1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pathology: Mechanisms of Disease
  4. Volume 12, 2017
  5. Article

Annual Review of Pathology: Mechanisms of Disease

Volume 12, 2017

Hydatidiform Moles: Genetic Basis and Precision Diagnosis

Abstract

Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. Overrepresentation of the paternal genome in sporadic hydatidiform moles (purely androgenetic in complete hydatidiform moles and diandric triploid in partial hydatidiform moles) is a fundamental genetic event leading to global alteration of imprinting gene expression in the molar trophoblast. Rare familial biparental hydatidiform moles (due to or mutations) share such global imprinting alterations, implying a common end point of pathogenesis. Despite being the cornerstone of diagnosis, routine morphologic assessment of hydatidiform moles continues to suffer from interobserver diagnostic variability, emphasizing the need for new diagnostic modalities. Analyses of p57 expression by immunohistochemistry and polymerase chain reaction–based DNA genotyping have emerged as powerful diagnostic methods for accurate classification of hydatidiform moles. Algorithmic approaches combining histology and these ancillary techniques provide the best diagnostic practice currently available.

Keyword(s): genetic basis, genotyping, hydatidiform mole, p57, precision diagnosis
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-052016-100237
2017-01-24
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/pathol/12/1/annurev-pathol-052016-100237.html?itemId=/content/journals/10.1146/annurev-pathol-052016-100237&mimeType=html&fmt=ahah

Literature Cited

  1. Hui P, Baergen R, Cheung A, Fukunaga M, Gersell D, Lage JM. 1.  et al. 2014. Gestational trophoblastic disease. WHO Classification of Tumours of Female Reproductive Organs 6 RJ Kurman, ML Carcangiu, CS Herrington, RH Young 155–67 Geneva: World Health Organ. [Google Scholar]
  2. Genest DR. 2.  2001. Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. Int. J. Gynecol. Pathol. 20:315–22 [Google Scholar]
  3. Buza N, Hui P. 3.  2013. Partial hydatidiform mole: histologic parameters in correlation with DNA genotyping. Int. J. Gynecol. Pathol. 32:307–15 [Google Scholar]
  4. Fukunaga M, Katabuchi H, Nagasaka T, Mikami Y, Minamiguchi S, Lage JM. 4.  2005. Interobserver and intraobserver variability in the diagnosis of hydatidiform mole. Am. J. Surg. Pathol. 29:942–47 [Google Scholar]
  5. Bracken MB, Brinton LA, Hayashi K. 5.  1984. Epidemiology of hydatidiform mole and choriocarcinoma. Epidemiol. Rev. 6:52–75 [Google Scholar]
  6. Berkowitz RS, Goldstein DP. 6.  2009. Molar pregnancy. N. Engl. J. Med. 360:1639–45 [Google Scholar]
  7. Wei PY, Ouyang PC. 7.  1963. Trophoblastic diseases in Taiwan. A review of 157 cases in a 10 year period. Am. J. Obstet. Gynecol. 85:844–49 [Google Scholar]
  8. Acosta-Sison H. 8.  1959. Observations which may indicate the etiology of hydatidiform mole and explain its high incidence in the Philippines and Asiatic countries. Philipp. J. Surg. Surg. Spec. 14:290–93 [Google Scholar]
  9. Shang ER. 9.  1982. A retrospective investigation on the incidence of hydatidiform mole in 20,548 fertile women. Zhonghua Yi Xue Za. Zhi. 62:282–85 [Google Scholar]
  10. Song HZ, Wu PC. 10.  1987. Hydatidiform mole in China: a preliminary survey of incidence on more than three million women. Bull. World Health Organ. 65:507–11 [Google Scholar]
  11. Nakano R, Sasaki K, Yamoto M, Hata H. 11.  1980. Trophoblastic disease: analysis of 342 patients. Gynecol. Obstet. Invest. 11:237–42 [Google Scholar]
  12. Takeuchi S. 12.  1987. Incidence of gestational trophoblastic disease by regional registration in Japan. Hum. Reprod. 2:729–34 [Google Scholar]
  13. Hayashi K, Bracken MB, Freeman DH Jr., Hellenbrand K. 13.  1982. Hydatidiform mole in the United States (1970–1977): a statistical and theoretical analysis. Am. J. Epidemiol. 115:67–77 [Google Scholar]
  14. Atrash HK, Hogue CJ, Grimes DA. 14.  1986. Epidemiology of hydatidiform mole during early gestation. Am. J. Obstet. Gynecol. 154:906–9 [Google Scholar]
  15. Womack C, Elston CW. 15.  1985. Hydatidiform mole in Nottingham: a 12-year retrospective epidemiological and morphological study. Placenta 6:93–105 [Google Scholar]
  16. Bagshawe KD, Dent J, Webb J. 16.  1986. Hydatidiform mole in England and Wales 1973–83. Lancet 2:673–77 [Google Scholar]
  17. Mazzanti P, La Vecchia C, Parazzini F, Bolis G. 17.  1986. Frequency of hydatidiform mole in Lombardy, Northern Italy. Gynecol. Oncol. 24:337–42 [Google Scholar]
  18. Franke HR, Risse EK, Kenemans P, Vooijs GP, Stolk JG. 18.  1983. Epidemiologic features of hydatidiform mole in the Netherlands. Obstet. Gynecol. 62:613–16 [Google Scholar]
  19. Flam F, Lundstrom-Lindstedt V, Rutqvist LE. 19.  1992. Incidence of gestational trophoblastic disease in Stockholm County, 1975–1988. Eur. J. Epidemiol. 8:173–77 [Google Scholar]
  20. Salehi S, Eloranta S, Johansson AL, Bergström M, Lambe M. 20.  2011. Reporting and incidence trends of hydatidiform mole in Sweden 1973–2004. Acta Oncol 50:367–72 [Google Scholar]
  21. Duff GB. 21.  1989. Gestational trophoblastic disease in New Zealand, 1980–1986. Aust. N.Z. J. Obstet. Gynaecol. 29:139–42 [Google Scholar]
  22. Paksoy N, Reich B. 22.  1989. The occurrence of trophoblastic disease in Western Samoa. N.Z. Med. J. 102:162–63 [Google Scholar]
  23. Steigrad SJ. 23.  1969. The incidence of neoplastic trophoblastic disease in Australia. Aust. N.Z. J. Obstet. Gynaecol. 9:100–2 [Google Scholar]
  24. Beischer NA, Bettinger HF, Fortune DW, Pepperell R. 24.  1970. Hydatidiform mole and its complications in the state of Victoria. J. Obstet. Gynaecol. Br. Commonw. 77:263–76 [Google Scholar]
  25. Agboola A. 25.  1979. Trophoblastic neoplasia in an African urban population. J. Natl. Med. Assoc. 71:935–37 [Google Scholar]
  26. Ayangade O. 26.  1979. Gestational trophoblastic disease in Nigeria—a 10 year review. East Afr. Med. J. 56:278–82 [Google Scholar]
  27. Diejomaoh FM, Omu AE, Okpere EE, Ezimokhai M, Tabowei O, Ajabor LN. 27.  1984. The problems of management of gestational trophoblastic neoplasms at the University of Benin Teaching Hospital, Benin City, Nigeria. Adv. Exp. Med. Biol. 176:417–28 [Google Scholar]
  28. Egwuatu VE, Ozumba BC. 28.  1989. Observations on molar pregnancy in Enugu, Nigeria. Int. J. Gynaecol. Obstet. 29:219–25 [Google Scholar]
  29. Rolon PA, Hochsztajn B, Llamosas F. 29.  1990. Epidemiology of complete hydatidiform mole in Paraguay. J. Reprod. Med. 35:15–18 [Google Scholar]
  30. Aguero O, Kizer S, Pinedo G. 30.  1973. Hydatidiform mole in Concepcion Palacios Maternity Hospital. Am. J. Obstet. Gynecol. 116:1117–20 [Google Scholar]
  31. Martin BH, Kim JH. 31.  1998. Changing face of gestational trophoblastic tumor. Int. J. Gynaecol. Obstet. 60:Suppl. 1S111–20 [Google Scholar]
  32. Kim SJ, Bae SN, Kim JH, Kim CJ, Han KT. 32.  et al. 1998. Epidemiology and time trends of gestational trophoblastic disease in Korea. Int. J. Gynaecol. Obstet. 60:Suppl. 1S33–38 [Google Scholar]
  33. Hando T, Ohno M, Kurose T. 33.  1998. Recent aspects of gestational trophoblastic disease in Japan. Int. J. Gynaecol. Obstet. 60:Suppl. 1S71–76 [Google Scholar]
  34. Wang JC, Wang PH, Yuan CC. 34.  2000. Review of trophoblastic disease at Taipei Veterans General Hospital. Zhonghua Yi Xue Za. Zhi. 63:399–406 [Google Scholar]
  35. Khashoggi TY. 35.  2003. Prevalence of gestational trophoblastic disease. A single institution experience. Saudi Med. J. 24:1329–33 [Google Scholar]
  36. Eysbouts YK, Bulten J, Ottevanger PB, Thomas CM, Ten Kate-Booij MJ. 36.  et al. 2016. Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. Gynecol. Oncol. 140:70–75 [Google Scholar]
  37. Roloan PA, de Lopez BH. 37.  1977. Epidemiological aspects of hydatidiform mole in the Republic of Paraguay (South America). Br. J. Obstet. Gynaecol. 84:862–64 [Google Scholar]
  38. Teoh ES, Dawood MY, Ratnam SS. 38.  1971. Epidemiology of hydatidiform mole in Singapore. Am. J. Obstet. Gynecol. 110:415–20 [Google Scholar]
  39. Ringertz N. 39.  1970. Hydatidiform mole, invasive mole and choriocarcinoma in Sweden 1958–1965. Acta Obstet. Gynecol. Scand. 49:195–203 [Google Scholar]
  40. Sebire NJ, Foskett M, Fisher RA, Rees H, Seckl M, Newlands E. 40.  2002. Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age. BJOG 109:99–102 [Google Scholar]
  41. Bayatpour MRJ. 41.  1993. Gestational trophoblastic disease among adolescents. Adolesc. Pediatr. Gynecol. 6:3 [Google Scholar]
  42. La Vecchia C, Franceschi S, Parazzini F, Fasoli M, Decarli A. 42.  et al. 1985. Risk factors for gestational trophoblastic disease in Italy. Am. J. Epidemiol. 121:457–64 [Google Scholar]
  43. Bandy LC, Clarke-Pearson DL, Hammond CB. 43.  1984. Malignant potential of gestational trophoblastic disease at the extreme ages of reproductive life. Obstet. Gynecol. 64:395–99 [Google Scholar]
  44. Yen S, MacMahon B. 44.  1968. Epidemiologic features of trophoblastic disease. Am. J. Obstet. Gynecol. 101:126–32 [Google Scholar]
  45. Lurain JR, Sand PK, Carson SA, Brewer JI. 45.  1982. Pregnancy outcome subsequent to consecutive hydatidiform moles. Am. J. Obstet. Gynecol. 142:1060–61 [Google Scholar]
  46. Sebire NJ, Fisher RA, Foskett M, Rees H, Seckl MJ, Newlands ES. 46.  2003. Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG 110:22–26 [Google Scholar]
  47. Kim JH, Park DC, Bae SN, Namkoong SE, Kim SJ. 47.  1998. Subsequent reproductive experience after treatment for gestational trophoblastic disease. Gynecol. Oncol. 71:108–12 [Google Scholar]
  48. Yapar EG, Ayhan A, Ergeneli MH. 48.  1994. Pregnancy outcome after hydatidiform mole, initial and recurrent. J. Reprod. Med. 39:297–99 [Google Scholar]
  49. Eagles N, Sebire NJ, Short D, Savage PM, Seckl MJ, Fisher RA. 49.  2015. Risk of recurrent molar pregnancies following complete and partial hydatidiform moles. Hum. Reprod. 30:2055–63 [Google Scholar]
  50. Braga A, Maesta I, Matos M, Elias KM, Rizzo J, Viggiano MG. 50.  2015. Gestational trophoblastic neoplasia after spontaneous human chorionic gonadotropin normalization following molar pregnancy evacuation. Gynecol. Oncol. 139:283–87 [Google Scholar]
  51. Cheah PL, Looi LM, Sivanesaratnam V. 51.  1993. Hydatidiform molar pregnancy in Malaysian women: a histopathological study from the University Hospital, Kuala Lumpur. Malays. J. Pathol. 15:59–63 [Google Scholar]
  52. Matsuura J, Chiu D, Jacobs PA, Szulman AE. 52.  1984. Complete hydatidiform mole in Hawaii: an epidemiological study. Genet. Epidemiol. 1:271–84 [Google Scholar]
  53. Natoli WJ, Rashad MN. 53.  1972. Hawaiian moles. Am. J. Roentgenol. Radium Ther. Nucl. Med. 114:142–44 [Google Scholar]
  54. McCorriston CC. 54.  1968. Racial incidence of hydatidiform mole: a study in a contained polyracial community. Am. J. Obstet. Gynecol. 101:377–82 [Google Scholar]
  55. Jacobs PA, Hunt PA, Matsuura JS, Wilson CC, Szulman AE. 55.  1982. Complete and partial hydatidiform mole in Hawaii: cytogenetics, morphology and epidemiology. Br. J. Obstet. Gynaecol. 89:258–66 [Google Scholar]
  56. Parazzini F, La Vecchia C, Franceschi S, Mangili G. 56.  1984. Familial trophoblastic disease: case report. Am. J. Obstet. Gynecol. 149:382–83 [Google Scholar]
  57. Sand PK, Lurain JR, Brewer JI. 57.  1984. Repeat gestational trophoblastic disease. Obstet. Gynecol. 63:140–44 [Google Scholar]
  58. Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R. 58.  et al. 2006. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat. Genet. 38:300–2 [Google Scholar]
  59. Qian J, Deveault C, Bagga R, Xie X, Slim R. 59.  2007. Women heterozygous for NALP7/NLRP7 mutations are at risk for reproductive wastage: report of two novel mutations. Hum. Mutat. 28:741 [Google Scholar]
  60. Kou YC, Shao L, Peng HH, Rosetta R, del Gaudio D. 60.  et al. 2008. A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol. Hum. Reprod. 14:33–40 [Google Scholar]
  61. Williams D, Hodgetts V, Gupta J. 61.  2010. Recurrent hydatidiform moles. Eur. J. Obstet. Gynecol. Reprod. Biol. 150:3–7 [Google Scholar]
  62. Parry DA, Logan CV, Hayward BE, Shires M, Landolsi H. 62.  et al. 2011. Mutations causing familial biparental hydatidiform mole implicate C6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am. J. Hum. Genet. 89:451–58 [Google Scholar]
  63. Reddy R, Akoury E, Phuong Nguyen NM, Abdul-Rahman OA, Dery C. 63.  et al. 2013. Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7. Eur. J. Hum. Genet. 21:957–64 [Google Scholar]
  64. 64. Iverson L, Jt. Proj. Investig 1959. Geographic variation in the occurrence of hydatidifiorm mole and choriocaricinoma. Ann. N. Y. Acad. Sci. 80:178–95 [Google Scholar]
  65. Rosenberg L, Palmer JR, Shapiro S. 65.  1989. Gestational trophoblastic disease and use of oral contraceptives. Am. J. Obstet. Gynecol. 161:1087–88 [Google Scholar]
  66. Palmer JR. 66.  1994. Advances in the epidemiology of gestational trophoblastic disease. J. Reprod. Med. 39:155–62 [Google Scholar]
  67. Matalon M, Modan M, Paz B, Modan B. 67.  1972. Trophoblastic disorders in Israel. Harefuah 83:566–68 [Google Scholar]
  68. Kajii T, Ohama K. 68.  1977. Androgenetic origin of hydatidiform mole. Nature 268:633–34 [Google Scholar]
  69. Szulman AE. 69.  1984. Syndromes of hydatidiform moles. Partial versus complete. J. Reprod. Med. 29:788–91 [Google Scholar]
  70. Kajii T. 70.  1986. The road to diploid androgenesis. The Japan Society of Human Genetics award lecture. Jinrui Idengaku Zasshi 31:61–71 [Google Scholar]
  71. Wallace DC, Surti U, Adams CW, Szulman AE. 71.  1982. Complete moles have paternal chromosomes but maternal mitochondrial DNA. Hum. Genet. 61:145–47 [Google Scholar]
  72. Edwards YH, Jeremiah SJ, McMillan SL, Povey S, Fisher RA, Lawler SD. 72.  1984. Complete hydatidiform moles combine maternal mitochondria with a paternal nuclear genome. Ann. Hum. Genet. 48:119–27 [Google Scholar]
  73. Azuma C, Saji F, Tokugawa Y, Kimura T, Nobunaga T. 73.  et al. 1991. Application of gene amplification by polymerase chain reaction to genetic analysis of molar mitochondrial DNA: the detection of anuclear empty ovum as the cause of complete mole. Gynecol. Oncol. 40:29–33 [Google Scholar]
  74. Jacobs PA, Wilson CM, Sprenkle JA, Rosenshein NB, Migeon BR. 74.  1980. Mechanism of origin of complete hydatidiform moles. Nature 286:714–16 [Google Scholar]
  75. Ohama K, Okamoto E, Nomura K, Fujiwara A, Fukuda Y. 75.  1981. [Genetic studies of hydatidiform mole with 46,XY karyotype]. Nippon Sanka Fujinka Gakkai Zasshi 33:1664–68 [Google Scholar]
  76. Banet N, DeScipio C, Murphy KM, Beierl K, Adams E. 76.  et al. 2014. Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping. Mod. Pathol. 27:238–54 [Google Scholar]
  77. Wake N, Takagi N, Sasaki M. 77.  1978. Androgenesis as a cause of hydatidiform mole. J. Natl. Cancer Inst. 60:51–57 [Google Scholar]
  78. Fisher RA, Nucci MR, Thaker HM, Weremowicz S, Genest DR, Castrillon DH. 78.  2004. Complete hydatidiform mole retaining a chromosome 11 of maternal origin: molecular genetic analysis of a case. Mod. Pathol. 17:1155–60 [Google Scholar]
  79. McConnell TG, Norris-Kirby A, Hagenkord JM, Ronnett BM, Murphy KM. 79.  2009. Complete hydatidiform mole with retained maternal chromosomes 6 and 11. Am. J. Surg. Pathol. 33:1409–15 [Google Scholar]
  80. Sebire NJ, Fisher RA, Rees HC. 80.  2003. Histopathological diagnosis of partial and complete hydatidiform mole in the first trimester of pregnancy. Pediatr. Dev. Pathol. 6:69–77 [Google Scholar]
  81. Golubovsky MD. 81.  2003. Postzygotic diploidization of triploids as a source of unusual cases of mosaicism, chimerism and twinning. Hum. Reprod. 18:236–42 [Google Scholar]
  82. Sunde L, Niemann I, Hansen ES, Hindkjaer J, Degn B. 82.  et al. 2011. Mosaics and moles. Eur. J. Hum. Genet. 19:1026–31 [Google Scholar]
  83. Lage JM, Weinberg DS, Yavner DL, Bieber FR. 83.  1989. The biology of tetraploid hydatidiform moles: histopathology, cytogenetics, and flow cytometry. Hum. Pathol. 20:419–25 [Google Scholar]
  84. Vejerslev LO, Dissing J, Hansen HE, Poulsen H. 84.  1987. Hydatidiform mole: genetic origin in polyploid conceptuses. Hum. Genet. 76:11–19 [Google Scholar]
  85. Bifulco C, Johnson C, Hao L, Kermalli H, Bell S, Hui P. 85.  2008. Genotypic analysis of hydatidiform mole: an accurate and practical method of diagnosis. Am. J. Surg. Pathol. 32:445–51 [Google Scholar]
  86. Genest DR, Ruiz RE, Weremowicz S, Berkowitz RS, Goldstein DP, Dorfman DM. 86.  2002. Do nontriploid partial hydatidiform moles exist? A histologic and flow cytometric reevaluation of nontriploid specimens. J. Reprod. Med. 47:363–68 [Google Scholar]
  87. Lawler SD, Fisher RA, Pickthall VJ, Povey S, Evans MW. 87.  1982. Genetic studies on hydatidiform moles. I. The origin of partial moles. Cancer Genet. Cytogenet. 5:309–20 [Google Scholar]
  88. Jacobs PA, Szulman AE, Funkhouser J, Matsuura JS, Wilson CC. 88.  1982. Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole. Ann. Hum. Genet. 46:223–31 [Google Scholar]
  89. Surti U, Szulman AE, Wagner K, Leppert M, O'Brien SJ. 89.  1986. Tetraploid partial hydatidiform moles: two cases with a triple paternal contribution and a 92,XXXY karyotype. Hum. Genet. 72:15–21 [Google Scholar]
  90. Sheppard DM, Fisher RA, Lawler SD, Povey S. 90.  1982. Tetraploid conceptus with three paternal contributions. Hum. Genet. 62:371–74 [Google Scholar]
  91. Murphy KM, Descipio C, Wagenfuehr J, Tandy S, Mabray J. 91.  et al. 2012. Tetraploid partial hydatidiform mole: a case report and review of the literature. Int. J. Gynecol. Pathol. 31:73–79 [Google Scholar]
  92. Scholz NB, Bolund L, Nyegaard M, Faaborg L, Jørgensen MW. 92.  et al. 2015. Triploidy—observations in 154 diandric cases. PLOS ONE 10:e0142545 [Google Scholar]
  93. Zaragoza MV, Surti U, Redline RW, Millie E, Chakravarti A, Hassold TJ. 93.  2000. Parental origin and phenotype of triploidy in spontaneous abortions: predominance of diandry and association with the partial hydatidiform mole. Am. J. Hum. Genet. 66:1807–20 [Google Scholar]
  94. McFadden DE, Robinson WP. 94.  2006. Phenotype of triploid embryos. J. Med. Genet. 43:609–12 [Google Scholar]
  95. Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B. 95.  et al. 1980. A cytogenetic study of 1000 spontaneous abortions. Ann. Hum. Genet. 44:151–78 [Google Scholar]
  96. Szulman AE, Philippe E, Boue JG, Boue A. 96.  1981. Human triploidy: association with partial hydatidiform moles and nonmolar conceptuses. Hum. Pathol. 12:1016–21 [Google Scholar]
  97. Ambani LM, Vaidya RA, Rao CS, Daftary SD, Motashaw ND. 97.  1980. Familial occurrence of trophoblastic disease—report of recurrent molar pregnancies in sisters in three families. Clin. Genet. 18:27–29 [Google Scholar]
  98. Helwani MN, Seoud M, Zahed L, Zaatari G, Khalil A, Slim R. 98.  1999. A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution. Hum. Genet. 105:112–15 [Google Scholar]
  99. Fisher RA, Khatoon R, Paradinas FJ, Roberts AP, Newlands ES. 99.  2000. Repetitive complete hydatidiform mole can be biparental in origin and either male or female. Hum. Reprod. 15:594–98 [Google Scholar]
  100. Nguyen NM, Slim R. 100.  2014. Genetics and epigenetics of recurrent hydatidiform moles: basic science and genetic counselling. Curr. Obstet. Gynecol. Rep. 3:55–64 [Google Scholar]
  101. Wang CM, Dixon PH, Decordova S, Hodges MD, Sebire NJ. 101.  et al. 2009. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J. Med. Genet 46:569–75 [Google Scholar]
  102. Moglabey YB, Kircheisen R, Seoud M, El Mogharbel N, Van den Veyver I, Slim R. 102.  1999. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum. Mol. Genet. 8:667–71 [Google Scholar]
  103. Hodges MD, Rees HC, Seckl MJ, Newlands ES, Fisher RA. 103.  2003. Genetic refinement and physical mapping of a biparental complete hydatidiform mole locus on chromosome 19q13.4. J. Med. Genet. 40:e95 [Google Scholar]
  104. Nguyen NM, Zhang L, Reddy R, Dery C, Arseneau J. 104.  et al. 2014. Comprehensive genotype-phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation. J. Med. Genet 51:623–34 [Google Scholar]
  105. Hayward BE, De Vos M, Talati N, Abdollahi MR, Taylor GR. 105.  et al. 2009. Genetic and epigenetic analysis of recurrent hydatidiform mole. Hum. Mutat. 30:E629–39 [Google Scholar]
  106. Estrada H, Buentello B, Zenteno JC, Fiszman R, Aguinaga M. 106.  2013. The p.L750V mutation in the NLRP7 gene is frequent in Mexican patients with recurrent molar pregnancies and is not associated with recurrent pregnancy loss. Prenat. Diagn. 33:205–8 [Google Scholar]
  107. Zhang P, Dixon M, Zucchelli M, Hambiliki F, Levkov L. 107.  et al. 2008. Expression analysis of the NLRP gene family suggests a role in human preimplantation development. PLOS ONE 3e2755
  108. Akoury E, Zhang L, Ao A, Slim R. 108.  2015. NLRP7 and KHDC3L, the two maternal-effect proteins responsible for recurrent hydatidiform moles, co-localize to the oocyte cytoskeleton. Hum. Reprod. 30:159–69 [Google Scholar]
  109. Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD. 109.  et al. 2012. An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36:464–76 [Google Scholar]
  110. Gkountela S, Li Z, Vincent JJ, Zhang KX, Chen A. 110.  et al. 2013. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat. Cell Biol. 15:113–22 [Google Scholar]
  111. Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I. 111.  et al. 2014. Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome Res 24:554–69 [Google Scholar]
  112. Singer H, Biswas A, Nuesgen N, Oldenburg J, El-Maarri O. 112.  2015. NLRP7, involved in hydatidiform molar pregnancy (HYDM1), interacts with the transcriptional repressor ZBTB16. PLOS ONE 10:e0130416 [Google Scholar]
  113. Caspary T, Cleary MA, Baker CC, Guan XJ, Tilghman SM. 113.  1998. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol. Cell. Biol. 18:3466–74 [Google Scholar]
  114. Zwart R, Sleutels F, Wutz A, Schinkel AH, Barlow DP. 114.  2001. Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Genes Dev 15:2361–66 [Google Scholar]
  115. Higashimoto K, Soejima H, Yatsuki H, Joh K, Uchiyama M. 115.  et al. 2002. Characterization and imprinting status of OBPH1/Obph1 gene: implications for an extended imprinting domain in human and mouse. Genomics 80:575–84 [Google Scholar]
  116. Mizuno Y, Sotomaru Y, Katsuzawa Y, Kono T, Meguro M. 116.  et al. 2002. Asb4, Ata3, and Dcn are novel imprinted genes identified by high-throughput screening using RIKEN cDNA microarray. Biochem. Biophys. Res. Commun. 290:1499–505 [Google Scholar]
  117. Ono R, Shiura H, Aburatani H, Kohda T, Kaneko-Ishino T, Ishino F. 117.  2003. Identification of a large novel imprinted gene cluster on mouse proximal chromosome 6. Genome Res 13:1696–705 [Google Scholar]
  118. Sandell LL, Guan XJ, Ingram R, Tilghman SM. 118.  2003. Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta. PNAS 100:4622–27 [Google Scholar]
  119. Ono R, Nakamura K, Inoue K, Naruse M, Usami T. 119.  et al. 2006. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat. Genet. 38:101–6 [Google Scholar]
  120. Hui P. 120.  2012. Developmental biology of the placenta. Gestational Trophoblastic Disease—Diagnostic and Molecular Genetic Pathology P Hui 15–39 New York: Springer [Google Scholar]
  121. Tycko B, Morison IM. 121.  2002. Physiological functions of imprinted genes. J. Cell Physiol. 192:245–58 [Google Scholar]
  122. Frost JM, Moore GE. 122.  2010. The importance of imprinting in the human placenta. PLOS Genet 6:e1001015 [Google Scholar]
  123. Feil R, Berger F. 123.  2007. Convergent evolution of genomic imprinting in plants and mammals. Trends Genet 23:192–99 [Google Scholar]
  124. Haig D, Westoby M. 124.  2006. An earlier formulation of the genetic conflict hypothesis of genomic imprinting. Nat. Genet. 38:271 [Google Scholar]
  125. Tilghman SM. 125.  1999. The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell 96:185–93 [Google Scholar]
  126. Constancia M, Kelsey G, Reik W. 126.  2004. Resourceful imprinting. Nature 432:53–57 [Google Scholar]
  127. Surani MA, Barton SC. 127.  1983. Development of gynogenetic eggs in the mouse: implications for parthenogenetic embryos. Science 222:1034–36 [Google Scholar]
  128. McGrath J, Solter D. 128.  1984. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37:179–83 [Google Scholar]
  129. Barton SC, Surani MA, Norris ML. 129.  1984. Role of paternal and maternal genomes in mouse development. Nature 311:374–76 [Google Scholar]
  130. Devriendt K. 130.  2005. Hydatidiform mole and triploidy: the role of genomic imprinting in placental development. Hum. Reprod. Update 11:137–42 [Google Scholar]
  131. Fallahian M, Sebire NJ, Savage PM, Seckl MJ, Fisher RA. 131.  2013. Mutations in NLRP7 and KHDC3L confer a complete hydatidiform mole phenotype on digynic triploid conceptions. Hum. Mutat. 34:301–8 [Google Scholar]
  132. Fisher RA, Lavery SA, Carby A, Abu-Hayyeh S, Swingler R. 132.  et al. 2011. What a difference an egg makes. Lancet 378:1974 [Google Scholar]
  133. Fisher RA, Hodges MD, Rees HC, Sebire NJ, Seckl MJ. 133.  et al. 2002. The maternally transcribed gene p57KIP2 (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum. Mol. Genet. 11:3267–72 [Google Scholar]
  134. Monk D. 134.  2015. Germline-derived DNA methylation and early embryo epigenetic reprogramming: the selected survival of imprints. Int. J. Biochem. Cell Biol. 67:128–38 [Google Scholar]
  135. El-Maarri O, Seoud M, Riviere JB, Oldenburg J, Walter J. 135.  et al. 2005. Patients with familial biparental hydatidiform moles have normal methylation at imprinted genes. Eur. J. Hum. Genet. 13:486–90 [Google Scholar]
  136. El-Maarri O, Seoud M, Coullin P, Herbiniaux U, Oldenburg J. 136.  et al. 2003. Maternal alleles acquiring paternal methylation patterns in biparental complete hydatidiform moles. Hum. Mol. Genet. 12:1405–13 [Google Scholar]
  137. Sanchez-Delgado M, Martin-Trujillo A, Tayama C, Vidal E, Esteller M. 137.  et al. 2015. Absence of maternal methylation in biparental hydatidiform moles from women with NLRP7 maternal-effect mutations reveals widespread placenta-specific imprinting. PLOS Genet 11:e1005644 [Google Scholar]
  138. Mahadevan S, Wen S, Balasa A, Fruhman G, Mateus J. 138.  et al. 2013. No evidence for mutations in NLRP7 and KHDC3L in women with androgenetic hydatidiform moles. Prenat. Diagn. 33:1242–47 [Google Scholar]
  139. Sebire NJ, Makrydimas G, Agnantis NJ, Zagorianakou N, Rees H, Fisher RA. 139.  2003. Updated diagnostic criteria for partial and complete hydatidiform moles in early pregnancy. Anticancer Res 23:1723–28 [Google Scholar]
  140. Szulman AE, Surti U. 140.  1978. The syndromes of hydatidiform mole. II. Morphologic evolution of the complete and partial mole. Am. J. Obstet. Gynecol. 132:20–27 [Google Scholar]
  141. Keep D, Zaragoza MV, Hassold T, Redline RW. 141.  1996. Very early complete hydatidiform mole. Hum. Pathol. 27:708–13 [Google Scholar]
  142. Fukunaga M. 142.  2000. Early partial hydatidiform mole: prevalence, histopathology, DNA ploidy, and persistence rate. Virchows Arch 437:180–84 [Google Scholar]
  143. Fukunaga M. 143.  1994. Histopathologic study of partial hydatidiform moles and DNA triploid placentas. Pathol. Int. 44:528–34 [Google Scholar]
  144. Buza N, Hui P. 144.  2010. Gestational trophoblastic disease: histopathological diagnosis in the molecular era. Diagnost. Histopathol. 16:526–37 [Google Scholar]
  145. Conran RM, Hitchcock CL, Popek EJ, Norris HJ, Griffin JL. 145.  et al. 1993. Diagnostic considerations in molar gestations. Hum. Pathol. 24:41–48 [Google Scholar]
  146. Howat AJ, Beck S, Fox H, Harris SC, Hill AS. 146.  et al. 1993. Can histopathologists reliably diagnose molar pregnancy?. J. Clin. Pathol. 46:599–602 [Google Scholar]
  147. Javey H, Borazjani G, Behmard S, Langley FA. 147.  1979. Discrepancies in the histological diagnosis of hydatidiform mole. Br. J. Obstet. Gynaecol. 86:480–83 [Google Scholar]
  148. Messerli ML, Parmley T, Woodruff JD, Lilienfeld AM, Bevilacqua L, Rosenshein NB. 148.  1987. Inter- and intra-pathologist variability in the diagnosis of gestational trophoblastic neoplasia. Obstet. Gynecol. 69:622–26 [Google Scholar]
  149. Vang R, Gupta M, Wu LS, Yemelyanova AV, Kurman RJ. 149.  et al. 2012. Diagnostic reproducibility of hydatidiform moles: Ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis. Am. J. Surg. Pathol. 36:443–53 [Google Scholar]
  150. Gupta M, Vang R, Yemelyanova AV, Kurman RJ, Li FR. 150.  et al. 2012. Diagnostic reproducibility of hydatidiform moles: Ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis for both recently trained and experienced gynecologic pathologists. Am. J. Surg. Pathol. 36:1747–60 [Google Scholar]
  151. Kerkmeijer LG, Massuger LF, Ten Kate-Booij MJ, Sweep FC, Thomas CM. 151.  2009. Earlier diagnosis and serum human chorionic gonadotropin regression in complete hydatidiform moles. Obstet. Gynecol. 113:326–31 [Google Scholar]
  152. Chew SH, Perlman EJ, Williams R, Kurman RJ, Ronnett BM. 152.  2000. Morphology and DNA content analysis in the evaluation of first trimester placentas for partial hydatidiform mole (PHM). Hum. Pathol. 31:914–24 [Google Scholar]
  153. Norris-Kirby A, Hagenkord JM, Kshirsagar MP, Ronnett BM, Murphy KM. 153.  2010. Abnormal villous morphology associated with triple trisomy of paternal origin. J. Mol. Diagn. 12:525–29 [Google Scholar]
  154. Redline RW, Hassold T, Zaragoza M. 154.  1998. Determinants of villous trophoblastic hyperplasia in spontaneous abortions. Mod. Pathol. 11:762–68 [Google Scholar]
  155. Ronnett BM, DeScipio C, Murphy KM. 155.  2011. Hydatidiform moles: ancillary techniques to refine diagnosis. Int. J. Gynecol. Pathol. 30:101–16 [Google Scholar]
  156. Berkowitz RS, Goldstein DP. 156.  1988. Diagnosis and management of the primary hydatidiform mole. Obstet. Gynecol. Clin. N. Am. 15:491–503 [Google Scholar]
  157. Berkowitz RS, Tuncer ZS, Bernstein MR, Goldstein DP. 157.  2000. Management of gestational trophoblastic diseases: subsequent pregnancy experience. Semin. Oncol. 27:678–85 [Google Scholar]
  158. Garner EI, Goldstein DP, Feltmate CM, Berkowitz RS. 158.  2007. Gestational trophoblastic disease. Clin Obstet. Gynecol. 50:112–22 [Google Scholar]
  159. Feltmate CM, Growdon WB, Wolfberg AJ, Goldstein DP, Genest DR. 159.  et al. 2006. Clinical characteristics of persistent gestational trophoblastic neoplasia after partial hydatidiform molar pregnancy. J. Reprod. Med. 51:902–6 [Google Scholar]
  160. Hancock BW, Nazir K, Everard JE. 160.  2006. Persistent gestational trophoblastic neoplasia after partial hydatidiform mole incidence and outcome. J. Reprod. Med. 51:764–66 [Google Scholar]
  161. Wielsma S, Kerkmeijer L, Bekkers R, Pyman J, Tan J, Quinn M. 161.  2006. Persistent trophoblast disease following partial molar pregnancy. Aust. N. Z. J. Obstet. Gynaecol. 46:119–23 [Google Scholar]
  162. Seckl MJ, Fisher RA, Salerno G, Rees H, Paradinas FJ. 162.  et al. 2000. Choriocarcinoma and partial hydatidiform moles. Lancet 356:36–39 [Google Scholar]
  163. Cheung AN, Khoo US, Lai CY, Chan KY, Xue WC. 163.  et al. 2004. Metastatic trophoblastic disease after an initial diagnosis of partial hydatidiform mole: genotyping and chromosome in situ hybridization analysis. Cancer 100:1411–17 [Google Scholar]
  164. Medeiros F, Callahan MJ, Elvin JA, Dorfman DM, Berkowitz RS, Quade BJ. 164.  2008. Intraplacental choriocarcinoma arising in a second trimester placenta with partial hydatidiform mole. Int. J. Gynecol. Pathol. 27:247–51 [Google Scholar]
  165. Sebire NJ, Foskett M, Fisher RA, Lindsay I, Seckl MJ. 165.  2005. Persistent gestational trophoblastic disease is rarely, if ever, derived from non-molar first-trimester miscarriage. Med. Hypotheses 64:689–93 [Google Scholar]
  166. Fisher RA, Hodges MD, Newlands ES. 166.  2004. Familial recurrent hydatidiform mole: a review. J. Reprod. Med. 49:595–601 [Google Scholar]
  167. Castrillon DH, Sun D, Weremowicz S, Fisher RA, Crum CP, Genest DR. 167.  2001. Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57 KIP2. Am. J. Surg. Pathol. 25:1225–30 [Google Scholar]
  168. Chilosi M, Piazzola E, Lestani M, Benedetti A, Guasparri I. 168.  et al. 1998. Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease. Lab. Invest. 78:269–76 [Google Scholar]
  169. Crisp H, Burton JL, Stewart R, Wells M. 169.  2003. Refining the diagnosis of hydatidiform mole: image ploidy analysis and p57KIP2 immunohistochemistry. Histopathology 43:363–73 [Google Scholar]
  170. Fukunaga M. 170.  2002. Immunohistochemical characterization of p57KIP2 expression in early hydatidiform moles. Hum. Pathol. 33:1188–92 [Google Scholar]
  171. Fukunaga M. 171.  2004. Immunohistochemical characterization of p57Kip2 expression in tetraploid hydropic placentas. Arch. Pathol. Lab. Med. 128:897–900 [Google Scholar]
  172. Hoffner L, Dunn J, Esposito N, Macpherson T, Surti U. 172.  2008. p57KIP2 immunostaining and molecular cytogenetics: Combined approach aids in diagnosis of morphologically challenging cases with molar phenotype and in detecting androgenetic cell lines in mosaic/chimeric conceptions. Hum. Pathol. 39:63–72 [Google Scholar]
  173. Hoffner L, Parks WT, Swerdlow SH, Carson JC, Surti U. 173.  2010. Simultaneous detection of imprinted gene expression (p57KIP2) and molecular cytogenetics (FICTION) in the evaluation of molar pregnancies. J. Reprod. Med. 55:219–28 [Google Scholar]
  174. Jun SY, Ro JY, Kim KR. 174.  2003. p57kip2 is useful in the classification and differential diagnosis of complete and partial hydatidiform moles. Histopathology 43:17–25 [Google Scholar]
  175. McConnell TG, Murphy KM, Hafez M, Vang R, Ronnett BM. 175.  2009. 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. Am. J. Surg. Pathol. 33:805–17 [Google Scholar]
  176. Merchant SH, Amin MB, Viswanatha DS, Malhotra RK, Moehlenkamp C, Joste NE. 176.  2005. p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the differential diagnosis of hydropic abortuses. Hum. Pathol. 36:180–86 [Google Scholar]
  177. Popiolek DA, Yee H, Mittal K, Chiriboga L, Prinz MK. 177.  et al. 2006. Multiplex short tandem repeat DNA analysis confirms the accuracy of p57KIP2 immunostaining in the diagnosis of complete hydatidiform mole. Hum. Pathol. 37:1426–34 [Google Scholar]
  178. Romaguera RL, Rodriguez MM, Bruce JH, Zuluaga T, Viciana A. 178.  et al. 2004. Molar gestations and hydropic abortions differentiated by p57 immunostaining. Fetal. Pediatr. Pathol. 23:181–90 [Google Scholar]
  179. Sarmadi S, Izadi-Mood N, Abbasi A, Sanii S. 179.  2011. p57KIP2 immunohistochemical expression: a useful diagnostic tool in discrimination between complete hydatidiform mole and its mimics. Arch. Gynecol. Obstet. 283:743–48 [Google Scholar]
  180. Bell KA, Van Deerlin V, Addya K, Clevenger CV, Van Deerlin PG, Leonard DG. 180.  1999. Molecular genetic testing from paraffin-embedded tissue distinguishes nonmolar hydropic abortion from hydatidiform mole. Mol. Diagn. 4:11–19 [Google Scholar]
  181. Murphy KM, McConnell TG, Hafez MJ, Vang R, Ronnett BM. 181.  2009. Molecular genotyping of hydatidiform moles: analytic validation of a multiplex short tandem repeat assay. J. Mol. Diagn. 11:598–605 [Google Scholar]
  182. Lai CY, Chan KY, Khoo US, Ngan HY, Xue WC. 182.  et al. 2004. Analysis of gestational trophoblastic disease by genotyping and chromosome in situ hybridization. Mod. Pathol. 17:40–48 [Google Scholar]
  183. Lipata F, Parkash V, Talmor M, Bell S, Chen S. 183.  et al. 2010. Precise DNA genotyping diagnosis of hydatidiform mole. Obstet. Gynecol. 115:784–94 [Google Scholar]
  184. Fisher RA, Tommasi A, Short D, Kaur B, Seckl MJ, Sebire NJ. 184.  2014. Clinical utility of selective molecular genotyping for diagnosis of partial hydatidiform mole; a retrospective study from a regional trophoblastic disease unit. J. Clin. Pathol. 67:980–84 [Google Scholar]
  185. Lawler SD, Povey S, Fisher RA, Pickthall VJ. 185.  1982. Genetic studies on hydatidiform moles. II. The origin of complete moles. Ann. Hum. Genet. 46:209–22 [Google Scholar]
  186. Ohama K, Kajii T, Okamoto E, Fukuda Y, Imaizumi K. 186.  et al. 1981. Dispermic origin of XY hydatidiform moles. Nature 292:551–52 [Google Scholar]
  187. Redline RW, Hassold T, Zaragoza MV. 187.  1998. Prevalence of the partial molar phenotype in triploidy of maternal and paternal origin. Hum. Pathol. 29:505–11 [Google Scholar]
  188. Kaiser-Rogers KA, McFadden DE, Livasy CA, Dansereau J, Jiang R. 188.  et al. 2006. Androgenetic/biparental mosaicism causes placental mesenchymal dysplasia. J. Med. Genet. 43:187–92 [Google Scholar]
  189. Lewis GH, DeScipio C, Murphy KM, Haley L, Beierl K. 189.  et al. 2013. Characterization of androgenetic/biparental mosaic/chimeric conceptions, including those with a molar component: morphology, p57 immnohistochemistry, molecular genotyping, and risk of persistent gestational trophoblastic disease. Int. J. Gynecol. Pathol. 32:199–214 [Google Scholar]
  190. Banet N, Descipio C, Murphy KM, Beierl K, Adams E. 190.  et al. 2013. Characteristics of hydatidiform moles: analysis of a prospective series with p57 immunohistochemistry and molecular genotyping. Mod. Pathol. 27:238–54 [Google Scholar]
  191. DeScipio C, Haley L, Beierl K, Pandit AP, Murphy KM, Ronnett BM. 191.  2011. Diandric triploid hydatidiform mole with loss of maternal chromosome 11. Am. J. Surg. Pathol. 35:1586–91 [Google Scholar]
  192. Van den Veyver IB, Al-Hussaini TK. 192.  2006. Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring. Hum. Reprod. Update 12:233–42 [Google Scholar]
  193. Deveault C, Qian JH, Chebaro W, Ao A, Gilbert L. 193.  et al. 2009. NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation. Hum. Mol. Genet. 18:888–97 [Google Scholar]
  194. Buza N, Hui P. 194.  2014. Egg donor pregnancy: a potential pitfall in DNA genotyping diagnosis of hydatidiform moles. Int. J. Gynecol. Pathol. 33:507–10 [Google Scholar]
  195. Buza N, Hui P. 195.  2014. Immunohistochemistry and other ancillary techniques in the diagnosis of gestational trophoblastic diseases. Semin. Diagn. Pathol. 31:223–32 [Google Scholar]
  196. Soper JT, Mutch DG, Schink JC. 196.  2004. Diagnosis and treatment of gestational trophoblastic disease: ACOG Practice Bulletin No. 53. Gynecol. Oncol. 93:575–85 [Google Scholar]
/content/journals/10.1146/annurev-pathol-052016-100237
Loading
Hydatidiform Moles: Genetic Basis and Precision Diagnosis
Annual Review of Pathology: Mechanisms of Disease 12, 449 (2017); https://doi.org/10.1146/annurev-pathol-052016-100237
/content/journals/10.1146/annurev-pathol-052016-100237
/content/journals/10.1146/annurev-pathol-052016-100237
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error