Hydatidiform Moles: Ancillary Techniques to Refine Diagnosis.

CONTEXT.­: Distinction of hydatidiform moles from nonmolar specimens and subclassification of hydatidiform moles as complete hydatidiform mole versus partial hydatidiform mole are important for clinical practice and investigational studies. Risk of persistent gestational trophoblastic disease and clinical management differ for these entities. Diagnosis based on morphology is subject to interobserver variability and remains problematic, even for experienced gynecologic pathologists. OBJECTIVES.­: To explain how ancillary techniques target the unique genetic features of hydatidiform moles to establish diagnostic truth, highlight the issue of diagnostic reproducibility and importance of diagnostic accuracy, and illustrate use of p57 immunohistochemistry and polymerase chain reaction-based DNA genotyping for diagnosis. DATA SOURCES.­: Sources are the author's 10-year experience using ancillary techniques for the evaluation of potentially molar specimens in a large gynecologic pathology practice and the literature. CONCLUSIONS.­: The unique genetics of complete hydatidiform moles (purely androgenetic), partial hydatidiform moles (diandric triploid), and nonmolar specimens (biparental, with allelic balance) allow for certain techniques, including immunohistochemical analysis of p57 expression (a paternally imprinted, maternally expressed gene) and genotyping, to refine diagnoses of hydatidiform moles. Although p57 immunostaining alone can identify complete hydatidiform moles, which lack p57 expression because of a lack of maternal DNA, this analysis does not distinguish partial hydatidiform moles from nonmolar specimens because both express p57 because of the presence of maternal DNA. Genotyping, which compares villous and decidual DNA patterns to determine the parental source and ratios of polymorphic alleles, distinguishes purely androgenetic complete hydatidiform moles from diandric triploid partial hydatidiform moles, and both of these from biparental nonmolar specimens. An algorithmic approach to diagnosis using these techniques is advocated.

Is Ki-67 of Diagnostic Value in Distinguishing Between Partial and Complete Hydatidiform Moles? A Systematic Review and Meta-analysis.

BACKGROUND/AIM: To demonstrate the value of Ki-67 in distinguishing between partial and complete hydatidiform moles. MATERIALS AND METHODS: We searched electronic databases included Medline, WOK, Cochrane Library and CNKI, through January 24, 2015. Experts were consulted, and references from related articles were examined. The meta-analysis was conducted with RevMan5.3, according to the PRISMA guidelines. Mantel-Haenszel estimates were calculated and pooled under a random effect model, with data expressed as odds ratio (OR) and 95% confidence interval (CI). RESULTS: We analyzed eight trials with a total of 337 participants who underwent uterine curettage and met the inclusion criteria. A significantly higher expression of Ki-67 was observed in complete than in partial hydatidiform moles (OR=3.28; 95%CI=1.80-5.96; p<0.0001). CONCLUSION: The Ki-67 expression was higher in complete than in partial hydatidiform moles. Therefore, Ki-67 may be of diagnostic value in distinguishing between partial and complete hydatidiform moles. However, the present study had only a limited number of samples, so investigation of a greater number of cases is needed to confirm this conclusion.

E-Cadherin, CD44v6, and Insulin-Like Growth Factor-II mRNA-Binding Protein 3 Expressions in Different Stages of Hydatidiform Moles.

E-cadherin, CD44v6, and IMP3 expression in partial, complete, and invasive hydatidiform moles (HMs) was evaluated. High E-cadherin expression with low CD44v6 expression was observed in partial, complete, and invasive HMs, as well as in normal placental tissues; and there was no significant difference in E-cadherin and CD44v6 expression among the four groups. However, IMP3 expression was gradually decreased in the order of normal placental tissues, partial HMs, complete HMs, and invasive HMs; wherein, invasive HMs had the lowest level. Low IMP3 expression may serve as a prognostic biomarker for HMs, and IMP3 may play a certain role in HMs progression.

Role of P57KIP2 Immunohistochemical Expression in Histological Diagnosis of Hydatidiform Moles.

PURPOSE: To determine the significance of P57KIP2 immunohistochemistry expression in the histopathological diagnosis of hydatidiform mole. MATERIALS AND METHODS: Hydatidiform mole patients at King Chulalongkorn Memorial Hospital between January 1999 and December 2011 were recruited. Two gynecologic pathologists reviewed histopathologic slides to confirm diagnosis. Formalin-fixed, paraffin-embedded tissue sections were stained using a bstandard immunostaining system with monoclonal antibodies against P57KIP2 protein. Correlations among pathological features, immunohistochemical expression and clinical data were analyzed. RESULTS: One hundred and twenty-seven hydatidiform mole patients were enrolled. After consensus review, 97 cases were diagnosed as complet (CHM) and 30 cases as partial (PHM). Discordance between the first and final H and E diagnoses was found in 19 cases (14.9%, k= 0.578). Significant pathological features to classify the type of hydatidiform mole are central cisterns, trophoblastic proliferation, trophoblastic atypia, two populations of villi, fetal vessels and scalloped borders. After performing immunohistochemistry for P57KIP2, 107 cases were P57KIP2 negative and 20 cases positive. Discordant diagnoses between final H and E diagnosis and P57KIP2 immunohistochemistry was identified in 12 cases (9.4%). Sensitivity of final H and E diagnosis for CHM was 89.7%; specificity was 95.0%. PHM sensitivity and specificity of final H and E diagnosis was 95.0% and 89.7%, respectively. CONCLUSIONS: Histopathological diagnosis alone has certain limitations in accurately defining types of hydatidiform mole; P57KIP2 immunohistochemistry is practical and can be a useful adjunct to histopathology to distinguish CHM from non-CHM.

The effect of adolescence and advanced maternal age on the incidence of complete and partial molar pregnancy.

OBJECTIVE: To compare the age-specific incidence of complete (CM) and partial molar (PM) pregnancy in a large tertiary care center in the United States. METHODS: Incidence rates of CM and PM per 10,000 live births were calculated using databases from Brigham and Women's Hospital, between 2000 and 2013. Age-specific rates were calculated for women younger than 20 years old (adolescents), 20-39 years old (average age), and 40 years and older (advanced maternal age). Pearson χ(2) test was used to evaluate potential differences among groups. Rate ratios (RR) and 95% confidence intervals (CI) were used to compare risk of molar pregnancy among average age women with that of adolescents and women of advanced age. Holm-Bonferonni adjustment was used to correct for multiple comparisons. RESULTS: Between 2000 and 2013, there were 255 molar pregnancies (140 CM and 115 PM) and 105,942 live births, corresponding to a molar pregnancy rate of 24 per 10,000 live births (95% CI 21-27). Rates of CM and PM were 13 (95% CI 11-16) and 11 (95% CI 9-14) per 10,000 live births respectively. The incidence of CM differed significantly among maternal age groups (p<0.001). Compared to average age women, adolescents were 7.0 times as likely to develop CM (95% CI 3.6-8.9, p<0.001), and women with advanced maternal age were nearly twice as likely (1.9, 95% CI 1.8-4.7, p=0.002). The rate of PM did not vary significantly among age groups (p=0.26). CONCLUSIONS: Adolescence and advanced maternal age were associated with increased risk of complete mole, but not partial mole.

STR DNA genotyping of hydatidiform moles in South China.

OBJECTIVE: To evacuate whether short-tandem-repeat (STR) DNA genotyping is effective for diagnostic measure to precisely classify hydatidiform moles. METHODS: 150 cases were selected based on histologic features that were previously diagnosed or suspected molar pregnancy. All sections were stained with hematoxylin as a quality control method, and guided the microscopic dissection. DNA was extracted from dissected chorionic villi and paired maternal endometrial FFPE tissue sections. Then, STR DNA genotyping was performed by AmpFlSTR(®) Sinofiler(TM) PCR Amplification system (Applied Biosystems, Inc). Data collection and analysis were carried out using GeneMapper(®) ID-X version 1.2 (Applied Biosystems, Inc). RESULTS: DNA genotyping was informative in all cases, leading to identification of 129 cases with abnormal genotype, including 95 complete and 34 partial moles, except 4 cases failed in PCR. Among 95 complete moles, 92 cases were monospermic and three were dispermic. Among 34 partial moles, 32 were dispermic and 2 were monospermic. The remaining 17 cases were balanced biallelic gestations. CONCLUSION: STR DNA genotyping is effective for diagnostic measure to precisely classify hydatidiform moles. And in the absence of laser capture microdissection (LCM), hematoxylin staining plus manual dissection under microscopic guided is a more economic and practical method.

Recurrent pregnancy loss in a woman with NLRP7 mutation: not all molar pregnancies can be easily classified as either "partial" or "complete" hydatidiform moles.

Recurrent hydatidiform moles is an uncommon occurrence. Over the past decade, genetic studies of women with multiple recurrent molar pregnancies have revealed that maternal mutations in two different genes, NLRP7 and C6orf221, result in recurrent moles. We report a 23 year old woman, born of unrelated parents, who has experienced three molar pregnancies in succession. Whilst the first pregnancy was classified as a complete hydatidiform mole, the second and third moles defied classification as complete or partial mole using conventional histology, p57 nuclear staining pattern and ploidy studies. Molecular and cytogenetic studies proved that all three molar pregnancies were diploid and biparental in origin. Gene sequencing analysis showed that the patient is homozygous for a previously described mutation in NLRP7. A SNP microarray ruled out the presence of deletion of the NLRP7 locus. This case draws attention to the fact that recurrent molar pregnancies may be the result of specific, identifiable gene mutations, even in patients from non-consanguineous backgrounds. When pathologists encounter patients with molar pregnancies that are diploid and p57 negative and yet have fetal elements such as nucleated red blood cells or immature fetal tissues, it should heighten their suspicion of a possible genetic basis and appropriate molecular genetic workup performed with counseling offered.

Diagnostic utility of microsatellite genotyping for molar pregnancy testing.

CONTEXT: Molecular genotyping by analysis of DNA microsatellites, also known as short tandem repeats (STRs), is an established method for diagnosing and classifying hydatidiform mole. Distinction of both complete hydatidiform mole and partial hydatidiform mole from nonmolar specimens is relevant for clinical management owing to differences in risk for persistent gestational trophoblastic disease. OBJECTIVE: To determine the technical performance of microsatellite genotyping by using a commercially available multiplex assay, and to describe the application of additional methods to confirm other genetic abnormalities detected by the genotyping assay. DESIGN: Microsatellite genotyping data on 102 cases referred for molar pregnancy testing are presented. A separate panel of mini STR markers, flow cytometry, fluorescence in situ hybridization, and p57 immunohistochemistry were used to characterize cases with other incidental genetic abnormalities. RESULTS: Forty-eight cases were classified as hydatidiform mole (31, complete hydatidiform mole; 17, partial hydatidiform mole). Genotyping also revealed 11 cases of suspected trisomy and 1 case of androgenetic/biparental mosaicism. Trisomy for selected chromosomes (13, 16, 18, and 21) was confirmed in all cases by using a panel of mini STR markers. CONCLUSIONS: This series illustrates the utility of microsatellite genotyping as a stand-alone method for accurate classification of hydatidiform mole. Other genetic abnormalities may be detected by genotyping; confirmation of the suspected abnormality requires additional testing.

Diagnostic reproducibility of hydatidiform moles: ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis for both recently trained and experienced gynecologic pathologists.

Distinction of hydatidiform moles from nonmolar specimens (NMs) and subclassification of hydatidiform moles as complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) are important for clinical practice and investigational studies; however, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunohistochemistry and genotyping. Cases were classified by 6 pathologists (3 faculty level gynecologic pathologists and 3 fellows) on the basis of morphology, masked to p57 immunostaining and genotyping results, into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists in each group) were also determined. Performance of experienced gynecologic pathologists versus fellow pathologists was compared, using genotyping results as the gold standard. Correct classification of CHMs ranged from 59% to 100%; there were no statistically significant differences in performance of faculty versus fellows in any round (P-values of 0.13, 0.67, and 0.54 for rounds 1 to 3, respectively). Correct classification of PHMs ranged from 26% to 93%, with statistically significantly better performance of faculty versus fellows in each round (P-values of 0.04, <0.01, and <0.01 for rounds 1 to 3, respectively). Correct classification of NMs ranged from 31% to 92%, with statistically significantly better performance of faculty only in round 2 (P-values of 1.0, <0.01, and 0.61 for rounds 1 to 3, respectively). Correct classification of all cases combined ranged from 51% to 75% by morphology and 70% to 80% with p57, with statistically significantly better performance of faculty only in round 2 (P-values of 0.69, <0.01, and 0.15 for rounds 1 to 3, respectively). p57 immunostaining significantly improved recognition of CHMs (P<0.01) and had high reproducibility (κ=0.93 to 0.96) but had no impact on distinction of PHMs and NMs. Genotyping provides a definitive diagnosis for the ∼25% to 50% of cases that are misclassified by morphology, especially those that are also unresolved by p57 immunostaining.

Diagnostic reproducibility of hydatidiform moles: ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis.

Distinction of hydatidiform moles (HMs) from nonmolar specimens (NMs) and subclassification of HMs as complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs) are important for clinical practice and investigational studies; yet, diagnosis based solely on morphology is affected by interobserver variability. Molecular genotyping can distinguish these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to diagnose CHMs, PHMs, and NMs, respectively. Eighty genotyped cases (27 CHMs, 27 PHMs, and 26 NMs) were selected from a series of 200 potentially molar specimens previously diagnosed using p57 immunostaining and genotyping. Cases were classified by 3 gynecologic pathologists on the basis of H&E slides (masked to p57 immunostaining and genotyping results) into 1 of 3 categories (CHM, PHM, or NM) during 2 diagnostic rounds; a third round incorporating p57 immunostaining results was also conducted. Consensus diagnoses (those rendered by 2 of 3 pathologists) were determined. Genotyping results were used as the gold standard for assessing diagnostic performance. Sensitivity of a diagnosis of CHM ranged from 59% to 100% for individual pathologists and from 70% to 81% by consensus; specificity ranged from 91% to 96% for individuals and from 94% to 98% by consensus. Sensitivity of a diagnosis of PHM ranged from 56% to 93% for individual pathologists and from 70% to 78% by consensus; specificity ranged from 58% to 92% for individuals and from 74% to 85% by consensus. The percentage of correct classification of all cases by morphology ranged from 55% to 75% for individual pathologists and from 70% to 75% by consensus. The κ values for interobserver agreement ranged from 0.59 to 0.73 (moderate to good) for a diagnosis of CHM, from 0.15 to 0.43 (poor to moderate) for PHM, and from 0.13 to 0.42 (poor to moderate) for NM. The κ values for intraobserver agreement ranged from 0.44 to 0.67 (moderate to good). Addition of the p57 immunostain improved sensitivity of a diagnosis of CHM to a range of 93% to 96% for individual pathologists and 96% by consensus; specificity was improved from a range of 96% to 98% for individual pathologists and 96% by consensus; there was no substantial impact on diagnosis of PHMs and NMs. Interobserver agreement for interpretation of the p57 immunostain was 0.96 (almost perfect). Even with morphologic assessment by gynecologic pathologists and p57 immunohistochemistry, 20% to 30% of cases will be misclassified, and, in particular, distinction of PHMs and NMs will remain problematic.

Diandric triploid hydatidiform mole with loss of maternal chromosome 11.

Distinction of hydatidiform moles (HM) from nonmolar specimens and their subclassification as complete (CHM) versus partial hydatidiform mole (PHM) are important for clinical practice and investigational studies to refine ascertainment of risk of persistent gestational trophoblastic disease (GTD), which differs among these entities. Immunohistochemical analysis of p57 expression, a paternally imprinted maternally expressed gene on 11p15.5, and molecular genotyping are useful for improving diagnosis. CHMs are characterized by androgenetic diploidy, with loss of p57 expression due to lack of maternal DNA. Loss of p57 expression distinguishes CHMs from both PHMs (diandric triploidy) and nonmolar specimens (biparental diploidy), which retain expression. We report a unique HM characterized by morphologic features suggesting an early CHM, including lack of p57 expression by immunohistochemistry, but with genetic features more in keeping with a PHM. Specifically, molecular genotyping by short tandem repeat markers provided evidence to support interpretation as a PHM by demonstrating allele patterns and ratios most consistent with diandric triploidy, with evidence of loss of the maternal copy of chromosome 11 to explain the lack of p57 expression. This case illustrates the value of combined traditional pathologic and ancillary molecular techniques for refined diagnosis of molar specimens. It also raises questions regarding which modalities should be used to ultimately define the subtypes of HMs and whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying risk of persistent GTD.

Incidence of postmolar gestational trophoblastic disease in androgenetic moles and the morphological features associated with low risk postmolar gestational trophoblastic disease.

In the present study, we evaluated the incidence of postmolar gestational trophoblastic disease (GTD) in molar pregnancy. We also validated the macroscopic diagnosis based on the Japan Society of Obstetrics and Gynecology (JSOG) classification. A total of 297 samples of hydropic villi were classified according to DNA polymorphisms as androgenetic moles, dispermic triploids, or biparental diploids (hydropic abortion), clinically corresponding to complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), and hydropic abortion, respectively. These samples were also classified morphologically based on the JSOG classification. A follow-up study was performed to investigate the incidence of postmolar GTD. A subset of 267 samples eligible for testing were analyzed and diagnosed as androgenetic moles (232 cases), dispermic triploids (20 cases), and biparental diploids (15 cases). Most of the macroscopically diagnosed CHM cases were genetically androgenetic in origin. The PHM cases consisted of 30 androgenetic moles and 12 dispermic triploids. We reviewed the outcomes of 200 patients (178 cases of androgenetic mole, 13 cases of dispermic triploids, and nine cases of biparental diploids). Twenty-eight cases (16%) of androgenetic moles developed postmolar GTD. None of the patients with dispermic triploids developed postmolar GTD. Among the 28 patients who developed postmolar GTD, the shortest diameter of the largest hydropic villi was significantly longer than that of patients not developing postmolar GTD. None of the patients with androgenetic moles who had hydropic villi <2 mm in their shortest diameter developed postmolar GTD. For the patients with dispermic triploids, the risk of postmolar GTD is extremely low. The risk of postmolar GTD is also low in patients with androgenetic moles with small hydropic villi. The JSOG classification based on the morphology of hydropic villi is reliable for the diagnosis of CHM, but inaccurate for the diagnosis of PHM or "microscopic" moles.

The risk of post-molar gestational trophoblastic neoplasia is higher in heterozygous than in homozygous complete hydatidiform moles.

BACKGROUND: Complete hydatidiform mole (CHM) is a high-risk pregnancy for gestational trophoblastic neoplasia (GTN). Patients with CHM have a 10-30% chance of trophoblastic sequelae. CHM includes androgenic homozygous (monospermic) and androgenic heterozygous (dispermic) moles. It is controversial whether the risk of GTN is higher with heterozygous than with homozygous CHM. A prospective cohort study was conducted to assess risk of GTN in homozygous and heterozygous CHM using short tandem repeat (STR) polymorphisms, and a meta-analysis of previous reports. METHODS: Twenty-eight consecutive molar pregnancies were evacuated and followed by regular hCG measurements to detect GTN. Persistent GTN was diagnosed according to the International Federation of Gynecology and Obstetrics 2000 system. Cytogenesis of the mole was determined by STR polymorphisms of molar tissue and parental blood. A meta-analysis of the GTN rate from previous reports was conducted using Mantel-Haenszel methods. RESULTS: Of 28 molar pregnancies, 24 were homozygous and three were heterozygous CHM. The remaining mole was diandric triploidy (a partial hydatidiform mole). Of the 24 homozygous CHMs, six (25%) cases developed GTN and received chemotherapy. Meanwhile, all three cases (100%) of heterozygous mole developed GTN and needed chemotherapy. The GTN risk was higher in heterozygous (P = 0.029, Fisher's exact test) than homozygous moles. A systematic review revealed only five previous reports (with more than 15 cytogenetically diagnosed cases), and the pooled relative risk of persistent GTN for heterozygous mole was not significant (odds ratio, 2.0; 95% confidence interval, 0.98-4.07). CONCLUSIONS: Heterozygous CHM had a higher risk for GTN than homozygous CHM.

Precise DNA genotyping diagnosis of hydatidiform mole.

OBJECTIVE: To estimate whether tissue DNA genotyping is effective for the confirmation and subclassification of hydatidiform moles. METHODS: Consecutive cases of products of conception were selected based on histologic alterations that are suspicious for molar pregnancy. DNA genotyping was performed by a multiplex polymerase chain reaction targeting 15 tetrameric polymorphic loci of the human genome. RESULTS: A total of 205 products of conception were included. DNA genotyping was informative in all, leading to the final identification of 60 cases of hydatidiform moles, including 17 complete and 43 partial moles. Among 17 cases of complete moles, 14 cases were monospermic and three were dispermic. Forty-three cases were confirmed as triploid partial moles, 42 of which were dispermic and one was monospermic. Among nonmolar cases, 32 gestations showed allelic changes indicating chromosomal alterations, including 28 cases of trisomy syndrome: trisomy 16 (eight cases), trisomy 21 (six cases), trisomy 7 (three cases), trisomy 13 (three cases), trisomy 4 (one case), trisomy 8 (one case), trisomy 18 (one case), XXY/Klinefelter syndrome (one case), and multiple trisomies (four cases). Monosomy 22 was seen in one case. Two nonmolar cases were triploid digynic-monoandric gestations. More complex chromosomal abnormalities were seen in one case. The remaining 113 cases were balanced biallelic gestations. CONCLUSION: Tissue DNA genotyping is a practical and highly accurate method for the confirmation and subclassification of hydatidiform moles. LEVEL OF EVIDENCE: III.

[New diagnostic approach to different hydatidiform mole types, hydropic abortions and relevant clinical management]. / Nové diagnosticki prístupy k ruzným typum hydatidózních mol, hydropickým abortum a príslusné klinické postupy.

OBJECTIVE: To describe new diagnostic approach to complete hydatidiform mole, immature complete hydatidiform mole, partial hydatidiform mole, proliferative mole and hydropic abortion. TYPE OF STUDY: Original research. SETTING: Trophoblastic Disease Center in the Czech Republic (TDC-CZ), Institute for the Care of Mother and Child, Prague. METHODS: Our study consists of 1321 partial hydatidiform moles, 805 complete hydatidiform moles, 524 proliferative moles, and over 2500 hydropic abortuses diagnosed and treated at theTDC-CZ, besides which 2896 of these lesions were examined at the TDC-CZ by referral. The material was examined by routine histopathological methods, which in selected cases was supplemented by immunohistological examination and correlated with cytogenetic and molecular genetic results and clinical features. RESULTS: The study describes the diagnostic procedures enabling the differential diagnosis between mature complete hydatidiform mole, immature complete hydatidiform mole, partial hydatidiform mole, proliferative mole and hydropic abortion. Fourteen histological parameters have been defined which are most common, individually or in combination, in various types of hydatidiform moles and hydropic abortions. Warning is given to errors in histological diagnosis correlated with cytogenetic and molecular genetic results. Proposed reliable method of eliminating the influence of these errors on the possible development of trophoblastic disease. CONCLUSION: The study describes differential diagnosis of complete hydatidiform mole, immature complete hydatidiform mole, partial hydatidiform mole, proliferative mole, hydropic abortion and relevant clinical management.

[Histopathology of gestational trophoblastic disease. An update]. / Gestationsbedingte Trophoblasterkrankungen. Aktuelle Aspekte.

The differential diagnosis of villous forms of gestational trophoblastic disease (GTD) includes hydropic abortion, complete and partial hytatidiform mole and placental mesenchymal dysplasia. In addition to histologic criteria, p57(KIP2) immunohistochemistry might be helpful. Choriocarcinoma represents the most immature form of GTD. This and downregulation of HSP-27 might contribute to the high chemosensitivity, compared to placental site (PSTT) and epitheloid trophoblastic tumor (ETT). Within the differential diagnosis of the non-villous forms of GTD an algorithmic approach of immunohistochemistry is very helpful. With an incidence of 1.6% of all abortions within the first trimester the exaggerated placental site reaction (EPS) is rare. There is no molecular indication that the EPS represents a precursor lesion of PSTT. The morphologic prediction of the behaviour of PSTT is not well established. Factors which might be associated with adverse outcome are age >35 years, interval since last pregnancy >2 years, growth outside the uterus, deep myometrial invasion, destructive growth, extensive coagulative necrosis, presence of cells with clear cytoplasm, high mitotic rate and a Ki-67 labeling index >50%. Recent molecular data suggest a neoplastic transformation of (cyto-) trophoblastic stem cells, within the pathogenesis of (non-villous) GTD. The detection of target molecules for a targeted therapy is currently irrelevant.

Diagnosis and subclassification of hydatidiform moles using p57 immunohistochemistry and molecular genotyping: validation and prospective analysis in routine and consultation practice settings with development of an algorithmic approach.

Distinction of hydatidiform moles (HM) from nonmolar specimens and subclassification of HMs as complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), or early CHM (eCHM) are important for clinical practice and investigational studies but diagnosis based solely on morphology suffers from poor interobserver reproducibility. Recent studies have demonstrated the use of p57 immunostaining and molecular genotyping for improving diagnosis of HMs. After performing a validation study of both techniques on 24 archival products of conception specimens (7 CHMs, 8 PHMs, 9 nonmolar), we prospectively analyzed 42 cases, largely obtained from a gynecologic pathology consultation practice, for which there was any consideration of a diagnosis of HM. After satisfactory experience with prospective cases, a modified approach was adopted, with p57 immunostaining used in conjunction with morphology to triage cases for molecular genotyping. Final diagnoses for the prospective cases based on combined morphology and ancillary testing were 24 CHMs (including 7 eCHMs), 7 PHMs, and 11 nonmolar specimens. P57 immunostaining, performed on all 66 cases, was negative in all CHMs, with the exception of 1 case of molecularly confirmed CHM with diffuse p57 expression, and positive in all PHMs and nonmolar specimens, with the exception of 3 cases of molecularly confirmed PHMs with an equivocal extent of p57 expression. Molecular genotyping of 51 cases (24 validation, 27 prospective) yielded data consistent with p57 results in the 47 cases with unequivocal p57 expression patterns and was used to establish the diagnoses for the 4 cases with aberrant or equivocal p57 results. All 17 genotyped CHMs demonstrated androgenetic diploidy, including the CHM with retained p57 expression; this case also demonstrated trisomy of chromosome 11 (retained maternal allele), accounting for the aberrant p57 expression. The remaining 14 CHMs were diagnosed by morphology and negative p57 results alone. All 15 PHMs demonstrated diandric triploidy. All genotyped nonmolar specimens demonstrated biparental diploidy. This study validates p57 immunostaining as a prospectively applicable triage assay for the diagnosis of CHMs based on morphology and a negative p57 result. Molecular genotyping is validated as a method to confirm a diagnosis of CHM by demonstrating androgenetic diploidy and to resolve p57-positive cases into diandric triploid PHMs, biparental diploid nonmolar specimens, and the rare CHM with aberrant p57 expression.

Dynamic staging and risk factor scoring for gestational trophoblastic disease.

It is proposed that a dynamic staging and risk factor scoring system is introduced for the classification of gestational trophoblastic disease as a logical development of the system presently used by the FIGO. Modern computer technology permits such change as the disease changes and particularly if it progresses. By allowing a change of both stage and risk factor score for each patient reported, a dynamic scoring system results. Moreover, such a system allows the introduction of more clinical detail than is permitted by the present FIGO system. FIGO combining its anatomic staging, first devised by Professor Song of Beijing, with the World Health Organization risk factor scoring, first devised by Professor Kenneth Bagshawe of Charing Cross Hospital, London, in 2002 was a significant progress. The most important change of the FIGO 2002 modification was that criteria were defined for the diagnosis of postmolar gestational trophoblastic neoplasia. However, hydatidiform mole still has no place in that classification. Also, the time when the staging occurs is not mandated. The present FIGO classification allows for no change in the status of the patient. A dynamic staging and risk factor scoring system would allow such changes to be recorded and, therefore, permit a more precise account of the patient's disease. A third issue is whether invasive mole should be included in the classification, as the Japanese Gynecologic Cancer Society insists is necessary. This problem may also be solved by the use of a dynamic risk factor scoring system.

Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring.

Highly recurrent hydatidiform moles (HMs) studied to date are not androgenetic but have biparental genomic contribution (BiHM). Affected women have an autosomal recessive mutation that causes their pregnancies to develop into HM. Although there is genetic heterogeneity, a major locus maps to chromosome 19q13.42, but a mutated gene has not yet been identified. Molecular studies have shown that maternal imprinting marks are deregulated in the BiHM trophoblast. The mutations that cause this condition are, therefore, hypothesized to occur in genes that encode transacting factors required for the establishment of imprinting marks in the maternal germline or for their maintenance in the embryo. Although only DNA methylation marks at imprinted loci have been studied in the BiHM, the mutation may affect genes that are essential for other forms of chromatin remodelling at imprinted loci and necessary for correct maternal allele-specific DNA methylation and imprinted gene expression. Normal pregnancies interspersed with BiHM have been reported in some of the pedigrees, but affected women repeatedly attempting pregnancy should be counselled about the risk for invasive trophoblastic disease with each subsequent BiHM.