Epidemiology and molecular pathogenesis of gtn
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Gestational trophoblastic diseases (GTD) are a group of pregnancy-related neoplasms originating from abnormal proliferation of trophoblast cells. They range from benign conditions like complete and partial hydatidiform moles to malignant tumors such as choriocarcinoma. The incidence of GTD varies significantly worldwide depending on factors like maternal age, prior molar pregnancies, and ethnicity. Molecular studies show that complete hydatidiform moles have a paternal chromosomal contribution and lack expression of maternally imprinted genes like p57, distinguishing them from partial moles which are triploid. Immunohistochemistry is useful in diagnosis and classification of GTD.
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Epidemiology and molecular pathogenesis of gtn
- 1. EPIDEMIOLOGY AND MOLECULAR PATHOGENESIS OF GESTATIONAL TROPHOBLASTIC DISEASES DR. N SRAVANTHI FELLOW IN GYNAECOLOGICAL ONCOLOGY KIDWAI MEMORIAL INSTITUTE OF ONCOLOGY
- 2. 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).
- 3. CLASSIFICATION Hydatidiform 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)
- 4. 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
- 5. 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
- 6. 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.
- 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.
- 8. 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.
- 9. 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.
- 10. 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
- 12. CYTOGENETICS Complete 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
- 14. DiSaia; Clinical Gynaecological oncology 8th Ed
- 15. 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.
- 16. 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
- 17. 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.
- 18. 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.
- 19. PATHOLOGY
- 20. CELLULAR CLASSIFICATION Hydatidiform 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)
- 21. 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).
- 22. 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
- 23. Inhibin
- 24. THANK YOU
Editor's Notes
- Before 1969 metastatic choriocarcinoma was nearly invariably fatal, whereas most patients are now cured and usually retain reproductive function. The basis for this dramatic change is earlier diagnosis, the ability to precisely measure human chorionic gonadotrophin (hCG) and the availability of effective chemotherapy. Trophoblastic disease needs to be treated by, or at least in consultation with, physicians experienced in the management of this disease spectrum. The morbidity and mortality is 9 times higher when the inexperienced physician treats such patients.
- The incidence and etiologic factors contributing to the development of GTD have been difficult to characterize. 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.4 Epidemiologic studies have reported wide regional variations in the incidence of hydatidiform mole.5 Estimates from studies conducted in North America, Australia, New Zealand, and Europe have shown the incidence of hydatidiform mole to range from 0.57–1.1 per 1000 pregnancies, whereas studies in Southeast Asia and Japan have suggested an incidence as high as 2.0 per 1000 pregnancies. 6 Investigations into possible ethnic and racial differences leading to an increased incidence of hydatidiform mole among American Indians, Eskimos, Hispanics, and African Americans as well as various Asian populations have not been able to attribute them to genetic traits, cultural factors, or simply differences in reporting.7-9 Data with respect to choriocarcinoma incidence rates are even more limited. Collection of data on the incidence of choriocarcinoma has been more difficult not only for reasons similar to those encountered with hydatidiform moles, but also because of the rarity of choriocarcinoma and the difficulty in clinically distinguishing postmolar choriocarcinoma from invasive mole. In Europe and North America, choriocarcinoma affects approximately 1 in 40,000 pregnancies and 1 in 40 hydatidiform moles, whereas in Southeast Asia and Japan choriocarcinoma rates are higher at 9.2 and 3.3 per 40,000 pregnancies, respectively. The incidence rates of both hydatidiform mole and choriocarcinoma have declined over the past 30 years in all populations.10,11
- NLRP7 is a cytoplasmic protein whose transcripts were found in a wide range of normal human tissues including oocytes at the germinal vesicle and metaphase II stages, Fallopian tubes (unpublished data) and endometrium (24,25). A recent study has shown that NLRP7 transcription declines during development from oocytes to day 3 but increases again by day 5 (25). To date, it is not clear how NLRP7 defects lead to RHMs and associated reproductive wastage. As a maternal effect gene, NLRP7 could cause recurrent fetal loss by leading to defective oocytes or/and by creating a hostile maternal environment for embryonic development in the Fallopian tubes and the uterine cavity. We recently demonstrated that patients with NLRP7 mutations have impaired inflammatory response against various stimuli, such as lipopolysaccharides, various microbial products and synthetic compounds, which induce strong inflammatory response in normal individuals (Deveault, manuscript in preparation).
- Cytotrophoblast: ● Present in early gestation; differentiates into villous or extravillous trophoblast (see below) and forms syncytiotrophoblasts by fusing on villous surface ● They are inconspicuous in term placenta ● Micro: small, round mononuclear cells with distinct cell border, minimal clear or eosinophilic cytoplasm and single vesicular nuclei ● Positive stains (early placenta): AE1/AE3 (keratin) and Ki-67 (25-50%) ● Negative stains (early placenta): EMA, hCG, HLA-G, HNK-1, HPL, inhibin-alpha, Mel-CAM (CD146) and PLAP Intermediate implantation site and extravillous (X-cells) trophoblasts: ● Infiltrate decidua and myometrium of placental site, invade and replace spiral arteries of the basal plate to establish maternal-fetal circulation and keep vessels patent ● Form trophoblastic shell ● Secrete PTH-related protein ● Micro: located in the basal plate, septa and chorion lavae; morphology varies by location In the basal plate, they are enlarged polyhedral to spindle cells with abundant amphophilic and vacuolated cytoplasmic and large, hyperchromatic nuclei and may resemble adjacent decidua In myometrium are more spindled and resemble adjacent smooth muscle cells; may fuse to become multinucleated cells (Am J Surg Pathol 1992;16:1226) ● Positive stains: cytokeratin (Mod Pathol 1990;3:282), hCG in multinucleated cells, HLA-G, hPL, Mel-CAM and PLAP (weak) ● Negative stains: EMA (usually), HNK-1 and Ki-67 ● Micro images: Intermediate trophoblast cells Intermediate villous trophoblast: ● Form the inner layer of the villous trophoblastic mantle ● Micro: larger than cytotrophoblasts, polygonal, abundant clear or eosinophilic cytoplasm, distinct cell borders and single nuclei ● Positive stains: cytokeratin, EMA, HLA-G, hPL and MEL-CAM (in cells with eosinophilic cytoplasm; towards distal end only), PLAP (in clear cells), Ki-67 (3-10%; >90%) ● Negative stains: EMA, hCG, hPL (may be weak), PLAP and HNK-1 ● Additional References: Am J Surg Pathol 2002;26:914 Syncytiotrophoblast: ● Form the outer layer of the villous trophoblastic mantle ● Synthesize and secrete hCG, hPL ● Micro: multinucleated giant cells with abundant eosinophilic or basophilic cytoplasm, often with multiple intracytoplasmic vacuoles and dense pyknotic nuclei ● Positive stains: hCG, hPL and inhibin-alpha ● Negative stains: HLA-G, Ki-67, Mel-CAM and PLAP ● EM description: vacuoles are due to dilated endoplasmic reticulum and lacunae from plasma membrane infoldings Hofbauer cells: ● Fetal macrophages located in villous stroma ● Micro: round-to-ovoid cells with eccentric nuclei and granular cytoplasm
- P57kip2 is the protein product of a paternally imprinted or maternal gene that inhibits cyclin-dependent kinases (CDK), thus serving to inhibit cell proliferation and to suppress tumor growth. Its lack of expression in trophoblastic disease plays a role in its abnormal proliferation and differentiation. P57kip2 immunohistochemical staining was absent in the trophoblastic layers of CHM and was positive in the trophoblastic layer of nonmolar villi and mesenchymal dysplasia
- Mel-CAM stains implantation-site intermediate trophoblastic cells, HLA-G stains intermediate trophoblastic cells, and CD10 is positive in most trophoblastic cell populations. α-inhibin stains syncytiotrophoblast and some intermediate trophoblastic cells, but not cytotrophoblast cells.