a “dissecting pattern

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of infiltrative growth” rather than a destructive one. As in normal placental sites, the vessel wall of the spiral arteries is replaced by fibrinoid material in intermediate trophoblastic cells. In the majority of cases, chorionic villi can be found, which acts as a very helpful diagnostic tool for the differential diagnosis against PSTT (see above). Contrary to normal placental site reaction, the number of trophoblastic giant cells of the intermediate trophoblastic type is increased (Fig. 5). These giant cells differ from syncytiotrophoblastic giant cells of CC and are characterised by closely packed hyperchromatic nuclei and the number of nuclei within the cell is harder to evaluate. The cytoplasma is sparse and not so eosiniphilic as in syncytial trophoblastic giant cells. Sometime the nuclei look a like “giant apoptosis” and show similarities to the giant cells of uterine leiomyomas with bizarre giant cells (symplastic leiomyomas). Immunohistochemically, they are negative or only weakly positive for b-HCG.

53 Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: • Of importance

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Immunohistochemistry The amount of trophoblastic proliferation can be highlighted by CK 18 or pan-cytokeratines immunohistochemically. On immunohistochemistry there is a broad overlap to PSTT (see below). As in normal placental site, the proliferative activity is very low (0-5 % Ki-67 labeling index). Differential Diagnosis In fractional curettings, the distinction from PSTT may be challenging or sometimes impossible [38]. In problematic cases, additional material should be embedded and examined. The occurrence of chorionic villi favors the diagnosis of EPS rather than PSTT. If the lesion is microscopic without clinically evident tumor development, the cells are separated by hyalinic material and decidual cells, lacking mitotic activity and no necroses are seen, the diagnosis of EPS should be made, added by the recommendation for close follow up of the patients. At this time there is no evidence that EPS may present a precursor lesion of PSTT [38, 39]. Prognosis

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6. 7.•

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EPS represents a benign lesion in almost all cases. But if the EPS is associated with CHM, there is an increased risk for the development of persistent GTD. In that context, the risk is more probably correlated to the trophoblastic proliferation of the CHM rather than the occurrence of the EPS itself [3•].

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Compliance with Ethics Guidelines 16. Conflict of Interest Lars-Christian Horn, Jens Einenkel, and Anne Kathrin Hoehn declare that they have no conflict of interest.

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