1. Gestational trophoblasticdiseaseShahin Hameed

2. Synopsis Introduction Definition Classification Epidemiology Etiology Clinical features Imaging Tumour spread & staging Prognostic factors 3. Synopsis Hydatidiform mole Complete mole Partial mole Invasive mole Metastatic mole Trophoblastic tumors (neoplastic) Gestational choriocarcinoma Placental site trophoblastic tumor Epithelioid trophoblastic tumor 4. Synopsis Trophoblastic tumor like lesion (benign) Placental site nodule Exaggerated placental site Summary References 5. Introduction 6. Definition .. Gestational trophoblastic disease constitutes a diverse group of lesions that includes abnormally formed placentas (hydatidiform moles), benign nonneoplastic lesions, and gestational trophoblastic neoplasms 7. Epidemiology Gestational trophoblastic disease (GTD) varieswidely among various populations As high as 1 in 120 pregnancies in some areas ofAsia and South America 8. The incidence of hydatidiform moles is greater inwomen older than 40 years and is also increased inthose younger than 20 years. Patients who have had prior GTD are more at risk ofhaving a second GTD after subsequent pregnancies. Other risk factors include: a diet low in vitamin A,lower socioeconomic status and blood group Awomen married to group 0 men 9. Aetiology Hydatiform moles arise from abnormalconceptions. Partial moles result from diandric triploidy,whereas complete moles result from diandry(fertilization of an empty ovum) Up to 50% of choriocarcinomas and 15% ofplacental site trophoblastic tumours followcomplete moles 10. Clinical features A complete molar pregnancy - first trimesterbleeding, a uterus larger than expected forgestational age and the absence of fetal parts onultrasound in association with a markedlyelevated beta-human chorionic gonadotropin (b-hCG) level Other signs include hyperemesis, toxaemiaduring the first or second trimester, theca luteincysts and hyperthyroidism. 11. Patients with partial molar gestations-spontaneousabortions, sometimes with increased b-hCG levels. GTD should always be considered when a patienthas continued vaginal bleeding following delivery orabortion. 12. Imaging A characteristic pattern of multiple vesicles(snowstorm pattern) is commonly seen withcomplete molar pregnancy. The diagnosis of partial molar pregnancy byultrasonography is more difficult. 13. Tumour spread and staging Choriocarcinoma spreads haematogenously andmay involve the lung (57-80%), vagina (30%),pelvis (20%), brain (17%), and liver (10%) Since b-hCG titres accurately reflect the clinicaldisease, histological verification is not required fordiagnosis. Staging should be based on history, clinicalexamination and appropriate laboratory andradiological studies. 14. Metastatic GTD is categorized by the WHOscoring system as low, medium and high risk The individual scores for each prognostic factorare added together to obtain a total score A total prognostic score less than or equal to 4 isconsidered low risk, a total score of 5-7 isconsidered middle risk, and a total score of 8 orgreater is considered high risk 15. Somatic genetics Overexpression of TP53 protein more commonlyobserved in complete moles and choriocarcinoma Overexpression of the p21 gene has also beendetected in complete moles and choriocarcinoma 16. Both complete mole and choriocarcinoma exhibitoverexpression of several growth factorsincluding c-Myc, epidermal growth factorsreceptor (EGFR), c-erbB-2, Rb, mdm2, and bcl-2as compared to normal placenta and partial mole Strong immunostaining of c-erbB-3 and epidermalgrowth factor receptor in extravillous trophoblastof complete mole was significantly correlated withthe development of persistent gestationaltrophoblastic tumour 17. Prognosis and predictivefactors Major adverse prognostic variables for GTD are:(1) Age >39(2) Prior term pregnancy(3) Interval from antecedent pregnancy of >12months(4) b-hCG >105 IU/litre(5) Tumour mass >5cm(6) Disease in liver and brain(7) Failure of 2 or more prior chemotherapies 18. Hydatidiform moles 19. Definition An abnormal placenta with villous hydrops and variable degrees of trophoblastic proliferation. 20. Complete hydatidiform mole A hydatidiform mole involving most of the chorionic villi and typically having a diploid karyotype 21. Histopathology The villous hydrops of a complete mole ischaracterized by extensive cavitation. The trophoblastic proliferation has a circumferentialdistribution, hyperplasia and cytological atypia . Intermediate trophoblast of the molar implantation sitecharacteristically displays marked cytologic atypia A gestational sac, amnion, umbilical cord and fetaltissue are not found 22. Recently been suggested that villous stromal nuclear negative staining for the paternally imprinted gene product p57 maybe diagnostically useful for confirming the diagnosis of a complete mole 23. Although villous cavitation may be minimal in an"early" mole, other characteristic villous stromalfeatures are present, including hypercellularity and amyxoid basophilic stroma In addition, unusual villous shapes with complexbulbous protrusions ("cauliflower like" villi) andtrophoblastic atypia are present 24. Somatic genetics Complete moles generally have a 46,XXkaryotype, and the molar chromosomes arecompletely of paternal origin Most complete moles appear to arise from ananuclear empty ovum fertilized by a (23X) haploidsperm that then replicates its own chromosomes 25. About 10% of complete moles have a 46,XYkaryotype The 46,XY complete mole arises from fertilization ofan anuclear empty egg by two sperm. While all chromosomes in a complete mole areentirely of paternal origin, the mitochondrial DNA isof maternal origin 26. Partial hydatidiform mole A hydatidiform mole having two populations ofchorionic villi, one of normal size and the otherhydropic, with focal trophoblastic proliferation. The lesion typically has a triploid karyotype 27. Histopathology Histologically, partial moles are characterized bythe concurrence of four features(1) Two populations of villi, one hydropic and one"normal"(2) Minimal trophoblastic hyperplasia involvingsyncytiotrophoblast.(3) Enlarged cavitated villi.(4) Other villi with scalloped borders, oftencontaining trophoblastic inclusions. 28. Stromal blood vessels often contain nucleated fetal red blood cells; other evidence suggesting fetal development including portions of the chorionic sac wall, amnion, umbilical cord and embryonic/fetal tissue are common 29. Differential diagnosis(1) Complete mole.(2) Hydropic abortus .(3) Several rare sporadic genetic syndromes suchas the Beckwith-Weidemann syndrome andplacental angiomatous malformation whichcollectively have been termed "placentalmesenchymal dysplasia" 30. Somatic genetics Partial moles generally have a triploid karyotype thatresults from fertilization of an apparently normalovum by two sperm When fetuses are identified with partial moles, theyusually have stigmata of triploidy including multiplecongenital anomalies and growth retardation 31. Invasive hydatidiform mole Invasive hydatidiform mole is defined as villi ofhydatidiform mole within the myometrium or itsvascular spaces. A clinical diagnosis of invasive mole can besuspected when -hCG titers plateau or increasefollowing evacuation of a mole 32. Pathologic Features .. Grossly, invasive mole in the uterus results in an irregular, often hemorrhagic lesion that penetrates into the myometrium. The lesion can grow through the myometrium, perforating the serosa or extending into the broad ligament and adnexa Most invasive moles follow complete hydatidiform mole and have the characteristic histological appearance of that lesion. 33. Metastatic hydatidiform mole Metastatic hydatidiform mole is defined as extrauterine molar villi within blood vessels or tissues, most commonly the vagina or the lung. 34. Trophoblastic tumours(neoplastic) 35. Gestational choriocarcinomaA malignant neoplasm composed of large sheets ofbiphasic, markedly atypical trophoblast withoutchorionic villi 36. Gestational choriocarcinoma may occur subsequentto a molar pregnancy (50% of instances), anabortion (25%), a normal gestation (22.5%) or anectopic pregnancy (2.5%) In rare cases an intraplacental choriocarcinoma isdiagnosed immediately following pregnancy fromplacental pathological examination 37. Morphology The choriocarcinoma is classically a soft, fleshy, yellow-white tumor with a marked tendency to form large pale areas of ischemic necrosis, foci of cystic softening, and extensive hemorrhage 38. Histopathology The classic pattern of choriocarcinoma has been described as bilaminar, dimorphic, or biphasic. Alternating arrangement of mononucleate trophoblastic cells and syncytiotrophoblastic cells that characterize choriocarcinoma. 39. The intermediate trophoblast in choriocarcinoma may show marked variation in the degree of cytologic atypia . Nuclear pleomorphism and hyperchromasia often are striking, and nucleoli can be prominent. 40. Vascular invasion often is prominent. Chorionic villi are not a component of choriocarcinoma Choriocarcinoma lacks the intrinsic endothelium- lined vascular channels in the center of a tumor, making it a unique malignant solid tumor. 41. Immunoprofile All trophoblastic cell types are stronglyimmunoreactive for cytokeratins Inaddition, the syncytiotrophoblast is stronglyimmunoreactive for b-hCG and weaklyimmunoreactive for human placental lactogen(hPL) Intermediate trophoblast shows the oppositeimmunoprofile 42. Treatment Includes evacuation of the contents of the uterus,surgery, and chemotherapy. Chemotherapy consists of the administration ofone or more of a group of drugs includingmethotrexate, actinomycin D, and etoposide. The results of chemotherapy for gestationalchoriocarcinoma are spectacular and haveresulted in up to 100% cure or remission in allpatients except some who had high-riskmetastatic trophoblastic disease. 43. Differential diagnosis The differential diagnosis of choriocarcinoma in endometrial curettings includes previllous trophoblast from an early gestation persistent molar tissue following hydatidiform mole placental site trophoblastic tumour epithelioid trophoblastic tumour undifferentiated carcinoma. 44. Somatic genetics Recent studies using cDNA microarray analysis have demonstrated decreased expression of heat shock protein-27 in choriocarcinoma, a finding which has been associated with chemotherapy responsiveness in other cancers 45. Placental site trophoblastictumour A monophasic neoplasm composed of intermediate trophoblast and cytotrophoblast without a significant component of syncytiotrophoblast 46. PSTTs comprise less than 2% of gestationaltrophoblastic neoplasms and present asneoplastic polygonal cells infiltrating theendomyometrium. PSTTs may be preceded by a normal pregnancy(one-half), spontaneous abortion (one-sixth), orhydatidiform mole (one-fifth) 47. Histopathology The tumour cells are medium to large sized andmononuclear or multinucleated with mild tomarked nuclear atypia, prominent nucleoli,eosinophilic to clear cytoplasm, scattered mitosesand occasional intranuclear inclusions They permeate the myometrium and vessels in amanner reminiscent of the implantation sitetrophoblast. 48. Differential diagnosis The differential diagnosis of placental site trophoblastic tumour includes Placental site nodule Exaggerated implantation site Epithelioid leiomyosarcoma Epithelioid trophoblastic tumour Poorly differentiated carcinoma . Extensive sampling and immunohistochemistry for keratin, b-hCG and hPL are helpful in distinguishing among the above lesions 49. Somatic genetics A Y- chromosomal locus and/or new (paternal) alleles not present in adjacent normal uterine tissue was demonstrated in all cases of placental site trophoblastic tumour studied confirming the placental origin of these neoplasms 50. Prognosis and predictive factors Patients with localized (Stage I or II) disease or a lessthan 2-year interval from the prior pregnancy todiagnosis have an excellent prognosis. Tumors diagnosed 4 or more years followingpregnancy, with lung involvement or with advancedstage have a poor prognosis. An elevated mitotic index predicts a poor outcome 51. Epithelioid trophoblastictumour A tumour composed of a monomorphic population of intermediate trophoblastic cells closely resembling those of the membranous chorion 52. Histopathology Tumour cells of the epithelioid trophoblastic tumour are smaller and less pleomorphic and grow in a nodular pattern 53. Because they are frequently found in the cervix,they may be confused with hyalinizing squamouscell carcinomas . Epithelioid trophoblastic tumours are focallyimmunoreactive for placental-like alkalinephosphatase (PLAP) and hPL but strongly anddiffusely immunoreactive for E-cadherin andepidermal growth factor receptor 54. Somatic genetics A Y-chromosomal locus and/or new (paternal) alleles not present in adjacent normal uterine tissue was demonstrated in all cases of epithelioid trophoblastic tumour studied 55. Prognosis and predictive factors Based on available data, the behaviour of epithelioid trophoblastic tumour resembles that of placental site trophoblastic tumour. 56. Trophoblastic tumours like lesions(benign) 57. Placental site nodule or plaque The placental site nodule or plaque is a wellcircumscribed lesion with abundant hyalinizedstroma infiltrated by scattered, degenerated-appearing intermediate trophoblastic cells that arenormally located on the fetal membrane These cells show no significant cytological atypia,but rare mitoses may be present 58. Pathologic Features Microscopically, the placental site nodule has adiscrete, well-circumscribed, lobulated bordersometimes showing small irregular nests of cellsprojecting into the surrounding tissue. Cluster of hyperchromatic and vacuolatedchorionic type intermediate trophoblast cellsembedded in hyaline matrix 59. Immunohistochemistry Strongly and diffusely positive for low-molecular-weight cytokeratin (CK; such as CK8/18) Only focally positive for human placental lactogen(hPL) and CD146 (Mel-CAM) Negative for mucin-4 60. The chorionic-type intermediate trophoblastic cells inplacental site nodules are positive for p63 There is a low level of proliferation in the cells ofplacental site nodules as indicated by a fewscattered Ki-67 labeled nuclei 61. Differential Diagnosis Small size, circumscription, extensive eosinophilic extracellular matrix, and paucity of mitotic figures distinguish this lesion from PSTT, ETT, and cervical squamous carcinoma The Ki-67 index in ETTs is significantly higher (>10%) than in placental site nodules (