Juniper publishers: Molar Pregnancy: Genetic, Histological, Clinical Features and the Risk for Gestational Trophoblastic Neoplasia
JUNIPER PUBLISHERS- JOURNAL OF GYNECOLOGY AND WOMEN’S
HEALTH
Journal of Gynecology and Women’s Health-Juniper
Publishers
Authored by Andréa Cristina de Moraes Malinverni*
Abstract
Hydatidiform mole (HM) is a complication of
pregnancy, genetically abnormal, characterized by several degrees of
trophoblastic proliferation and hydropic degeneration of chorionic villi
with potential for malignant transformation. The HM is classified as
complete hydatidiform mole (CHM) and partial hydatiform mole (PHM). The
distinction between CHM and PHM and non-molar abortions (NM) is very
important since the risk for the development of postmolar gestational
trophoblastic neoplasia is higher in CHM. This article is a brief review
of relevant topics about genetic, histological and clinical features of
molar pregnancy.
Keywords: Molar pregnancy; Hydatidiform mole; Partial hydatidform mole; Complete hydatidform mole; Gestational trophoblastic neoplasiaIntroduction
Molar pregnancy represents an obstetric complication
of the first half of gestation in which the abnormal developmental of
the placenta is characterized by excessive villous edema and the
proliferation of the trophoblast [1].
The excessive villous stromal edema culminates with central cisterns
formation, visible at macroscopic and ultrasonographic examination.
Based on the morphological, genetic and clinical aspects, HM can be
classified as complete (CHM) or partial (PHM) hydatidiform mole [1,2].
The CHM presents hydropic chorionic villi,
trophoblastic hyperplasia and high levels of human chorionic
gonadotropin hormone (β-hCG) [3].
However, in the PHM the placenta has normal and hydropic villi with the
presence of fetal or embryonic elements, trophoblastic hyperplasia with
pseudoinclusions, dual villous populations and lower levels of
chorionic gonadotrophin [1,4].
HM is considered the most frequent form of
gestational trophoblastic dIsease (GTD), with estimated global incidence
of 1 to 3 per 1000 pregnancies. The incidence in Asian countries and
Latin America is higher than that reported in Europe and North America.
In Brazil there is no specific official record and it is estimated to
occur in 1: 200-400 pregnancies, but this rate is based on data from
reference centers for GTD which is quite high and probably does not
reflect the population as a whole [5-7].
The risk for gestational trophoblastic neoplasia after the patient has
had a CHM was observed in 10-30% and rarely occurs after PHM (0.5-5%) [1,5,8].
The distinction between CHM and PHM is very important
because in CHM there is higher risk of progression of developing
gestational trophoblastic neoplasia. Some cases of PHM have abnormal
villous morphology that can be confused with NM. The clinical
investigations and immunostaining with molecular studies are important
to distinguish the diagnosis of PHM and NM.
Genetic aspects of hydatidiform mole
In the 70’s some molecular investigations established the genetic bases of hydatidiform [9].
Genetically, CHM is diploid and 80% has 46XX karyotype in which all
chromosomes are of paternal origin. This is because an enucleated egg
without maternal genes was fertilized by a haploid
sperm (monospermia) followed by duplication forming a homozygous egg 46,
XX. In the remaining 20% of CHM, the karyotype is 46, XY, due to the
fertilization of an anucleated egg by two haploid sperm (dyspermia). In
both cases we can say that CHM karyotype is androgenetic diploid [1,8,10].
Sometimes CHM can be related to mutations in the gene NLRP7 with an increase the risk to recurrent hydatidiform mole [11].
In the first-trimester miscarriages, Triplody is one of the most common
chromosome abnormalities present in 18% of first-trimester
miscarrisges. [12,13].
The mechanism of genetic formation of the triploidy may result from
fertilization of a normal haploid egg by two normal sperm or
fertilization of a haploid egg by a diploid sperm. Another possibilite
is a fertilization of a diploid egg by normal haploid sperm. This is
also true for PHM, which 70% of the cases has 69, XXY karyotype, but
this finding can be different: 69, XXX or 69, XYY. The PHM has a
maternal haploid component and two paternal (diandrica triploidy) which
differs genetically from non-molar triploidy [1,8,14].
Several genetic methodologies aid to improve the
diagnosis of HM. The conventional karyotyping is the most used technique
to identify the numerical and structural chromosomal abnormalities and
confirms the presence of triploidy in HPM and diploidy in CHM. However,
it cannot be used with formalin-fixed paraffin-embedded or alcohol
tissues, only in fresh samples [12,13,15].
Flow cytometry is a method for analyzing ploidy in fresh and
paraffin-embedded samples. It only allows the detection of polyploidy
(triploidy) and does not detect trisomy and monosomy. Thus it separates a
PHM from a CHM, but cannot distinguish between non-molar digynic
triploid gestations and PHM [16-18].
Fluorescence in situ hybridization (FISH) is an indispensable technique
in the study of the physical mapping of human genome because it allows a
precise regional chromosomal location of single copy genes or repeated
sequences of DNA. It can be used in paraffin-embedded samples, analyzes
the ploidy and identifies the most common chromosomal abnormalities
related to NM abortions according to the probes were used [12,19].
Molecular genotyping of microsatellites has been widely used in
distinguishing HM. This technique can be performed with DNA from fresh
or paraffin- embedded samples, allows analyzing alterations for ploidy
and the parental origin of the genetic components present in the sample [20-23]. Each of these methods has their particularities, advantages and disadvantages [21,22,24,25].
Histological characteristics of HM
The diagnosis of HM is based on its morphology. In
classical cases, around the 2nd trimester, the abnormally large villi
have a vesicular or a grape-like appearance. Histologically, HM presents
variable degrees of circumferential trophoblastic hyperplasia and
epithelial atypia. Usually they are more pronounced on CHM. PHM displays
irregular villous contours with geographic appearance becoming frequent
epithelial pseudoinclusions into the villous stroma. Different from
CHM, a compound of a mixture of normal and abnormal villi, less number
of vesicles and prominent stromal fibrosis. Cellular debris (stromal and
vascular karyorrhexis) occurs in both types of HM, mainly in CHM [26].
The presence of membranes, fetal tissues or nucleated RBCs is uncommon
in CHM unless it is twin pregnancy. This typical morphological pattern
has changed over the years due to molar evacuation in early gestational
age before the 11th week. [26,27].
At this stage the vesicles are less visible at macroscopy and cisterns
are rare on histological examination. In early CHMs the villi has a
typical “budding” arrangment, myxoid basophilic stroma with or without a
collapsed vascular network. Some cases can be confused with non-molar
abortion on pathology and US examination [28].
The p57 gene search by immunohistochemistry, allows for distinguishing
CHM from PHM and non-molar abortions as the gene CDKN1C is maternally
expressed and therefore, can be detected only in sample with maternal
DNA. As expected, CHM is negative for p57 while non-molar and PHM
present positivity in villous stroma and cytotrophoblast cells [29].
Clinical features of patients
The clinical features of CHM and PHM depend on the
gestational age of diagnosis. Currently, due to an early detection of
failed pregnancy by ultrasonography scan associated to high level of
human chorionic gonadotropin the mean in the mean gestational age at
diagnosis of HM has been decreasing. CHM has been diagnosed at 9 weeks
and PHM at 12 weeks [6].
It contributes to a milder clinical presentation of HM resembling to
miscarriage. Vaginal bleeding remains as the most common clinical
feature occurring in 42% of cases of CHM and in 15% of cases of PHM [6].
Only 27.3% of PHM cases are diagnosed previously to evacuation and the
diagnosis is made by the histhopatological exam. Classical symptoms of
HM as hyperemesis, preeclampsia, hyperthyroidism and theca-lutein cyst
as well as respiratory distress are becoming less common. However, early
diagnosis of CHM did not reduce the progression to gestational
trophoblastic neoplasia [27]. Similar results were reported in Brazil [30].
Risk of gestational trophoblastic neoplasia
After the molar evacuation is recommended a weekly
hCG measurement until three negatives values and after that, 6 monthly
negative values in cases of CHM [31].
Some investigators have shortened the surveillance in cases of PHM to 2
negative values (<5mIU/mL). Besides the hCG surveillance it is
important the use of an effective contraceptive method. The diagnosis of
GTN is based on the FIGO 2000 criteria:
- Weekly hCG plateauing for at least 4 consecutive measurements for a period of at least 3 weeks (days 0,7,14,21),
- Weekly hCG rising for at least 3 consecutive measurements for a period of least 2 weeks (days 0,7,14)
- Persistence of hCG more than 6 months after evacuation,
- 95% of postmolar GTN are classified as low risk GTN (I to III, score 0-6) and the treatment is made with single chemotherapy agent, methotrexate or actinomicin D, reaching almost 100% of cure. High risk postmolar GTN (IV, score>7) is treated with EMA-CO and the survival in 5 years is of 8.2% [32-33].
Conclusion
CHM and PHM have been diagnosed in the first
trimester of pregnancy resulting in a further decrease in some clinical
classical presenting symptoms. The risk of development of post molar GTN
has not been affected. After molar evacuation, the HM is usually
classified based on morphological criteria and the use of
immunohistochemical and molecular methods have improved the
understanding of molar pregnancies. Further research about oncogenes and
other immunomodulator molecules are important as prognostic markers.
Confict of Interest
All contributors approved the submission to the Journal, and there is no conflict of interests.
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