gestational trophoblastic diseases

GESTATIONAL TROPHOBLASTIC DISEASES:

GESTATIONAL TROPHOBLASTIC DISEASES

GESTATIONAL TROPHOBLASTIC DISEASES:

GESTATIONAL TROPHOBLASTIC DISEASES DEFINITION : A spectrum of tumors & tumor like conditions characterized by proliferation of pregnancy associated trophoblastic tissue of progressive malignant potential.

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Three components make up the trophoblast: cytotrophoblast, syncytiotrophoblast intermediate trophoblast The cytotrophoblast is a stem cell with high mitotic activity but without hormonal synthesis. The syncytiotrophoblast, which constitutes the villous trophoblast, has low mitotic activity. The syncytiotrophoblast is responsible for the synthesis of the (beta-hCG) and can be identified with immunohistochemical stains. The intermediate trophoblast has features of the other two components and is responsible for endometrial invasion and implantation

GESTATIONAL TROPHOBLASTIC DISEASES:

GESTATIONAL TROPHOBLASTIC DISEASES WHO CLASSIFICATION (modified) HYDATIDIFORM MOLE 1. COMPLETE 2. PARTIAL INVASIVE MOLE CHORIOCARCINOMA PLACENTAL SITE TROPHOBLASTIC TUMOR EPITHELOID TROPHOBLASTIC TUMOR MISCELLANEOUS TROPHOBLASTIC LESIONS 1. EXAGGERATED PLACENTAL SITE 2. PLACENTAL SITE NODULE

HYDATIDIFORM MOLE:

HYDATIDIFORM MOLE DEFINITION : CYSTIC SWELLING OF THE CHORIONIC VILLI, ACCOMPANIED BY VARIABLE TROPHOBLASTIC PROLIFERATION

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Incidence: 1:2000 pregnancies in United States and Europe 1:200 in Asia 10 times more in women over 45 years old. The increasing use of ultrasound in early pregnancy has probably led to the earlier diagnosis of molar pregnancy

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1 -Maternal age : Young mothers (under age 20 years) have a slightly higher prevalence of GTD, although not nearly so great as those mothers over age 35 years. 2- Women who have had a previous molar gestation 3- The risk increases with the number of spontaneous abortions . 4- Women with blood type A may be more likely to develop choriocarcinoma (but not hydatidiform mole); Hydatidiform Mole RISK FACTORS:

Hydatidiform Mole:

Hydatidiform Mole A hydatidiform mole is an abnormality of fertilization It is the result of fertilization of anucleated ovum ( has no chromosomes) with a sperm which will duplicate giving rise to 46 chromosomes of paternal origin only. It is the result of fertilisation of an ovum by 2 sperms so the chromosomal number is 69 chromosomes COMPLETE MOLE PARTIAL MOLE

PATHOGENESIS:

PATHOGENESIS Two sperms fertilize a single ovum, Development of certain or all fetal parts Triploid karyotype of 69XXX, 69XXY, OR 69XYY. Diploid or tetraploid karyotype may exist.

PATHOGENESIS:

PATHOGENESIS 69xxx 69xxy 69xyy 46xxy

Differentiation Between Complete And Partial Mole :

Differentiation Between Complete And Partial Mole Partial Mole Complete Mole Feature Present Absent Embryonic or foetal tissue Focal Diffuse Swelling of the villi Focal Diffuse Trophoblastic hyperplasia Paternal and maternal 69 XXY or 69 XYY Paternal 46 XX (96%) or 46 XY (4%) Karyotype Rare 5-10% Malignant Changes

PARTIAL HYDATIDIFORM MOLE :

PARTIAL HYDATIDIFORM MOLE CLINICAL PRESENTATION: Late 1 st or early 2 nd trimester spontaneous abortion Occasionally presents with incerased maternal hCG

PARTIAL HYDATIDIFORM MOLE :

PARTIAL HYDATIDIFORM MOLE GROSS: Spongy villous tissue with small 1 – 2 mm fluid filled vesicles. Fetal fragments or malformed fetus may be seen occasionally

PARTIAL HYDATIDIFORM MOLE :

PARTIAL HYDATIDIFORM MOLE MICROSCOPIC: DIAGNOSTIC CRITERIA – Villous trophoblastic hyperplasia ( usually predominantly syncytiotrophoblast ) Dimorphic population of large & small villi without intermediate forms Hydropic villi > 0.5 mm Irregular villous contour often with multicellular trophoblast inclusions within villous stroma

PARTIAL HYDATIDIFORM MOLE :

PARTIAL HYDATIDIFORM MOLE MICROSCOPIC: OTHER CRITERIA – Maze like villous capillary vascular pattern Atypical implantation site trophoblast Molar villi with well defined central cisterns Villous stromal karyomegaly ( nuclei 2 – 3 times normal size)

PARTIAL HYDATIDIFORM MOLE differential diagnosis:

PARTIAL HYDATIDIFORM MOLE differential diagnosis HYDROPIC ABORTU S Lacks dimorphic population: large & small villi with intermediate forms Generally lacks vilious trophoblast hyperplasia Lacks atypical implantation site COMPLETE HYDATIDIFORM MOLE Uniform hydropic villi with central cisterns Lacks secondary population of small villi Villous trophoblast hyperplasia is generally more diffuse & atypical, & involves cytotrophoblast & syncytiotrophoblast equally.

COMPLETE HYDATIDIFORM MOLE :

COMPLETE HYDATIDIFORM MOLE CLINICAL PRESENTATION : Early presentation ( < 8 wks) 1) Anembryonic missed abortion by USG Late presentation ( > 8 wks) 1) large for dates 2) vaginal bleeding 3) elevated hCG 4) hyperemesis , preeclampsia, thyrotoxicosis , or bilateral adenexal masses

COMPLETE HYDATIDIFORM MOLE:

COMPLETE HYDATIDIFORM MOLE GROSS: Described as a “ bunch of grapes “ Individual vesicles measure between 1 mm to 30 mm in diameter. Total weight is usually over 200 g There is no identifiable embryo, cord or amniotic membranes

COMPLETE HYDATIDIFORM MOLE:

COMPLETE HYDATIDIFORM MOLE MICROSCOPIC: CLASSIC COMPLETE HYDATIDIFORM MOLE Diffuse, circumferential villous trophoblast hyperplasia Involves both cyto & syncytiotrophoblast Uniform hydropic villi , many with well defined central cisterns Lack of fetal vessels & nucleated RBC’s Frequent atypical implantation site

COMPLETE HYDATIDIFORM MOLE:

COMPLETE HYDATIDIFORM MOLE MICROSCOPIC: EARLY COMPLETE HYDATIDIFORM MOLE Focal cytotrophoblast & syncytiotrophoblast hyperplasia of both villi & undersurface of the chorion Redundant bulbous terminal villi ( + focal hydrops ) Hypercellular myxoid villous stroma often with stromal karyorrhexis Labyrinthine network of villous stromal canaliculi Atypical implantation site Fetal vessels or nucleated RBC’s may be seen.

COMPLETE HYDATIDIFORM MOLE:

COMPLETE HYDATIDIFORM MOLE IMMUNOHISTOCHEMISTRY P57KIP2 immunostaining is negative in the nuclei of stromal & cytotrophoblast cells in complete mole Positive in partial mole & hydropic abortus

COMPLETE HYDATIDIFORM MOLE differential diagnosis:

COMPLETE HYDATIDIFORM MOLE differential diagnosis HYDROPIC ABORTUS Generally lacks trophoblast hyperplasia Lacks atypical implantation site Hypocellular vilous stroma & intervillous fibrin p57KIP2 Positive PARTIAL HYDATIDIFORM MOLE p57KIP2 Positive

INVASIVE MOLE:

INVASIVE MOLE Also known as chorioadenoma destruens A hydatidiform mole in which villi penetrate deeply into the myometrium &/or its blood vessels Nearly always of complete type but occasionally of partial type Occurs in 16 % of all complete moles Due to exaggerated expression of the capacity of normal trophoblast for invasion.

INVASIVE MOLE:

INVASIVE MOLE The myometrial penetration in invasive mole is usually extensive & may lead to persistent hemorrhage, but serosa is usually intact. Vascular onvasion may result in trophoblastic nodules in sites outside uterus, such as vagina, lung, brain & spinal cord. Invasive mole has all features of a malignant neoplasm except that it is self limited. It invades the stroma , produces tumor emboli, & it metastasizes distantly.

INVASIVE MOLE:

INVASIVE MOLE The Invasive mole is distinguished from the usual mole by its invasiveness & from choriocarcinoma by the presence of villi , which are also present in the “metastatic foci“.

CHORIO CARCINOMA:

CHORIO CARCINOMA Clinical features : Rapidly growing & invasive , with frequent metastasis. Generally curable with multiagent chemotherapy Can follow any pregnancy at any stage

CHORIO CARCINOMA:

CHORIO CARCINOMA Clinical features : Frequency of preceding pregnancy types : Hydatidiform mole – 45 % Term pregnancy – 25% Spontaneous abortion – 25 % Ectopic pregnancy – 5 %

CHORIO CARCINOMA:

CHORIO CARCINOMA Cytogenetics Diploid or near diploid, with frequent polyploid subpopulations Gains or losses of chromosomes 1,3,8,10 & 12

CHORIO CARCINOMA:

CHORIO CARCINOMA Clinical staging : - 0 elevated hCG - 1 uterine corpus involvement - 2 lung metastases - 3 pelvic and/ or vaginal metastases - 4 distant metastases

CHORIO CARCINOMA:

CHORIO CARCINOMA Adverse prognostic factors: Older age Preceding nonmolar pregnancy Longer interval to preceding pregnancy Tumor size > 5 cm hCG level > 10^5 mIU /liter Number of metastases Metastases to brain, liver or GI tract Previous chemotherapy

CHORIO CARCINOMA:

CHORIO CARCINOMA Gross findings: Soft, dark red, hemorrhagic, round nodular tumor masses.

CHORIO CARCINOMA:

CHORIO CARCINOMA Microscopic findings: Clusters of cytotrophoblast separated by streaming masses of syncytiotrophoblast Dimorphic plexiform pattern Hemorrhage & necrosis usually + nt Villi are characteristically absent, there presence is said to rule out the diagnosis of choriocarcinoma

CHORIO CARCINOMA:

CHORIO CARCINOMA Microscopic findings in other organs: Due to increased secretions of hCG & other hormones by tumor cells Hyperplasia of endocervical glands Decidual reaction (both endometrial & ectopic) Arias stella phenomenon Bilateral enlargement of the ovaries by theca lutein cyst ( “ hyperreactio luteinalis) Detection of theca lutein cyst long after after a case treated, is usually a sign of persistent disease Hyperplasia of mammary lobules

CHORIO CARCINOMA:

CHORIO CARCINOMA IMMUNOHISTOCHEMISTRY: CYTOTROPHOBLAST SYNCYTIO TROPHOBLAST CYTOKERATIN + VE +VE hCG -- +VE hPL -- +VE PLAP -- Variable Desmin -- -- Vimentin -- -- CEA -- -- AFP -- --

CHORIO CARCINOMA: differential diagnosis:

CHORIO CARCINOMA: differential diagnosis Placental site trophoblasic tumor Less hemorrhagic by gross examination Tumor cells have dense eosinophillic cytoplasm & larger , more irregular & hyperchromatic nuclei than malignant cytotrophoblast Syncytiotrophoblasts are rare Epitheloid trophoblastic tumor Tumors with features intermediate between choriocarcinoma & PSTT Extremely rare; tumors are often seen in patients with previously treated choriocarcinoma

PLACENTAL SITE TROPHOBLASTIC TUMOR :

PLACENTAL SITE TROPHOBLASTIC TUMOR Placental site trophoblastic tumor is currently accepted term for a rare form of trophoblastic disease formely described as Atpical choriocarcinoma & trophoblastic pseudotumor About 75 % cases follow a normal pregnancy, with only 5 % of the reported patients having had a preceding molar pregnancy.

PLACENTAL SITE TROPHOBLASTIC TUMOR:

PLACENTAL SITE TROPHOBLASTIC TUMOR Clinical features : Rare , generally indolent tumors 15 % to 20 % manifest malignant behaviour Resistant to chemotherapy Low serum hCG, generally < 10,000 mIU /ml

PLACENTAL SITE TROPHOBLASTIC TUMOR :

PLACENTAL SITE TROPHOBLASTIC TUMOR Gross findings: Presents as a uterine mass; generally nodular or polypoid . Occasionally diffusely infiltrative

PLACENTAL SITE TROPHOBLASTIC TUMOR :

PLACENTAL SITE TROPHOBLASTIC TUMOR Microscopic findings: Cohesive sheets of mononuclear intermediate trophoblast Zonal necrosis & prominent vascular invasion & remodelling Individual cells generally mononuclear Occasionally binucleate with abundant eosinophillic cytoplasm Enlarged, round to oval nuclei with coarse clumped chromatin & prominent nucleoli

PLACENTAL SITE TROPHOBLASTIC TUMOR :

PLACENTAL SITE TROPHOBLASTIC TUMOR IMMUNOHISTOCHEMISTRY: hPL strongly +ve while hCG is focally +ve Keratin +ve CD66a(CEACAM1) +ve CD146(Mel-CAM) +ve Pregnancy associated major basic protein +ve HLA -G

PLACENTAL SITE TROPHOBLASTIC TUMOR : differential diagnosis:

PLACENTAL SITE TROPHOBLASTIC TUMOR : differential diagnosis Placental site nodule Well circumscribed aggregates of intermediate trophoblast embedded in a fibrinoid matrix Low cellularity Bland cytologic features Cytokeratin +ve hPL, hCG, PLAP variable Exaggerated implantation site Seen with abortions Intermediate trophoblast infiltrate decidua & myometrium as single or small groups of cells Multinucleate placental site giant cells Lacks necrosis & destructive myometrial invasion

EPITHELIOID TROPHOBLASTIC TUMOR:

EPITHELIOID TROPHOBLASTIC TUMOR Clinical features : Rare , generally presents with vaginal bleeding - extra uterine disease common - 50 % follow a previous hydatidiform mole or choriocarcinoma, often after a long interval Can develop from a resistant nodule within choriocarcinoma following multi agent chemotherapy Low serum hCG level < 10,000 mIU /ml

EPITHELIOID TROPHOBLASTIC TUMOR:

EPITHELIOID TROPHOBLASTIC TUMOR Gross findings: Presents as a uterine or cervical mass; generally nodular. Solid & cystic Discrete & hemorrhagic

EPITHELIOID TROPHOBLASTIC TUMOR:

EPITHELIOID TROPHOBLASTIC TUMOR Microscopic findings: Composed of relatively uniform population of intermediate trophoblastic cells forming nests & solid masses. Extensive necrosis. Hyaline matrix with geographic configuration. Appearance closely simulates carcinoma.

EPITHELIOID TROPHOBLASTIC TUMOR :

EPITHELIOID TROPHOBLASTIC TUMOR IMMUNOHISTOCHEMISTRY: diffuse reactivity for :- Keratin +ve Alpha – inhibin +ve EMA +ve E- Cadherin +ve hCG & Hpl focally +ve

EPITHELIOID TROPHOBLASTIC TUMOR : differential diagnosis:

EPITHELIOID TROPHOBLASTIC TUMOR : differential diagnosis Chorio carcinoma No multi nucleate syncytiotrophoblast Less associated hemorrhage More abundant cytoplasm in mononuclear tumor cells Lower serum hCG titers Placental site trophoblastic tumor Intermediate trophoblast lacks abundant eosinophillic cytoplasm Negative or focal HPL immunopositivity Lacks implantation site arterial remodelling Higher serum hCG titers

EPITHELIOID TROPHOBLASTIC TUMOR : differential diagnosis:

EPITHELIOID TROPHOBLASTIC TUMOR : differential diagnosis Squamous cell carcinoma ETT lacks positivity for HPV Expresses cytokeratin & alpha inhibin ETT lacks overlying squamous atypia Epithelioid leiomyosarcoma ETT lacks positivity for smooth muscle markers ETT exprssses low & high MW keratins ETT lacks typical smooth muscle cells

EXAGGERATED PLACENTAL SITE REACTION (EPSR) :

EXAGGERATED PLACENTAL SITE REACTION (EPSR) Also known as syncytial endometritis in past. Result of excessive but otherwise normal infiltration of the implantation site by intermediate trophoblast EPSR is to be favored when the lesion is :- Microscopic in size Lacks mitotic activity Hyaline material between trophoblastic cells Admixed with decidua & villi

EXAGGERATED PLACENTAL SITE REACTION (EPSR) :

EXAGGERATED PLACENTAL SITE REACTION (EPSR)

PLACENTAL SITE NODULES:

PLACENTAL SITE NODULES Single or multiple Mostly well circumscribed. Variably cellular round or flat lesions that tend to be extensively hyalinized . Most cells have abundant amphophillic or acidophillic cytoplasm, irregularly shaped nuclei & very scanty mitotic activity Diffusely +ve for PLAP but only focally +ve or –ve hPL & CD146( Mel - CAM)

PLACENTAL SITE NODULES:

PLACENTAL SITE NODULES

WHO PROGNOSTIC INDEX SCORE:

WHO PROGNOSTIC INDEX SCORE Prognostic factor 0 1 2 4 Age in yrs < 39 > 39 ---- ---- Antecedent pregnancy Hydatidiform mole Abortion Term ---- Interval ( mon ) 4 4-6 7-12 >12 B-hCG(IU/ml) <10^3 10^3 - 10^4 10^4 - 10^5 > 10^5 ABO groups ( F x M) ---- O x A, A x O B, AB ---- Largest tumor ---- 3 – 5 cm > 5 cm ---- Site of metastases ---- Spleen, kidney GI tract, liver Brain No of metastases ---- 1 - 4 4 - 8 > 8 Prior chemotherapy ---- ---- Single drug Two or more drugs

WHO PROGNOSTIC INDEX SCORE:

WHO PROGNOSTIC INDEX SCORE The total score is obtained by adding the individual scores for each prognostic factor Low risk = 0 – 4 Intermediate risk = 5 – 7 High risk = > 8

HUMAN CHORIONIC GONADOTROPHIN:

HUMAN CHORIONIC GONADOTROPHIN Secreted by active trophoblast of the placenta. Detected in the blood 7-9 days after ovulation. A concentration of 100mIU/ml is reached 2 days after the date of an expected menses. Peak level of HCG ( app. 100,000mIU/ml ) - 10 weeks of gestations Declining and remaining at app 10,000- 20,000mIU//ml by 12-14 weeks of gestation.

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RATE OF HCG RISE Below 1200 IU/L Doubles every 48-72hrs From 1200 to 6000IU/L Doubles every 72-96 hrs Above 6000IU/L Doubles every 4 days

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DIAGNOSTIC IMPLICATIONS OF SERUM HCG LEVELS Single HCG value –Not very informative rate of increase in HCG levels varies as a pregnancy progresses. Normal HCG values vary up to 20 times between different pregnancies, An HCG that does not double every two to three days does not necessarily indicate a problem with the pregnancy. Some normal pregnancies will have quite low levels of HCG, and result in perfect babies.

CORRELATION BETWEEN HCG LEVEL, AND SONOGRAPHY FINDINGS:

CORRELATION BETWEEN HCG LEVEL, AND SONOGRAPHY FINDINGS Serum HCG levels 1800 IU/L-Gestational sac should be visible by USG Serum HCG levels 5000IU/L-Cardiac pulsation should be visible. More than 5000 IU/L rules out Ectopic pregnancy.

Serum HCG levels :

Serum HCG levels From conception From Lmp IU/L 7days 3weeks 0to5 14days 28days 3to426 21days 35days 18 to 7,340 28days 42days 1080 to56,500 35-42days 49-56days 7,650 to 229,000 43-64days 57-78days 25,700 to 288,200 57-78days 79-100days 13,300 to 253,000 17-24weeks 2 nd trimester 4060 to 65,400 After several days postpartum Non-pregnant levels

DIAGNOSTIC CRITERIA BY USG:

DIAGNOSTIC CRITERIA BY USG Enlarged and cystic placenta with ill-defined fetal echoes, surrounded by a strongly refringent ring. Transverse diameter is 1.5 times more than of AP diameter.

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HCG levels -Management Indications of chemotherapy Serum hCG> 20, 000 IU/L at >4 weeks. Rising hCG. i.e. 2 consecutive rising serum samples. hCG plateau. i.e. 3 consecutive serum samples not rising or falling significantly. hCG still abnormal at 6 months post evacuation.

THANKS:

THANKS BY : Dr Ravi Jain