Gestational Trophoblastic Disease

Dr.CSBR.Prasad, M.D.

1. Chromosome # in ova and sperms2. What do you understand by the terms

Haploid / Diploid 3. What do you mean by triploidy4. Name the substance secreted by

trophoblastic tissue

• Gestational trophoblastic disease encompasses a heterogeneous group of lesions characterized by an abnormal proliferation of trophoblast.

• Recent light-microscopic studies, complemented by immunocytochemical and cytogenetic techniques, have demonstrated profound differences in the pathogenesis, morphology, and clinical behavior of various forms of the disease.

• Hydatidiform moles (complete, partial, and invasive) represent abnormally formed placentas with specific genetic abnormalities that are related to villous trophoblast, whereas choriocarcinoma and the placental site trophoblastic tumor are true neoplasms and are related to previllous and extravillous trophoblast, respectively.

Trophoblastic DiseasesTrophoblastic Diseases

• They are characterized by pregnancy associated trophoblastic proliferations

• They range from tumor like conditions to malignancy

• Hydatidiform mole is a common complication of gestation (1 in 1000 to 2000)

• They can be monitored by measuring HCG levels (to detect early recurrence and response to Tx)

• Choriocarcinomas are highly responsive to chemotherapy

Trophoblastic DiseasesTrophoblastic Diseases

WHO WHO Histilogical classification of Histilogical classification of

Gestational trophoblastic diseaseGestational trophoblastic disease

• Hydatidiform mole Complete Partial• Invasive hydatidiform mole• Choriocarcinoma • Placental site trophoblastic tumor• Trophoblastic laesions, miscellaneous Excaggerated placental site Placental site nodule • Unclassified trophoblastic lesions

Hydatidiform MoleHydatidiform Mole

Definition: A hydatidiform mole represents a

noninvasive abnormal placenta characterized by grossly evident hydropic swelling of chorionic villi accompanied by trophoblastic proliferation.

Hydatidiform moleHydatidiform mole• Several studies have shown that the risk of hydatidiform

mole is increased for women over the age of 45 years and for women under the age of 20 years.

• Although other factors, including smoking, occupation, a history of infertility, consanguinity, blood groups of parents, age at menarche, patterns of menstruation, and use of different types of contraceptives have been analyzed to determine their association with the development of hydatidiform moles, none of these factors appear to be significant.

• Cytogenetic studies have shown that chromosomal abnormalities play a key role in the development of both complete and partial moles.

• Most complete hydatidiform moles are diploid with a 46,XX karyotype, but rare examples are triploid or tetraploid; all the chromosome complements are paternally derived.

• In the diploid complete mole, both X chromosomes result from duplication of a haploid sperm pronucleus in an empty ovum that has lost its maternal chromosomal haploid set.

• Duplication of a 23,Y sperm results in a nonviable 46,YY cell. Approximately 3 to 13 percent of complete moles have a 46,XY chromosome complement, presumably as a result of dispermy, in which an empty ovum is fertilized by two sperm pronuclei, one with an X and the other with a Y chromosome.

• The embryo or fetus is absent in the complete mole; cases in which a fetus is present represent twin gestations, one of which is molar.

Hydatidiform mole

CHROMOSOMAL ORIGIN OF A COMPLETE HYDATIDIFORM MOLE

Partial Mole

Partial moles have

a triploid karyotype and evidence of an embryo or fetus

there is no consensus that all partial moles have these features.

69

Partial Mole

• When triploidy is present in a partial mole, the chromosomal complement is XXY in 70 percent of the cases, XXX in 27 percent, and XYY in 3 percent.

• These abnormal conceptuses result from the fertilization of an egg with a haploid set of chromosomes by either two sperms, each with a set of haploid chromosomes, or by a single sperm with a diploid 46,XY complement.

• Partial moles have a triploid karyotype and evidence of an embryo or fetus, there is no consensus that all partial moles have these features.

CHROMOSOMAL ORIGIN OF A TRIPLOID PARTIAL HYDATIDIFORM MOLE

Karyotypes of the partial mole most frequently show triploidy (69 chromosomes), with two paternal sets and a maternal chromosome complement.

Why molar pregnancies occur?• The formation of a mole is associated with an

excess of paternal compared with maternal haploid contributions.

• The higher the ratio of paternal to maternal chromosomes, the greater the molar change.

• Complete moles show a 2:0 ratio of paternal to maternal chromosomes, whereas partial moles show a 2:1 ratio.

• This hypothesis is supported by experimental evidence in mice.

Complete mole

Definition: The complete hydatidiform mole is

characterized by gross hydropic swelling of most of the chorionic villi. It typically has a diploid karyotype.

Clinical features – Complete mole• Complete moles typically present between the 11th

and 25th week of pregnancy at an average gestational age of 16 weeks.

• Marked uterine enlargement is common and is often accompanied by severe vomiting (hyperemesis gravidarum) and pregnancy-induced hypertension and occasionally by hyperthyroidism.

• Vaginal bleeding or passage of molar vesicles. • Ovarian enlargement due to multiple theca-lutein

cysts (hyperreactio luteinalis)• Pelvic ultrasonography often discloses a classic

"snowstorm" appearance.

Complete mole - Gross

• The complete mole is typically voluminous, consisting of 300 to 500 cm3 or more of bloody tissue.

• The most characteristic feature of the complete mole is the presence of grape-like transparent vesicles 1 to 2 cm in diameter.

• When the complete mole is encountered in a hysterectomy specimen, the uterus is enlarged, and molar vesicles protrude when it is opened.

This ultrasound views of the pelvis demonstrates a large cystic mass in the uterine cavity which is consistent with a hydatidiform mole.

This is a hydatidiform mole. Molar pregnancies are uncommon and occur when there is fertilization of an ovum by a sperm but loss of maternal chromosomes, leaving a 46XX karyotype composed only of paternal chromosomes, enough to form a placenta, but not a fetus. The result is a mass of tissue with grape-like swollen villi

Grape-like villi

Large avascular villi and areas of trophoblastic proliferation.

There are large avascular villi lined by cytotrophoblastic cells

along with atypical trophoblastic proliferation (inset—Normal villi)

Partial mole

Definition: The partial hydatidiform mole has two

populations of chorionic villi, one of normal size and the other grossly hydropic. It usually has a triploid karyotype.

• Occur between the ninth and thirty-fourth week of pregnancy at an average gestational age of about 19 weeks.

• Usually the patient presents with abnormal uterine bleeding and is clinically thought to have a spontaneous or missed abortion. This presentation differs from that of complete moles, which are usually diagnosed before curettage.

• The uterus is typically normal in size or small for the gestational age, and serum hCG levels generally do not show the marked elevation seen in association with the complete mole.

Clinical features – Partial mole

Partial mole - Gross

• Generally, the amount of tissue in a partial mole is less than that found in a complete mole; the total volume is often no greater than 200 cm3.

• The gross specimen contains large hydropic villi similar to those seen in the complete mole mixed with nonmolar placental tissue.

• A fetus is nearly always present with a partial mole.

Partial mole

Partial mole

Partial mole - Microscopy• The partial mole is characterized by a mixture of large edematous

villi and normal-sized villi.• In comparison with the complete mole, the degree of hydropic

swelling in the partial mole tends to be less pronounced. At least some of the hydropic villi contain a central acellular cistern.

• The chorionic villi often have a scalloped outline, compared to the typically round, distended appearance of the villi in the complete mole.

• Trophoblastic inclusions. • The villous capillaries of the partial mole frequently contain fetal

(nucleated) erythrocytes.• The trophoblast covering the villi is typically only focally and mildly

hyperplastic.

Partial mole

Cystic villusCystic villus

IHC

The immunohistochemical localization of hCG, hPL, and PlAP in complete and partial moles is confined mostly to the syncytiotrophoblast.

Marker to differentiatehydatidiform mole and partial mole

p57

This is not expressed in syncytiotrophoblasts and in stromal cells in complete moles.

p57 is maternally derived cell cycle inhibitor gene.

CLINICAL FEATURES OF COMPLETE AND PARTIAL MOLES

Feature Complete Partial Clinical presentation

Spontaneous abortion

Missed or spontaneous abortion

Gestational age 16-18 weeks 18-20 weeks

Uterine size Often large for dates

Often small for dates

Serum hCG ++++ + Behavior 10-30%

develop persistent GTD

4-11% develop persistent GTD

Invasive mole

Definition:

An invasive hydatidiform mole is one in which hydropic chorionic villi are within the myometrium or its vascular spaces or at distant sites, notably the vagina or lung.

“Mole that penetrates and even perforates the uterine wall”.

Invasive mole

• Invasive hydatidiform mole is a sequela to hydatidiform mole, complete or partial.

• The pathologic diagnosis of invasive mole is made by establishing the presence of molar villi growing into the myometrium and broad ligament.

• The diagnosis of an invasive mole cannot be made on examination of curettage specimens except when curetted fragments of myometrium contain invasive molar villi.

Invasive mole - Gross

On gross inspection, an invasive mole in the uterus appears as an irregular hemorrhagic lesion that invades the myometrium. It may grow through the myometrium, perforating the serosa and extending into the broad ligament with involvement of the adnexa.

Invasive mole.

Invasion

Hemorrhage

Invasive mole

• The villi are enlarged but often not as enlarged as the villi of a typical complete mole.

• Invasion of myometrium by hydropic villi.• Invasion may be seen involving the parametrium and BVs.• Proliferation of both cytotrophoblast and syncytiotrophoblasts.• Immunohistochemistry. Invasive moles display a pattern of

staining similar to that of complete moles because most invasive moles are derived from complete moles.

• Hydropic villi may metastasize to distant site, but fail to grow as true mets (they usually regress).

• Persistent elevation of ß-HCG and lutenization of ovaries.

Choriocarcinoma

Definition:Choriocarcinoma is a malignant

neoplasm composed of trophoblast arranged in a dimorphic pattern and lacking chorionic villi.

Choriocarcinoma

• The reported prevalence of choriocarcinoma varies widely throughout the world, being

greatest in Asia, Africa, and Latin America

& substantially lower in North America,

Europe, and Australia.

Choriocarcinoma

• Women over the age of 40 years are at increased risk for choriocarcinoma.

• Choriocarcinoma may be associated with any form of gestation. More abnormal types of pregnancy are more likely to be associated with choriocarcinoma.

• Blood group A is more frequent and group O less common in patients with choriocarcinoma.

• Generally, choriocarcinoma follows an identifiable gestational event such as a hydatidiform mole, an abortion, or a term gestation by a few months.

Choriocarcinoma

• Epithelial malignant neoplasm of trophoblastic cells derived from any form of previously normal or abnormal pregnancy.

• They are rapidly invasive, widely metastsizing malignant neoplasm.

• BUT, reponds to chemotherapy well.

Incidence :

Uncommon. 1 in 20K to 30K pregnancies.50% occur in hydatidiform moles25% occur in previous abortions22% occur in normal pregnanciesRest occur in ectopic pregancies & teratomas

Choriocarcinoma

Choriocarcinoma - Gross

• The typical gross appearance of choriocarcinoma is that of a circumscribed hemorrhagic mass, due to its rapid proliferation combined with blood vessel invasion.

• The tumors vary from pinpoint-sized lesions to large destructive masses. The central portion of the lesion is typically hemorrhagic and necrotic, with only a thin rim of viable tumor at the periphery.

This abdominal CT scan view of the pelvis demonstrates a solid and cystic mass (arrow) in the region of the uterus extending into the pelvis which is consistent with a choriocarcinoma.

Choriocarcinoma – microscopy

• No chorionic villi• The classic histologic pattern of choriocarcinoma is

dimorphic or biphasic, indicating an alternating arrangement of cytotrophoblast and syncytiotrophoblast or intermediate trophoblast and syncytiotrophoblast.

• Atypical mitotic activity• Spread: Blood, permeation thru lymphatics• Mets: Lung, brain, bones and Liver.

Choriocarcinoma

Burnt out primary:

With secondaries in lungs and other sites the primary can be completely absent.

This is due to their ability to invade larger vessels there by causing ischemia and necrosis of the primary tumor.

Choriocarcinoma – microscopy

• US may show small masses in the uterus• Irregular spotting (bloody, brown and

offensive)• Mets may be found by chest x-ray• ß-HCG level are levated enormously• Wide spread mets are common (Lungs 50%,

vagina 30%)

Choriocarcinoma – clinical features

Treatment:Depends on type & stage of tumor.Options: evacuation, surgery, chemo

(MTX, actinomycin – 100% cure rate)

NOTE: Non-gestational choriocarcinomas are much more resistant to Tx.

Choriocarcinoma

Gestational Trophoblastic Disease

Type Histological features Clinical features

Complete Hydatidiform Mole

Composed of large, avascular villi with trophoblastic proliferation

Occurs when a fertilized ovum contains only paternal chromosomes (usually 46, XX karyotype); produces marked uterine enlargement; "snowstorm" effect with no fetus on ultrasonography; some give rise to choriocarcinoma

Partial Hydatidiform Mole

Some villi are enlarged with minimal trophoblastic proliferation. Fetus may be present.

Typically are triploid (69, XXX or 69, XXY or 69, XYY); a malformed fetus is present that rarely goes to term; rarely gives rise to choriocarcinoma

Choriocarcinoma A malignant proliferation of syncytiotrophoblast with no villi; often hemorrhagic; no fetus is present

HCG levels are often extremely high; can metastasize; many are sensitive to chemotherapy

Placental Site Trophoblastic Tumor

A rare localized proliferation of intermediate trophoblast that can produce a grossly visible nodule

Most are bening; rare malignant cases

Placental Site Nodule or Plaque

A rare proliferation of intermediate trophoblast that is microscopic

Of no major consequence

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