Placenta
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Last major update May 2003
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Placenta - table of contents
Primary references, normal anatomy, normal histology, placental development, placental hormones, common misdiagnoses
Infectious conditions: acute villitis, chorioamnionitis, chronic intervillositis, villitis of unknown etiology, specific infectious organisms
Placental gross/microscopic abnormalities, non-neoplastic: accessory (succenturiate) lobe, acute chorionic vasculitis, amnion nodosum, amniotic band syndrome, amniotic rupture, bilobate placenta, Breus mole, chronic deciduitis, circumvallate, circummarginal, confined placental mosaicism, cysts, decidual vasculopathy, diffuse chorioamniotic hemosiderosis, fat deposits, fetal nucleated red blood cells, fetal thrombotic vasculopathy, fibrin, fistula lined by intermediate trophoblast, geographic villi, hemorrhage, hemorrhagic endovasculitis, hypoxia, iron deposits, low placental weight, maternal floor infarction, meconium staining, overweight placentas, placenta accreta, placental edema, placental infarct, placental polyp, placenta previa, placental site involution, retroplacental hematoma, squamous metaplasia, subamniotic vernix caseosum, Tinney Parker changes, uteroplacental insufficiency, villous dysmaturity, yolk sac remnant
Placental findings in specific newborn/fetal or maternal conditions: aneuploidy, Beckwith-Widemann syndrome, blighted ovum, ectopic pregnancy, fetal death, fetal neurologic impairment / cerebral palsy, hydrops fetalis, missed abortion, recurrent fetal loss, scleroderma, septic abortion, sickle cell disease, smoking, spontaneous abortion, system lupus erythematosus, thrombosis of fetal arteries, toxemia of pregnancy (pre-eclampsia and eclampsia), triploidy, trisomy, Turner’s syndrome, twins, twins-acardia, twins-fetal papyraceus, twin-twin transfusion syndrome
Umbilical cord: normal, acute funisitis, amniotic web, embryonic remnants, furcuate insertion, hematoma, knots, long cord, marginal insertion, marked segmental thinning, necrotizing funisitis, nuchal cord, prolapsed cord, short cord, single umbilical artery, supernumerary vessels, teratoma, thin cord, torsion, velamentous insertion
Non-trophoblastic neoplasms: chorangioma, chorangiomatosis, chorangiosis, congenital primitive epithelial tumor of liver, giant pigmented nevi of newborn, hemangioendothelioma, hepatocellular adenoma-like lesion of placenta, lymphoma, metastases to placenta, transient myeloproliferative disease of newborn
Gestational trophoblastic disease: general, exaggerated placental site, placental site nodule, hydatidiform moles-general, complete mole, partial/incomplete mole, invasive mole, choriocarcinoma, epithelioid trophoblastic tumor, placental site trophoblastic tumor
Miscellaneous: staging, features of tumors to report, grossing placentas, standard diagnostic report
Primary references
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), March 1977 to May 2003
Archives of Pathology and Laboratory Medicine (Archives), January 1976 to May 2003
Human Pathology (Hum Path), March 1970 to March 2003
Modern Pathology (Mod Path), January 1988 to April 2003
Rosai, J: Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996
Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999
Please refer to these primary references for more detailed discussions and photographs
Normal anatomy
15-20 cm disk, 1.5 to 3.0 cm thick, 450-600 g
Membranes: usually insert directly into placental edge
Membrane layers are amnion, exocoelomic space, chorion, decidual capsularis
Amnion: innermost covering of amniotic cavity; flat epithelial cells resting on basement membrane; squamous metaplasia common, especially near insertion of cord
Exocoelomic space: between amnion and chorion; usually obliterated, but causes membranes to slide against each other
Chorion: connective tissue membrane containing fetal vessels, internal to amnion, external to villi
Chorion laeve: chorion associated with the membrane and not with the decidua basalis; villi are oriented toward the uterine cavity, but atrophy to form the smooth (laeve) chorion; trophoblast are vacuolated
Chorion frondosum: chorion associated with the decidua basalis, located in the placenta proper
Basal plate: portion of placenta attached to uterus
Gross images: image1
Chorionic plate: portion of placenta closest to fetus
Gross images: image1
Micro images: image1
Cotyledon: grossly noted unit of placenta, from primary stem villi
Lobule: functional subunit from secondary stem villi
Normal histology
Trophoblast is either villous (on chorionic villi) or extravillous
Cytotrophoblast
Present in early gestation; differentiates into villous or extravillous trophoblast
Forms syncytiotrophoblast by fusing on villous surface
Differentiate into intermediate trophoblast at the margin of anchoring villi
Inconspicuous in term placenta
Micro: small, round, mononuclear cells with distinct cell border, minimal clear or eosinophilic cytoplasm, single vesicular nuclei
Positive stains (early placenta): AE1/AE3 (keratin), Ki-67 (25-50%)
Negative stains (early placenta): EMA, hCG, HLA-G, HNK-1, HPL, inhibin-alpha, Mel-CAM (CD146), PLAP
Syncytiotrophoblast
Synthesizes and secretes hCG, hPL
Micro: multinucleated giant cells with abundant eosinophilic or basophilic cytoplasm, often with multiple intracytoplasmic vacuoles and dense pyknotic nuclei
Micro images: image1, image2, image3
Positive stains: hCG, hPL, inhibin-alpha
Negative stains: HLA-G, Ki-67, Mel-CAM, PLAP
EM: vacuoles are due to dilated endoplasmic reticulum and lacunae from plasma membrane infoldings
Intermediate (extravillous) trophoblast
Aka X cells
Infiltrate decidua and myometrium, invade and replace spiral arteries of the basal plate to establish maternal-fetal circulation and keep vessels patent; form trophoblastic shell
Present in villi and membranes, most prominent at implantation site
Secrete PTH-related protein
Morphology varies by location (see below)
Micro images: image1
Positive stains: cytokeratin (Mod Path 1990;3:282)
Villous intermediate trophoblast
Present in trophoblastic columns adjacent to villus
Micro: larger than cytotrophoblasts, polygonal, abundant clear or eosinophilic cytoplasm, distinct cell borders, single nuclei
Positive stains: cytokeratin, HLA-G, HNK-1, Mel-CAM (towards distal end only), Ki-67 (>90%)
Negative stains: EMA, hCG, hPL (may be weak), PLAP
Implantation site intermediate trophoblast
Infiltrate endomyometrium of placental site
Micro: enlarged polyhedral to spindle cells with abundant amphophilic and vacuolated cytoplasmic and large, hyperchromatic nuclei; resemble adjacent decidua; in myometrium are more spindled and resemble adjacent smooth muscle cells; may fuse to become multinucleated cells (AJSP 1992;16:1226)
Positive stains: cytokeratin, hCG in multinucleated cells, HLA-G, hPL, Mel-CAM, PLAP (weak)
Negative stains: EMA (usually), HNK-1, Ki-67
Chorionic intermediate trophoblast
In chorion lavae, have either eosinophilic or clear cytoplasm; function unknown
Micro: enlarged round to polyhedral cells with abundant clear or eosinophilic cytoplasm and single nuclei
Positive stains: cytokeratin, EMA, HLA-G, hPL and MEL-CAM (in cells with eosinophilic cytoplasm), PLAP (in clear cells), Ki-67 (3-10%)
Negative stains: hCG, HNK-1
Reference: AJSP 2002;26:914
Implantation: occurs on postovulation day 6-7; by day 10, ovum is implanted in stroma
Vessels develop from extraembryonic mesenchyme; placenta vascularized by day 21
Villous vessels appear at 6 weeks, at 8 weeks contain nucleated red blood cells (nRBC), by 10 weeks have 10% nRBC, nRBC absent at 12 weeks
Villi in first trimester: 170 microns (large), outer layer of syncytiotrophoblast and inner cytotrophoblast, loose stroma with primitive fibroblasts and Hofbauer cells (macrophages) are plentiful, vessels are small and centrally placed and contain only nucleated red blood cells
Micro images: image1
Villi in second trimester: 70 microns, primarily syncytiotrophoblasts, cytotrophoblast layer attenuated, villi contain collagen and numerous vessels; stroma more compact
Micro images: image1
Villi in third trimester: smaller than second trimester; syncytiotrophoblast knots in 30%, dilated fetal capillaries fuse with syncytiotrophoblast to form vasculosyncytial membranes, stroma is reduced to thin strands; trophoblastic inclusions are common
Micro images: diagram, term placenta - image1, hCG immunostain
Mean placental weight by gestational age:
Prior to 28 weeks: 253 grams
28-32 weeks: 314 grams
33-36 weeks: 391 grams
37-40 weeks: 456 grams
>40 weeks: 496 weeks
Endothelial growth factor: stimulates proliferation of the trophoblast
Estrogens and progesterone: by end of first trimester, placenta produces enough to maintain the pregnancy and corpus luteum is no longer needed
Human chorionic adrenocorticotropin (hACTH): small amounts produced, functions similar to ACTH
Human chorionic gonadotropin (hCG): synthesis begins before implantation; hCG maintains maternal corpus luteum that secretes progesterone and estrogens; basis for early pregnancy tests; levels peak at 8 weeks; resembles LH
Human chorionic thyrotropin (hCT): small amounts produced, functions similar to TSH
Human placental growth hormone; differs from pituitary growth hormone by 13 amino acids; regulates maternal blood glucose levels so that the fetus has adequate nutrient supply
Human placental lactogen (hPL): similar to growth hormone; influences growth, maternal mammary duct proliferation, and lipid and carbohydrate metabolism
Insulin-like growth factors: stimulate proliferation and differentiation of cytotrophoblast
Placental alkaline phosphatase (PLAP): alkaline phosphatase normally produced by syncytiotrophoblast and primordial germ cells; also produced in seminoma, intratubular germ cell neoplasia, rarely in other non-germ cell tumors; may be involved in migration of primordial germ cells in developing fetus
Relaxin: produced by decidua; softens the cervix and pelvic ligaments in preparation for childbirth
SP1: pregnancy specific beta-1 glycoprotein; present in syncytiotrophoblast and extravillous trophoblast; not in cytotrophoblast
Common misdiagnoses
Common underdiagnoses are hemorrhagic endovasculitis (84.6%), fetal thrombotic vasculopathy (75%), massive perivillous fibrin deposition (68.4%), maternal floor infarction (66.7%), retroplacental hemorrhage (60.6%), intervillous thrombus (57.1%), decidual angiopathy (33.3%), placental infarction (25.4%), acute chorioamnionitis (22.7%), chronic villitis (21.7%), Archives 2002;126:706
Common incorrect diagnosis is infarction (correct diagnosis is perivillous fibrin deposits or intervillous thrombus)
Infectious conditions
Acute villitis
Usually due to ascending infection from vaginal tract, causes premature rupture of membranes
Associated with prematurity and sepsis in first days of life
Present in 5-25% of placentas
Associated with hemorrhagic vasculitis, vascular obliteration
Not due to meconium staining, which does not directly cause inflammation
TORCH infections: Toxoplasmosis, Other (syphilis), Rubella, CMV, HSV
TORCH infections cause fetal hepatosplenomegaly, pneumonia, coagulopathy, placentitis
Causes: Candida albicans, Camplyobacter, CMV, coccidiodes, group B streptococci, Herpes simplex, Listeria, rubella, syphilis, toxoplasmosis, tuberculosis
Grading: mild (<5% of villi), moderate (5-25%) or severe (25%+)
Gross: cloudy placenta
Micro: villi agglutination common
Chorioamnionitis
Usually caused by ascending infection of bacteria (fusobacterium in 18%, detect with Warthin-Starry stain, Archives 1985;109:739), may cause premature rupture of membranes
Often two or more microbes
Severe cases are associated with group B streptococcus infection
Major cause of fetal/neonatal infection, stillbirth, prematurity and perinatal morbidity and mortality
Clinical diagnosis: maternal fever > 37.8 C during labor plus two of the following: maternal or fetal tachycardia, uterine tenderness, foul odor, leukocytosis
Prolonged (subacute) inflammation with amniotic necrosis is associated with chronic lung disease (bronchopulmonary dysplasia, Wilson-Mikity syndrome), Hum Path 2002;33:183
Associated with occult congenital syphilis in stillborn, Archives 1994;118:44
More frequent and severe with younger gestational age
Note: fetal hypoxia and meconium staining of membranes do NOT cause inflammatory changes in placenta
Gross: cloudy amniotic fluid with purulent exudate; congestion of chorion and amnion; gray-yellow to grey-blue membranes if severe or chronic; light green is suggestive of fusobacteria; acute chorioamnionitis may be grossly normal
Micro: neutrophilic infiltrate of free membranes and those overlying chorionic plate; variable funisitis; may have septic intervillous thrombus; may be accompanied by mild to severe fetal vascular response in chorionic plate vessels
Grading:
Extraplacental chorioamnionitis: mild-neutrophils in decidua only, moderate-neutrophils in chorion and subamniotic connective tissue, severe-necrotizing inflammation
Chorioamnionitis: mild/stage 1-neutrophils in placental chorionic plate only, moderate/stage 2-neutrophils throughout chorionic plate and subamniotic connective tissue, severe/stage 3-necrotizing inflammation or multifocal abscesses
Micro images: image1, image2, figure 1B
Chronic chorioamnionitis: lymphocytic infiltration of chorioamnion, associated with chronic villitis of unknown etilogy (71%), maternal hypertension (20%), preterm infants (40%), intrauterine growth retardation (15%), Hum Path 1998;29:1457
Chronic intervillositis
Histiocytic infiltrate in intervillous spaces without villitis
Associated with perinatal mortality of 80%, making it an important (although uncommon) cause of recurrent spontaneous abortion, Archives 1993;117:1032, Hum Path 2000;31:1389
Maternal risk factors: diabetes, hypertension, intravenous drug abuse, preeclampsia, systemic lupus erythematosus
May have immunologic origin (IgM and complement deposits are seen in vascular lesions)
High recurrence rate (67%)
Micro: prominent histiocytic infiltrate within intervillous spaces (may be “massive”, see below), villous fibrinoid deposits, atherosis; acute chorioamnionitis, villi usually unremarkable but rarely chronic villitis; prominent syncytial knots associated with malarial infection
Negative stains: hCG (may be present in syncytiotrophoblasts but marked reduction compared to usual)
Massive chronic intervillositis
Associated with malarial infection (18% of placentas with malarial parasites, predominantly primigravida women, associated with low birth weight, AJSP 1998;22:1006, Hum Path 2001;32:1022)
Also associated with growth retardation and adverse pregnancy outcome
Case report of patient with 10 spontaneous abortions with recurring massive chronic intervillositis, Hum Path 1995;26:1245
Micro: massive macrophagic inflammatory infiltrate in intervillous spaces with fibrin deposition but no villous inflammation
Villitis of unknown etiology
Chronic inflammatory cells within stroma of chorionic villi, with no known cause
Associated with intrauterine growth retardation (particularly in recurrences), stillbirths and prematurity
10% of all placentas in Western countries, 25% of small for gestational age newborns
Associated with chronic chorioamniotis and rarely with chronic intervillositis
Immune etiology suspected since resembles changes seen with rubella, CMV, syphilis; may be due to nonculturable virus or other fastidious micro
Initially fetal and later maternal cells cross the trophoblasts and generate an inflammatory response
More important if >5% of total villi are involved
Micro: villi often hyalinized; frequently in basal or parabasal villi; reduced vasculature; lymphocytes and macrophages within villi
Specific infectious organisms
Bacteroides fragilis
Rare cause of chorioamnionitis
Diagnose with immunofluorescence (small organisms with safety pin configuration)
Candida albicans
Gross: umbilical cord has pale yellow plaques (specific for candida)
Micro: focal, subamniotic lesions embedded in fibrinoid exudate and surrounded by inflammatory cells; exudate and inflammatory cells also in dense bands, Hum Path 1983;14:984
Chlamydia trachomatis
Usually associated with conjunctivitis, less commonly with pneumonia
Associated with chorioamnionitis and severe endometritis
CMV
Causes 10% of chronic villitis cases; but often has no clinical symptoms, Hum Path 1994;25:815
Most severe manifestations of CMV are in fetus/infants with plasmacytic villitis and inclusion bodies, Archives 1984;108:403
Immunohistochemistry helpful since histology often non-specific, Hum Path 1992;23:1234
Gross: bloated placenta
Micro: rare intranuclear and cytoplasmic inclusions; associated with intravillous hemosiderin; hyperplasia of fetal-derived placental macrophages (Hofbauer cells); lymphocytic villitis (T cells); plasmacellular villitis, Archives 1992;116:21; hyalinized villi, plasma cells, may have granulomatous reaction
Coccidiodomyosis
Probably not spread transplacentally; neonatal disease probably due to transpartum or postpartum aspiration, Archives 1981;105:347, Archives 1978;102:512
Cryptococcus
Case report in mother taking steroids for systemic lupus erythematosus, Archives 1994;118:757
Case report of HIV infected mother with massive pulmonary embolus and disseminated infection; yeast cells in perivillous space, Hum Path 1989;20:920
Micro: intervillous and perivillous yeast cells; increased fetal macrophages; no chorioamnionitis or villitis;
Fusobacterium
Infection present in 18% with histologic chorioamnionitis
Produces phospholipase A2 and causes prematurity
Micro: pleomorphic and filamentous bacteria difficult to detect with routine stains; use Warthin-Starry, Giemsa or Brown and Hopps stain
Hemophilius influenza
Newborns have pneumonia, meningitis and sepsis
Associated with prematurity
Micro: short gram-negative bacilli, highlighted by Brown and Hopps stain
Herpes simplex virus (HSV)
Rare, may be accompanied by necrotizing funisitis (HSV2), Hum Path 1994;25:715
Micro: characteristic viral inclusions, but no inflammation; “bland necrosis” in villi
Molecular: HSV infection of decidua capsularis, Archives 1991;115:1141
DD
of necrotizing funisitis: syphilis
Human immunodifficiency virus (HIV)
p24 antigen present in placental Hofbauer cells, vascular endothelium, intermediate trophoblast, Hum Path 1992;23:411
Human papillomavirus (HPV)
More common in spontaneous abortion specimens than elective abortion specimens
Usually infects syncytiotrophoblasts, Hum Path 1998;29:170
Listeria
Micro: placental granulomas and microabscesses
Micro images: image1
Malaria
In chronic infections, parasites coexist with pigment covered with fibrin
In acute infections, parasites only, no pigment covered with fibrin
50% with parasites in placenta had no parasites in peripheral blood
Active infections are associated with chronic intervillositis (in 18%), basal membrane thickening, fibrinoid necrosis and prominent syncytial knots
References: AJSP 1998;22:1006, Hum Path 2001;32:1022, Hum Path 2000;31:85
Measles
Case report of monozygotic twins with maternal infection, Mod Path 2001;14:1300
One twin died in utero; placenta showed massive fibrin deposition, residual trophoblasts had measles inclusion bodies but fetal organs were negative for measles virus; surviving twin had focal intervillous fibrin deposits and a few measles positive syncytiotrophoblasts, but no evidence of measles after 7 months
Gross images: image1
Micro images: image1
EM images: image1
Mycoplasma
Role of Ureaplasma urealyticum or Mycoplasma hominis in chorioamnionitis and perinatal morbildity/mortality is controversial
M. hominis is normal flora in female genital tract
Parvovirus B19
Destroys early RBCs (normoblasts), causing marked erythroid hypoplasia of bone marrow and occasional giant erythroblasts
Abundant intranuclear inclusions observed in placenta or other tissues of infected fetuses
Psittacosis
Occurs in pregnant women exposed to products of conception of animals (usually sheep) infected with chylamidia psittaci
Usually causes flu-like illness in adults, but may be severe and progressive febrile illness during pregnancy with DIC, impaired renal function, heachache, abnormal liver enzymes
Micro: intense, acute intervillositis, perivillous fibrin deposition with villous necrosis, large irregular basophilic intracytoplasmic inclusions within syncytiotrophoblast, Mod Path 1997;10:602
Syphilis
Often associated with stillbirth or early neonatal death
Most cases with positive PCR have negative histology, so do PCR of placental tissue if suspect syphilis
Umbilical cord often normal; 36% have necrotizing funisitis
Micro: enlarged hypercellular (immature) villi, proliferative fetal vascular changes, acute or chronic villitis, spirochetes on Steiner stain; lymphoplasmacytic infiltrate, may not have prominent plasma cells, Hum Path 1996;27:366, Hum Path 1993;24:779; associated with intravillous hemosiderin
Positive stains: visualize spirochetes in cord using silver stain and immunofluorescent stains, Hum Path 1995;26:784
Varicella zoster virus
Mothers often (33%) develop varicella pneumonia
Infants tend not to develop infection after maternal infection
Case report of spontaneous abortion in first trimester, Hum Path 1998;29:94
Micro: extensive basal chronic (lymphocytic) villitis with occasional multinucleated giant cells
Reference: Hum Path 1996;27:191
Placental gross/microscopic abnormalities, non-neoplastic
Accessory (succenturiate) lobe
Present in 3% of placentas, often attached by fetal membranes
Vasculature between the lobes is unsupported by placenta and at risk for fetal hemorrhage, thromboemboli
Gross images: image1
Acute chorionic vasculitis
Vasculitis involving fetal vessels of chorionic plate or umbilical cord
More severe as more vessels are involved and if a vessel is severely involved
Severity: chronic vasculitis (least severe), umbilical vasculitis (1-2 vs. 3 vessels), umbilical vasculitis plus inflammation of Wharton’s jelly, necrotizing funisitis (most severe)
Duration: subchorionitis (short), chorionitis, chorioamnionitis, subnecrotizing, necrotizing (long)
Intensity: mild, intermediate, severe
Amnion nodosum
May be due to desquamated skin or membrane injury
Associated with fetal renal agenesis, oligohydramnios and pulmonary hypoplasia
Gross: multiple superficial amniotic lesions, 0.2 to 0.4 cm, usually near insertion of umbilical cord
Micro: nodules of protuberant fibrinous material with entrapped squamous cells; associated with stratified squamous metaplasia
Amniotic band syndrome
Early amniotic rupture sequence with strands across fetal surface
Amnion ruptures and baby grows between amnion and chorion
Necrosis at tips of fingers, associated with cranial defects
Earlier amnion rupture is associated with more severe fetal defects
Amniotic rupture
Due to amniotic sac inadequate to contain the fetus
Associated with fetal amniotic band syndrome, which rarely occurs in its absence, AJSP 1984;8:117
Sporadic; recurrence is rare in subsequent pregnancies
Micro: vernix granulomas in separated amniotic mesenchyme and in denuded mesenchyme of chorionic plates confirm antepartum amniotic rupture
Can diagnose from biopsy of maternal placental bed if desquamated stratified squamous epithelial cells in edema fluid between muscle fibers surrounded by marked neutrophilic infiltrate, uterine venules with fibrin clots containing squamous epithelial cells; veins with plugs of amniotic thrombi, Archives 1997;121:167
In prolonged amniotic leakage, may see subchorionic squames or subchorionic foreign-body reaction, Archives 1986;110:47
Bilobate placenta
2 lobes of equal size, separated by fetal membranes or connected by narrow isthmus of placental tissue
Uncertain clinical significance, but at risk of fetal bleeding from velamentous/intramembranous vessels
Maternal postpartum bleeding occurs if portion retained in utero
Aka massive subchorionic hematoma
Massive and recent hemorrhage involving entire subchorionic area; bulges into amniotic cavity
Seen in missed abortions
May be identified on ultrasound, Archives 1983;107:438
Chronic deciduitis
Diagnose based on severity and extent of lymphocytes and presence of plasma cells in basal decidua, Hum Path 2000;31:292
Placenta with extrachorial part; chorion is folded or rolled back on itself and has a peripheral protuberance
Associated with low birth weight babies, marginal hemorrhage, more common in multigravidas
If cysts and other gross aberrations present, may be associated with fetal and maternal abnormalities
Extrachorial placenta with thin and flat margin
Minimal clinical significance, more common in multigravidas
Confined placental mosaicism
Mosaicism (combination of cells with different chromosomal content) confined to placenta and not affecting baby
Example: placenta mosaic for trisomy 16, baby normal
Cysts
Usually lined by intermediate trophoblast (X cells), present anywhere throughout placenta
Intermediate trophoblast cells have fetal origin; more abundant in degenerate and ischemic placentas of growth retarded fetuses
Gross: usually 3 cm or less
Micro: basophilic cells surround proteinaceous eosinophilic material
DD of cysts: rarely partial moles, villous stromal degeneration; cysts associated with triploidy and fetal nucleated red blood cells
Decidual vasculopathy
Atherosis (associated with hypertension) in maternal basal plate
Early: fibrinoid necrosis of vessel walls with perivascular mononuclear infiltrate
Late: subendothelial macrophages and lipid deposition, also seen in eclampsia, small for gestational age infants, Archives 1991;115:722
Micro images: contributed by Dr. Yan Lemeshev, Texas (USA): atherosis with fibrinoid necrosis of vessel walls and lipid laden subendothelial macrophages
Diffuse chorioamnionic hemosiderosis
Hemosiderin-laden macrophages in the amnion and chorion of membranes and chorionic plate, plus old blood clot
Micro images: figure 1C
Fat deposits
Associated with intravenous lipid emulsions, Archives 1995;119:555
Fetal nucleated red blood cells
Not present in normal term placentas/newborns
A response to chronic fetal hypoxia from uteroplacental insufficiency, abruptio placentae, maternal diabetes, ABO blood group incompatibility, chronic feto-maternal transfusion, hemolytic disease, acute fetal blood loss or chromosomal disorders
Micro: dark color, smooth nuclear surface, smaller than mature red blood cells and lymphocytes
Mild-easily seen in placentas of preterm newborns, rare in term placentas
Moderate-readily present in placentas of any gestational age
Severe-marked number in placentas of any gestatiobnal age
Micro images: image1
Fetal thrombotic vasculopathy
Thrombi in fetal circulation; cause clustered fibrotic avascular villi associated with severe CNS injury and renal vein thromboses in neonates, Hum Path 1999;30:759
Avascular villi are associated with intrauterine growth retardation, acute and chronic monitoring abnormalities, oligohydramnios, maternal coagulation disorders; also chronic villitis, membrane hemosiderin, meconium in all 3 membrane layers, villous chorangiosis
Avascular villi: 2.5%+ of villous parenchyma affected, foci in multiple sections or single lesion 0.25 cm2 or larger
Clinical abnormalities associated with 30%+ avascular villi, Hum Path 1995;26:80
May be caused by hereditary hypercoaguable states of factor V (Leiden) or prothrombin mutations, Hum Path 2000;31:1036
Gross: triangular pale areas
Micro: thrombosed and avascular villi
Significant if diffusely present and involves terminal villi (impairs gas exchange)
May cause intrauterine growth retardation, oligohydramnios, elevated alpha-fetoprotein, hyperechoic placental mass, spontaneous abortion, prematurity, intrauterine fetal death, neurologic impairment (12-78% recur)
Insignificant if basal (Nitabach’s layer) or affect stem villi
Increased intervillous fibrin is associated with early preterm placentas (20 to 31 weeks), Archives 1994;118:698
Associated with chromosome anomalies (trisomy 18, 13, 21, triploid, XO) if no trophoblast hyperplasia; normal in second trimester
Gross images: trisomy 18 infant with overlapping digits #1; #2; #3
Hemorrhage
Often at edge of placental disc
Associated with marginal cord insertion and velamentous vessels, placental implantation in lower uterine segment
Hemorrhagic endovasculitis
Aka hemorrhagic vasculopathy
Alteration of fetal-placental blood vessels associated with perinatal morbidity and mortality and abnormalities of growth and development, abnormal fetal heart rate tracings, tissue hypoxia
Associated with chronic villitis of unknown etiology, chorionic vessel thrombi, villous erythroblastosis, villous fibrosis, primary infarcts, meconium staining, maternal hypertension
Micro: changes in placental vessels include thrombosis, endothelial and medial hyperplasia and lumen narrowing or obliteration, microangiopathic process suggested by RBC fragmentation and villous stroma containing hemosiderin and RBC fragments
Micro images: image1
References: Archives 2002;126:157, Archives 1980;104:371
Hypoxia
Superficial implantation site causes insufficent vascular remodeling
Underperfusion of intervillous space is associated with infarction, arteriopathy (vasculitis, preeclampsia / fibrinoid necrosis, thickening of intima / media)
Underperfusion of chorionic villous circulation is associated with avascular villi, thrombosis (? due to procoagulant), hemorrhagic endovasculitis changes (gradual closing of circulation, mimics changes in stillbirths), may see increase in nucleated RBCs
White infarct: changes conform to outline of one villous tree
Stasis: interference with venous drainage, due to chronic cord compromise
Micro: increase in syncytial knots, terminal villous deficiency (too few, too small, due to hypoxia; terminal villi grow in third trimester unless ischemia is present)
Iron deposits
Associated with fetal growth anomalies if present in 7.5% + of villi
Normal if along trophoblastic basement membrane
Fetal factors: prematurity, fetal malformations or trisomy, small for date fetus, neonatal high hemoglobin, lower than expected body size in later childhood for fetus
Maternal factors: low pregnancy weight gain, low maternal pregravid body weight, high maternal hemoglobin during pregnancy, gestational hypertension, paid employment during pregnancy, low parity, maternal diabetes, CMV, HSV or other chronic infections, other causes of reduced uteroplacental blood flow
Micro: impaired villous growth
Maternal floor infarction
Misnamed; characterized by heavy deposition of fibrin in decidua beneath the placenta, may extend into intervillous space and envelop villi causing them to atrophy
Associated with recurrent reproductive failure (50% had abortions or stillbirths)
Present in 17% of placentas with stillborns
May be caused by ischemic or infectious damage to decidua basalis, including low maternal blood volume
Associated with acute chorioamnionitis, Hum Path 1985;16:823
Gross: palpably firm
Micro: 0.4 cm bands of degenerate placental basal tissue composed of fibrinoid material and intermediate trophoblast (X cells), necrosis of decidua and fibrin deposition, atheroma in decidual arteries
Passage of meconium in utero is due to bowel peristalsis and relaxation of anal sphincter; may indicate fetal distress; associated with meconium aspiration
Must differentiate between deposition of slimy green meconium across placental surface that is washed off with a gentle rinse (normal fetus that pases meconium shortly after delivery) and true mecomium staining (exposure to meconium for several hours)
Damage to fetus increases with length of exposure to meconium; over time, soluble meconium components diffuse into placenta and cord, induce vasoconstriction and cause fetal hypoperfusion
Present in cord macrophages; causes necrosis of individual myoctes; may cause funisitis without chorioamnionitis
Before 34 weeks, pigment present is usually hemoglobin
Meconium associated vasculopathy: avascular fetal vasculopathy secondary to remote thrombus
Gross: initially slimy green membranes, later muddy brown; flattened segment of umbilical cord, slimy green to muddy brown membranes and cord surface
Gross images: image1
Micro:
pigmented macrophages with apoptotic like nuclei
mild-superficial necrotic or sloughed amniotic epithelium with meconium containing macrophages confined to the surface
moderate-ballooning of vacuolated amniotic epithelium with obvious meconium containing macrophages adjacent to chorionic tissue; indicates meconium discharge at least 2-3 hours before delivery
severe-moderate histologic findings but with more macrophages; may have meconium induced necrosis of umbilical vessels with myocyte necrosis; indicates fetal meconium discharge 6-12 hours before delivery
Micro images: image1
Usually due to villous edema
Fetal factors: acute antenatal hypoxia including low Apgar scores, respiratory distress syndrome, neurologic abnormalities (may persist), hydrops/neonatal death (erythroblastosis fetalis, tumors, fetal renal vein thrombosis), chronic intrauterine infection, immunohemolytic anemia, fetomaternal hemorrhage, polyhydramnios, Hum Path 1987;18:387
Maternal factors: diabetes, anemia, malnutrition, retroplacental hematoma, TORCH infections
Placenta accreta
Placenta adherent to uterus
Rarely diagnosed in delivered placenta; usually only when uterus is removed
Causes postpartum bleeding and fever, although microscopic findings can also occur without symptoms
Often no obvious findings in women with vaginal deliveries after prior cesarean section
Accreta often used as a general term since the degree of invasiveness is not uniform
Accreta: partial or complete absence of decidua with adherence of placenta directly to myometrium
Increta: villi invade myometrium
Percetra: villous infiltration extends through full thickness of myometrium; may cause uterine rupture
Risk factors: 60% of cases are associated with placenta previa (placenta implants in lower uterine segment or
cervix, often with serious antepartum bleeding and premature labor); also more common in cesarean section scars, multigravidas and ‘elderly’ reproductive women; associated with retained placenta, postpartum hemorrhage
Due to deficiency in decidua OR abnormal invasiveness
Case report, Archives 2002;126:1557
Gross: ragged tissue or incomplete cotyledons on maternal floor; superficial acute hemorrhage near insertion of cord (due to excessive traction on cord during labor)
Micro: chorionic villi in direct contact with myometrial smooth muscle fibers, absence / reduction of decidua basalis layer, layer of fibrin, hemosiderin laden macrophages
Micro images: image1, figures 2 (H&E), figure 3 (actin)
Huge spaces with macrophages
Placental infarct
Villous necrosis secondary to local obstruction of maternal uteroplacental circulation
Minor areas of infarction present in 25% of placentas
Associations: hypertension, preeclampsia, Rh incompatibility, connective tissue disorders, normal fetal outcome
Infarcts usually due to retroplacental hematoma (abruptio placenta, associated with cocaine) or thrombosed maternal vessel
Need >30% placental involvement to affect fetal income (neonatal asphyxia, low birth weight, intrauterine fetal death)
Infarcts away from edge may indicate reduced uteroplacental blood flow; usually not significant if at placental edge
Note: most placentas from pregnacies with preeclamptic toxemia show no infarcts
Gross: acute infarcts are dark, red-brown and differ from adjacent placenta; often at placental edge; old infracts appear firm, white and granular
Gross images: image1
Micro: ghosted out villi with obliteration of intervillous space / villi agglutination, marked congestion of villous vessels, lobular distribution; no villous stromal fibrosis, no cytotrophoblastic proliferation; cells are all eosinophilic and exhibit karyorhexis
Micro images: old - image
DD: hematomas (usually lobular), subchorionic fibrous plaques, perivillous fibrin deposition (usually venous lesions), intervillous laminated thrombi, intraplacental choriocarcinoma (looks grossly like an infarct)
Placental polyp
Case report of “chronic” polyp 9 years after induced abortion of last known pregnancy, Hum Path 1988;19:1467
Micro: necrotic and hyalinized chorionic villi without identifiable lining trophoblast; intermediate trophoblast most viable; base of polyp composed of decidua with dilated blood vessels
Placenta implants near cervix ahead of fetus
Major cause of third trimester vaginal bleeding, may require emergency cesarean section
Gross: marginally ruptured membranes (less significance if cesarean section)
Gross images: image1
Placental site subinvolution
Can cause vaginal bleeding weeks after delivery, even if no residual placental tissue
May be due to deficiency in immunologic factors necessary for normal involution of uteroplacental arteries
Micro: curettings contain large maternal vessels from placental site with thrombi (normally, thrombi become organized and remain as scars)
Retroplacental hematoma with intraplacental extension
Aka abruptio placenta
Usually NO predisposing event; fetal death if 50% separation
If major, may be due to diseased artery
Recommended to not use Kleihauer-Betke test for fetal-maternal hemorrhage to diagnose, Archives 1995;119:1032
Intraplacental extension: indentation or rupture of the basal plate, diffuse intradecidual hemorrhage, or villous changes, such as recent infarction, villous stromal hemorrhage, or irregular intervillous thrombi.
Gross: loose blood clots or blood clots tenuously adherent to placental floor if acute; remote episodes have brown-tan, old fibrin and necrotic tissue at abruption site and adjacent membranous tissue
Micro: hemosiderin, thrombus
Micro images: image1
Pearly white plaques
Subamniotic vernix caseosum
Pale white areas on placental membranes due to minute tears in amnion
Tinney Parker changes
Associated with diabetes, infarcts and hypertension
Check maternal vessels in decidua
Uteroplacental insufficiency
Causes: abnormal placentation, altered placental development, maternal vascular thrombosis
Villous dysmaturity
Implies abnormal villous maturation
Cause usually unknown
Associated with neonatal hepatitis if placenta also has pigment-laden Hofbauer cells
Micro: enlarged villi, trophoblast lacks normal syncytiotrophoblast, reduction in syncytial knots
Micro image: image1
Placental findings in specific newborn, fetal or maternal conditions
Aneuploidy
Associated with early fetal hydrops
Placental changes include trophoblastic hypoplasia, stromal edema, cavitation, reduced vascularization, ramification of main villous trunks
Placental changes may be due to reduction in villous circulation leading to generalized stromal edema, Hum Path 1998;29:1195
Associated with massive placental hydrops involving stem villi but no associated trophoblast hyperplasia, Hum Path 1991;22:591
Blighted ovum
No development or early demise of embryo
Hydropic villi with moderate amount of edema (since trophoblasts normally transport water)
In contrast to mole, no central cistern formation, no trophoblastic proliferation
If karyotype is abnormal, 52% are trisomy, 20% are triploid, 15% are XO, 6% are tetraploid; pre week 8 are usually aneuploid with embryonic growth disorganization
Triploid cases resemble partial moles without embryos; but sporadic and not recurrent; invasive mole rare; grossly have hydropic villi (many, not all), microscopically show focal trophoblastic invaginations, cisterns, irregular surfaces, dysmorphic external features
Autosomal trisomies have smaller villi, no cisterns, are associated with future anomalous conceptions
Ectopic pregnancy
90% in tubes, also ovary, abdomen, cornua of uterus
Occur in 1 per 150 pregnancies
Risk factors: 50% have pelvic inflammatory disease or peritubal adhesions (appendicitis, endometriosis, surgery, leiomyomas); 50% have normal tubes
Tubal pregnancies: most common cause of hematosalpinx, may have placental separation without rupture, although rupture at 6 weeks is more common; rupture is a medical emergency; diagnose/rule out with ultrasound, serum hCG, laparoscopy
Fetal death
Usually chorioamnionitis, deciduitis or villitis are present; should perform cultures
Associated with maternal problems (diabetes, preeclampsia, urinary tract infection) as well as placental problems (vasculopathy, ischemia, infarcts, chorangiosis), Archives 1976;10:367
Gross: severely macerated fetuses have been dead for days
Micro: initially see nuclear debris in blood vessels or villus vessels with early bridging; also increased syncytial knots in placenta; calcifications may be seen but are nonspecific; usually takes > 24 hours to see microscopic evidence of intrauterine death; villous fibrosis occurs later
Micro images: image1, image2, trichrome stain
Fetal neurologic impairment / cerebral palsy
Placental lesions independently associated with neurologic impairment include severe fetal chorioamnionitis, diffuse chorioamnionic hemosiderosis, extensive avascular villi; also chorionic vessel thrombi, increased nucleated red blood cells, retroplacental hematoma, meconium-associated vascular necrosis, diffuse chronic villitis, perivillous fibrin
Risk of neurologic impairment is increased with number of lesions present, Archives 2000;124:1785
Nonocculsive thrombi of chorionic plate vessels and severe villous edema is associated with neurologic impairment, Archives 1998;122:1091
Cerebral thrombi and infarcts may be present, Hum Path 1997;28:246
Presence of thrombi may indicate a coagulopathy in parents
Fistula lined by intermediate trophoblast
Case report of postcaesarean section uterovesical fistula lined by persistent intermediate trophoblast, AJSP 1995;19:1440
Hydrops fetalis
Causes: Rh incompatibility, chromosomal abnormalities (45 X0), hematologic disorders, infections, congenital anomalies
Placenta usually edematous with microscopic but not gross villous edema, nucleated RBC’s, occasional intravillous hematopoiesis; no cistern formation, Hum Path 1985;16:785
Micro: usually hydropic villi
Villi without fetus
Cisterns, but villi all round and similar, no trophoblast hyperplasia
Maternal or fetal etiology (not paternal as in molar pregnancy)
DD: molar pregnancy
First trimester – recurrent aneuploidy
Second trimester – uterine abnormalities
Third trimester – vasculopathy / coagulopathy, chronic villitis, intervillositis, massive perivillous fibrin deposition
Causes of fetal loss by compartments: maternal vessels (can have thrombi); interface (see fibrin, villositis); fetal vessels (twisted vessels, arteriopathy, meconium)
Scleroderma
Frequent intrauterine fetal demise and preterm delivery
Also frequent decidual vasculopathy due to mural macrophages and IgM and IgG deposition, similar to hypertensive pregnancies, Hum Path 1998;29:1524
Septic abortion
Due to coliforms or anaerobic streptococci
Must identify organisms in tissue before making diagnosis of septic abortion; presence of neutrophilis is insufficient for diagnosis (neutrophils may be a reaction to necrotic decidua)
Sickle cell disease
Case report at Archives 2000;124:1565
Micro images: image1
EM: umbilical vein shows smooth muscle proliferation, increase in basement membrane thickness, necrosis, reduplication of inner elastic lamina, Hum Path 1999;30:13
Smoking
Associated with single umbilical artery, increased branching of cord vessels
Spontaneous abortion
Occur in 10-15% of clinically recognized pregnancies and 22% of pregnancies detected via hCG levels
Fetal factors: fetal genetic abnormalities
Maternal factors: developmental, cervical incompetence, inadequate implantation, leiomyomas, infection (toxoplasmosis, Listeria, mycoplasma, rubella, Campylobacter, syphilis, CMV); autoimmune disease, usually causes midtrimester abortions
Normal karyotype: associated with maternal age < 20 years, chronic intervillositis, increased perivillous fibrin deposition with intermediate trophoblast, decidual plasma cells, Hum Path 1999;30:93
Abnormal karyotype: associated with developmental stage < 6 weeks, hydropic villi > 1 mm, villi with 2+ dysmorphic features
Cannot diagnose intrauterine pregnancy with certainty if no fetal parts, no villi, no trophoblasts, although enlarged hyalinized spiral arteries, fibrinoid matrix are suggestive
Decidual reaction, gestational hyperplasia (glandular secretion, stromal edema) and Arias-Stella reaction are suggestive of pregnancy (not necessarily intrauterine), but non-specific (also occur with hormones)
Treatment: D & C to remove residual trophoblastic tissue and examine for gestational trophoblastic disease
Gross: variable fetal parts (examine carefully for anomalies); report if gestational sac present and if intact or ruptured; if ruptured, state if contains a cord stump or not
Micro: decidual necrosis and decidual blood vessel thrombi, neutrophilic infiltrate, old/recent hemorrhage, edematous avascular villi; villous trophoblastic hyperplasia (associated with abnormal karyotype, Mod Path 1998;11:762)
Second trimester abortions (any cause) show focal decidual necrosis, intradecidual hemorrhage, congestion/ thrombosis of maternal vessels
Cytogenetics: obtain if recurrent or malformed fetus; cytogenetic abnormalities are associated with embryonic growth disorganization leading to early death
DD: mole (both may have villous trophoblastic hyperplasia but abortion lacks gross villous swelling and cistern formation, villi are surrounded by attenuated, not hyperplastic trophoblast, and lack atypia, Mod Path 1998;11:762)
Systemic lupus erythematosus
Associated with intrauterine growth retardation
Vascular changes may lead to vascular occlusion, decreased placental perfusion and subsequent villous infarction
Case report of marked decidual vasculopathy and villous infarction in first trimester missed abortion in SLE patient with anticardiolipin antibodies and serum lupus anticoagulant, Hum Path 1996;27:201
Gross: placental infracts
Micro: decidual vasculopathy, placental infarcts, acute atherosis (resembles actue vascular rejection in kidney transplants)
Thrombosis of fetal arteries
More common in diabetic women (who also have more syncytial knots, fibrotic villi, Langhans cells, villous fibrinoid necrosis)
Associated with coagulopathies
May embolize to fetal organs, cause perinatal asphyxia, avascular villi
Gross: triangular or hemispheric pale areas, seen better after formalin fixation, otherewise similar to remaining placenta
Micro: fibrosed and avascular villi, thrombosed fetal artery at apex of lesion
Micro images: avascular villi (figure 1A)
DD: placental infarct
Toxemia of pregnancy (preeclampsia and eclampsia)
Preeclampsia: idiopathic hypertension of pregnancy with proteinuria and edema, begins at 32 weeks (early with preexisting kidney disease or hypertension or hydatidiform moles)
6% of pregnant women, usually in last trimester, usually first pregnancies
Early-due to superficial implantation, caused by defective integrin expression
Late-triggered by trophoblast, excessive or ischemic trophoblast in maternal circulation
Eclampsia: convulsions, disseminated intravascular coagulation (DIC) affecting liver, kidney, brain, heart, placenta
Due to thrombosis of arterioles and capillaries
Placenta - larger and more numerous infarcts than normal; retroplacental hematoma
Brain - gross or microscopic hemorrhage; small vessel thrombi
Kidney - endothelial cell swelling, fibrinogen-derived amorphous dense deposits on endothelial side of glomerular basement membrane; severe disease may cause bilateral renal cortical necrosis
Liver - hemorrhage, fibrin thrombi
Pathophysiology: hypertension due to alterations in renin-angiotensin axis (failure to develop resistance to angiotensin)
Treatment: deliver baby
Gross: large placentas, often with superficial implantation
Micro: villous ischemia (increased syncytial knots, thickening of trophoblastic basement membrane, villous hypovascularity, villous agglutination and infarction), fibrinoid necrosis of uterine vessels, acute atherosis; more tortuous or densely distributed spiral and basal arteries than normal (Hum Path 1997;28:353), inappropriate trophoblastic immaturity (Hum Path 1995;26:594)
Micro images: image1
Triploidy
Associated with villous dysmorphism and cisterns
Associated with villous hydrops, no umbilical cord, no fetal tissue, no anucleate RBCs, Hum Path 1995;26:201
Trisomy 21: Associated with elevated serum hCG and AFP, reduced serum estradiol, hypovascular placentas
Fetal karyotype 45 XO
Gross: most fetuses are dead and macerated; neck swelling up to 3x head size due to cystic hydroma, webbed neck; also short stature, streak ovaries; usually not repeated in subsequent pregnancies
Micro: edematous villi
1 in 80 births in US, 1/3 are monozygous
Types: Dichorionic diamniotic (fused or not), monochorionic diaminiotic, monochorionic monoamniotic
Dichorionic: may be mono or dizygotic; lack vascular anastomoses
DiDi (dichorionic diamniotic): "hamburger" between two amniotic membranes vs. monochorionic-diamniotic with "nothing" (translucent septum) in the middle
Didi may also be entirely separate or fused; when fused, fetal vessels don’t cross area of fusion; check for didi near villi
Didi placental partitions usually opaque with grossly visible blood vessels
Micro images: image1
Case report of acardiac twinning in dichorionic twin placentas, Hum Path 1998;29:1028
Monochorionic are monozygotic (time of splitting determines if 1 or 2 amnions present); have major vascular anastomoses between the twins; interplacental partition does not include chorionic or decidual tissue since only one placental disk present; arteries are superficial to veins, but are histologically similar
Monochorionic have higher mortality due to premature labor; monoamniotic have 33% perinatal mortality due to cord complications (twist, knot)
Monochorionic diamniotic: vascular districts merge, portions are shared by both fetuses
Use vascular injection to identify deep AV anastomoses
Micro images: image
Monochorionic monoamniotic (MoMo)
T zone: where septum meets fetal surface of placenta
Conjoined twins; monochorionic monoamniotic
Identical twins: have septum in placenta
1% of monozygotic twin gestations
Bizarre, malformed fetus without heart, perfused by normal twin, often 2 vessel cord (1 artery, 1 vein)
Monochorionic implantation
Gross image of placentas: image1
Early intrauterine fetal death of twin, compressed against membranes by the other twin
Twin-twin transfusion syndrome
Unbalanced flow of blood through arteriovenous anastomoses
Worse clinical outcome if AV anastomoses without arterioarterial or venovenous anastomoses
Growth discrepancy and mortality usually marked in second trimester
Donor twin is anemic, small and pale with small organs; donor placenta resembles Rh incompatibility with large, pale, bulky parenchyma, large edematous villi, enlarged capillaries
Recipient twin is large and plethoric with large organs; at risk for high-output cardiac failure; placenta has small, firm, mature villi
Both twins are at risk (70% mortality)
After death of donor twin, may get an acute reverse transfusion
Treatment: serial amniocentesis, removal of a fetus, surgical interruption of common vasculature
Umbilical cord
55-65 cm long with outer amniotic epithelium, bulk is composed of mucoid Wharton’s jelly
2 arteries, 1 vein, although 2 arteries often merge near end of cord
Diameter 1 cm or more
Central insertion into placenta at midgestation, insertion may become more eccentric as gestation proceeds
Umbilical arteries: double layered muscular wall, no internal elastic lamina
Umbilical vein: larger diameter, thin wall with single layer of disorganized circular smooth muscle and an internal elastic lamina; no intima
Micro images: image1, Wharton’s jelly
Acute funisitis
Funisitis: inflammation of umbilical cord
A type of fetal inflammatory response to intrauterine infection
Associated with heavy meconium staining, premature rupture of membranes, poor outcome
Causes: Listeria and Candida infections (cause abscesses and targetoid lesions in 25% of infected pregnant women), Actinomyces, HSV (causes necrotizing funisitis), syphilis
Higher incidence of major perinatal morbidity in preterm vs. term placentas, Hum Path 2001;32:623
Micro: neutrophilic infiltratiobn of umbilical vein or arteries; necrosis of myocytes, meconium macrophages, mild neutrophilic inflammation
Mild-focal inflammation, moderate-diffuse inflammation, severe-necrotizing inflammation
Amnion goes up the cord
No clinical significance
DD: amniotic band syndrome
Allantoic duct [lumen is central between the artery], omphalomesenteric duct [epithelial lined lumen in cord lying subamnionically], embryonic vessels, together found in 23% of cases
Usually at fetal end of umbilical cord, Hum Path 1989;20:458
No clinical significance
Loss of covering of Wharton’s jelly before insertion into chorionic plate
No clinical significance
Hematoma
Significant if 4 cm long or more, 1.5 cm or more in diameter
Associated with 2 vessel cord, decreased/absent fetal movement
Knots
True knots: no clinical significance if loose; intrauterine fetal death if tight
Gross: edema, grooving, narrowness, tightness; may have intravascular thrombus
Gross images: true knot #1; #2
Gross images contributed by anonymous: true knot with placental infarction and intrauterine fetal demise
False knot: varicosity or lack of Wharton’s jelly
no clinical significance
Gross images: image1
>100 cm (as measured by obstetrician)
Associated with knots, entanglements, obstruction, thrombi
Prolapse may cause fetal distress/demise
Telephone cord cord: extra twisting of long cord, no clinical significance unless causes torsion
Marginal insertion of umbilical cord
Aka battledore placenta
Weak association with poor perinatal outcome
Gross images: image1
Marked segmental thinning
Rare, 1.5% of placentas at urban hospital
Associated with severe congenital anomalies (anencephaly, genitourinary anomalies), complications (meconium-stained amniotic fluid, variable decelerations during labor, twinning, nuchal cord, Archives 1994;118:826)
Micro: tunica media vasorum virtually absent in at least one cord level; usually <30% of vessel circumference; vein affected in 76% of cases; 1-2 arteries in 24%; similar changes in stem vessels of placenta
Stillbirth common (31%)
Causes: syphilis (11%), HSV, Candida infections; also prolonged rupture of membranes (62%), preterm labor
Also associated with chronic villitis (58%), acute chorioamnionitis (100%), Hum Path 1992;23:1278
Usually vein involvement occurs first
Fetal sepsis is rare
Gross: barber-pole pattern of yellow-white bands between vessels and cord surface; with candida infections have small focal yellow-gray necrotizing lesions on cord surface
Micro: perivascular concentric rings of inflammatory cells, necrotic cell debris, calcium deposits, neovascularization; special form of chronic inflammation of the umbilical cord characterized by numerous mixed inflammatory cells forming ring-like bands around the umbilical vessels
Similar inflammation of chorionic plate, if present
Cord wrapped around baby’s neck
Gross images: image1
Dusky (necrotic) portion of cord
Associated with footling breech births
<32 cm long (as measured by obstetrician)
Associated with impaired fetal mobility including oligohydramnios, maternal uterine malformation, amniotic band syndrome, hematoma/hemorrhage; fetal anomalies of body wall
Only two vessels (one artery and one vein) instead of usual two arteries and one vein
One artery may be present but hypoplastic
Occurs in 1% of all cords
Associated with congenital anomalies in 30%, involving heart, kidney, skeleton; also small size for date, prematurity, maternal diabetes, epilepsy, toxemia, twins (almost always present in acardiac twins)
The single artery may be a persistent vitelline artery in cases of caudal regression and syringomelia
No increased risk of mortality in newborns that survive the neonatal period
Must confirm microscopically
Micro images: image1
Supernumerary vessels
4 or more vessels
Additional vessels may be arteries or veins
DD: embryonic nests, tangential artifacts
Teratoma
Rare, case report at Hum Path 1985;16:190
Thin cord
Diameter < 1 cm
Associated with tobacco use, oligohydramnios
Wrinkled and discolored thin cord with 42 week+ gestational age associated with deficient placental function and oligohydramnios
Torsion
Associated with fetal death
May be due to loss of Wharton’s jelly in affected area, Archives 1978;102:32
1% of placentas
Insertion directly into extraplacental membranes
Vessels split before entering placenta; associated with fetal blood loss (often massive), fetal distress, common in twins
May cause massive fetal hemorrhage if located at the cervical opening
Gross images: image1
Non-trophoblastic neoplasms
Chorangioma
Benign mass of capillaries in placenta
Present in 1% of placentas that are carefully examined; usually small, incidental, no clinical significance
Large chorangiomas are associated with shunting of blood across the tumor, high output congestive heart failure, polyhydramnios, placenta previa, cutaneous hemangiomas, premature delivery
May be associated with living in high mountainous countries
Gross: well circumscribed, purple-red, homogenous mass lesion; usually < 0.5 cm, under chorionic plate and at placental margins
Micro: mass of small capillaries; may have mitotic figures or degenerative changes; may show nonspecific trophoblast hyperplasia similar to partial moles, although lesions are not composed of trophoblastic tissue
May be capillary, cavernous, endotheliomatous, fibrosing, fibromatous or atypical (see below)
No reported invasion or metastases, Archives 1999;123:536
Micro images: image1
Positive stains: CK18 (indicates origin from chorionic plate and anchoring villi)
EM: endothelial cells and various vascular structures, AJSP 1980;4:87
Atypical chorangioma
Rare, cellular with increased mitotic activity; variable nuclear atypia, necrosis, solid areas
May resemble sarcoma
Chorangiomatosis
Associated with preeclampia, multiple gestation, premature delivery at 32 to 26 weeks, Hum Path 2000;31:945
Diffuse multifocal subtype asssociated with extreme prematurity (< 32 weeks), congenital malformations, intrauterine growth retardation, delayed villous maturation, avascular villi, placentomegaly
Gross: focal, segmental or diffuse multifocal
Chorangiosis
10 vessels in each of 10 villi in 10 fields in 3 or more random, noninfarcted placental areas using a 10x lens
Normal villi rarely have more than 5 capillary lumina
A type of villous dysmaturity with capillary hypervasculity, not stromal hypercellularity
May be due to chronic placental hypoperfusion or low-grade tissue hypoxemia; both occur in pre-eclampsia
Associated with neonatal morbidity/mortality
Associated with maternal pre-eclampsia/eclampsia, diabetes mellitus, placentomegaly, drug ingestion; urinary tract infection; also living at high altitudes
Associated placental findings include single umbilical artery and other umbilical cord anomalies, retroplacental hematoma (abruptio placentae), placenta previa, chorangioma, amnion nodosum, delayed villous maturity, chronic villitis
Micro images: image1
DD: congestion (normal number of vessels), tissue ischemia (shrunken villi)
Reference: Archives 1984;108:71
Congenital primitive epithelial tumor of liver
Case report of tumor diagnosed based on review of placenta, Hum Path 2000;31:259
Giant pigmented nevi of newborn
Melanocytes present in placenta, but process is benign
Hemangioendothelioma
Case report of multifocal tumor of liver, adrenal gland and placenta, Hum Path 1997;28:866
Hepatocellular adenoma-like lesion of placenta
Benign, may represent specialized monodermal teratoma or ectopic tissue; AJSP 1998;22:355; AJSP 1986;10:436
Lymphoma
Rare, almost always of maternal origin
Lymphoma-maternal origin
Case report of anaplastic large cell lymphoma disseminated to placenta in 20 year old woman with classic findings for this subtype, AJSP 1997;21:1236
Micro: tumor cells involve intervillous spaces, spare villi and fetal circulation
Lymphoma-fetal origin
Case report of 20 week stillborn with EBV associated B cell lymphoma, AJSP 1999;23:595
Micro: tumor cells within villi, sparing intervillous space
Molecular: positive for EBER1 RNA
Metastases to placenta
Most common are primary cervical and breast cancer
Adenoid cystic carcinoma of trachea, Hum Path 1989;20:193
Bronchial small cell carcinoma, Archives 1989;113:556
Leukemia/lymphoma: usually placenta and fetus are spared, even with widespread metastatic disease
Melanoma: may spread to fetus, Archives 1997;121:508
Neuroblastoma (fetal): diagnosed based on tumor emboli in fetal placental vessels, Archives 1997;121:741
Transient myeloproliferative disease of newborn
Rare, associated with trisomy 21
Resembles congenital leukemia but resolves in weeks to months
Placenta shows villous dysmaturity with chorangiosis and prominent intravascular aggregates of primitive appearing cells with focal, early vascular wall invasion, Hum Path 2000;31:396
Gestational trophoblastic disease
Gestational trophoblastic disease-general
Related to trophoblastic proliferation
Includes tumors (hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumor) and tumor-like lesions (exaggerated placental site, placental site nodule)
Tumors are uncommon (1/1000 pregnancies)
Patients at extremes of reproductive age are at higher risk to develop complete mole; no age effect for partial moles; paternal age apparently irrelevant
Treatment for tumors: methotrexate; effective even if tumor widely metastatic (cure rates close to 100%) so that traditional anatomic staging parameters are not effective prognostic indicators; follow with serum hCG
NIH classification
Benign (complete, partial mole)
Malignant, nonmetastatic
Malignant, metastatic
Good prognsis, low risk
Poor prognosis, high risk: duration > 4 months, pretreatment hCG > 40,000, brain or liver metastases, gestational trophoblastic disease after term gestation, failed therapy
Exaggerated placental site
Benign, nonneoplastic lesion of increased implantation site intermediate trophoblastic cells that extensively infiltrate endomyometrium
Associated with 2% of normal pregnancies or abortions in first trimester
Not an inflammatory lesion
Resembles placental site trophoblastic tumors, but is focal and not confluent
Treatment: not necessary; follow with hCG only if cannot rule out placental site trophoblastic tumor
Micro: excess number of mononuclear and multinucleated implantation-site intermediate trophoblast cells (compared to normal implantation site) that infiltrate the endomyometrium as single cells and cords of cells; no necrosis; no destruction of endometrial glands; may have necrotic decidua
Positive stains: CK18, HLA-G (AJSP 2002;26:914), hPL, inhibin (weak), Mel-CAM
Negative stains: hCG, Ki-67 (close to 0, Hum Path 1998;29:27), PLAP
DD: placental site trophoblastic tumor (macroscopic not microscopic tumor, mean Ki-67 is 14% of cells vs. 0%, no associated decidua or villi, confluent masses of implantation-site intermediate trophoblastic cells, often no multinucleated trophoblastic cells)
Placental site nodule
Benign, cells resemble those in chorion lavae
Usually incidental finding in endometrial biopsy or endocervical curetting of woman of reproductive age
Gross: nodular or plaquelike lesion(s) at placental site, yellow-tan, up to 1 cm, often in endometrial curettings
Micro: usually well-circumscribed, extensively hyalinized nodules, single or multiple, oval or plaquelike; variable cellularity; composed of chorionic-type intermediate trophoblast cells with abundant eosinophilic, amphophilic or clear (glycogen-rich) cytoplasm, irregular / degenerative appearing nuclei; no/rare mitotic figures, AJSP 1990;14:1001; may contain mallory bodies, Archives 1993;117:547
Positive stains: CK18, EMA, HLA-G (AJSP 2002;26:914), inhibin-alpha (strong), Ki-67 (3-10%), PLAP
Negative stains: hCG, hPL (may be weak), Mel-CAM (may be weak)
DD: placental site trophoblastic tumor (larger, not well circumscribed, no extensive hyalinization, mitotically active, strong staining for hPL and PLAP, weak staining for PLAP), squamous cell carcinoma of cervix (necrosis, mitotically active, CK18-, inhibin-alpha negative, Hum Path 1999;30:687), epithelioid trophoblastic tumor
Hydatidiform moles-general
Abnormal placenta with marked enlargement of chorionic villi caused by central edema of stroma, abnormal blood vessels, high serum hCG that increases more rapidly than normal, variable trophoblastic hyperplasia
Either complete or incomplete/partial
Incidence: 1 per 1,000-2,000 pregnancies
Risk factors: prior mole, first pregnancy, born in southeast Asia, maternal age <19 or 40+, diet deficient in Vitamin A precursors
Associated with excess paternal component (in mice, causes excess trophoblastic development) vs excess maternal component (in mice, causes stunted trophoblast)
Treatment: curettage, hysterectomy
Complete mole
Caused by abnormal gametogenesis and fertilization; all nuclear DNA is paternal , none is maternal
Usually is no fetus
Risk factors: delivery in Indonesia (incidence: 1/82), Taiwan, India, Philippines, Mexico (vs. US: incidence 1/2000), age 30+, Vitamin A deficiency, history of previous mole
Usually presents at 15 weeks gestational age with excess uterine enlargement; may pass molar vesicles or have vaginal bleeding due to spontaneous abortion; marked elevation in hCG continues to rise after week 14
Preeclampsia often occurs in first trimester (usually in last trimester in nonmolar gestations); also hyperemesis gravidarum
Rarely molar tissue secretes TSH, causes hyperthyroidism, theca-lutein cysts
“Snowstorm” pattern on fetal ultrasound
Treatment: D & C, chest Xray (for metastases), follow hCG levels for 60 days; if still elevated, give chemotherapy (20% of cases)
Post D & C, 2-12% experience respiratory distress from “metastasis” to lung and fluid overload, 10-17% progress to invasive moles, 2% to choriocarcinoma; 1% will have another molar pregnancy
Poor prognostic factors: large for date uterus, ovarian enlargement due to theca-lutein cysts
Respond better to chemotherapy if fibrin-like material at tumor-host interface and have abundant syncytiotrophoblast
Cannot determine risk of choriocarcinoma by histologic grading
Gross: placenta has grape-like appearance, villi fill uterus, exhibit hydropic degeneration, no embryo present, no cord, no membranes; mole often 500 ml of bloody tissue, although some may pass spontaneously; smaller if diagnosed earlier in pregnancy
Micro: trophoblastic proliferation (diffuse, circumferential, composed of cytotrophoblast, syncytiotrophoblast and intermediate trophoblast) AND edema of ALL villi; central cistern formation (acellular central space, often fluid filled, separated from surface by small rim of mesenchymal cells); villi usually avascular, may have patchy villous calcification, may exhibit atypia (nuclear and cytoplasmic enlargement, variable nuclear outlines, hyperchromasia); variable necrosis and patchy calcification
Note: some villi are surrounded by attenuated layer of degenerating trophoblast with sparse vessels, helper T cells at implantation site; implantation cite often associated with hyperplasia of intermediate trophoblast resembling exaggerated placental site but with high Ki-67 staining (vs. 0 in exaggerated placental site)
Presence of villi or atypical trophoblast after evacuation of molar pregnancy indicates persistent trophoblastic disease
Very early features are redundant bulbous terminal villi, hypercellular villous stroma, labyrinthine network of villous stromal canaliculi, focal cytotrophoblast and syncytiotrophoblast hyperplasia on both villi and the undersurface of the chorionic plate and enlarged hyperchromatic implantation site trophoblast, Hum Path 1996;27:708
Micro images: image1
Positive stains: hCG (stronger than partial mole, less than choriocarcinoma), p53 (Mod Pathol 1996;9:392)
Negative stains: p57KIP2
p57 KIP2 - cyclin-dependent kinase inhibitor, paternally imprinted, expressed predominantly from maternal allele in most tissues; not expressed in complete hydatidiform moles, except in intervillous trophoblast islands
Molecular: 50% diploid, 43% tetraploid, Archives 1996;120:569, ploidy analysis useful for diagnosis, Archives 1998;122:1000
Diploid moles - 85% are 46 XX and both X are androgenic (“daddy’s girl”, empty ovum is fertilized by sperm that duplicates without cytokinesis, no maternal nuclear DNA, but there is maternal mitochondrial DNA); 15% are 46 XY and also androgenic (? fertilization of empty ovum by 2 sperm)
FISH analysis can establish dizygotic origin of twin pregnancies with complete mole and coexisting fetus, Hum Path 1995;26:1175
DD: partial mole (positive staining for p57, AJSP 2001;25:1225, Hum Path 2002;33:1188), spontaneous abortion (polarized trophoblastic proliferation, no trophoblast atypia, less edema, no central cistern formation)
Incomplete / partial mole
20% of all moles; triploid or tetraploid, some are trisomy 16
Contain extra set of paternal chromosomes, either from second sperm or one diploid sperm (diandric)
Note: zygotes composed of diploid maternal component (digynic) are usually nonmolar
86% of triploid abortuses have histologic features of partial moles, although usually triploidy is the result of extra maternal chromosomes and not diandry, Hum Path 1996;27:1018
Don’t diagnose as incomplete/partial mole unless features are CLASSIC
Note: 9% of spontaneous abortions are partial moles, but most triploid abortions resemble partial moles
Note: not all triploid conceptuses show molar transformation, although most die at age 8 weeks
Gestational age usually 19 weeks or more
Embryo is usually present, although often abnormal (blighted ovum) or with syndactyly of digits 3 & 4 of both hands and feet
Usually small for date uterus; hCG not markedly elevated as in complete mole; may be associated with toxemia of pregnancy; may present as missed or spontaneous abortion
4-12% develop persistent gestational trophoblastic disease; very low risk of choriocarcinoma; invasive mole rare; persistent intrauterine disease may develop
Treatment: closely monitor hCG, chest Xray
Gross: usually smaller volume of tissue than complete mole (200 ml or less); fetus with congenital anomalies may be present
Gross images: image1
Micro: mixture of edematous villi similar to complete mole and relatively normal villi; less conspicuous central cistern formation (internal clefting); circumferential mild trophoblastic hyperplasia, smaller villi usually have stromal fibrosis; mild trophoblast hyperplasia without atypia; villi scalloping (invaginations of trophoblast tissue into villous stroma, appears circular in cross section, resemble “coast of Norway” or inclusions), villi have vessels with nucleated RBCs if fetal development present
Positive stains: p57KIP2, p53 (Mod Pathol 1996;9:392)
Molecular: 58% XXY; 40% XXX; 2% XYY; ploidy analysis useful for diagnosis, Archives 1998;122:1000
DD: placentas associated with trisomy or normal pregnancy (polar trophoblastic hyperplasia), blighted ovum (early demise of embryo, usually is smaller, villi only slightly enlarged, only focal cisterns, no grossly enlarged villi, no trophoblastic atypia), choriocarcinoma or placental site trophoblastic tumor (no villi), hydropic villi (no gross villous swelling, no cistern formation), spontaneous abortion (polarized trophoblastic proliferation, no trophoblast atypia, less edema, no central cistern formation)
References: Hum Path 2000;31:914, Hum Path 1981;12:1016
Invasive mole
Aka chorioadenoma destruens
Associated with high serum hCG after evacuation of a mole
Occurs in 16% of all complete moles, represents exaggerated expression of capacity of normal trophoblast for invasion
Tumor may invade parametrial tissue, broad ligament and blood vessels, but serosa is usually intact; may perforate uterus
Villi may embolize to distant sites (lung, vagina, brain, spinal cord), may have hemorrhagic complications, but do not grow (not true metastases) and eventually regress
May cause life-threatening hemorrhage if perforates uterus (not common)
Treatment: chemotherapy (often cannot differentiate tumor from choriocarcinoma)
Gross: irregular hemorrhagic lesion penetrating into myometrium
Micro: mole, usually complete, with villi that penetrates myometrium, its vessels or broad ligament, invasion by hydropic chorionic villi with cytotrophoblast and syncytiotrophoblast; villi may be obscured by trophoblastic proliferation and require careful scrutiny to identify
DD: choriocarcinoma (high hCG but no villi in metastatic foci; both treated similarly), placenta increta or percreta (no hydropic villi, no abnormal trophoblastic proliferation, present during parturition), trophoblastic emboli in lungs after normal pregnancy
Choriocarcinoma
Most aggressive form of gestational trophoblastic disease
Carcinoma derived from trophoblastic cells secondary to a prior pregnancy (normal or abnormal)
Apparently derived from intermediate trophoblast, AJSP 2002;26:914
Incidence: 1 per 40 moles (usually complete), 1 per 150,000 normal pregnancies in US vs. 1 per 2,500 pregnancies in Nigeria
Risk factors: highest risk for pregnancies of blood type A women and blood type A men (RR: 10.4:1);
50% arise from prior moles, 25% from prior abortions, 22% from normal pregnancies (AJSP 1981;5:267), 3% from ectopic pregnancies or teratomas
Clinical: usually arises from uterus or elsewhere if ectopic pregnancy; bloody, brown, foul-smelling discharge
Rapidly invasive and metastasizing; may present with metastases but have small or necrotic primary tumor
Metastases commonly to lungs, vagina, brain, liver, kidney, bowel; may resemble clear cell carcinoma
Serum hCG ~ 18,000, causes changes in other organs, including endocervical glandular hyperplasia, decidual reaction, Arias-Stella, bilateral enlargement of ovaries by theca-lutein cysts (hyperreactio luteinalis), breast epithelial ductal hyperplasia; abnormal development of uterine spiral arteries (resembles progesterone administration)
Rarely metastasizes to infant, Archives 1990;114:1079
Rarely adjacent to normal villi of normal placenta, associated with placental site trophoblastic tumor or epithelioid trophoblastic tumor
Poor prognosis: age > 39, term pregnancy, long interval to diagnosis, high hCG, blood groups B or AB, large tumor, metastases to brain, GI, liver, >8 metastases, prior multiagent chemotherapy
May have better prognosis if intense inflammatory infiltrate at interface between tumor and stroma
Treatment: chemotherapy associated with 100% survival if restricted to uterus vs. 83% survival for all metastatic gestational trophoblastic disease
Surgery for hemorrhage
Monitor via serum hCG and chest Xrays
Gross: soft, fleshy, yellow-white, necrotic, hemorrhagic; may be microscopic or large
Micro: mixture of cytotrophoblast and syncytiotrophoblast in plexiform pattern; 20-50 cytotrophoblast nuclei in packets are surrounded by syncytiotrophoblast; intermediate trophoblast cells may be present (1-90% of mononuclear cells, occasionally multinucleated) with variable atypia; no villi; occasional atypical mitotic figures; may have marked nuclear pleomorphism and hyperchromasia and prominent nucleoli; invades perpendicular to smooth muscle bundles; may have extensive necrosis with minimal trophoblastic tissue; prominent vascular invasion; precursor lesion may exhibit increased trophoblastic proliferation
Positive stains: all tumor cells - keratin, CEA; intermediate trophoblastic cells - HLA-G, hPL, Mel-CAM; syncytiotrophoblast - hCG; mononucleate cells - Ki-67 (>90%)
Negative stains: PLAP
Cytogenetics: establish androgenetic nature of tumor (if from prior mole), differentiate gestational from germ cell choriocarcinoma
EM: syncytiotrophoblasts (complex cells with multiple nuclei, dense cytoplasm containing dilated endoplasmic reticulum, lysosomes, vesicles, often with numerou microvilli in cell membranes, may have features of epithelial differentiation including tonofilaments and desmosomes), cytotrophoblast are primitive epithelial cells, intermediate trophoblasts are scattered with transitional features (Hum Path 1989;20:370)
DD: trophoblast without villi (usually minimal trophoblastic tissue, no necrosis, no invasion), hydatidiform mole, placental site trophoblastic tumor
DD (extrauterine sites): invasive moles (have villi), germ cell tumors (large adnexal mass, other germ cell tumor elements present, AFP+, high serum AFP), carcinomas with focal choriocarcioma differentiation (usually have areas of typical carcinoma), pleomorphic carcinomas with tumor giant cells (hCG-, hPL-, MelCAM-, normal serum hCG)
Epithelioid trophoblastic tumor
Rare (<50 cases reported) trophoblastic tumor resembling poorly differentiated carcinoma in women of reproductive age
May be diagnosed 10 years+ after last known pregnancy; may also follow elective abortion or mole
Usually presents with abnormal vaginal bleeding and elevated serum hCG
Rarely diagnosed initially in lungs
May be associated with choriocarcinoma
Caused by neoplastic transformation of chorionic-type intermediate trophoblast
Appears to be less aggressive than choriocarcioma but may recur or metastasize; 10% die of disease
Treatment: hysterectomy, pulmonary resections, chemotherapy (partial response)
Gross: 1-4 cm, tan-brown discrete expansile nodule in endomyometrium or lower uterine segment, with hemorrhage and necrosis
Micro: atypical mononuclear trophoblastic cells in nests, cords and sheets; expansile invasion pattern often with rim of lymphocytes at periphery; cells surrounded by fibrillar, hyaline material that may coalesce; prominent cellular necrosis; lumina of blood vessels contain fibrinoid material but NO tumor cells; may replace or reepithelialize endocervical or endometrial surface epithelium; mean 2 mitotic figures/10 HPF; apoptotic cells common; cells resemble those in placental site nodule
Positive stains: CK18, HLA-G, inhibin-alpha, Ki-67 (20%)
Negative stains: hCG, hPL and Mel-CAM (may be focal+)
DD: placental site trophoblastic tumor (diffuse Mel-CAM+, hPL+), placental site nodule (microscopic, no necrosis, hypocellular, high Ki-67), keratinizing squamous cell carcinoma of cervix (fewer stratified epithelial layers, even when it replaces surface endocervical cells, cells perpendicular not parallel to basement membrane, CK18-, inhibin-alpha negative)
Placental site trophoblastic tumor (PSTT)
Formerly known as atypical choriocarcinoma, trophoblastic pseudotumor
Rare; due to neoplastic transformation of implantation-site intermediate trophoblast
Usually reproductive age women, but occasionally age 50+
75% occur long after normal pregnancy, 5% follow molar pregnancy
Present with amenorrhea or abnormal bleeding with enlarged uterus and high serum hCG
Rarely associated with virilization
Associated with distinctive renal glomerular lesion (occlusive eosinophilic deposits in glomerular capillary lumina) accompanied by proteinuria and hematura, Hum Path 1985;16:35
Poor prognostic factors: 5+ mitotic figures/10 HPF, Ki-67 > 50%, high cellularity, extensive necrosis, preponderance of cells with clear cytoplasm and atypical nuclei
2 malignant cases reported at AJSP 1993;17:1003
Treatment: curettage or hysterectomy; monitor hCG, may be resistant to chemotherapy, 10% mortality due to metastases to lungs, liver, abdominal cavity and brain
Gross: myometrial mass projecting into uterine cavity or intramural or microscopic; ill defined or localized, may have hemorrhage or necrosis; may perforate uterus
Micro: implantation-site intermediate trophoblasts forming confluent masses that deeply invade myometrium in large nests, interdigitating pattern or masses; tumor cells are polyhedral or spindled; also multinucleated intermediate trophoblastic cells with vacuolated cytoplasm; no cytotrophoblast, no villi; extensive deposition of fibrinoid material; invasion of blood vessels with fibrinoid deposition
Positive stains: hCG (multinucleate cells only), HLA-G, hPL, keratin, Ki-67 (>10%), Mel-CAM
Negative stains: PLAP
Molecular: usually diploid
EM: prominent paranuclear filaments not present in intermediate trophoblasts of choriocarcinoma, Hum Path 1989;20:370
DD: epithelioid leiomyoma, leiomyosarcoma (lacks distinctive feature of vascular invasion with fibrinoid deposition of placental site trophoblastic tumor, hPL-, inhibin-alpha negative, desmin+, actin+), mole, choriocarcinoma (has dimorphic population of cytotrophoblast and syncytiotrophoblasts, hemorrhage, infiltration), exaggerated placental site reaction (non-neoplastic proliferations of trophoblast), placental site nodules (well circumscribed, tend to be extensively hyalinized, minimal mitotic activity, may have Mallory bodies, small, circumscribed), sarcomas (keratin negative)
May need more tissue to differentiate from a curretting
Miscellaneous
Primary tumor (T)
TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
T1 (FIGO I): confined to uterus
T2 (FIGO II): limited to genital structures
Regional lymph nodes (N)
No designation for these tumors
Distant Metastasis (M)
MX: distant metastasis cannot be assessed
M0: no distant metastasis
M1: distant metastasis
M1a (FIGO III): metastases to lungs
M1b (FIGO IV): all other distant metastases
Prognostic Index Scores
Low risk: score of 7 or less (usually treat with single-agent chemotherapy)
High risk: score of 8 or more (usually treat with multiple-agent chemotherapy)
Factors and associated risk score
Age: 0 if < 40, 1 if age 40 or more
Antecedent pregnancy: 0 if hydatidiform mole, 1 if abortion, 2 if term pregnancy
Interval months from index pregnancy: 0 if < 4 months, 1 if 4-6 months, 2 if 7-12 months, 4 if > 12 months
Pretreatment hCG: 0 if < 1000, 1 if 1000-9999, 2 if 10K to 99,999, 4 if 100K or more
Largest tumor size: 0 if < 3 cm, 1 if 3-4 cm, 2 if 5 cm or more
Site of metastases: 0 if lung, 1 if spleen or kidney, 2 if GI tract, 4 if brain or liver
Number of metastases: 1 if 1-4, 2 if 5-8, 4 if 9+
Previous failed chemotherapy: 2 if single drug, 4 if 2+ drugs
Stage grouping
Stage 1 : T1 M0, unknown risk
Stage 1A: T1 M0, low risk
Stage 1B: T1 M0, high risk
Stage 2 : T2 M0, unknown risk
Stage 2A: T2 M0, low risk
Stage 2B: T2 M0, high risk
Stage 3 : Any T, M1a, unknown risk
Stage 3A: Any T, M1a, low risk
Stage 3B: Any T, M1a, high risk
Stage 4 : Any T, M1b, unknown risk
Stage 4A: Any T, M1b, low risk
Stage 4B: Any T, M1b, high risk
Features of tumor to report
Anatomic site and location
Size
Depth of invasion
Histologic type
Histologic grade
Type of invasion (infiltrating, pushing, mixed)
Angiolymphatic invasion
Adjacent organs
Margins
Lymph nodes: total, number positive, location, tumor size
Results of special stains
Grossing placentas
Strategies for which placentas to examine are (a) “embed and hold”, (b) examine for specific indications or (c) examine all placentas
Specific indications: clinician concern, maternal conditions (diabetes, hypertension, prematurity, postmaturity, history of reproductive failure, oligohydramnios, fever, infection, substance abuse, repetitive bleeding, retroplacental hematoma), fetal conditions (stillbirth or perinatal death, multiple births, congenital abnormalities, growth retardation, prematurity, hydrops, thick meconium, admission to intensive care, APGAR score of 0-3 at 5 minutes, neurologic problems, fever, infection), gross placental abnormalities
Placental membranes: examine for color (green to muddy brown is suspicious for meconium; yellow-gray is suspicious for chorioamnionitis), insertion (beyond placental edge or not), clots (may suggest retroplacental hematoma), accessory lobes (associated with lacerated vessels), abnormal shapes (usually incidental), maternal floor for incomplete cotyledons (associated with placenta accreta)
Determine distance of point of apparent membrane rupture from placental margin
Trim membranes from placental margin
Cord:
Examine site of umbilical cord insertion into placenta for hematoma, and cut at placenta; examine cord for knots (true or false), measure length and thickness, determine if 2 or 3 vessels
Placental disk:
Weigh and measure trimmed placenta (without extraplacenta membrane and cords) and examine for amnion nodosum, accessory lobes, fetal placental surface lesions
Serial section placenta along fetal surface to look for infarcts, hemorrhage, maternal floor calcification, infarction, tumors
Miscellaneous:
Use sharp blades to avoid stripping amnion
Multiple births
As above, but also examine interplacental partition; some advocate injection of vasculature
Artifacts:
Caused by freezing placenta (distorts villi, obscures meconium), Bouin’s fixative (obscures fusobacterium, hinders cytochemical staining), formalin fixation (distends fetal vessels, increases weight by 8%, Archives 1991;115:726)
Sections to submit:
Membrane roll beginning near point of apparent membrane rupture (more sections if suspect chorioamnionitis)
1-2 sections of cord (4 cm or more from placental insertion to avoid anastomoses)
Thin sections from maternal surface
Fetal surface
Any gross abnormalities
Standard gross dictation:
Received in _____, labelled _______, is a discoid placenta that weights ____ g when trimmed of membranes and cord. The membranes are tan-brown and translucent, with minimal adherent blood clot. The cord is inserted centrally / paracentrally / marginally, has 3 vessels and is __ cm long and __ cm in diameter. The maternal surface is intact. The fetal surface is unremarkable. Cut surfaces show beefy red parenchyma but no significant areas of infarct or hemorrhage or other gross abnormalities.
Describe any gross abnormalities as appropriate
Reference: Practice Guidelines from CAP, surgicals - Archives 1997;121:449, perinatal autopsies - Archives 1997;121:368
__ trimester placenta (list weight):
No chorioamnionitis, no villitis, no funisitis
GaPbcdef
Ga = gravida (# of pregnancies); Pb = live births (para), c – pre term births, e – first trimester losses, f - living children from these pregnancies
Recommended to not comment on effect of placental abnormalities on prognosis of newborn, since clinical information is usually not available
End of Placenta chapter