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EPIDEMIOLOGY AND MOLECULAR
PATHOGENESIS OF GESTATIONAL
TROPHOBLASTIC DISEASES
DR. N SRAVANTHI
FELLOW IN GYNAECOLOGICAL ONCOLOGY
KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY
INTRODUCTION
• Gestational trophoblastic diseases (GTD) represents a derangement in the development of the conceptus, associated with unregulated trophoblastic proliferation and invasion, with the propensity for hematogenous metastasis in GTN.
• The diseases are characterized by paraneoplastic disorders from secretion of gestational hormones, most notably hCG.
• GTD is the only group of female reproductive neoplasms derived from paternal genetic material (androgenic origin).
CLASSIFICATIONHydatidiform mole
• Complete HM
• Partial HM
• Invasive Mole
Trophoblastic tumors• Benign
• Placental site nodule (PSN)
• Exaggerated placental site (EPS)
• Neoplastic
• Gestational choriocarcinoma
• Placental site trophoblastic tumor (PSTT)
• Epithelioid trophoblastic tumor (ETT)
INCIDENCE OF GTD
• Dramatic differences in incidence rates for GTD reported from hospitals and regions throughout the world.
• The problems in accumulating reliable epidemiologic data can be attributed to a number of factors, such as
• inconsistencies in case definitions,
• inability to adequately characterize the population at risk,
• no centralized databases,
• lack of well-chosen control groups against which to compare possible risk factors,
• and rarity of the diseases
INCIDENCE OF GTD• Reported incidence varies worldwide.• Lowest in Paraguay - 23 per 100,000 pregnancies
• Highest in Indonesia 1299 per 100,000 pregnancies
• In United States -
• GTDs = 110 - 120 per 100,000 pregnancies
• Choriocarcinoma = 2 - 7 per 100,000 pregnancies
• Age standardized incidence rate of choriocarcinoma = 0.18 per 100,000 women (Between 15 - 49 years with 1960 world population as standard).
National cancer institute, Cancer.Gov, 2015
INCIDENCE OF GTD
• In Indian Population, Incidence of choriocarcinoma is 19.1 per 1000 pregnancies.
Pai KN. (1967)
A study of choriocarcinoma: its incidence in India and its aetiopathogenesis.
In Choriocarcinoma: Transactions of a Conference of the International Union Against Cancer (Eds JM. Holland, M Hreshchyshyn),Springer-Verlag, Berlin, p.54—7.
RISK FACTORS
• The two established risk factors that have emerged are
Extremes of maternal age and
Prior molar pregnancy
• A variety of exposures have been examined, with no clear associations found
with tobacco smoking, alcohol consumption, diet, and oral contraceptive use.
• Association with paternal age is inconsistent
Altieri A, Franceschi S, Ferlay J, et al.
Epidemiology and aetiology of gestational trophoblastic diseases.
Lancet Oncol 4 (11): 670-8, 2003.
RISK FACTORS – “MATERNAL AGE”
• Advanced or very young maternal age has consistently correlated with higher
rates of complete hydatidiform mole.
• The risk associated with maternal age is bimodal, with increased risk both for
mothers younger than 20 years and older than 35 years (and particularly for
mothers >45 years).
• Relative risk ranges from 1.1 to 11 for both the younger and older age ranges
compared with ages 20 to 35 years.
RISK FACTORS – “MATERNAL AGE”
• Compared to women aged 21-35 years, the risk of complete mole is
1.9 times higher for women both >35 years and <21 years as well
as 7.5 times higher for women > 40 years.
RISK FACTORS – “PREVIOUS GTD”
• After one molar pregnancy : risk of subsequent CHM or PHM is
1 – 2 %.
• After two molar gestations : risk of third mole is 15 – 20%.
Bagshaw et. Al. Lancet 1986
Garret et al. J. Reprod Med 2008
Sebire Nj et al. BJOG 2003
• Risk is not decreased by change of partner.
Tuncer et. al. Gynecol Oncol 1999
MOLECULAR PATHOGENESIS
CYTOGENETICSComplete Hydatidiform Mole (CHM)• DIPLOID
• 46 XX karyotype, Androgenetic
• Genetic material is exclusively derived from paternal DNA.
• Around 10% 46 XY (Dispermic fertilization)
Partial hydatidiform Mole (PHM)
• TRIPLOID
• 69XXX/ 69XXY (Diandric)
• haploid set of maternal DNA and two sets of paternal DNA
DiSaia; Clinical Gynaecological oncology 8th Ed
CYTOGENETICS
• Patients with recurrent disease can have biparental molar rather than typical androgenetic disease, which might be familial or sporadic.
• Genetic studies in such families showed that the related genes are at chromosome 19q13.3–13.4,31 and subsequent analysis noted NLRP7 mutations in this region.
CYTOGENETICS
• Data show clustering of mutations in the leucine-rich region of NLRP7, suggesting that this region is crucial for normal function.
• Some androgenetic diploid complete moles and possibly even triploid partial hydatidiform moles might also carry NLRP7 mutations, but confirmation from large studies is needed.
Deveault et al,
NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation
Human Molecular Genetics, 2009, Vol. 18, No. 58; 888-897
IMMUNOHISTOCHEMISTRY• Cytotrophoblast is typically positive for keratins and CD10, but
negative for hCG, inhibin, and HPL, while• syncytiotrophoblast cells are strongly positive for hCG, placental
lactogen alkaline phosphatase (PLAP), inhibin, and CD10, but weakly positive for hPL.
• p57 is a paternally imprinted, maternally expressed gene for which immunohistochemistry has recently become available.
• As CHM are androgenetic in origin, this paternally derived gene is not expressed in stromal villous cells and cytotrophoblast, in contrast to positive staining in cytotrophoblast and stromal cells of PHM.
• Thus, p57 can serve as a reliable marker for the diagnosis of CHM.
IMMUNOHISTOCHEMISTRY
• p57 is a paternally imprinted, maternally expressed gene for which immunohistochemistry has recently become available.
• Serves to inhibit cell proliferation and to suppress tumor growth. Lack of expression in trophoblastic disease plays a role in its abnormal proliferation and differentiation
• As CHM are androgenetic in origin, this paternally derived gene is not expressed in stromal villous cells and cytotrophoblast, in contrast to positive staining in cytotrophoblast and stromal cells of PHM.
• Thus, p57 can serve as a reliable marker for the diagnosis of CHM.
PATHOLOGY
CELLULAR CLASSIFICATIONHydatidiform mole
• Complete HM
• Partial HM
• Invasive Mole
Trophoblastic tumors• Benign
• Placental site nodule (PSN)
• Exaggerated placental site (EPS)
• Neoplastic
• Gestational choriocarcinoma
• Placental site trophoblastic tumor (PSTT)
• Epithelioid trophoblastic tumor (ETT)
PATHOLOGY
• Molar pregnancies and gestational trophoblastic neoplasms all take their origin
from the placental trophoblast.
• Normal trophoblast is composed of cytotrophoblast, syncytiotrophoblast, and
intermediate trophoblast.
• Syncytiotrophoblast invades the endometrial stroma with implantation of the
blastocyst and is the cell type that produces human chorionic gonadotropin (hCG).
Villous IT Implantation IT Chorionic IT
Reservoir for IT, endo invasion Feto maternal circulationImmunologic bar
Ground substance
Beta HCG
Cytoytophoblast Intermed trophoblast Syncyt trophoblast
•
Intermediate Trophoblast
Syncytiotrophoblast
Cytotrophoblast–reserve cell
Inhibin
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