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Gestational trophoblastic disease (GTD) encompasses a large group of neoplastic diseases arising from trophoblastic tissue. The most common diseases are the following:

Hydatidiform mole-Complete and Incomplete mole
Invasive mole (Chorioadenoma destruens)
Epithelioid trophoblastic tumor
Placental site trophoblastic tumor

In addition, there are some proliferations of trophoblastic tissue which are benign but may histologically mimic disease.

Miscellaneous trophoblastic lesions:
Exaggerated placental site
Placental site nodule or plaque

Patients with molar pregancy, the most common form of GTD, may present with vaginal bleeding and excessive uterine enlargement for gestational age, usually between 11-25 weeks of pregnancy. Pregnancy induced hypertension may occur in 1/4 of patients. Other presenting signs include hyperthyroidism and hyperemesis gravidarum. Characteristically, the serum HCG is elevated. An ultrasound of the uterus reveals a characteristic snowstorm pattern, representing the hydropic chorionic villi which characterizes the disease. After evacuation of the uterus, careful clinical followup with serial measurements of the serum HCG is necessary to ensure there is no recurrence and all of the disease has been removed.

The clinical presentations of the other forms of GTD are covered in the following discussion and tables.


Disease Associations  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Laboratory/Radiologic/Other Diagnostic Testing  
Differential Diagnosis  
Prognosis and Treatment


Commonly Used Terms  
Internet Links  


Complete mole
1/1000 pregnancies
Most frequent form of molar pregnancy and GTD
Incomplete mole
25-74% of all molar pregnancies

1/20,000 pregnancies

The more abnormal the pregnancy, the more likely this will occur

1/160,000 normal getstations
1/15386 abortions
1/5333 ectopic pregnancies
1/40 molar pregnancies

Epithelioid trophoblastic tumor
Very rare
Placental site trophoblastic tumor
Rarest form of GTD

Usually disorders of reproductive age

Increased risk of moles at the extremes of reproductive age

Complete mole
11-25 weeks of pregnancy
Incomplete mole
9-34th weeks of pregnancy
Invasive mole
May occur simultaneously with intracavitary molar pregnancy
GEOGRAPHY-Hydatidiform mole
Rate per 1000
9.9 pregnancies
8.3 deliveries
5.0 deliveries
4.6 pregnancies
2.6 deliveries
1.9 pregnancies
1.4 pregnancies
1.1 pregnancies
0.8 live births
0.6 pregnancies
0.2 pregnancies
Low socioeconomic conditions  
Diet Possible dietary deficiency of carotene
Blood groups  

Choriocarcinoma more frequent

Stronger for women of type A and husbands of type O and conversely for group O women and type A husbands

B or AB
Worse prognosis



History of prior spontaneous abortions More common in hydatidiform mole and choriocarcinoma
Term pregnancy and live births Protective effect
Increases with an increased number of live births



46XX with both X chromosomes androgenic or paternal origin-Results from duplication of the haploid sperm in an empty ovum

3-13% have normal 46XY but both XY chromosomes are paternal-Results from dispermy, fertilization of an empty ovum by two sperm

Complete hydatidiform mole retaining a chromosome 11 of maternal origin: molecular genetic analysis of a case.

Fisher RA, Nucci MR, Thaker HM, Weremowicz S, Genest DR, Castrillon DH.

Department of Cancer Medicine, Faculty of Medicine, Imperial College London, Charing Cross Hospital, London, UK.
Mod Pathol. 2004 Sep;17(9):1155-60. Abstract quote  

Hydatidiform moles are pregnancies characterized by abnormal development of both embryonic and extraembryonic tissues and are associated with the misexpression of imprinted genes. The vast majority of complete hydatidiform moles are diploid and androgenetic, whereas partial hydatidiform moles are triploid, with an extra set of chromosomes of paternal origin.

Here, we present an unusual complete mole that showed strong expression of two imprinted, maternally transcribed genes, CDKN1C (encoding p57(KIP2)) and PHLDA2 (TSSC3/IPL), both part of a large imprinted gene domain on chromosome 11. Using microsatellite genotyping and fluorescent in situ hybridization, we show that this paradoxical gene expression was due to retention of a maternal copy of chromosome 11 in addition to the two paternal copies normally present in complete moles.

These findings demonstrate that, despite being predominantly androgenetic, some complete moles contain small amounts of DNA of maternal origin. Furthermore, these results provide an explanation for rare false negatives that can arise when p57(KIP2) is used as a diagnostic marker for complete moles.

Triploidy (69 chromosomes) with maternal chromosome complement

Most are 69XXY, 69XXX, and rarely 69XYY
Results from fertilization of an egg with a haploid set of chromosomes by either two sperms, each with a haploid set of chromosomes or by a single sperm with a diploid genome of 46 XY (diandric-paternally derived triploidy)

Placental site trophoblastic tumor of the mediastinum.

Went PT, Dirnhofer S, Stallmach T, Taverna C, Singer G.
Hum Pathol. 2005 May;36(5):581-4. Abstract quote  

Summary Choriocarcinoma has been described as the most frequent subtype of mediastinal germ cell tumors showing trophoblastic differentiation.

We report a unique case of a placental site trophoblastic tumor, which developed in the mediastinum of a 14-year-old boy 2 years after the resection of a mature teratoma. The recurrent tumor was composed of a grossly hemorrhagic and necrotic mass.

Histologically, diffusely infiltrating large polygonal cells with focal nodular growth and a teratomatous part containing mature intestinal, respiratory, and squamous epithelium with adjacent cutaneous adnexal structures were found. The typical morphologic features included vessel wall infiltration by the neoplastic cells with fibrinoid deposits and geographic necroses within the tumor masses. Characteristic diffuse positivity for melanoma cell adhesion molecule and human leucocyte antigen G was found on immunohistochemical investigation, confirming the diagnosis of placental site trophoblastic tumor. The patient died 1 year later after polychemotherapy.

The outcome of this rare tumor is similar to the reported poor clinical outcome in patients with mediastinal choriocarcinomas.

Comparative genomic hybridization study of placental site trophoblastic tumour: a report of four cases.

Hui P, Riba A, Pejovic T, Johnson T, Baergen RN, Ward D.

Department of Pathology, Weil Medical College of Cornell University, USA.
Mod Pathol. 2004 Feb;17(2):248-51. Abstract quote  

Placental site trophoblastic tumour (PSTT) is a neoplastic proliferation of the implantation intermediate trophoblast. Although clinicopathological studies are not uncommon in case reports or small series, molecular and genetic studies are quite limited.

Four archived cases of PSTT were successfully analysed by comparative genomic hybridization (CGH) in this study. Regional chromosomal gains were observed in two cases. One case showed chromosomal gains in the regions of 19p13.2, 21q11-21 and 22q12. The second case demonstrated a single regional chromosomal gain involving 21q21. No chromosomal loss is observed. The remaining two cases showed a balanced CGH profile without detectable chromosomal gain or loss.

In summary, although chromosomal alterations detectable by CGH are not common, rare chromosomal gains do occur in PSTT. The recurrent chromosomal gain involving chromosomal 21q observed in two of our cases deserves additional studies to ascertain whether it carries any pathobiological significance.

Immunohistochemical characterization of p57 expression in early hydatidiform moles.

Fukunaga M.

Department of Pathology, Jikei University School of Medicine, Tokyo, Japan.


Hum Pathol 2002 Dec;33(12):1188-92 Abstract quote

The differentiation of complete mole (CM), an aberrant androgenetic conceptus, from partial mole (PM) and hydropic abortion (HA) in early gestations is very important for patient management. In this study, 10 diploid voluntary artificial abortions (ABs), 20 diploid HAs, 20 triploid PMs, and 44 diploid CMs (including 4 persistent diseases), all of which were in the first trimester, were evaluated by immunohistochemistry of formalin-fixed tissues using a monoclonal antibody against p57(KIP2) protein (p57), a putative paternally imprinted inhibitor gene. DNA ploidy in all cases was analyzed by flow cytometry.

In all ABs, nuclear p57 was strongly expressed in cytotrophoblasts, intermediate trophoblasts, villous stromal cells, and decidual stromal cells but was absent in syncytiotrophoblast. In diploid CMs, p57 expression in cytotrophoblasts and villous stromal cells was either absent (37 cases) or very low (7 cases). Villous intermediate trophoblasts stained for p57 in 12 cases of CM. On the other hand, 16 HAs and 19 PMs showed p57 levels comparable to those observed in ABs. Decidual stromal cells provided a reliable internal control in all cases.

These findings support the hypothesis that misexpression of p57 is involved in the abnormal development of androgenetic CMs. This immunohistochemical analysis is a useful tool for the differential diagnosis of CMs.


Determination of DNA ploidy by fluorescence in situ hybridization (FISH) in hydatidiform moles: Evaluation of FISH on isolated nuclei.

Yver M, Carles D, Bloch B, Bioulac-Sage P, Martin Negrier ML.
Hum Pathol. 2004 Jun;35(6):752-8. Abstract quote  

In the past 20 years, the diagnosis of hydatidiform moles has become more difficult because of the widespread use of early uterine evacuation. Differentiating hydropic degeneration, partial, and complete moles is important because of their different prognosis. However, clinical diagnosis is less obvious, and the pathologist has to separate the different entities on the basis of very subtle morphologic criteria.

In difficult cases, ploidy may be determined by various methods, including fluorescence in situ hybridization (FISH) on routine histological sections from paraffin-embedded specimens. However, FISH analysis is often difficult because of the presence of numerous truncated nuclei. In this context, we have tested the advantages of FISH on isolated nuclei, a well-known variant of the technique that might be more sensitive.

We reviewed 24 cases of products of abortion: hydropic degenerations, complete hydatidiform moles, partial moles, and nonmolar triploidies. After histological review, FISH on isolated nuclei proved conclusive in all cases. The results could be easily interpreted thanks to the reduced number of truncated nuclei. The percentage of cells with 2 signals was always >70% in the diploid cases and >60% in the triploid cases.

In conclusion, this sensitive technique seems to be a valuable tool for the diagnosis of moles.

Analysis of gestational trophoblastic disease by genotyping and chromosome in situ hybridization.

Lai CY, Chan KY, Khoo US, Ngan HY, Xue WC, Chiu PM, Tsao SW, Cheung AN.

1Department of Pathology, The University of Hong Kong, Hong Kong, China.

Mod Pathol. 2004 Jan;17(1):40-48. Abstract quote  

Hydatidiform mole is classified into partial and complete subtypes according to histopathological and genetic criteria. Distinction between the two by histology alone may be difficult. Genetically, a complete mole is diploid without maternal contribution, whereas a partial mole is triploid with a maternal chromosome complement.

To assess the accuracy of histological diagnosis by correlating with the genetic composition, we performed fluorescent microsatellite genotyping to detect the presence or absence of maternal genome in a hydatidiform mole and carried out chromosome in situ hybridization to analyze the ploidy. For genotyping analysis, paraffin sections of 36 complete and nine partial moles, diagnosed according to histological criteria, were microdissected and DNA was separately extracted from the decidua and molar villi.

Six pairs of primers that flank polymorphic microsatellite repeat sequences on five different chromosomes were used. In all, 34 cases, including 31 complete moles and three partial moles diagnosed histologically, showed no maternal contribution by genotyping; thus these could be genetically considered as complete mole. The other 11 cases (five complete moles and six partial moles previously diagnosed by histology) showed the presence of maternal contribution and were genetically diagnosed as partial moles. The genotyping results correlated with histological evaluation in 88% (37/45) of hydatidiform mole and correlated with chromosome in situ hybridization findings in all the cases, that is, triploid hydatidiform moles had maternal-derived alleles, while diploid hydatidiform moles were purely androgenetic. Compared with genetic diagnosis, histological evaluation was more reliable for the diagnosis of a complete mole (91%, 31/34) than that of a partial mole (55%, 6/11) (P=0.0033). Seven complete moles and three partial moles diagnosed genetically developed gestational trophoblastic neoplasia.

To conclude, genotyping and chromosome in situ hybridization can provide reliable adjunct to histology for the classification of a hydatidiform mole, especially in cases with difficult histological evaluation and early gestational age. As a partial mole still carries a risk of developing gestational trophoblastic neoplasia, follow-up is considered necessary for both complete and partial moles.

Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM).

Chew SH, Perlman EJ, Williams R, Kurman RJ, Ronnett BM.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Hum Pathol 2000 Aug;31(8):914-24 Abstract quote

Partial hydatidiform moles (PHM) have defined villous abnormalities and are usually triploid. Their diagnosis often can be made by morphology alone, without confirmation of ploidy, but considerable interobserver variability exists. Other genetic abnormalities such as trisomy can result in placentas with abnormal villous morphology (AVM) similar to that seen in PHMs, leading to diagnostic confusion.

Twenty-three cases originally diagnosed as either PHM or AVM were independently reviewed by 3 pathologists. The consensus diagnosis was PHM in 14 cases and AVM in 9. Cases with AVM showed insufficient features for an unequivocal diagnosis of PHM.

DNA content was determined on paraffin-embedded tissue by fluorescence in situ hybridization (fsSH) using a chromosome 1 centromeric probe and by image cytometry (IC). Thirteen of 14 cases (93%) classified as PHM were triploid by both FISH and IC. Seven cases of AVM were diploid by FISH and IC, and 1 was triploid by FISH and IC. One of the 9 cases of AVM was determined to be trisomy 18 by karyotyping.

This good correlation of consensus diagnosis with ploidy data was much greater than that obtained based on original diagnoses. Comparative genomic hybridization performed on 6 cases of AVM showed gain of chromosome 21 in 1 case and loss of X in another.

PHMs displayed at least 3 of the following histologic features: 2 discrete populations of villi, circumferential mild trophoblastic hyperplasia, trophoblastic inclusions, prominent scalloping of villi, cistern formation. Nontriploid AVMs displayed at most 2 of the diagnostic features of PHM.

Placentas with genetic abnormalities other than triploidy can display morphologic changes suggestive of PHM and can be misinterpreted as such by routine light microscopy. Stringent application of morphologic criteria improves the correlation of the diagnosis of PHM with triploidy.


Complete mole Hydropic chorionic villi
Large for dates uterus
Incomplete mole

Often small for dates uterus, resembling a missed abortion

Volume of tissue usually <200 ml

Villi are grossly enlarged but smaller than seen in a complete mole
Fragments of normal placenta and a fetus may be found

Invasive mole Requires demonstration of molar villi invading into the myometrium or deported to extrauterine sites

Usually presents with abnormal uterine bleeding but symptoms of metastases may be the first symptom

Dark red hemorrhagic mass with a shaggy irregular surface

Epithelioid trophoblastic tumor

Similar presentation as choriocarcinoma and invades the myometrium in an expansile rather than permeative growth

Not associated with central necrosis or hemorrhage

Elevated serum HCG

Placental site trophoblastic tumor

Variable in size but may present with diffuse nodular enlargement of the myometrium-occasionally polypoid projecting into the uterine cavity

Invasive tumor frequently extends into the uterine serosa and adnexal structures

Epithelioid Trophoblastic Tumor of the Broad Ligament: A Case Report and Review of the Literature

Kuo, Kuan-Ting MD*; Chen, Mei-Jou MD†; Lin, Ming-Chieh MD*

From the Departments of *Pathology and †Gynecology and Obstetrics, National Taiwan University Hospital, Medical Collage, National Taiwan University, Taipei, Taiwan.


American Journal of Surgical Pathology : Volume 28(3) March 2004 pp 405-409 Abstract quote

We report an epithelioid trophoblastic tumor, a recently delineated type of gestational trophoblastic tumor (GTT), discovered in the right broad ligament of a 41-year-old woman.

The patient had gestational trophoblastic disease and was treated with methotrexate regimen 15 times 10 years earlier. The yellowish, spongy tumor with tiny hemorrhage spots was located in the right broad ligament, adherent to the right ovary. Microscopically, the tumor was circumscribed, with a pushing border, and the epithelial-differentiated tumor cells grew in cords, nests, and sheets within which were aggregates of hyaline material and necrotic debris. Most tumor cells were mononuclear with distinct cell borders, eosinophilic cytoplasm, and had nuclei with occasional indistinct nucleoli. Scattered multinucleated cells consistent with syncytiotrophoblastic cells were also present. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (AE1/AE3, CAM 5.2, CK18), and focal reactivity, mainly in syncytiotrophoblastic cells, for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha.

The histologic and immunohistochemical features were characteristic of epithelioid trophoblastic tumor and helped to distinguish the tumor from other trophoblastic tumors and squamous cell carcinoma. Our unusual findings in this case included a high level of serum beta-human chorionic gonadotropin, an unusual tumor location, and a higher Ki-67 proliferative index of 47.2%.


Placental site trophoblastic tumor in a late recurrence of a nonseminomatous germ cell tumor of the testis.

Suurmeijer AJ, Gietema JA, Hoekstra HJ.

Department of Pathology, University Hospital Groningen, Groningen, The Netherlands.
Am J Surg Pathol. 2004 Jun;28(6):830-3. Abstract quote  

Placental site trophoblastic tumor (PSTT) is a well-defined entity in the female genital tract. In the male genital tract, a single case of PSTT in the testis of a young boy has been reported. Despite its very rare occurrence, PSTT of the testis has been incorporated in the latest WHO classification of tumors of the male genital tract.

In this article, a case of a PSTT in a late retroperitoneal recurrence of a testicular nonseminomatous germ cell tumor in an adult male patient is presented. The tumor was discovered due to an elevated serum level of beta-human chorionic gonadotropin 4 years after chemotherapy. Upon review of the primary testicular tumor, small foci of intermediate trophoblastic tumor cells were discerned.

This case illustrates that tumor cells resembling intermediate trophoblastic cells may metastasize to regional retroperitoneal lymph nodes. Because of their resistance to chemotherapy, these cells may invade surrounding tissue in due time, acquiring the typical morphology of PSTT.


Interobserver and intraobserver variability in the diagnosis of hydatidiform mole.

Fukunaga M, Katabuchi H, Nagasaka T, Mikami Y, Minamiguchi S, Lage JM.

Department of Pathology, Jikei University, Tokyo, Japan.
Am J Surg Pathol. 2005 Jul;29(7):942-7. Abstract quote  

Surgical pathologists often encounter hydropic villi in products of conception at the first trimester and must determine whether the villi represent complete hydatidiform mole (CM), partial hydatidiform mole (PM), or hydropic abortion (HA). The distinction between these is important for determining the appropriate treatment of patients.

This study assessed interobserver and intraobserver variability in the histologic diagnosis of hydatidiform mole among 5 placental pathologists. To evaluate interobserver variability, one representative slide from each of 50 mixed cases of PM, CM, and HA of the first trimester were circulated among 5 placental pathologists. All pathologists used the same histologic criteria by Szulman and Surti. For the second round, the same cases were submitted with DNA ploidy data. For the third round, the slides were recoded and distributed to assess intraobserver agreement. Kappa (kappa) value was calculated for the interobserver agreement in the first and second rounds. There was agreement among 4 or 5 pathologists for only 30 of 50 cases in the first round. There were problems in differentiating between PM and HA in most of the remaining 20 cases. The kappa values varied from poor (kappa = -0.104) to excellent (kappa = 0.761) in the first round. In the second round, there was agreement in 39 of 50 cases and the level of agreement remarkably increased, ranging from fair to good (kappa = 0.552) to excellent (kappa = 0.851). The number of discrepant cases, PM versus HA, was reduced to 4. In 7 cases, there were difficulties in distinguishing CM from HA. The intraobserver agreement ranged from 50% to 90%. Poor interobserver agreement was demonstrated when histology alone was used for diagnosis. Discordance was most frequently seen in PM versus HA and resulted from difficulty in evaluating trophoblastic hyperplasia. Polar trophoblastic growth seen in HA could also be observed in PM. The addition of ploidy data resulted in a significant improvement in concordance.

Ploidy study is useful in equivocal cases. Significant interobserver and intraobserver variability was observed even among placental pathologists. New histologic criteria adaptable to differentiation of early lesions are needed.
Gestational Trophoblastic Diseases: Recent Advances in Histopathologic Diagnosis and Related Genetic Aspects.

Hui P, Martel M, Parkash V.

From the *Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; and daggerDepartment of Pathology, Hospital of Saint Raphael, New Haven, Connecticut.

Adv Anat Pathol. 2005 May;12(3):116-125. Abstract quote  

Gestational trophoblastic disease refers to a spectrum of proliferative disorders of the placental trophoblast, with a wide range of histologic appearances and clinical behaviors.

This review discusses the more recent developments in the diagnosis of these entities. Changes in criteria for the histologic diagnosis of these lesions due to earlier clinical diagnosis are reviewed, and the ability to make more accurate diagnoses due to the introduction of newer antibodies such as p57 is highlighted.

A discussion of epithelioid trophoblastic tumor, a newly introduced tumor subtype, with its differential diagnosis from placental-site trophoblastic tumor and squamous cell carcinoma is also presented.

Last, a brief discussion on the role of genetic studies and the future direction of research in elucidating the nature of this intriguing group of lesions is presented.
Complete mole Enlarged edematous chorionic villi with central cisterns
Usually avascular villi
Haphazard circumferential trophoblastic proliferation around the villus
Incomplete mole

Molar change is focal with a mixture of edematous villi and small relatively normal sized villi

Central cisterns are less conspicuous

Smaller villi with stromal fibrosis

Invaginations of trophoblast into the villous stroma giving a scalloped appearance, appearing as inclusions within the stroma

Invasive mole

Molar villi with trophoblast within the myometrium or at an extrauterine stie

Villi are usually 4-5 mm in diameter but hydropic changes are not as marked as in complete moles


Masses and sheets of trophoblastic cells without villi invading the surrounding tissue and permeating vascular spaces

Central hemorrhage and necrosis with a rim of viable tumor

Admixture of intermediate, cyto- and syncytio-trophoblastic cells with considerable nuclear atypia

Epithelioid trophoblastic tumor

Highly atypical mononucleate trophoblastic cells and indistinct syncytiotrophoblastic cells with a striking epithelioid appearance

Grow as diffusely infiltrating cords and nests surrounded by a dense eosinophilic hyaline material

In general, lacks the dimorphic pattern of choriocarcinoma

Epithelioid Trophoblastic Tumor of the Uterus in a Postmenopausal Woman A Case Report and Review of the Literature

Laura E. Coulson, M.D.; Christina S. Kong, M.D.; Charles Zaloudek, M.D.

From the Department of Pathology, University of California, San Francisco and San Francisco General Hospital, San Francisco, California, U.S.A.

Am J Surg Pathol 2000;24:1558-1562 Abstract quote

We report an epithelioid trophoblastic tumor (ETT), a recently delineated type of gestational trophoblastic tumor (GTT), discovered in the uterus of a 66-year-old woman.

She had been treated for a hydatidiform mole 17 years previously without chemotherapy. The resected uterus contained a solid/cystic tumor located entirely within the myometrium. Microscopically, there was an epithelial-like growth pattern. The tumor was circumscribed, with a pushing border, and the tumor cells grew in cords, nests, and sheets within which were aggregates of hyaline material and necrotic debris. Most tumor cells were mononuclear and had an epithelioid appearance with distinct cell borders, eosinophilic cytoplasm, and nuclei with occasional indistinct nucleoli. Scattered multinucleated cells consistent with syncytiotrophoblastic cells were also present. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (CK7, AE1/AE3, CAM 5.2, CK18) and epidermal growth factor receptor, and focal reactivity, mainly in syncytiotrophoblastic cells, for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The histologic and immunohistochemical features were characteristic of ETT, and helped to distinguish the tumor from other trophoblastic tumors and squamous cell carcinoma. An unusual observation was a high mitotic count, reflected in a Ki-67 proliferative index of 68.6%.

Our findings indicate that ETT, like other types of GTT, can occur in postmenopausal women, even years after a gestational event.

Placental site trophoblastic tumor

Monomorphic cell population of pleomorphic intermediate trophoblastic cells invading singly and in cords and sheets

Irregular hyperchromatic nuclei with dense eosinophilic to amphophilic cytoplasm with occasional vacuoles

Abundant extracellular eosinophilic fibrinoid is present within the tumor

Blood vessel walls are extensively replaced by trophoblastic cells and fibrinoid material

Extensive necrosis may be present



Immunohistochemical Expression of Cell Cycle Proteins E2F-1, Cdk-2, Cyclin E, p27kip1, and Ki-67 in Normal Placenta and Gestational Trophoblastic Disease

Maria Olvera, M.D., Selena Harris, M.D., Charles A. Amezcua, M.D., Althea McCourty, B.S., Sherif Rezk, M.D., Charles Koo, M.D., Juan C. Felix, M.D. and Russell K. Brynes, M.D.

Departments of Pathology (MOCAA, AM, SR, JCF, RKB) and Obstetrics and Gynecology (SH), Los Angeles County + University of Southern California Healthcare Network, Los Angeles, California; and Department of Pathology (CK), Kaiser Permanente Hospital, Los Angeles, California

Mod Pathol 2001;14:1036-1042 Abstract quote

The role of cell cycle protein expression in gestational trophoblastic disease is poorly understood.

In this study we investigated the immunostaining patterns of G1 restriction point and G1-S regulatory proteins E2F-1, Cdk2, cyclin E, p27kip1, and the proliferation marker Ki-67 on routinely processed sections of 29 hydatidiform moles (10 partial moles and 19 complete moles, including 9 persistent moles), 7 choriocarcinomas, and 7 normal placentas. Ki-67 trophoblast staining decreased with increasing gestational age of the placenta, and showed maximal expression in gestational trophoblastic disease. Cyclin-dependent kinase activity, as reflected by Cdk2 expression patterns, also decreased with placental maturation. E2F-1 was uniquely expressed by trophoblasts of moles and choriocarcinoma. Cyclin E was maximally expressed by complete moles and choriocarcinomas, and showed an inverse relationship with the cyclin-dependent kinase inhibitor p27kip1. Abnormal trophoblastic proliferations may be mediated through interactions of Cdk-2, E2F-1, cyclin E, and p27kip1. Overexpression of cyclin E was associated with more aggressive forms of gestational trophoblastic disease. However, we did not find distinguishing features between complete moles that spontaneously resolved after evacuation and persistent moles that required chemotherapy.

The different expression patterns of cyclin E and E2F-1 in partial and complete moles may be useful in distinguishing these two entities. Furthermore, loss of p27kip1 in malignant trophoblast may represent a necessary step in the development of choriocarcinoma.

Discrimination of Complete Hydatidiform Mole From Its Mimics by Immunohistochemistry of the Paternally Imprinted Gene Product p57 KIP2

Diego H. Castrillon, M.D., Ph.D.; Deqin Sun, M.S.; Stanislawa Weremowicz, Ph.D.; Rosemary A. Fisher, Ph.D.; Christopher P. Crum, M.D.; David R. Genest, M.D.

From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Women's and Perinatal Pathology Division (D.H.C., D.S., C.P.C., and D.R.G.), and the Cytogenetics Division (S.W.), Boston, Massachusetts, and the Department of Cancer Medicine, Imperial College School of Medicine and Charing Cross Hospital (R.A.F.), London, U.K.

Am J Surg Pathol 2001;25:1225-1230 Abstract quote

The p57 KIP2 protein is a cell cycle inhibitor and tumor suppressor encoded by a strongly paternally imprinted gene.

We explored the utility of p57 KIP2 as a diagnostic marker in hydatidiform mole, a disease likely the result of abnormal dosage and consequent misexpression of imprinted genes.

Using a monoclonal antibody on paraffin-embedded, formalin-fixed tissue sections, the authors evaluated p57 KIP2 expression in normal placenta and in 149 gestations including 59 complete hydatidiform moles, 39 PHMs, and 51 spontaneous losses with hydropic changes. p57 KIP2 was strongly expressed in cytotrophoblast and villous mesenchyme in normal placenta, all cases of partial hydatidiform moles (39 of 39) and all spontaneous losses with hydropic changes (51 of 51). In contrast, p57 KIP2 expression in cytotrophoblast and villous mesenchyme was absent or markedly decreased in 58 of 59 complete hydatidiform moles.

In all gestations p57 KIP2 was strongly expressed in decidua and in intervillous trophoblast islands, which served as internal positive controls for p57 KIP2 immunostaining. p57 KIP2 immunohistochemistry can reliably identify most cases of complete hydatidiform mole irrespective of gestational age and is thus a useful diagnostic adjunct, complementary to ploidy analysis, in the diagnosis of hydatidiform mole.


HLA-G immunoreactivity is specific for intermediate trophoblast in gestational trophoblastic disease and can serve as a useful marker in differential diagnosis.

Singer G, Kurman RJ, McMaster MT, Shih IeM.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA

Am J Surg Pathol 2002 Jul;26(7):914-20 Abstract quote

HLA-G is a nonclassical MHC class I antigen that has been shown to be a specific marker for normal intermediate trophoblast (IT).

In this study HLA-G immunoreactivity assessed with an HLA-G specific antibody (4H84) was detected in all 14 cases of choriocarcinoma, 14 placental site trophoblastic tumors, 13 epithelioid trophoblastic tumors, 16 placental site nodules, and nine exaggerated placental sites. In contrast, HLA-G immunoreactivity was not detected in 34 nontrophoblastic uterine neoplasms. HLA-G immunoreactivity was present in all the IT cells of exaggerated placental sites and placental site trophoblastic tumors and in 70-100% of IT cells in placental site nodules and epithelioid trophoblastic tumors.

The pattern of distribution of HLA-G in different subpopulations of IT confirms the relationship of various trophoblastic lesions to different types of IT (exaggerated placental site and placental site trophoblastic tumor to implantation site IT and placental site nodule and epithelioid trophoblastic tumor to chorionic-type IT) and suggests that choriocarcinoma is related to villous-type IT because the majority of mononucleate cells in this neoplasm were HLA-G immunoreactive.

In conclusion, HLA-G immunoreactivity appears to be specific for IT in gestational trophoblastic disease and can serve as a useful marker in the differential diagnosis of these lesions.

Multiplex short tandem repeat DNA analysis confirms the accuracy of p57(KIP2) immunostaining in the diagnosis of complete hydatidiform mole.

Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.


Hum Pathol. 2006 Nov;37(11):1426-34. Epub 2006 Aug 10. Abstract quote

Detailed histopathologic examination remains to be the basis for the diagnosis of hydatidiform mole (HM). However, poor sampling, necrosis, and earlier uterine evacuation can lead to uncertainty in the diagnosis. Also, the criteria are subjective, resulting in considerable interobserver variability. The p57(KIP2) gene is paternally imprinted and maternally expressed, and the presence of its protein product serves as a surrogate marker for the nuclear maternal genome. Because a complete HM (CHM) is the only type of conceptus lacking a maternal contribution, p57(KIP2) immunostaining is correspondingly absent, whereas it is present in CHM mimics. Although analysis of DNA microsatellite polymorphisms is a reliable method for the diagnosis and classification of HM, it is not universally available.

To assess the relative accuracy of p57(KIP2) immunostaining and molecular diagnosis by nuclear DNA microsatellite polymorphisms in discriminating CHM from its mimics, we analyzed archival tissue from 33 case patients (7 with a definitive diagnosis of CHM, 16 with a possible diagnosis of HM, and 10 with normal placentas) by both methods.

Concordant results were obtained in all cases, and p57(KIP2) immunostaining accurately identified all cases of CHM from the groups with a definitive or possible diagnosis of HM. p57(KIP2) immunohistochemistry is a time- and cost-effective means of distinguishing CHM from its mimics in challenging cases.
p63 Expression Is Useful in the Distinction of Epithelioid Trophoblastic and Placental Site Trophoblastic Tumors by Profiling Trophoblastic Subpopulations.

Shih IM, Kurman RJ.

Departments of Pathology, Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD.
Am J Surg Pathol. 2004 Sep;28(9):1177-1183. Abstract quote  

Human trophoblast is composed of a heterogeneous population of cells, which give rise to a variety of trophoblastic tumors and tumor-like lesions.

In this report, we analyzed the expression pattern of the p63 gene, a transcription factor belonging to the p53 family, in different trophoblastic subpopulations and in trophoblastic lesions. p63 has various isoforms that are classified into two groups designated TA and DeltaNp63 isoforms. The TA isoforms have a p53-like suppressor function, whereas the DeltaNp63 isoforms exert an oncogenic effect. Based on immunohistochemistry and RT-PCR, it appears that cytotrophoblast expresses the DeltaNp63 isoform whereas chorionic-type intermediate trophoblast in the fetal membranes, placental site nodules, and epithelioid trophoblastic tumors expresses the TAp63 isoform. Intermediate trophoblast in the implantation site and placental site trophoblastic tumors does not express p63.

Based on the expression patterns of p63 and the previously described expression patterns of other trophoblastic markers, including HLA-G, cytokeratin 18, hPL, and Ki-67, we developed an immunohistochemical algorithm to diagnose trophoblastic lesions. A validation set of 22 trophoblastic lesions and 34 nontrophoblastic tumors were classified correctly using this algorithm.

In conclusion, the findings in this study demonstrate that different trophoblastic subpopulations and their related trophoblastic lesions are characterized by distinctive patterns of p63 expression. Recognizing these distinctive expression patterns helps to further elucidate the biology of trophoblast and can also provide a useful tool for the differential diagnosis of trophoblastic lesions.


Prognostic Factors  
Complete mole

In more than 60% of patients who required chemotherapy, there were large for dates uteri and ovarian enlargment secondary to theca-lutein cysts

16% develop into invasive moles and 2.5% develop into choriocarcinoma

0.6-1.5% of patients are at risk of having recurrent molar pregnancies

Incomplete mole

5% will have persistent or metastatic GTD requiring chemotherapy

Choriocarcinoma is rare

Invasive mole

Choriocarcinoma occurs 6-10x more frequently than following a hydatidiform mole

Metastases may occur in 20-40% of cases


Metastases especially to brain and liver can occur in 20-60% of patients

With chemotherapy, overall survival rate is about 90%

Death usually occurs from hemorrhage and pulmonary insufficiency

Epithelioid trophoblastic tumor May have course similar to choriocarcinoma
Placental site trophoblastic tumor

May cause perforation of the uterus

About15-20% die of metastastic disease and may not be sensitive to chemotherapy-aggressive cases may have extensive necrosis with high mitotic rates

Risk factors affecting staging Serum HCG>100,000 mlU/ml
Duration of disease>6 months from termination of antecedent pregnancy

Disease confined to the uterus

Confined to uterus with no risk factors
Confined to uterus with 1 risk factor
Confined to uterus with 2 risk factors
II Tumor extending outside uterus but limited to genital structures (adnexa, vagina, broad ligament)
No risk factors
1 risk factor
2 risk factors
III Tumor extending to lungs with or without known genital tract involvement
No risk factors
1 risk factor
2 risk factors
IV All other metastatic sites
No risk factors
1 risk factor
2 risk factors
5 Year Survival

In diseases treated with surgery and combination chemotherapy:

Disease confined to uterus-100%
Metastatic disease-83%

Metastasis Lungs, brain, liver
Treatment Combination surgery with chemotherapy
MAC-methotrexate, actinomycin D, and chlorambucil

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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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