Abnormal Development - Hydatidiform Mole

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Introduction

Hydatidiform Mole

(hydatidiform mole, hydatid mole, molar pregnancy, gestational trophoblastic disease) A type of fertilisation abnormality, when only the conceptus trophoblast layers proliferates and not the embryoblast, no embryo develops, this is called a "hydatidiform mole". Due to the continuing presence of the trophoblastic layer, this abnormal conceptus can also implant in the uterus or ectopically. The trophoblast cells will secrete human chorionic gonadotropin (hCG), as in a normal pregnancy, and may appear maternally and by pregnancy test to be "normal". Prenatal diagnosis by ultrasound analysis demonstrates the absence of a embryo.

  • Complete Mole - Only paternal chromosomes.
  • Partial Mole - 3 sets of chromosomes ( (triploidy) instead of the usual 2.


There are several forms of hydatidiform mole: partial mole, complete mole and persistent gestational trophoblastic tumor. Many of these tumours arise from a haploid sperm fertilizing an egg without a female pronucleus (the alternative form, an embryo without sperm contribution, is called parthenogenesis). The tumour has a "grape-like" placental appearance without enclosed embryo formation. Following a first molar pregnancy, there is approximately a 1% risk of a second molar pregnancy.


  • The incidence of hydatidiform mole varies between ethnic groups, and typically occurs in 1 in every 1500 pregnancies.
  • All hydatidiform mole cases are sporadic, except for extremely rare familial cases.
  • A maternal gene has been identified for recurrent hydatidiform mole (chromosome 19q13.3-13.4 in a 15.2 cM interval flanked by D19S924 and D19S890).[1]
Historically  
100px|link=Embryology History - William Smellie

William Smellie

Hippocrates (c.400 bc) first described a molar pregnancy.

Rembrandt's painting "The Anatomy Lesson of Dr Nicolaes Tulp" (1632), also illustrated a molar pregnancy.

William Smellie (1697-1763) in 1752 was the first to introduce the terminology "mole" and "hydatidiform".

Links: hydatidiform mole | fertilization | meiosis | oocyte | Week 2 - Abnormalities | Placenta - Abnormalities | Abnormal Development
  Historic: 1920 Hydatiform Degeneration | 1921 Hydatiform Degeneration in Uterine Pregnancy | 1921 Hydatiform Degeneration in Tubal Pregnancy

Some Recent Findings

  • Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles[2] "Androgenetic complete hydatidiform moles are human pregnancies with no embryos and affect 1 in every 1,400 pregnancies. They have mostly androgenetic monospermic genomes with all the chromosomes originating from a haploid sperm and no maternal chromosomes. Androgenetic complete hydatidiform moles were described in 1977, but how they occur has remained an open question. We identified bi-allelic deleterious mutations in MEI1, TOP6BL/C11orf80, and REC114, with roles in meiotic double-strand breaks formation in women with recurrent androgenetic complete hydatidiform moles. We investigated the occurrence of androgenesis in Mei1-deficient female mice and discovered that 8% of their oocytes lose all their chromosomes by extruding them with the spindles into the first polar body. We demonstrate that Mei1-/- oocytes are capable of fertilization and 5% produce androgenetic zygotes. Thus, we uncover a meiotic abnormality in mammals and a mechanism for the genesis of androgenetic zygotes that is the extrusion of all maternal chromosomes and their spindles into the first polar body."
  • The genetics of recurrent hydatidiform moles (analysis of 113 patients)[3] "Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles."
  • Identification of nonsynonymous TP53 mutations in hydatidiform moles[4] "Here we screened for specific missense mutations on several TP53 hotspots in 49 HMs using a highly sensitive pyrosequencing approach and revealed the significant existence of such mutations in HM tissues. A particularly high frequency (∼59% of the cases) of p53 inactivating mutation on exon 7 has been detected. Our identification of hitherto unreported TP53 mutations in HM suggests the presence of p53 mutants and reflects the advantages of using pyrosequencing for point mutation detection in clinical samples. Traditional sequencing method may have overlooked such mutations that only occur in a small population of trophoblasts."
More recent papers  
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Search term: Hydatidiform Mole

<pubmed limit=5>Hydatidiform Mole</pubmed>

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Gestational Trophoblastic Disease: Clinical and Imaging Features[5] "Gestational trophoblastic disease (GTD) is a spectrum of both benign and malignant gestational tumors, including hydatidiform mole (complete and partial), invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The latter four entities are referred to as gestational trophoblastic neoplasia (GTN). These conditions are aggressive with a propensity to widely metastasize. GTN can result in significant morbidity and mortality if left untreated. ...While GTN after a molar pregnancy is usually diagnosed with serial β-hCG titers, imaging plays an important role in evaluation of local extent of disease and systemic surveillance. Imaging also plays a crucial role in detection and management of complications, such as uterine and pulmonary arteriovenous fistulas."
  • Risk of recurrent molar pregnancies following complete and partial hydatidiform moles[6] "What is the risk of further molar pregnancies for women with one or more hydatidiform moles (HM) in relation to molar subtype. SUMMARY ANSWER: Women with a complete hydatidiform mole (CM) have a 1 in 100 and 1 in 4 risk of further CM after one or two consecutive CM, respectively, while women with a partial hydatidiform mole (PM) have only a small increase in risk for further molar pregnancies. WHAT IS KNOWN ALREADY: Women with a molar pregnancy have an increased risk of further HM. A small subgroup of women with recurrent HM has an autosomal recessive condition, familial recurrent hydatidiform moles (FRHM), that predisposes them to molar pregnancies."
  • NLRP7, Involved in Hydatidiform Molar Pregnancy (HYDM1), Interacts with the Transcriptional Repressor ZBTB16[7] "Mutations in the maternal effect gene NLRP7 cause biparental hydatidiform mole (HYDM1). HYDM1 is characterized by abnormal growth of placenta and lack of proper embryonic development. The molar tissues are characterized by abnormal methylation patterns at differentially methylated regions (DMRs) of imprinted genes. It is not known whether this occurs before or after fertilization, but the high specificity of this defect to the maternal allele indicates a possible maternal germ line-specific effect. ...Hence, the biological significance of the NLRP7-ZBTB16 interaction remains to be revealed. However, a clear effect of harvesting ZBTB16 to the cytoplasm when the NLRP7 protein is overexpressed may be linked to the pathology of the molar pregnancy disease." Molecular Development - Epigenetics
  • Minimally-aggressive gestational trophoblastic neoplasms[8] "We have previously defined a new syndrome "Minimally-aggressive gestational trophoblastic neoplasms" in which choriocarcinoma or persistent hydatidiform mole has a minimal growth rate and becomes chemorefractory. Previously we described a new treatment protocol, waiting for hCG rise to >3000 mIU/ml and disease becomes more advanced, then using combination chemotherapy. Initially we found this treatment successful in 8 of 8 cases, here we find this protocol appropriate in a further 16 cases. Initially we used hyperglycosylated hCG, a limited availability test, to identify this syndrome. Here we propose also using hCG doubling rate to detect this syndrome."

International Classification of Diseases

ICD-10

Hydatidiform mole

Use additional code from category O08.-, if desired, to identify any associated complication.

Excl.: malignant hydatidiform mole (D39.2)

  • O01.0 - Classical hydatidiform mole
    • Complete hydatidiform mole
  • O01.1 - Incomplete and partial hydatidiform mole
  • O01.9 - Hydatidiform mole, unspecified
    • Trophoblastic disease NOS
    • Vesicular mole NOS
  • O08 - Complications following abortion and ectopic and molar pregnancy

Note: This code is provided primarily for morbidity coding. For use of this category reference should be made to the morbidity coding rules and guidelines in Volume 2.

  • D39.2 8 Placenta
    • Chorioadenoma destruens
    • Hydatidiform mole:
      • invasive
      • malignant

Excl.: hydatidiform mole NOS (O01.9)

Mole Types

Complete mole pathology and multiple fibroids within the uterus.[9]

Complete Mole

Only paternal chromosomes.

  • Chromosomal genetic material from the ovum (egg) is lost, by an unknown process.
  • Fertilization then occurs with one or two sperm and an androgenic (from the male only) conceptus (fertilized egg) is formed.
  • With this conceptus the embryo (fetus, baby) does not develop at all but the placenta does grow.
  • placenta it is abnormal and forms lots of cysts and has no blood vessels.
  • These cysts look like a cluster of grapes and that is why it is called a hydatidiform ("grape-like") mole.
  • A hydatidiform mole miscarries by about 16 to 18 weeks gestational age.
  • Since the diagnosis can be made by ultrasound before that time, it is better to have an evacuation of the uterus (D & C) so that there is no undue bleeding and no infection.
  • Human chorionic gonadotropin (hCG) levels will assist in making the diagnosis.

Partial Mole

Ultrasound of partial mole confirmed by triploidy[10]

Three sets of chromosomes instead of the usual two and this is called triploidy.

  • chromosomal (genetic) material from the ovum (egg) is retained and the egg is fertilized by one or two sperm.
  • with partial mole there are maternal chromosomes and there is a fetus.
  • the three sets of chromosomes means the fetus is always grossly abnormal and will not survive.


(Text modified from: International Society for the Study of Trophoblastic Diseases, see also JRM Gestational Trophoblastic Disease)

Diagnostic

  • Ultrasound can indicate the absence of an embryonic heartbeat and a "bunch of grapes" appearance.
  • HCG level (>100000 mIU/ml)
  • Excessive uterine enlargement
  • Theca lutein cyst size ≥6 cm are considered a high risk for developing post molar tumors


A recent retrospective study of a large patient cohort[11] identified clinical characteristics (table below) between the complete and partial hydatidiform moles types. After mole evacuation most patients in both groups reach normal serum hCG concentrations within 14 weeks.

Mole Type Average serum hCG Post hCG normalization Gestational age
complete 4400 ng/mL 7 weeks 11.5 weeks
partial 875 ng/mL 6 weeks 13.0 weeks

Tumour Growth

Like any tumour, unless removed there is a risk of progression:

  1. Stage I: Tumor confined to uterus (non-metastatic)
  2. Stage II: Tumor involving pelvic organs and/or vagina
  3. Stage III: Tumor involving lungs, with or without involving pelvic structures and/or vagina
  4. Stage IV: Tumor involving distant organs
Uterine and ovarian metastasis[12] Pulmonary metastasis[12]
Hydatidiform mole metastasis Hydatidiform mole pulmonary metastasis

Choriocarcinoma

A highly malignant epithelial tumour often associated with hydatidiform mole.

Placental Mesenchymal Dysplasia

A rare disorder due to a similar "grape-like" placental appearance, this rare disorder has been mistaken both clinically and macroscopically for a partial hydatidiform molar pregnancy. Characterized by an increased size placenta with cystic villi and dilated vessels. This disorder also has a high incidence of intrauterine growth restriction (IUGR) and fetal death.

Twin Pregnancy Mole

Hydatidiform mole and co-existent healthy fetus is a very rare condition with only 30 cases documented in detail in the literature.[13]


Ectopic Molar Pregnancy

Ectopic molar pregnancy 01.jpg

Left-sided unruptured ampullary ectopic pregnancy at laparoscopy.[14]


Links: Ectopic Implantation

References

  1. Moglabey YB, Kircheisen R, Seoud M, El Mogharbel N, Van den Veyver I & Slim R. (1999). Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum. Mol. Genet. , 8, 667-71. PMID: 10072436
  2. Nguyen NMP, Ge ZJ, Reddy R, Fahiminiya S, Sauthier P, Bagga R, Sahin FI, Mahadevan S, Osmond M, Breguet M, Rahimi K, Lapensee L, Hovanes K, Srinivasan R, Van den Veyver IB, Sahoo T, Ao A, Majewski J, Taketo T & Slim R. (2018). Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles. Am. J. Hum. Genet. , 103, 740-751. PMID: 30388401 DOI.
  3. Nguyen NMP, Khawajkie Y, Mechtouf N, Rezaei M, Breguet M, Kurvinen E, Jagadeesh S, Solmaz AE, Aguinaga M, Hemida R, Harma MI, Rittore C, Rahimi K, Arseneau J, Hovanes K, Clisham R, Lenzi T, Scurry B, Addor MC, Bagga R, Nendaz GG, Finci V, Poke G, Grimes L, Gregersen N, York K, Bolze PA, Patel C, Mozdarani H, Puechberty J, Scotchie J, Fardaei M, Harma M, Gardner RJM, Sahoo T, Dudding-Byth T, Srinivasan R, Sauthier P & Slim R. (2018). The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients. Mod. Pathol. , 31, 1116-1130. PMID: 29463882 DOI.
  4. Chan KK, Wong ES, Wong OG, Ngan HY & Cheung AN. (2018). Identification of nonsynonymous TP53 mutations in hydatidiform moles. Mutat. Res. , 809, 20-23. PMID: 29655027 DOI.
  5. Shaaban AM, Rezvani M, Haroun RR, Kennedy AM, Elsayes KM, Olpin JD, Salama ME, Foster BR & Menias CO. (2017). Gestational Trophoblastic Disease: Clinical and Imaging Features. Radiographics , 37, 681-700. PMID: 28287945 DOI.
  6. Eagles N, Sebire NJ, Short D, Savage PM, Seckl MJ & Fisher RA. (2015). Risk of recurrent molar pregnancies following complete and partial hydatidiform moles. Hum. Reprod. , 30, 2055-63. PMID: 26202916 DOI.
  7. Singer H, Biswas A, Nuesgen N, Oldenburg J & El-Maarri O. (2015). NLRP7, Involved in Hydatidiform Molar Pregnancy (HYDM1), Interacts with the Transcriptional Repressor ZBTB16. PLoS ONE , 10, e0130416. PMID: 26121690 DOI.
  8. Cole LA. (2012). Minimally-aggressive gestational trophoblastic neoplasms. Gynecol. Oncol. , 125, 145-50. PMID: 22198244 DOI.
  9. Aguilera M, Rauk P, Ghebre R & Ramin K. (2012). Complete hydatidiform mole presenting as a placenta accreta in a twin pregnancy with a coexisting normal fetus: case report. Case Rep Obstet Gynecol , 2012, 405085. PMID: 22928132 DOI.
  10. Kinare A. (2008). Fetal environment. Indian J Radiol Imaging , 18, 326-44. PMID: 19774194 DOI.
  11. Eysbouts Y, Brouwer R, Ottevanger P, Massuger L, Sweep F, Thomas C & van Herwaarden A. (2017). Serum Human Chorionic Gonadotropin Normogram for the Detection of Gestational Trophoblastic Neoplasia. Int. J. Gynecol. Cancer , 27, 1035-1041. PMID: 28498241 DOI.
  12. 12.0 12.1 Aminimoghaddam S & Maghsoudnia A. (2017). Unusual Presentation of Invasive Mole: A Case Report. J Reprod Infertil , 18, 205-209. PMID: 28377901
  13. Piura B, Rabinovich A, Hershkovitz R, Maor E & Mazor M. (2008). Twin pregnancy with a complete hydatidiform mole and surviving co-existent fetus. Arch. Gynecol. Obstet. , 278, 377-82. PMID: 18273627 DOI.
  14. Bousfiha N, Erarhay S, Louba A, Saadi H, Bouchikhi C, Banani A, El Fatemi H, Sekkal M & Laamarti A. (2012). Ectopic molar pregnancy: a case report. Pan Afr Med J , 11, 63. PMID: 22655097

Reviews

Kalogiannidis I, Kalinderi K, Kalinderis M, Miliaras D, Tarlatzis B & Athanasiadis A. (2018). Recurrent complete hydatidiform mole: where we are, is there a safe gestational horizon? Opinion and mini-review. J. Assist. Reprod. Genet. , 35, 967-973. PMID: 29737470 DOI.

Hui P, Buza N, Murphy KM & Ronnett BM. (2017). Hydatidiform Moles: Genetic Basis and Precision Diagnosis. Annu Rev Pathol , 12, 449-485. PMID: 28135560 DOI.

Candelier JJ. (2016). The hydatidiform mole. Cell Adh Migr , 10, 226-35. PMID: 26421650 DOI.

Kani KK, Lee JH, Dighe M, Moshiri M, Kolokythas O & Dubinsky T. (2012). Gestatational trophoblastic disease: multimodality imaging assessment with special emphasis on spectrum of abnormalities and value of imaging in staging and management of disease. Curr Probl Diagn Radiol , 41, 1-10. PMID: 22085657 DOI.

Ronnett BM, DeScipio C & Murphy KM. (2011). Hydatidiform moles: ancillary techniques to refine diagnosis. Int. J. Gynecol. Pathol. , 30, 101-16. PMID: 21293291 DOI.

Sharp AN, Heazell AE, Crocker IP & Mor G. (2010). Placental apoptosis in health and disease. Am. J. Reprod. Immunol. , 64, 159-69. PMID: 20367628 DOI.

Seckl MJ, Sebire NJ & Berkowitz RS. (2010). Gestational trophoblastic disease. Lancet , 376, 717-29. PMID: 20673583 DOI.

Articles

Kan ASY, Lau ETK, So CH, Chan WP, Wong WC, Lee KC, Pertile MD & Tang MHY. (2018). A fetus coexisting with a complete hydatidiform mole with trisomy 9 of maternal origin. J. Obstet. Gynaecol. Res. , 44, 955-959. PMID: 29436108 DOI.

Hong T, Hills E & Aguinaga MDP. (2017). Radiographically occult pulmonary metastases from gestational trophoblastic neoplasia. Radiol Case Rep , 12, 292-294. PMID: 28491173 DOI.

Jauniaux E & Verheijen R. (2016). Diagnosis and management of hydatidiform mole and its complications: 2000 years of a medical challenge. BJOG , 123, 1183. PMID: 27206034 DOI.

Cavaliere A, Ermito S, Dinatale A & Pedata R. (2009). Management of molar pregnancy. J Prenat Med , 3, 15-7. PMID: 22439034

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Mall FP. On the frequency of localized anomalies in human embryos and infants at birth. (1917) Amer. J Anat. 22:49-72.

Meyer AW. Hydatiform degeneration in tubal and uterine pregnancy. (1920) Carnegie Instn. Wash. Publ., Contrib. Embryol., 40: 327- 364.


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Cite this page: Hill, M.A. (2019, March 26) Embryology Abnormal Development - Hydatidiform Mole. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Hydatidiform_Mole

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