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Complete hydatidiform moles (CHM) are purely androgenetic conceptions, with most (∼85%) arising from fertilization of an egg lacking maternal DNA by a single sperm that duplicates (homozygous/monospermic 46,XX) and a small subset arising via fertilization by 2 sperms (heterozygous/dispermic 46,XY or 46,XX). It remains controversial if heterozygous/dispermic CHMs have a significantly greater risk of persistent gestational trophoblastic disease. Analysis of zygosity of CHMs with and without invasion at presentation, including invasive CHMs with concurrent atypical trophoblastic proliferations concerning for or consistent with choriocarcinoma, has not been specifically addressed. In a prospective series of 1024 products of conception specimens subjected to immunohistochemical analysis of p57 expression and molecular genotyping with short tandem-repeat markers, 288 CHMs were diagnosed, of which 126 were genotyped, including 16 invasive CHMs. Zygosity was compared between those with and without invasion. Of the 16 study cases, 12 (75%) were homozygous/monospermic XX and 4 (25%) were heterozygous/dispermic (3 XY and 1 XX). Of the 110 genotyped noninvasive CHMs, 96 (87%) were homozygous/monospermic XX and 14 (13%) were heterozygous/dispermic (12 XY, 2 XX). Comparison of the zygosity results for the invasive CHMs (study group) with the noninvasive CHMs in the database did not demonstrate a statistically significant difference (P=0.24, Fisher exact test). In addition, of the 3 cases associated with metastatic gestational trophoblastic disease (pulmonary nodules) at presentation, 2 were homozygous/monospermic XX, indicating that this form is not without risk of significant gestational trophoblastic disease. Thus, the current study has demonstrated a higher frequency of heterozygous/dispermic CHMs among invasive cases compared with those lacking invasion, but does not support the use of zygosity data for risk assessment of CHMs. A persistent, unresolved diagnostic challenge identified in some invasive CHMs is interpretation of accompanying florid atypical trophoblastic proliferations which raise concern for choriocarcinoma. Future studies should address the need for reproducible diagnostic criteria and molecular biomarkers for distinguishing florid hyperplastic from malignant neoplastic trophoblastic proliferations.

Immunohistochemical analysis of cyclin-dependent kinase inhibitor 1C (CDKN1C, p57, Kip2) expression and molecular genotyping accurately classify hydatidiform moles into complete and partial types and distinguish these from non-molar specimens. Characteristics of a prospective series of all potentially molar specimens encountered in a large gynecologic pathology practice are summarized. Initially, all specimens were subjected to both analyses; this was later modified to triage cases for genotyping based on p57 results: p57-negative cases diagnosed as complete hydatidiform moles without genotyping; all p57-positive cases genotyped. Of the 678 cases, 645 were definitively classified as complete hydatidiform mole (201), partial hydatidiform mole (158), non-molar (272), and androgenetic/biparental mosaic (14); 33 were unsatisfactory, complex, or problematic. Of the 201 complete hydatidiform moles, 104 were p57-negative androgenetic and an additional 95 were p57-negative (no genotyping), 1 was p57-positive (retained maternal chromosome 11) androgenetic, and 1 was p57-non-reactive androgenetic; 90 (85%) of the 106 genotyped complete hydatidiform moles were monospermic and 16 were dispermic. Of the 158 partial hydatidiform moles, 155 were diandric triploid, with 154 p57-positive, 1 p57-negative (loss of maternal chromosome 11), and 1 p57-non-reactive; 3 were triandric tetraploid, with 2 p57-positive and 1 p57-negative (loss of maternal chromosome 11). Of 155 diandric triploid partial hydatidiform moles, 153 (99%) were dispermic and 2 were monospermic. Of the 272 non-molar specimens, 259 were p57-positive biparental diploid, 5 were p57-positive digynic triploid, 2 were p57-negative biparental diploid (no morphological features of biparental hydatidiform mole), and 6 were p57-non-reactive biparental diploid. Of the 14 androgenetic/biparental mosaics with discordant p57 expression, 6 were uniformly mosaic and 8 had a p57-negative androgenetic molar component. p57 expression is highly correlated with genotyping, serves as a reliable marker for diagnosis of complete hydatidiform moles, and identifies androgenetic cell lines in mosaic conceptions. Cases with aberrant and discordant p57 expression can be correctly classified by genotyping.

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.

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.

Distinction of hydatidiform moles from nonmolar specimens and their subclassification as complete (complete hydatidiform mole) versus partial hydatidiform mole (PHM) are important for clinical practice and investigational studies to refine ascertainment of risk of persistent gestational trophoblastic disease, 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. Here, we describe a first trimester abortus with morphologic features consistent with a hydatidiform mole and p57 expression pattern supporting a diagnosis of PHM. Short tandem repeat (STR) genotyping and fluorescent in-situ hybridization analysis showed tetraploidy with 3 paternal and 1 maternal chromosome complements. To our knowledge, this is the first description of a tetraploid PHM confirmed to be triandric by STR analysis, and the first description of p57 immunostaining in a confirmed triandric tetraploid PHM. This case highlights the complex nature of the genetics that can be encountered in molar specimens and illustrates that STR genotyping, in contrast to fluorescent in-situ hybridization or ploidy analysis, offers the advantage of determining the parental origin of chromosome complements for refined diagnosis of hydatidiform moles.

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.

Distinction of hydatidiform moles from nonmolar specimens and subclassification of hydatidiform moles as complete hydatidiform mole (CHM), partial hydatidiform mole (PHM), or early CHM are important for both clinical practice and investigational studies. The risk of persistent gestational trophoblastic disease and hence, clinical management, differs for CHMs, PHMs, and nonmolar specimens. However, diagnosis based solely on morphology suffers from poor interobserver reproducibility and remains problematic even for experienced gynecologic pathologists. The unique genetic features of CHMs (androgenetic diploidy), PHMs (diandric triploidy), and nonmolar specimens (biparental diploidy) allow for certain molecular techniques, including immunohistochemical analysis of p57 expression (a paternally imprinted maternally expressed gene) and molecular genotyping, to refine the diagnosis of hydatidiform moles. Although p57 immunostaining alone can identify CHMs, which lack p57 expression because of the lack of maternal DNA, this analysis cannot distinguish PHMs from nonmolar specimens as both express p57 because of the presence of maternal DNA. Short tandem repeat genotyping, which can determine the parental source of polymorphic alleles, can distinguish among all of these entities by discerning androgenetic diploidy, diandric triploidy, and biparental diploidy to rigorously diagnose CHMs, PHMs, and nonmolar specimens, respectively. An algorithmic approach using these techniques to refine morphologic diagnosis has been developed for routine practice. This review discusses current issues in the diagnosis of hydatidiform moles, including the limitations of morphologic diagnosis, the need for refined diagnosis to assure accurate ascertainment of risk of persistent gestational trophoblastic disease associated with the different subtypes of hydatidiform moles, the use of ancillary immunohistochemical and molecular techniques for providing such refined diagnosis, and problems that can be encountered with these techniques.