Gestational Trophoblastic Disease

Gestational trophoblastic disease constitutes a spectrum of

tumors and tumor-like conditions characterized by proliferation of
placental tissue, either
 villous
 trophoblastic.

The lesions include

hydatidiform mole (complete and partial),

invasive mole, and

the frankly malignant choriocarcinoma and

placental-site trophoblastic tumor.

Gestational trophoblastic disease (GTD) is defined as

 a spectrum of abnormal conceptions and neoplasms

 arising from villous or extravillous trophoblast

 that are associated with pregnancy

trophoblast

 the peripheral cells of the blastocyst,

  which attach the blastocyst to the uterine wall and

 become the placenta and the membranes that nourish and

protect the developing organism

The best studied are the complete hydatidiform moles, which are

 genetically abnormal gestations

 carrying a significant risk of subsequently developing
gestational trophoblastic neoplasia, including
choriocarcinoma.

A pathologic diagnosis of a hydatidiform mole should prompt the

clinician to serially monitor the patient's serum beta human
chorionic gonadotropin (β-hCG) for regression.
HYDATIDIFORM MOLE
Hydatidiform mole is characterized histologically by
 cystic swelling of the chorionic villi,
 accompanied by variable trophoblastic proliferation.

The most important reason for the correct recognition of moles is

that they are associated with an increased risk of

persistent trophoblastic disease (invasive mole)

choriocarcinoma.

In the past, most patients presented in the fourth or fifth month

of pregnancy with vaginal bleeding
Currently, hydatidiform moles are being diagnosed at earlier
gestational ages (8.5 versus 17.0 weeks) due to

 routine ultrasound and

 close monitoring of early pregnancy.

Molar pregnancy can develop at any age, but the risk is higher at

the far ends of reproductive life: in teens and between the ages of
40 and 50 years.

For poorly explained reasons, the incidence varies considerably in

different regions of the world.

Hydatidiform mole is a rather infrequent complication of

gestation in the United States, occurring about once in every 1000
to 2000 pregnancies,
but is quite common in the Far East; the incidence is 1 in 100 in
Indonesia.

Two types of benign, noninvasive moles—complete and partial—

can be identified by cytogenetic and histologic studies.

Risk factors for gestational trophoblastic disease include a range

of epidemiologic and genetic parameters and are most strongly
associated with subtypes of GTD at greatest risk for either
persisting or evolving into malignancy.

The principal risk factors are:

 advanced maternal age

 Asian ethnicity

 lower socioeconomic status (in selected populations)

 one or more prior molar pregnancies

Persistent GTD” is a clinical diagnosis applied to persistently
elevated serum β-hCG following molar pregnancy and often
treated empirically w/o pathologic sampling to distinguish
persistent/invasive mole versus ChorioCa

Complete Mole
Complete mole results from
 fertilization of an egg that has lost its chromosomes, and
 the genetic material is completely paternally derived

o Ninety percent have a 46,XX diploid pattern, all derived from

duplication of the genetic material of one sperm (a
phenomenon called androgenesis).

o The remaining 10% are from the fertilization of an empty

egg by two sperm (46,XX and 46,XY).

Histologically, in complete mole all or most of the villi are

enlarged and
edematous, and
there is diffuse trophoblast hyperplasia.

Although fetal vessels and fetal parts are extremely rare in

complete moles since the embryo dies very early in development,
they do occur.

Patients have 2.5% risk of subsequent choriocarcinoma.

Features of early complete hydatidiform mole.

A, Moderately enlarged villi; the concentrically arranged

trophoblast is conspicuous.

B, Hypercellular, “fibroadenoma-like” villous stroma with a bluish

appearance caused by immature fibroblasts, accompanied by
modest but often circumferential trophoblastic proliferation.

C, irregular villous contours resembling knuckles or toes.

D, The implantation site trophoblast is often the most

conspicuous trophoblastic atypia in early complete mole.
Partial Mole

Partial moles result from fertilization of an egg with two sperm.

In these moles the karyotype is triploid (e.g., 69,XXY) or even

occasionally tetraploid (92,XXXY).

Fetal parts are more commonly present than in complete moles.

In partial moles

 some of the villi are edematous, and

 other villi show only minor changes;

The trophoblastic proliferation is

  focal
 less marked

Although partial moles have an increased risk of persistent molar

disease,

they are not considered to have an increased risk for choriocarcinoma.

Morphology.

The classic gross appearance is of

 a delicate,
 friable mass of

 thin-walled,

 translucent,

 cystic,

 grapelike

structures consisting of swollen edematous (hydropic) villi.

Fetal parts are frequently seen in partial moles.

On histologic examination complete moles show abnormalities

that involve all or most of the villous tissue.

The chorionic villi are

 enlarged,
 scalloped in shape with

 central cavitation (cisterns), and

 lack adequately developed vessels.

The most impressive abnormality is, however,

 an extensive trophoblast proliferation

 that involves the entire circumference of the villi, in
addition to

 “extravillous” islands of trophoblast proliferation.

The implantation site often displays

 atypia
 an exuberant proliferation of implantation trophoblast.

In contrast, partial moles demonstrate villous enlargement and

architectural disturbances in only a proportion of villi.

The trophoblastic proliferation is moderate but still may be

circumferential.

Histologic distinction of complete mole from partial molar

gestations is important.

In equivocal cases immunostaining for p57, a cell cycle inhibitor,

may aid the diagnosis.

The p57KIP2 gene is maternally transcribed but paternally

imprinted

It shows expression in

 maternal decidual tissue as well as

  cytotrophoblast and

 stromal cells of the villi,

when maternal genetic material is present in the conceptus.

In contrast, since both the X chromosomes in complete moles

are derived from the father, there is no expression of p57
protein in the cytotrophoblast or stromal cells of the villi in
complete moles

dissecting microscope
Either of two types of optical microscope used to magnify
materials undergoing dissection

Clinical Features.
Most women with partial and early complete moles present with
 spontaneous pregnancy loss or
 undergo curettage because of abnormalities in ultrasound
showing diffuse villous enlargement.
In complete moles quantitative analysis of human chorionic
gonadotropin (HCG) shows levels of hormone greatly exceeding
those produced during a normal pregnancy of similar gestational
age.

Serial hormone determination indicates a rapidly mounting level

that climbs faster than for the usual normal single or even
multiple pregnancy.

The vast majority of moles are removed by thorough curettage.

Monitoring serum concentrations of HCG is necessary to

determine the early development of persistent trophoblastic
disease, since up to 10% of moles develop into persistent or
invasive moles.

In addition, 2.5% of complete moles evolve into gestational

choriocarcinoma.
Therefore, serum HCG levels are usually followed until they fall to
and remain at zero for 6 months to a year.

INVASIVE MOLE

This is defined as a mole that

 penetrates or
 even perforates the uterine wall.

There is

invasion of the myometrium by hydropic chorionic villi,

accompanied by proliferation of both cytotrophoblast and

syncytiotrophoblast.

The tumor is locally destructive and may invade parametrial

tissue and blood vessels.
Hydropic (edematous) villi

may embolize to distant sites, such as lungs and brain,

but do not grow in these organs as true metastases, and
even without chemotherapy they eventually regress.

The tumor is manifested clinically by

 vaginal bleeding and

 irregular uterine enlargement.

It is always associated with

a persistently elevated serum HCG and

varying degrees of luteinization of the ovaries (the process
by which a postovulatory ovarian follicle transforms into a
corpus luteum through

 vascularization,
  follicular cell hypertrophy, and

 lipid accumulation, giving the yellow color).

The tumor

 responds well to chemotherapy

 but may result in uterine rupture and necessitate
hysterectomy.

CHORIOCARCINOMA
Gestational choriocarcinoma is a malignant neoplasm of
trophoblastic cells
derived from a previously normal or abnormal pregnancy,
which can even include extrauterine ectopic pregnancy.

Choriocarcinoma is

 rapidly invasive and

 metastasizes widely,
  but once identified responds well to chemotherapy.

Incidence.
This is an uncommon condition that arises in 1 in 20,000 to 30,000
pregnancies in the United States.
It is much more common in some African countries; for example,
it occurs in 1 in 2500 pregnancies in Ibadan, Nigeria.

It is preceded by several conditions;

50% arise in hydatidiform moles,
25% in previous abortions,
approximately 22% in normal pregnancies (intraplacental
choriocarcinoma),
with the remainder occuring in ectopic pregnancies.

Very rarely, a nongestational choriocarcinoma may develop from

germ cells in
 the ovaries or
 the mediastinum.
About 1 in 40 complete hydatidiform moles may be expected to
give rise to a choriocarcinoma,
in contrast to 1 in approximately 150,000 normal pregnancies.

Morphology.

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

Histologically, it does not produce chorionic villi and

It consists entirely of a mixed proliferation of

syncytiotrophoblasts and cytotrophoblasts.
Mitoses are

 abundant
 sometimes abnormal.

The tumor

 invades the underlying myometrium,

 in some cases extends out onto the uterine serosa and
into adjacent structures.

 frequently penetrates blood vessels and lymphatics, and

Due to rapid growth it is subject to

 hemorrhage,
 ischemic necrosis

 secondary inflammation.
In fatal cases metastases are found in

 the lungs,
 brain,

 bone marrow,

 liver, and other organs.

On occasion, metastatic choriocarcinoma is discovered without

a detectable primary in the uterus (or ovary), presumably
because the primary has undergone complete necrosis

Clinical Features.
Uterine choriocarcinoma usually does not produce a large, bulky
mass,

but it manifests as
 irregular vaginal spotting of a bloody,
 brown fluid.

This discharge may appear in the course of

  an apparently normal pregnancy,
 after a miscarriage (loss of an embryo or fetus before the
20th week of pregnancy), or
 after curettage.

Sometimes the tumor does not appear until months after these
events.

Usually, by the time the tumor is discovered,

radiographs of the chest and bones already disclose the presence
of metastatic lesions.

The titers of HCG are elevated to levels above those encountered

in hydatidiform moles.

Occasionally, tumors produce little hormone, and some tumors

become so necrotic as to become functionally inactive.

Widespread metastases are characteristic. Frequent sites of

involvement are
 the lungs (50%) and
  vagina (30% to 40%),
 followed in descending order of frequency by the brain,
liver, and kidney.

The treatment of gestational choriocarcinoma (and other

trophoblastic neoplasms) depends on the type and stage of the
tumor and includes

evacuation of the contents of the uterus,

surgery, and

chemotherapy.

The results of chemotherapy for gestational choriocarcinoma are

fantastic and result in nearly 100% remission and a high rate of

cures.

Many of the cured patients have had normal subsequent

pregnancies and deliveries.
By contrast, nongestational choriocarcinomas are much more
resistant to therapy.

The difference is believed to be due to the expression of paternal

antigens in gestational choriocarcinomas that can evoke an
immune response from the mother.