Diagnosis of Hydatidiform Moles by Polymorphic Deletion Probe Fluorescence in Situ Hybridization
2011; Elsevier BV; Volume: 13; Issue: 4 Linguagem: Inglês
10.1016/j.jmoldx.2011.02.002
ISSN1943-7811
AutoresSarah Chiang, Ladan Fazlollahi, Anh Nguyen, Rebecca A. Betensky, Drucilla J. Roberts, A. John Iafrate,
Tópico(s)Genetic Syndromes and Imprinting
ResumoBecause products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception. Because products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception. Hydatidiform moles (HMs) are a type of gestational trophoblastic disease that results from abnormal fertilization and subsequent trophoblastic proliferation. In the United States, the incidence of HMs is approximately 0.1%, ranging from 108 to 121 per 100,000 pregnancies.1Hayashi K. Bracken M.B. Freeman Jr, D.H. Hellenbrand K. Hydatidiform mole in the United States (1970–1977): a statistical and theoretical analysis.Am J Epidemiol. 1982; 115: 67-77Crossref PubMed Scopus (72) Google Scholar, 2Matsuura J. Chiu D. Jacobs P.A. Szulman A.E. Complete hydatidiform mole in Hawaii: an epidemiological study.Genet Epidemiol. 1984; 1: 271-284Crossref PubMed Scopus (35) Google Scholar, 3Smith H.O. Hilgers R.D. Bedrick E.J. Qualls C.R. Wiggins C.L. Rayburn W.F. Waxman A.G. Stephens N.D. Cole L.W. Swanson M. Key C.R. Ethnic differences at risk for gestational trophoblastic disease in New Mexico: a 25-year population-based study.Am J Obstet Gynecol. 2003; 188: 357-366Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar By clinicopathologic features and karyotype analysis, HMs can be subclassified into two distinct groups: complete HMs (CHMs) and partial HMs (PHMs). The distinction between CHMs and PHMs is clinically important because of the risks of recurrence, persistent gestational trophoblastic disease, and malignant transformation. Patients with a history of any single molar pregnancy have a 1% risk of recurrence with a subsequent pregnancy; those with a history of two molar pregnancies have a 10% to 28% risk.4Garrett L.A. Garner E.I. Feltmate C.M. Goldstein D.P. Berkowitz R.S. Subsequent pregnancy outcomes in patients with molar pregnancy and persistent gestational trophoblastic neoplasia.J Reprod Med. 2008; 53: 481-486PubMed Google Scholar, 5Bagshawe K.D. Dent J. Webb J. Hydatidiform mole in England and Wales 1973–83.Lancet. 1986; 2: 673-677Abstract PubMed Scopus (264) Google Scholar, 6Sebire N.J. Fisher R.A. Foskett M. Rees H. Seckl M.J. Newlands E.S. Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy.Br J Obstet Gynecol. 2003; 110: 22-26Crossref Scopus (170) Google Scholar, 7Berkowitz R.S. Im S.S. Bernstein M.R. Goldstein D.P. Gestational trophoblastic disease: subsequent pregnancy outcome, including repeat molar pregnancy.J Reprod Med. 1998; 43: 81-86PubMed Google Scholar, 8Sand P.K. Lurain J.R. Brewer J.I. Repeat gestational trophoblastic disease.Obstet Gynecol. 1984; 63: 140-144PubMed Google Scholar The incidence of persistent gestational trophoblastic disease after a CHM is reportedly 18% to 29%,9Berkowitz R.S. Goldstein D.P. Chorionic tumors.N Engl J Med. 1996; 335: 1740-1748Crossref PubMed Scopus (263) Google Scholar, 10Curry S.L. Hammond C.B. Tyrey L. Creasman W.T. Parker R.T. Hydatidiform mole: diagnosis, management, and long-term followup of 347 patients.Obstet Gynecol. 1975; 45: 1-8PubMed Google Scholar, 11Lurain J.R. Brewer J.I. Torok E.E. Halpern B. Natural history of hydatidiform mole after primary evacuation.Am J Obstet Gynecol. 1983; 145: 591-595PubMed Scopus (140) Google Scholar, 12Morrow C.P. Kletzky O.A. Disaia P.J. Townsend D.E. Mishell D.R. Nakamura R.M. Clinical and laboratory correlates of molar pregnancy and trophoblastic disease.Am J Obstet Gynecol. 1977; 128: 424-430Abstract Full Text PDF PubMed Scopus (119) Google Scholar and the risk after a PHM is 0% to 11%.13Feltmate C.M. Growdon W.B. Wolfberg A.J. Goldstein D.P. Genest D.R. Chinchilla M.E. Lieberman E.S. Berkowitz R.S. Clinical characteristics of persistent gestational trophoblastic neoplasia after partial hydatidiform molar pregnancy.J Reprod Med. 2006; 51: 902-906PubMed Google Scholar, 14Hancock B.W. Nazir K. Everard J.E. Persistent gestational trophoblastic neoplasia after partial hydatidiform mole incidence and outcome.J Reprod Med. 2006; 51: 764-766PubMed Google Scholar The incidence of choriocarcinoma in the United States is 0.18 per 100,000 pregnancies.15Altieri A. Franceschi S. Ferlay J. Smith J. La Vecchia C. Epidemiology and aetiology of gestational trophoblastic diseases.Lancet Oncol. 2003; 4: 670-678Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar Approximately 50% of all choriocarcinomas arise from CHMs, with rare cases of choriocarcinoma arising after a diagnosis of PHM.16Seckl M.J. Fisher R.A. Salerno G. Rees H. Paradinas F.J. Foskett M. Newlands E.S. Choriocarcinoma and partial hydatidiform moles.Lancet. 2000; 356: 36-39Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar HMs can be subcategorized into CHMs and PHMs by their unique genetic features. Most CHMs arise from monospermic fertilization of an anucleate ovum, followed by endoreduplication; these cases have a 46,XX karyotype. Less than 10% of CHMs result from dispermic fertilization and can have either a 46,XX or a 46,XY karyotype. In either event, both types of CHM are entirely paternally derived and lack a maternal chromosomal component. However, there are rare familial cases of CHMs that are biparental in origin and contain both maternal and paternal chromosomal components. PHMs arise from either dispermic fertilization of a haploid ovum or monospermic fertilization of a haploid ovum, followed by endoreduplication, and can have the following karyotypes: 69,XXX; 69,XXY; and 69,XYY. Thus, PHMs are, by definition, triploid diandric monogynic molar pregnancies and must be distinguished from triploid monoandric digynic products of conception (POCs), which are nonmolar and, thus, have a different prognosis.17Sebire N.J. Fisher R.A. Rees H.C. Histopathological diagnosis of partial and complete hydatidiform mole in the first trimester of pregnancy.Pediatr Dev Pathol. 2003; 6: 69-77Crossref PubMed Scopus (98) Google Scholar The histopathological features of CHMs and PHMs are well described; in many cases, the diagnosis can be made by morphological assessment alone if the classic features are present. However, because of the earlier clinical detection and surgical evacuation of abnormal pregnancies, the histopathological features that are often used to distinguish CHMs, PHMs, and nonmolar abortions (NMAs) are more subtle and less readily identifiable, leading to increasing difficulties in the proper subclassification of HMs.17Sebire N.J. Fisher R.A. Rees H.C. Histopathological diagnosis of partial and complete hydatidiform mole in the first trimester of pregnancy.Pediatr Dev Pathol. 2003; 6: 69-77Crossref PubMed Scopus (98) Google Scholar Previous studies18Fukunaga M. Katabuchi H. Nagasaka T. Mikami Y. Minamiguchi S. Lage J.M. Interobserver and intraobserver variability in the diagnosis of hydatidiform mole.Am J Surg Pathol. 2005; 29: 942-947Crossref PubMed Scopus (117) Google Scholar, 19Howat A.J. Beck S. Fox H. Harris S.C. Hill A.S. Nicholson C.M. Williams R.A. Can histopathologists reliably diagnose molar pregnancy?.J Clin Pathol. 1993; 46: 599-602Crossref PubMed Scopus (103) Google Scholar, 20Conran R.M. Hitchcock C.L. Popek E.J. Norris H.J. Griffin J.L. Geissel A. McCarthy W.F. Diagnostic considerations in molar gestations.Hum Pathol. 1993; 24: 41-48Abstract Full Text PDF PubMed Scopus (77) Google Scholar have shown that there is significant interobserver variability in the diagnosis of HMs among pathologists. Because POCs contain both maternal and villous tissue, the genotypes of mother and zygote based on genetic polymorphisms can be used to discern maternal and paternal chromosomal contribution and, thus, aid in the diagnosis of HMs. Polymorphic deletion probes (PDPs) are a recently developed type of fluorescence in situ hybridization (FISH) probe that target deletion variants that are highly polymorphic and allow in situ determination of genetic identity.21Wu D. Vu Q. Nguyen A. Stone J.R. Stubbs H. Kuhlmann G. Sholl L.M. Iafrate A.J. In situ genetic analysis of cellular chimerism.Nat Med. 2009; 15: 215-219Crossref PubMed Scopus (13) Google Scholar Because PDPs target biallelic polymorphisms, any given individual may have a homozygous FISH genotype (+/+ if both chromosomal loci do not possess the deletion polymorphism or −/− if both loci are deleted) or a heterozygous FISH genotype (+/− if one of two loci does not possess the deletion). PDPs can genetically distinguish between mother and zygote in situ and can show an absence of maternal DNA when mutually exclusive genotype pairings are observed: +/+ FISH genotype in decidua and −/− in villi or −/− in decidua and +/+ in villi. Thus, we used a panel of PDPs that target three autosomal deletion loci, one each on chromosomes 2p, 4q, and 8p, to determine the genetic identities of maternal and villous tissue in molar and nonmolar POCs in situ. The genotypes of mother and zygote, based on polymorphic deletions, were compared; and ploidy of villous stromal cells was determined to investigate the utility of PDP FISH in the diagnosis of HMs. Forty archival cases of POCs, including 13 CHMs, 13 PHMs, 13 NMAs, and an equivocal case of hydropic abortion (HA), diagnosed between January 1, 2004, and December 31, 2009, were retrieved from the obstetric pathology service files of Massachusetts General Hospital, Boston, by searching the pathology electronic database. Clinicopathologic features, including patient age, obstetric history, and clinical impression, were obtained from medical record review. Cytogenetic analysis reports were available for review in two CHMs, six PHMs, four NMAs, and the equivocal HA. Flow cytometry reports were available for review in seven CHMs, eight PHMs, and the equivocal HA. Approval from the Partners Human Research Committee Institutional Review Board was obtained before the initiation of this study. All available H&E-stained slides were reviewed by two pathologists (S.C. and D.J.R.), and the diagnoses were confirmed by consensus. The morphological criteria for the diagnosis of a CHM include a compilation of several of the following features: uniform population of large, round, hydropic villi with budding architecture; prominent cistern formation; moderate to marked, circumferential, trophoblastic proliferation of at least two lineages; stromal karyorrhectic debris; and lack of fetal red blood cells or fetal tissue. A definitive diagnosis of CHM was made in cases that fulfill the previously mentioned morphological criteria and lack p57 expression by immunohistochemistry (IHC). The diagnosis of a PHM was based on a compilation of several of the following features: a mixed population of normal and moderately hydropic scalloped villi, trophoblastic pseudoinclusions, mild and focal syncytiotrophoblastic proliferation, and the presence of embryonic tissue.17Sebire N.J. Fisher R.A. Rees H.C. Histopathological diagnosis of partial and complete hydatidiform mole in the first trimester of pregnancy.Pediatr Dev Pathol. 2003; 6: 69-77Crossref PubMed Scopus (98) Google Scholar A definitive diagnosis of PHM was made in cases that fulfill the morphological criteria for PHM and have confirmation of triploidy by either karyotype or flow cytometry. IHC studies for p57 (p57KIP2 Ab-3 clone KP39 mouse monoclonal antibody; Lab Vision Corporation, Fremont, CA) were performed on all 13 cases of CHM using the avidin-biotin immunoperoxidase method. Heat-induced antigen retrieval was performed on deparaffinized 5-μm tissue sections at 95°C in 10 mmol/L citrate buffer (pH 6.0) for 30 minutes. Slides were counterstained with hematoxylin. The presence or absence of nuclear staining was evaluated in villous stromal cells, cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, and decidua. Nuclear staining in decidua served as an internal positive control. The p57 immunostain was interpreted as a "positive" result when staining was diffusely positive in all of these cell types. The p57 immunostain was interpreted as a "negative" result if there was complete or near complete (<10% of cells) absence of nuclear staining in villous stromal cells and cytotrophoblasts. Two-color FISH was performed as previously described.21Wu D. Vu Q. Nguyen A. Stone J.R. Stubbs H. Kuhlmann G. Sholl L.M. Iafrate A.J. In situ genetic analysis of cellular chimerism.Nat Med. 2009; 15: 215-219Crossref PubMed Scopus (13) Google Scholar Fosmid clones G248P87627D2 (chromosome 2p PDP) and G248P800808F11 (chromosome 4q PDP) and bacterial artificial chromosome clones RP11-97D17 (chromosome 8p PDP), RP11-460N15 (chromosome 2p control probe), RP11-58C6 (chromosome 4q control probe), and RP11-100B16 (chromosome 8p control probe) were obtained from BAC/PAC Resources (Children's Hospital Oakland Research Institute, Oakland, CA). Fosmid and bacterial artificial chromosome DNAs were isolated from bacteria with the Qiagen Plasmid Maxi Kit (Qiagen, Valencia, CA), amplified using the REPLI-G Kit (Qiagen), and labeled using a commercial Nick Translation Kit (Abbott Molecular, Abbott Park, IL) with Spectrum Orange-11-dUTP or Spectrum Green-11-dUTP. Briefly, 5-μm tissue sections from formalin-fixed, paraffin-embedded (FFPE) tissue blocks were mounted on charged slides. A serial H&E-stained section was used to identify well-preserved areas of maternal and villous tissue. After deparaffinization, the unstained sections were subjected to two 30-minute rounds of pepsin digestion at 37°C, followed by wash in 2× standard sodium citrate. Slides were air dried, and hybridization mix (3 μL/slide) containing the appropriate PDP (labeled orange) and a nonpolymorphic control probe (labeled green) was applied to the slides, followed by denaturation of the probe and target at 80°C for 5 minutes and overnight hybridization at 37°C. Two 5-minute posthybridization washes in 2× standard sodium citrate were performed at 37°C. Nuclei were counterstained with DAPI. Images were acquired with an Olympus BX61 fluorescent microscope equipped with a charge-coupled device camera and analyzed with Cytovision software (Genetix, San Jose, CA). The genotypes of mother and zygote, as detected by PDP FISH, were recorded and agreed on by two pathologists (S.C. and A.J.I.). Only maternal decidual or tubal stromal cells and villous stromal cells with at least two copies of the nonpolymorphic control probe were scored. For diploid cells, the following genotypes were possible: homozygous (+/+ and −/−) and heterozygous (+/−). For triploid cells, the following genotypes were possible: homozygous (+/+/+ and −/−/−) and heterozygous (+/+/− and +/−/−). 8p PDP control probe signal quantitation of 50 villous stromal cell nuclei (because of multinucleation within syncytiotrophoblasts, only villous stromal cells were scored) in each case of NMA, CHM, and PHM were used to generate a signal threshold that would allow for determination of triploidy. Combined 8p PDP FISH and immunofluorescence was performed on deparaffinized 5-μm tissue sections using a modified avidin-biotin immunofluorescence method. Pressure-cooker antigen retrieval was performed by heating tissue sections in Borg Decloaker solution (Biocare Medical, Concord, CA) for 3 minutes, followed by cooling sections to room temperature. Slides were washed and incubated in PBS buffer for 5 to 10 minutes. Slides were then incubated in avidin D for 20 minutes, biotin for 20 minutes, mouse anti-p57 (1:200 dilution in PBS) for 60 minutes, horse anti-mouse IgG (1:100 dilution in PBS) (Vector Labs, Burlingame, CA) for 30 minutes, and Cy5-streptavidin (1:100 dilution in PBS) (Invitrogen, Camarillo, CA) for 30 minutes between washes in PBS. Slides were dehydrated in ethanol and dried in a 65°C oven for 5 minutes. Two-color FISH using chromosome 8p PDP was performed as previously described. Posthybridization washes were performed in 0.4× standard sodium citrate/0.3% NP-40 at 72°C for 2 minutes, followed by 2× standard sodium citrate/0.1% NP-40 at room temperature for 1 minute. A definitive diagnosis of CHM can be made when the maternal and villous genotypes are mutually exclusive in at least one of the three PDP loci. In cases without mutually exclusive maternal and villous genotypes, the likelihood of the observed villous genotype and the maternal genotype was calculated under two possible cases: CHM and NMA. For the likelihood computation under the assumption of CHM, there were two subclasses to consider: dispermic fertilization and haploid fertilization. Based on a literature search, the frequency of dispermic fertilization was assumed to be 3% to 29%. A likelihood ratio was then computed to compare the likelihood of the observed data under the assumption of CHM relative to the likelihood of the observed data under the assumption of NMA. A large ratio indicates that the data are more supportive of CHM than NMA. This served to order the possible outcomes and thereby provide a rationale diagnostic algorithm specifically for the cases lacking mutually exclusive genotypes. Although the actual likelihood ratio is a function of the unknown frequency, the ordering of observed outcomes is independent of this unknown frequency. The sensitivity and specificity of the sequence of resulting diagnostic algorithms were then computed. Based on theoretical calculations, the appropriate nested sequence of diagnostic algorithms for CHM for consideration is as follows: 1Diagnose CHM when maternal and villous FISH genotypes are mutually exclusive. This has theoretical 100% specificity and 56% sensitivity (assuming that the rate of dispermic fertilization is 10%).2Diagnose CHM when maternal and villous genotypes are mutually exclusive or when the villous tissue is homozygous at all three probes, regardless of the maternal genotype. This has theoretical 87.5% specificity and 91.8% sensitivity. For the purpose of diagnosing PHMs, the frequencies of triploid cells were estimated using the 13 cases of PHM, the 13 cases of CHM, and the 13 NMAs and their 8p PDP and control results. The rates were estimated using those cells for which there were one, two, or three control probes. The estimates of triploidy were 0.8% among the NMAs, 1.2% to 3.4% among the CHMs, and 45.3% among the PHMs. Given these widely disparate estimates, it was assumed that the true rate for NMAs and CHMs is 35%. Based on this assumption, a cutoff for diagnosing PHM was derived, with high sensitivity and specificity (based on simple binomial probability calculations). Forty FFPE POC specimens with consensus final pathological diagnoses of NMA, PHM, CHM, and an equivocal HA were obtained from the pathology archives of Massachusetts General Hospital. The age of the patients ranged from 24 to 41 years (mean, 33.4 years) for those with NMAs, from 20 to 53 years (mean, 32.7 years) for those with CHMs, and from 29 to 39 years (mean, 33.5 years) for those with PHMs. The age of the patient with the equivocal HA was 21 years. There were no statistically significant differences between the ages of women with CHMs, PHMs, and NMAs. Of 40 patients, 35 (87.5%) had at least one prior pregnancy. Of 13 patients in each group, six (46.2%) with CHMs, five (38.5%) with PHMs, and eight (61.5%) with NMAs had at least one prior abortion; however, none of these patients had a history of molar pregnancy. Molar pregnancy was clinically suspected in 10 (76.9%) of 13 CHMs, nine (69.2%) of 13 PHMs, and the equivocal HA. The remaining cases were considered missed abortions. Of the NMAs, eight cases (61.5%) were missed abortions, two cases (15.4%) were ectopic pregnancies, and three cases (23.1%) were therapeutic abortions. The clinicopathologic features for CHMs, NMAs, PHMs, and the equivocal HA are summarized in Table 1, Table 2, Table 3, and Table 4, respectively.Table 1Clinicopathologic Features, IHC, and Molecular Genetic Analysis of CHMsCase no.Age (years)Obstetric historyp57KaryotypeFCFISHFinal diagnosis2p4q8pDECVDECVDECV133G4P1021 with moleN46,XXND+/++/+−/−⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/+⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/−+/+CHM234G6P1041 with MABNNDD+/+⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.−/−⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/−+/++/−−/−CHM334G1P0000 with CHMNNDD−/−⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/+⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/−+/++/+⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.−/−⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.CHM434G2P1001 with CHMNNDD+/+⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.−/−⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/++/++/−+/+CHM526G1P0000 with CHMNNDND+/++/++/+⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.−/−⁎Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results.+/−+/+CHM653G4P3003 with moleNNDND+/++/++/−+/++/++/+CHM728G2P1001 with MABNNDD+/++/++/++/++/++/+CHM827G2P1001 with CHMN46,XXND+/−+/++/++/++/−+/+CHM940G2P0010 with CHMNNDD+/++/++/++/++/++/+CHM1020G2P0010 with CHMNNDD+/−+/++/−−/−+/−−/−CHM1122G2P0010 with MABNNDND+/++/++/++/++/++/+CHM1235G7P6000 with moleNNDD+/++/++/−+/++/++/+CHM1340G3P1011 with moleNNDND+/−+/++/−−/−−/−−/−CHMCHM, complete hydatidiform mole; CV, chorionic villi; D, diploid; DE, decidua; FC, flow cytometry; G, gravida; MAB, missed abortion; N, negative; ND, not done; P, para (term, preterm, abortion, living). Cases 1 to 5 represent CHM in which DE and CV show informative mutually exclusive FISH results. Open table in a new tab Table 2Clinicopathologic Features and Molecular Genetic Analysis of NMAsCase no.Age (years)Obstetric historyKaryotypeFISHFinal diagnosis2p4q8pDECVDECVDECV1431G2P1001 with MAB45,X+/++/+⁎Case 14 demonstrates homozygosity in villous stromal cells with all three probes.+/++/+⁎Case 14 demonstrates homozygosity in villous stromal cells with all three probes.+/++/+⁎Case 14 demonstrates homozygosity in villous stromal cells with all three probes.NMA1530G2P1001 with TABND+/++/++/++/+−/−+/−NMA1632G4P1021 with EPND+/−+/++/++/−+/++/−NMA1734G2P1001 with MABND+/++/++/−−/−+/−+/−NMA1829G2P0010 with EPND+/−+/−+/−−/−+/++/−NMA1935G4P0030 with MAB46,XY−/−−/−+/−+/−+/−+/+NMA2041G3P0020 with MAB47,XY,+13+/++/−+/++/++/++/−NMA2135G1P0000 with MABND+/++/++/++/−+/−−/−NMA2233G5P2022 with TABND−/−−/−+/++/++/−+/−NMA2324G7P2042 with TABND−/−−/−+/++/−−/−+/−NMA2438G2P0010 with MABND−/−−/−+/++/++/−+/−NMA2541G5P2022 with MABND+/−+/−+/−−/−+/−+/+NMA2631G2P1001 with MAB47,XY,+13,rob(13;13)(q10;q10)dn+/++/++/−+/++/−+/−NMACV, chorionic villi; DE, decidua; EP, ectopic pregnancy; G, gravida; MAB, missed abortion; ND, not done; NMA, nonmolar abortion; P, para (term, preterm, abortion, living); TAB, therapeutic abortion. Case 14 demonstrates homozygosity in villous stromal cells with all three probes. Open table in a new tab Table 3Clinicopathologic Features and Molecular Genetic Analysis of PHMsCase no.Age (years)Obstetric historyKaryotypeFCFISHFinal diagnosis2p4q8pDECVDECVDECV2731G5P1123 with PHM69,XXYND+/−+/+/−+/++/+/−−/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/+/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.PHM2834G1P0000 with moleNDT+/−−/−/−−/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/+/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/−+/−/−PHM2931G4P2013 with MABNDD/T+/−+/+/−+/+⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/−/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/−+/−/−PHM3029G2P1001 with moleNDT+/+⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/−/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/++/+/−+/−+/+/+PHM3137G2P1001 with PHM69,XXYND+/++/+/+−/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/+/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/−+/+/+PHM3239G2P1001 with PHM70,XXY,+8ND+/−+/+/−+/−+/+/−−/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.+/+/+/−⁎Cases 27 to 32 represent definitive diandric monogynic triploidy.PHM3331G3P0000 with MABNDT+/−+/+/++/−+/+/++/++/+/−PHM3434G2P1001 with MABNDT+/−+/−/−+/++/+/+−/−−/−/−PHM3534G6P3023 with MABNDT+/−+/+/++/++/+/++/++/+/−PHM3629G2P1000 with mole69,XXXT+/++/+/++/−+/+/+−/−−/−/−PHM3737G2P0010 with PHMNDT−/−−/−/−+/−+/−/−+/−+/−/−PHM3831G2P0101 with PHM69,XXXND+/−+/−/−+/−+/+/−+/−+/+/−PHM3939G6P2032 with PHM69,XXYND+/−+/+/−+/−+/+/−+/−+/−/−PHMCV, chorionic villi; D, diploid; DE, decidua; FC, flow cytometry; G, gravida; MAB, missed abortion; ND, not done; P, para (term, preterm, abortion, living); PHM, partial hydatidiform mole; T, triploid. Cases 27 to 32 represent definitive diandric monogynic triploidy. Open table in a new tab Table 4Clinicopathologic Features and Molecular Genetic Analysis of a Possible Twin Gestation with a CHM and a FetusCase no.Age (years)Obstetric historyKaryotypeFCFISHFinal diagnosis2p4q8pDECVFPDECVFPDECVFPVCVSVCVSVCVS4021G1P0000 with PHM6 XX, 1 XXXX, 3 XX missing autosomesD+/−+/++/++/++/−−/−−/−−/−+/−+/−+/++/−Singleton pregnancy with a mosaic androgenetic/biparental placentaCV, chorionic villi; D, diploid; DE, decidua; FC, flow cytometry; FP, fetal parts; G, gravida; P, para (term, preterm, abortion, living); PHM, partial hydatidiform mole; VC, villous cytotrophoblast; VS, villous stroma. Open table in a new tab CHM, complete hydatidiform mole; CV, chorionic villi; D, diploid; DE, decidua; FC, flow cytometry; G, gravida; MAB, missed abortion; N, negative; ND, not done; P, para (term, preterm, abortion, living). CV, chorionic villi; DE, decidua; EP, ectopic pregnancy; G, gravida; MAB, missed abortion; ND, not done; NMA, nonmolar abortion; P, para (term, preterm, abortion, living); TAB, therapeutic abortion. CV, chorionic villi; D, diploid; DE, decidua; FC, flow cytometry; G, gravida; MAB, missed abortion; ND, not done; P, para (term, preterm, abortion, living); PHM, partial hydatidiform mole; T, triploid. CV, chorionic villi; D, diploid; DE, decidua; FC, flow cytometry; FP, fetal parts; G, gravida; P, para (term, preterm, abortion, living); PHM, partial hydatidiform mole; VC, villous cytotrophoblast; VS, villous stroma. Karyotyping data were available for four NMAs, two CHMs, six PHMs, and the equivocal HA. Three NMAs showed the following abnormal ka
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