gestational and placental disorders. 1-early pregnancy 1-early pregnancy -spontaneous abortion...

GESTATIONAL AND PLACENTAL DISORDERS

1-Early pregnancy1-Early pregnancy

-Spontaneous abortion-Spontaneous abortion

-Ectopic pregnancy-Ectopic pregnancy 2-Complications of late 2-Complications of late

pregnancypregnancy

-Placenta accreata-Placenta accreata

-Twin placenta-Twin placenta

-Placental inflammation-Placental inflammation

-Toxemia of pregnancy (preeclampsia--Toxemia of pregnancy (preeclampsia-eclampsia)eclampsia)

3-Gestastational Trophoblastic Disease3-Gestastational Trophoblastic Disease Trophoblastic neoplasms:Trophoblastic neoplasms: -Choriocarcinoma-Choriocarcinoma -Placental si-Placental sitte trophoblastic tumoure trophoblastic tumour -Epitheloid trophoblastic tumour-Epitheloid trophoblastic tumour Molar pregnanciesMolar pregnancies Hydatiform mole (complete-partial-invasive)Hydatiform mole (complete-partial-invasive) Non trophoblastic-non molar Non trophoblastic-non molar

trophoblastic lesionstrophoblastic lesions -Placental si-Placental sitte nodulee nodule -Exaggerated placental site-Exaggerated placental site

Disorders of Early PregnancyDisorders of Early Pregnancy

1-SPONTANEOUS ABORTION1-SPONTANEOUS ABORTION Ten per cent to 15% of recognized

pregnancies terminate in spontaneous abortion

The mechanisms leading to early loss of pregnancy are still mysterious.

The causes-fetal and maternal Fetal: Defective implantation Fetal: Defective implantation -Some genetic or acquired abnormalities -Some genetic or acquired abnormalities

constitute the major origins of spontaneous constitute the major origins of spontaneous abortion. abortion.

Numerous studies have indicated chromosome Numerous studies have indicated chromosome abnormalities in more than half of spontaneous abnormalities in more than half of spontaneous abortuses.abortuses.

Maternal:Maternal:

-Inflammatory diseases: -Inflammatory diseases: ToxoplasmaToxoplasma, , MycoplasmaMycoplasma, , ListeriaListeria, and viral , and viral infections, both localized to the infections, both localized to the placenta and systemic;placenta and systemic;

- Uterine abnormalities;- Uterine abnormalities;

- Trauma. - Trauma.

Morphologic changes: Focal areas of decidual necrosis with Focal areas of decidual necrosis with

intense neutrophilic infiltration, thrombi intense neutrophilic infiltration, thrombi within decidual blood vessels, within decidual blood vessels, hemorrhage, hemorrhage, andand necrotic decidua. necrotic decidua.

Spontaneous abortions, no fetal Spontaneous abortions, no fetal products can be identified, products can be identified,

They are present, they should be They are present, they should be carefully examined for anomalies that carefully examined for anomalies that would suggest specific genetic or would suggest specific genetic or karyotypic defects. Chromosomal karyotypic defects. Chromosomal studies are recommended studies are recommended

(1) in habitual or recurrent abortion and (1) in habitual or recurrent abortion and (2) when there is a malformed fetus (2) when there is a malformed fetus

2-ECTOPIC PREGNANCY2-ECTOPIC PREGNANCY Implantation of the fetus in any site other

than a normal uterine location. The most common site is within the tubes

(approximately 90%).The ovary, the abdominal cavity, and the intrauterine portion of the fallopian tube (cornual pregnancy).

1/ 150 pregnancies. The most important predisposing condition in

35% to 50% of patients is PID with chronic salpingitis.

Other factors: peritubal adhesions due to appendicitis or endometriosis, leiomyomas, and previous surgery.

Intrauterine devices may also increase risk.

MorphologyMorphology In tubal pregnancy, the placenta is poorly In tubal pregnancy, the placenta is poorly

attached to the wall of the tube. Intratubal attached to the wall of the tube. Intratubal hemorrhage may thus occur from partial hemorrhage may thus occur from partial placental separation without tubal ruptureplacental separation without tubal rupture

Tubal pregnancy is the most common cause Tubal pregnancy is the most common cause of hematosalpinx and should always be of hematosalpinx and should always be suspected when a tubal hematoma is suspected when a tubal hematoma is present. present.

More often- causes tubal rupture and More often- causes tubal rupture and intraperitoneal hemorrhageintraperitoneal hemorrhage

Less commonly- the tubal pregnancy may Less commonly- the tubal pregnancy may undergo spontaneous regression and undergo spontaneous regression and resorption of the entire gestation.resorption of the entire gestation.

Less commonly, the tubal pregnancy is Less commonly, the tubal pregnancy is extruded through the fimbriated end into extruded through the fimbriated end into the abdominal cavity (tubal abortion). the abdominal cavity (tubal abortion).

Potential sites for ectopic pregnancy, including the fallopian tube, ovary, cornu, and (rarely) abdominal viscera.

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Disorders of Late PregnancyDisorders of Late Pregnancy

Umblical cord-knods- compressionUmblical cord-knods- compression Ascending inflammation Retroplacental hemorrhageRetroplacental hemorrhage Intervillous hemorrhageIntervillous hemorrhage Abnormal placentationAbnormal placentation

A, Diagram of placental anatomy. Within the outer boundary of myometrium is a layer of decidua, from which the maternal vessels originate and deliver blood to and from the intervillous spaces. Umbilical vessels branch and terminate in

placental villi, where nutrient exchange takes place. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 5 March 2006 06:57 PM)

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B, Normal term placenta (fetal surface) with umbilical cord.


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Placenta accreta Caused by partial or complete absence of

the decidua with adherence of the placenta directly to the myometrium.

Important for two reasons: (1) postpartum bleeding, often life-

threathening, occurs because of failure of placental separation

(2) in up to 60% of cases, it is associated with placenta previa, a condition in which the placenta implants in the lower uterine segment or cervix, often with serious antepartum bleeding and premature labor.

Many cases of placenta previa-associated accreta occur in patients with cesarean section scars.

Twin pregnanciesTwin pregnancies arise from fertilization of two ova (dizygotic) arise from fertilization of two ova (dizygotic)

or from division of one fertilized ovum or from division of one fertilized ovum (monozygotic). (monozygotic).

There are three basic types of twin placentas: There are three basic types of twin placentas: 1-dichorionic diamnionic (which may be 1-dichorionic diamnionic (which may be

fused),fused), 2- monochorionic diamnionic, 2- monochorionic diamnionic, 3- monochorionic monoamnionic. 3- monochorionic monoamnionic. One complication of twin pregnancy is twin-One complication of twin pregnancy is twin-

twin transfusion twin transfusion

Diagrammatic representation of the various types of twin placentation and their membrane relationships.


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Twin-twin transfusion syndrome resulting in the death of both fetuses because of excessive (left) or deficient (right) blood volume.


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PLACENTAL INFLAMMATIONS AND

INFECTIONS Placenta (placentitis, villitis)Placenta (placentitis, villitis) the fetal membranes (chorioamnionitis)the fetal membranes (chorioamnionitis) the umbilical cord (funisitis).the umbilical cord (funisitis). They reach the placenta by two pathways:They reach the placenta by two pathways: (1) ascending infection through the birth canal -- (1) ascending infection through the birth canal --

most often bacterial-premature rupture of most often bacterial-premature rupture of membranes - Sexual intercourse has been membranes - Sexual intercourse has been implicated in enhancing ascending infections.implicated in enhancing ascending infections.

(2) hematogenous (transplacental) infection(2) hematogenous (transplacental) infection The amniotic fluid may be cloudy with purulent The amniotic fluid may be cloudy with purulent

exudate, and the chorion-amnion histologically exudate, and the chorion-amnion histologically contains a leukocytic polymorphonuclear contains a leukocytic polymorphonuclear infiltration with accompanying edema and infiltration with accompanying edema and congestion of the vesselscongestion of the vessels

Placental infections derived from ascending and blood-borne routes. Acute chorioamnionitis. A, On gross examination, the placenta contains greenish

opaque membranes


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. B, A photomicrograph illustrates a dense bandlike inflammatory exudate on the amniotic surface (top).


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C, Acute necrotizing intervillositis, from a fetal-maternal infection by listeria.


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Bacterial infections of the placenta Bacterial infections of the placenta and fetal membranes may arise by and fetal membranes may arise by the hematogenous spread of bacteria the hematogenous spread of bacteria directly to the placenta. directly to the placenta.

The villi are most often affected The villi are most often affected histologically (villitis) histologically (villitis)

Classically, TORCH (toxoplasmosis Classically, TORCH (toxoplasmosis and others [syphilis, tuberculosis, and others [syphilis, tuberculosis, listeriosis], rubella, cytomegalovirus, listeriosis], rubella, cytomegalovirus, herpes simplex) should be herpes simplex) should be considered, although the cause is considered, although the cause is usually obscure and may involve usually obscure and may involve immunologic phenomena immunologic phenomena

TOXEMIA OF PREGNANCY TOXEMIA OF PREGNANCY

(PREECLAMPSIA AND ECLAMPSIA)(PREECLAMPSIA AND ECLAMPSIA)

Toxemia of pregnancy refers to a symptom Toxemia of pregnancy refers to a symptom complex characterized by hypertension, complex characterized by hypertension, proteinuria, and edema (preeclampsia). proteinuria, and edema (preeclampsia).

6% of pregnant women, usually in the last 6% of pregnant women, usually in the last trimester and more commonly in primiparas trimester and more commonly in primiparas than in multiparas. than in multiparas.

More seriously ill, developing convulsions; More seriously ill, developing convulsions; this more severe form of toxemia is termed this more severe form of toxemia is termed eclampsia.eclampsia.

Patients with eclampsia develop Patients with eclampsia develop disseminated intravascular coagulation disseminated intravascular coagulation (DIC) with lesions in the liver, kidneys, (DIC) with lesions in the liver, kidneys, heart, placenta, and sometimes the brain. heart, placenta, and sometimes the brain.

PathogenesisPathogenesis

The many theories on the nature of The many theories on the nature of toxemia of pregnancytoxemia of pregnancy

Three events that seem to be of Three events that seem to be of prime importance in this disorder prime importance in this disorder are addressed:are addressed:

1-Placental ischemia1-Placental ischemia 2-Hypertension2-Hypertension 3-DIC 3-DIC

Proposed sequence of events in the pathogenesis of toxemia of pregnancy. The main features are (1) decreased uteroplacental perfusion; (2) increased vasoconstrictors and

decreased vasodilators, resulting in local and systemic vasoconstriction; and (3) disseminated intravascular coagulation (DIC).

An abnormality of placentation- An abnormality of placentation- placental ischemia-placental ischemia- involve defects in both trophoblast invasion and the involve defects in both trophoblast invasion and the development of the physiologic alterations in the development of the physiologic alterations in the placental vessels required to perfuse the placental placental vessels required to perfuse the placental bed adequatelybed adequately

Immunologic, genetic, and other factors have been Immunologic, genetic, and other factors have been postulated as causes of these abnormalities. postulated as causes of these abnormalities.

The net effect is a The net effect is a shallow implantationshallow implantation with with incomplete conversion of decidual vessels to vessels incomplete conversion of decidual vessels to vessels adequate for the pregnancy state.adequate for the pregnancy state.

Investigators have hypothesized that an intrinsic Investigators have hypothesized that an intrinsic defect in the invading trophoblastdefect in the invading trophoblast may contribute to may contribute to altered vascular flowaltered vascular flow

- the inability of the invading cytotrophoblast-- the inability of the invading cytotrophoblast-influence remodeling of uterine vasculature, reducing influence remodeling of uterine vasculature, reducing blood flow and leading to blood flow and leading to placental ischemia, the placental ischemia, the basis for the toxemic placentabasis for the toxemic placenta..

- decreased uteroplacental perfusion induces - decreased uteroplacental perfusion induces stimulation of vasoconstrictor substances stimulation of vasoconstrictor substances (thromboxane, angiotensin, endothelin)(thromboxane, angiotensin, endothelin)

the inhibition of vasodilator influences (prostaglandin the inhibition of vasodilator influences (prostaglandin I2, prostaglandin E2, I2, prostaglandin E2, nitric oxide ) from the ischemic ) from the ischemic placenta.placenta.

DIC, hypertension, and organ damage then developDIC, hypertension, and organ damage then develop

During toxemia, the placental During toxemia, the placental ischemia leads to a higher output of ischemia leads to a higher output of thromboplastic substances, and thromboplastic substances, and antithrombin III levels are reduced. antithrombin III levels are reduced.

The characteristic lesions in The characteristic lesions in eclampsia are in large part due to eclampsia are in large part due to thrombosis of arterioles and thrombosis of arterioles and capillaries throughout the body, capillaries throughout the body, particularly in the liver, kidneys, particularly in the liver, kidneys, brain, pituitary, and placenta.brain, pituitary, and placenta.

One mechanism involves renin-angiotensin and One mechanism involves renin-angiotensin and prostaglandins.prostaglandins.

Normal pregnant women develop a resistance to Normal pregnant women develop a resistance to the vasoconstrictive and hypertensive effects of the vasoconstrictive and hypertensive effects of angiotensin, but women with toxemia lose such angiotensin, but women with toxemia lose such resistance, developing a tendency to hypertension.resistance, developing a tendency to hypertension.

Prostaglandins of the E series, produced in the Prostaglandins of the E series, produced in the uteroplacental vascular bed during pregnancy, are uteroplacental vascular bed during pregnancy, are thought to mediate the normal resistance of thought to mediate the normal resistance of pregnant women to angiotensin, and prostaglandin pregnant women to angiotensin, and prostaglandin production is indeed decreased in the placenta of production is indeed decreased in the placenta of toxemic women. toxemic women.

Thus, the increase in angiotensin hypersensitivity, Thus, the increase in angiotensin hypersensitivity, characteristic of toxemia, may be due to decreased characteristic of toxemia, may be due to decreased synthesis of prostaglandin by the toxemic placenta. synthesis of prostaglandin by the toxemic placenta. There is also evidence that renin production by the There is also evidence that renin production by the toxemic placenta is increased, another potentially toxemic placenta is increased, another potentially vasoconstrictive event.vasoconstrictive event.

The The liverliver lesions- irregular, focal, subcapsular, lesions- irregular, focal, subcapsular, and intraparenchymal hemorrhages. and intraparenchymal hemorrhages.

On histologic examination, there are fibrin On histologic examination, there are fibrin thrombi in the portal capillaries with foci of thrombi in the portal capillaries with foci of characteristic peripheral hemorrhagic necrosis. characteristic peripheral hemorrhagic necrosis.

The The kidneykidney lesions are variable. Glomerular lesions are variable. Glomerular lesions are diffuse, when assessed by electron lesions are diffuse, when assessed by electron microscopy. They consist of striking swelling of microscopy. They consist of striking swelling of endothelial cells, the deposition of fibrinogen-endothelial cells, the deposition of fibrinogen-derived amorphous dense deposits on the derived amorphous dense deposits on the endothelial side of the basement membrane, and endothelial side of the basement membrane, and mesangial cell hyperplasia. - bilateral renal mesangial cell hyperplasia. - bilateral renal cortical necrosiscortical necrosis

The The brainbrain may have gross or microscopic foci of may have gross or microscopic foci of hemorrhage along with small-vessel thromboses. hemorrhage along with small-vessel thromboses.

Similar changes are often found in the Similar changes are often found in the heartheart and and the the anterior pituitaryanterior pituitary..

MorphologyMorphology

The The placentaplacenta is the site of variable changes, is the site of variable changes, most of which reflect ischemia and vessel most of which reflect ischemia and vessel injury. injury.

(1) Placental infarcts, which occur in normal (1) Placental infarcts, which occur in normal full-term placentas, are larger and more full-term placentas, are larger and more numerous. numerous.

(2) There is increased frequency of (2) There is increased frequency of retroplacental hematomas.retroplacental hematomas.

(3) There is evidence of increased villous (3) There is evidence of increased villous ischemia; formation of prominent syncytial ischemia; formation of prominent syncytial knots, thickening of trophoblastic basement knots, thickening of trophoblastic basement membrane, and villous hypovascularitymembrane, and villous hypovascularity

(4) A characteristic finding in the walls of (4) A characteristic finding in the walls of uterine vessels is striking fibrinoid necrosis uterine vessels is striking fibrinoid necrosis and intramural lipid deposition (acute and intramural lipid deposition (acute atherosis) atherosis)

Acute atherosis of uterine vessels in eclampsia. Note fibrinoid necrosis of the vessel walls, subendothelial macrophages and perivascular lymphocytic

infiltrate.


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Clinical CourseClinical Course Preeclampsia usually starts after the 32 nd week Preeclampsia usually starts after the 32 nd week

of pregnancy but begins earlier in patients with of pregnancy but begins earlier in patients with hydatidiform mole or pre-existing kidney disease hydatidiform mole or pre-existing kidney disease or hypertension. or hypertension.

The onset is typically insidious, characterized by The onset is typically insidious, characterized by hypertension and edema, with proteinuria hypertension and edema, with proteinuria following within several days. following within several days.

Headaches and visual disturbances are common. Headaches and visual disturbances are common. Eclampsia is suspected by central nervous Eclampsia is suspected by central nervous

system involvement, including convulsions and system involvement, including convulsions and eventual coma. eventual coma.

Mild and moderate forms of toxemia can be Mild and moderate forms of toxemia can be controlled by bed rest, a balanced diet, and controlled by bed rest, a balanced diet, and antihypertensive agents, but induction of antihypertensive agents, but induction of delivery is the only definitive treatment of delivery is the only definitive treatment of established preeclampsia and eclampsia. established preeclampsia and eclampsia.

Proteinuria and hypertension usually disappear Proteinuria and hypertension usually disappear within 1 or 2 weeks after delivery except in within 1 or 2 weeks after delivery except in patients in whom these findings predate the patients in whom these findings predate the pregnancy. pregnancy.

INTRAUTERINE GROWTH INTRAUTERINE GROWTH

RESTRICTIONRESTRICTION Intrauterine growth restriction is an

important cause of infant mortality and morbidity and is defined as a birth weight below the 10th percentile

Major causes:fetal disorders such as chromosomal abnormalities and malformations (20%)

maternal vascular disease- toxemia (30%). Other causes include thrombolytic

disorders, maternal and fetal infections, autoimmune disorders (chronic villitis), fetal vascular disorders (fetal thrombosis), and other metabolic

Gestational Trophoblastic Disease

Gestational trophoblastic disease constitutes a spectrum of tumors and tumor-like conditions characterized by proliferation of pregnancy-associated trophoblastic tissue of progressive malignant potential.

The hydatidiform mole (complete and partial)

The invasive mole The frankly malignant

choriocarcinoma.

The hydatidiform mole is a common The hydatidiform mole is a common complication of gestation, occurring about complication of gestation, occurring about once in every 1000 to 2000 pregnancies in once in every 1000 to 2000 pregnancies in the United States the United States

It has become possible, by monitoring the It has become possible, by monitoring the circulating levels of human chorionic circulating levels of human chorionic gonadotropin, to determine the early gonadotropin, to determine the early development of persistent trophoblastic development of persistent trophoblastic disease. disease.

Choriocarcinoma, once a dreaded and Choriocarcinoma, once a dreaded and uniformly fatal complication, is now highly uniformly fatal complication, is now highly responsive to chemotherapy.responsive to chemotherapy.

HYDATIDIFORM MOLE (COMPLETE HYDATIDIFORM MOLE (COMPLETE

AND PARTIAL)AND PARTIAL) Hydatidiform mole is characterized by cystic Hydatidiform mole is characterized by cystic

swelling of the chorionic villi, accompanied swelling of the chorionic villi, accompanied by variable trophoblastic proliferation. by variable trophoblastic proliferation.

The most important reason for the correct The most important reason for the correct recognition of true moles is that they may recognition of true moles is that they may precede choriocarcinoma.precede choriocarcinoma.

Most patients present in the fourth or fifth Most patients present in the fourth or fifth month of pregnancy with vaginal bleeding month of pregnancy with vaginal bleeding and with a uterus that is usually, but not and with a uterus that is usually, but not always, larger than expected for the always, larger than expected for the duration of pregnancy. duration of pregnancy.

These moles can occur at any age during These moles can occur at any age during active reproductive life, but the risk is active reproductive life, but the risk is higher in pregnant women in their teens or higher in pregnant women in their teens or between the ages of 40 and 50 years. between the ages of 40 and 50 years.

Feature Complete Mole Partial Mole

Karyotype 46,XX (46,XY) Triploid

Villous edema All villi Some villi

Trophoblast proliferation

Diffuse; circumferential

Focal; slight

Atypia Often present Absent

Serum hCG Elevated Less elevated

HCG in tissue ++++ +

Behavior 2% choriocarcinoma

Rare choriocarcinoma

fetal parts no may be present

MorphologyMorphology Moles develop within the uterus, but they may Moles develop within the uterus, but they may

occur in any site, including ectopic pregnancies.occur in any site, including ectopic pregnancies. Partial moles may be diagnosed in early Partial moles may be diagnosed in early

spontaneous abortions or later, following fetal spontaneous abortions or later, following fetal development. Careful dissection may disclose a development. Careful dissection may disclose a small, usually collapsed amniotic sac. Fetal parts small, usually collapsed amniotic sac. Fetal parts are frequently seen in partial moles but are are frequently seen in partial moles but are never found in complete moles (unless there is a never found in complete moles (unless there is a twin pregnancy). twin pregnancy).

Currently, complete moles are being diagnosed Currently, complete moles are being diagnosed and removed at an earlier mean gestational age and removed at an earlier mean gestational age (8.5 versus 17.0 weeks) due to routine (8.5 versus 17.0 weeks) due to routine ultrasound and close monitoring of early ultrasound and close monitoring of early pregnancy, combined with more efficient pregnancy, combined with more efficient histologic recognition of early complete histologic recognition of early complete hydatidiform mole.hydatidiform mole.

The classic presentation is a uterine cavity filled The classic presentation is a uterine cavity filled with a delicate, friable mass of thin-walled, with a delicate, friable mass of thin-walled, translucent, cystic, grapelike structures translucent, cystic, grapelike structures consisting of swollen edematous (hydropic) villi consisting of swollen edematous (hydropic) villi

Histologic examinationHistologic examination partial molespartial moles demonstrate villous hydrops and demonstrate villous hydrops and

architectural disturbances in only a proportion architectural disturbances in only a proportion of villi. The trophoblastic proliferation is of villi. The trophoblastic proliferation is minimal and limited to the syncitiotrophoblast. minimal and limited to the syncitiotrophoblast.

In contrast, In contrast, complete molescomplete moles show hydropic show hydropic swelling of most chorionic villi and virtual swelling of most chorionic villi and virtual absence or inadequate development of absence or inadequate development of vascularization of villi. vascularization of villi.

More advanced complete moles exhibit the More advanced complete moles exhibit the classic spectrum of diffuse villous swelling, classic spectrum of diffuse villous swelling, central cavitation (cisterns) and extensive central cavitation (cisterns) and extensive concentric villous and extravillous trophoblastic concentric villous and extravillous trophoblastic proliferation.proliferation.

Complete hydatidiform mole suspended in saline showing numerous swollen (hydropic) villi.


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A, Photomicrograph of partial hydatidiform mole revealing swollen villi and slight hyperplasia of the surface trophoblast.


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B, Complete hydatidiform mole with extensive cytotrophoblastic hyperplasia (lower field) (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.).


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C, Complete moles lack expression of p57 in the cytotrophoblast (arrowheads) and villous stroma (arrow).


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D, Normal placenta immunostained for p57 exhibits staining in both stromal (arrows) and cytotrophoblast (arrowheads) nuclei. (Courtesy of Dr. Diego C. Castrillon, Brigham and

Women's Hospital, Boston, MA.)


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Clinical CourseClinical Course

Most patients with partial and early complete moles Most patients with partial and early complete moles present with spontaneous pregnancy loss or undergo present with spontaneous pregnancy loss or undergo curettage due to abnormalities in ultrasound. curettage due to abnormalities in ultrasound.

Watery fluid and bits of tissue seen as small, Watery fluid and bits of tissue seen as small, grapelike masses may be seen in the uterine grapelike masses may be seen in the uterine contents. Ultrasound examination will confirm the contents. Ultrasound examination will confirm the diffuse villous enlargement. diffuse villous enlargement.

In complete moles, quantitative analysis of human In complete moles, quantitative analysis of human chorionic gonadotropin shows levels of hormone chorionic gonadotropin shows levels of hormone greatly exceeding those produced by a normal greatly exceeding those produced by a normal pregnancy of similar age. pregnancy of similar age.

The vast majority of moles are removed by thorough The vast majority of moles are removed by thorough curettage. curettage.

Virtually no partial and only 2.5% of complete moles Virtually no partial and only 2.5% of complete moles evolve into a malignant trophoblastic neoplasm evolve into a malignant trophoblastic neoplasm (choriocarcinoma). (choriocarcinoma).

10% of complete moles develop into invasive moles. 10% of complete moles develop into invasive moles. Because unattended complete moles may persist and Because unattended complete moles may persist and recur, distinction of these moles from non-molar recur, distinction of these moles from non-molar hydropic and partial molar gestations is important. hydropic and partial molar gestations is important.

INVASIVE MOLE This is defined as a mole that penetrates and This is defined as a mole that penetrates and

may even perforate the uterine wall.may even perforate the uterine wall. There is invasion of the myometrium by There is invasion of the myometrium by

hydropic chorionic villi, accompanied by hydropic chorionic villi, accompanied by proliferation of both cytotrophoblast and proliferation of both cytotrophoblast and syncytiotrophoblast syncytiotrophoblast

The tumor is locally destructive and may invade The tumor is locally destructive and may invade parametrial tissue and blood vessels.parametrial tissue and blood vessels.

Hydropic villi may embolize to distant sites, Hydropic villi may embolize to distant sites, such as lungs and brain, but do not grow in such as lungs and brain, but do not grow in these organs as true metastases,these organs as true metastases,

The tumor is manifested clinically by vaginal The tumor is manifested clinically by vaginal bleeding and irregular uterine enlargement. bleeding and irregular uterine enlargement.

It is always associated with a persistent elevated It is always associated with a persistent elevated human chorionic gonadotropin level and varying human chorionic gonadotropin level and varying degrees of luteinization of the ovaries.degrees of luteinization of the ovaries.

The tumor responds well to chemotherapy but The tumor responds well to chemotherapy but may result in uterine rupture and necessitate may result in uterine rupture and necessitate hysterectomy.hysterectomy.

B, On cross-section, the tumor invades into the myometrium. (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital,

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CHORIOCARCINOMA

Gestational choriocarcinoma is an Gestational choriocarcinoma is an epithelial malignant neoplasm of epithelial malignant neoplasm of trophoblastic cells derived from any trophoblastic cells derived from any form of previously normal or abnormal form of previously normal or abnormal pregnancy.pregnancy.

Although most cases arise in the Although most cases arise in the uterus, ectopic pregnancies provide uterus, ectopic pregnancies provide extrauterine sites of origin. extrauterine sites of origin.

Choriocarcinoma is a rapidly invasive, Choriocarcinoma is a rapidly invasive, widely metastasizing malignant widely metastasizing malignant neoplasm, but once it is identified, it neoplasm, but once it is identified, it responds well to chemotherapy. responds well to chemotherapy.

IncidenceIncidence In 1 in 20,000 to 30,000 pregnancies in the In 1 in 20,000 to 30,000 pregnancies in the

United States. United States. It is much more common in some African It is much more common in some African

countries; for example, it occurs in 1 in 2500 countries; for example, it occurs in 1 in 2500 pregnancies in Ibadan, Nigeria. pregnancies in Ibadan, Nigeria.

It is preceded by several conditions:It is preceded by several conditions: 50% arise in hydatidiform moles, 50% arise in hydatidiform moles, 25% in previous abortions,25% in previous abortions, approximately 22% in normal pregnancies approximately 22% in normal pregnancies

(intraplacental choriocarcinoma).(intraplacental choriocarcinoma). The remainder occur in ectopic pregnancies and The remainder occur in ectopic pregnancies and

genital and extragenital teratomas. genital and extragenital teratomas. About 1 in 40 hydatidiform moles may be About 1 in 40 hydatidiform moles may be

expected to give rise to a choriocarcinoma, in expected to give rise to a choriocarcinoma, in contrast to 1 in approximately 150,000 normal contrast to 1 in approximately 150,000 normal pregnancies. pregnancies.

Morphology Classically a soft, fleshy, yellow-white tumor with a Classically a soft, fleshy, yellow-white tumor with a

marked tendency to form large pale areas of ischemic marked tendency to form large pale areas of ischemic necrosis, foci of cystic softening, and extensive necrosis, foci of cystic softening, and extensive hemorrhage hemorrhage

On histologic examination, it is a purely epithelial tumor On histologic examination, it is a purely epithelial tumor that does not produce chorionic villi and that grows by that does not produce chorionic villi and that grows by the abnormal proliferation of both cytotrophoblast and the abnormal proliferation of both cytotrophoblast and syncytiotrophoblast syncytiotrophoblast

It is sometimes possible to identify anaplasia within such It is sometimes possible to identify anaplasia within such abnormal proliferation, replete with abnormal mitoses. abnormal proliferation, replete with abnormal mitoses.

The tumor invades the underlying myometrium, The tumor invades the underlying myometrium, frequently penetrates blood vessels and lymphaticsfrequently penetrates blood vessels and lymphatics

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

In its rapid growth, it is subject to hemorrhage, ischemic In its rapid growth, it is subject to hemorrhage, ischemic necrosis, and secondary inflammation.necrosis, and secondary inflammation.

In fatal cases, metastases are found in the lungs, brain, In fatal cases, metastases are found in the lungs, brain, bone marrow, liver, and other organs.bone marrow, liver, and other organs.

On occasion, metastatic choriocarcinoma is discovered On occasion, metastatic choriocarcinoma is discovered without a detectable primary in the uterus (or ovary), without a detectable primary in the uterus (or ovary), presumably because the primary has undergone total presumably because the primary has undergone total necrosis.necrosis.

A, Choriocarcinoma presenting as a bulky hemorrhagic mass invading the uterine wall. B, Photomicrograph of choriocarcinoma illustrating both

neoplastic cytotrophoblast and syncytiotrophoblast. (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.)


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Clinical CourseClinical Course

Irregular spotting of a bloody, brown, Irregular spotting of a bloody, brown, sometimes foul-smelling fluid. sometimes foul-smelling fluid.

This discharge may appear in the course of This discharge may appear in the course of an apparently normal pregnancy, after a an apparently normal pregnancy, after a miscarriage, or after a curettage. miscarriage, or after a curettage.

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

Usually, by the time the tumor is discovered Usually, by the time the tumor is discovered locally, radiographs of the chest and bones locally, radiographs of the chest and bones already disclose the presence of metastatic already disclose the presence of metastatic lesions. The titers of human chorionic lesions. The titers of human chorionic gonadotropin are elevated to levels above gonadotropin are elevated to levels above those encountered in hydatidiform moles. those encountered in hydatidiform moles. Occasional tumors, however, produce little Occasional tumors, however, produce little hormone, and some tumors have become so hormone, and some tumors have become so necrotic as to become functionally inactive. necrotic as to become functionally inactive.

Widespread metastases are characteristic of Widespread metastases are characteristic of these tumors. Favored sites of involvement these tumors. Favored sites of involvement are the lungs (50%) and vagina (30% to are the lungs (50%) and vagina (30% to 40%), followed in descending order of 40%), followed in descending order of frequency by the brain, liver, and kidney. frequency by the brain, liver, and kidney.

The treatment of trophoblastic neoplasms- the The treatment of trophoblastic neoplasms- the uterus, surgery, and chemotherapy.uterus, surgery, and chemotherapy.

Chemotherapy consists of the administration Chemotherapy consists of the administration of one or more of a group of drugs including of one or more of a group of drugs including methotrexate, actomycin D, and methotrexate, actomycin D, and etoposide . .

The results of chemotherapy for gestational The results of chemotherapy for gestational choriocarcinoma are spectacular and have choriocarcinoma are spectacular and have resulted in up to 100% cure or remission in resulted in up to 100% cure or remission in all patients except some who had high-risk all patients except some who had high-risk metastatic trophoblastic disease. metastatic trophoblastic disease.

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

PLACENTAL SITE TROPHOBLASTIC TUMOR

In contrast to syncytial cytotrophoblast, which In contrast to syncytial cytotrophoblast, which is present on the chorionic villi, is present on the chorionic villi, intermediate intermediate trophoblasttrophoblast is found in the implantation site is found in the implantation site and placental membranes. and placental membranes.

Intermediate trophoblast is composed of Intermediate trophoblast is composed of mononuclear cells with abundant cytoplasm mononuclear cells with abundant cytoplasm that distinguish them from the syncytial that distinguish them from the syncytial cytotrophoblast. cytotrophoblast.

In contrast to syncytiotrophoblasts (which In contrast to syncytiotrophoblasts (which produce human chorionic gonadotropin), produce human chorionic gonadotropin), intermediate trophoblast cells are weakly intermediate trophoblast cells are weakly immunoreactive for human placental lactogen. immunoreactive for human placental lactogen.

Intermediate trophoblasts compose the Intermediate trophoblasts compose the placental site trophoblast and residual placental site trophoblast and residual placental site (implantation site nodule) placental site (implantation site nodule) following pregnancy, and may give rise to following pregnancy, and may give rise to placental site trophoblastic tumorsplacental site trophoblastic tumors (PSTTs) (PSTTs)

PSTTs comprise less than 2% of gestational PSTTs comprise less than 2% of gestational trophoblastic neoplasms and present as trophoblastic neoplasms and present as neoplastic polygonal cells infiltrating the neoplastic polygonal cells infiltrating the endomyometrium. endomyometrium.

PSTTs may be preceded by a normal PSTTs may be preceded by a normal pregnancy (one-half), spontaneous abortion pregnancy (one-half), spontaneous abortion (one-sixth), or hydatidiform mole (one-fifth).(one-sixth), or hydatidiform mole (one-fifth).

Beta human chorionic gonadotropin levels Beta human chorionic gonadotropin levels may be high. may be high.

Overall, about 10% result in disseminated Overall, about 10% result in disseminated metastases and death.metastases and death.

Distinction of PSTTs from normal Distinction of PSTTs from normal exaggerated placental implantation site exaggerated placental implantation site trophoblast may be difficult and can be trophoblast may be difficult and can be achieved by using biomarkers (Mel-Cam and achieved by using biomarkers (Mel-Cam and Ki-67) that detect increased proliferation in Ki-67) that detect increased proliferation in the trophoblastic cells. the trophoblastic cells.

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