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EPIDEMIOLOGY AND MOLECULAR PATHOGENESIS OF GESTATIONAL TROPHOBLASTIC DISEASES DR. N SRAVANTHI FELLOW IN GYNAECOLOGICAL ONCOLOGY KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY

Epidemiology and molecular pathogenesis of gtn

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Page 1: Epidemiology and molecular pathogenesis of gtn

EPIDEMIOLOGY AND MOLECULAR

PATHOGENESIS OF GESTATIONAL

TROPHOBLASTIC DISEASES

DR. N SRAVANTHI

FELLOW IN GYNAECOLOGICAL ONCOLOGY

KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY

Page 2: Epidemiology and molecular pathogenesis of gtn

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).

Page 3: Epidemiology and molecular pathogenesis of gtn

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)

Page 4: Epidemiology and molecular pathogenesis of gtn

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

Page 5: Epidemiology and molecular pathogenesis of gtn

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

Page 6: Epidemiology and molecular pathogenesis of gtn

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.

Page 7: Epidemiology and molecular pathogenesis of gtn

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.

Page 8: Epidemiology and molecular pathogenesis of gtn

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.

Page 9: Epidemiology and molecular pathogenesis of gtn

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.

Page 10: Epidemiology and molecular pathogenesis of gtn

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

Page 11: Epidemiology and molecular pathogenesis of gtn

MOLECULAR PATHOGENESIS

Page 12: Epidemiology and molecular pathogenesis of gtn

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

Page 13: Epidemiology and molecular pathogenesis of gtn
Page 14: Epidemiology and molecular pathogenesis of gtn

DiSaia; Clinical Gynaecological oncology 8th Ed

Page 15: Epidemiology and molecular pathogenesis of gtn

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.

Page 16: Epidemiology and molecular pathogenesis of gtn

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

Page 17: Epidemiology and molecular pathogenesis of gtn

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.

Page 18: Epidemiology and molecular pathogenesis of gtn

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.

Page 19: Epidemiology and molecular pathogenesis of gtn

PATHOLOGY

Page 20: Epidemiology and molecular pathogenesis of gtn

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)

Page 21: Epidemiology and molecular pathogenesis of gtn

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).

Page 22: Epidemiology and molecular pathogenesis of gtn

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

Page 23: Epidemiology and molecular pathogenesis of gtn

Inhibin

Page 24: Epidemiology and molecular pathogenesis of gtn

THANK YOU