Placenta
Last revised 20 January 2008
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