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4 main categories
Definition / general
  • Most placental pathologic findings can be organized into 1 of 4 major categories of placental injury (Mod Pathol 2021;34:1074)
  • This framework is used by the 2016 Amsterdam Consensus Classification (Arch Pathol Lab Med 2016;140:698)
  • These categories are also used as top line diagnoses in pathology reporting, with supporting histopathologic findings listed underneath (see Sample pathology report)
  • Existing placenta articles in this chapter are organized below within the 4 category framework
Other categories of placental pathology
Sample pathology report
  • Placenta:
    • Relatively small, mature placenta (285 g, less than third percentile for 38 weeks)
    • Findings consistent with maternal vascular malperfusion:
      • Accelerated villous maturation
      • Increased syncytial knots and perivillous fibrin
      • Multifocal villous infarction

Accessory lobe / bilobate placenta
Accessory lobe
  • One or multiple accessory lobes connected to the main disc by blood vessels that are at risk for hemorrhage and thromboemboli
  • Seen in 3% of placentas
  • Also called succenturiate lobe
  • Due to focal noninvolution of chorionic laevae
  • Gross description: main placental disc is attached to a smaller portion of placenta by fetal vessels and membranes
Bilobate placenta
  • Two lobes of equal size, separated by fetal membranes or connected by narrow isthmus of placental tissue
  • Umbilical cord inserts in the membranes between the two discs and is at risk for rupture
  • If incompletely removed, there is a risk of maternal postpartum hemorrhage
  • Gross description: two lobes of equal size separated by membranes
Gross images

Images hosted on other servers:

Accessory lobe


Acute chorioamnionitis
Definition / general
  • Acute chorioamnionitis is defined by the presence of acute inflammation (neutrophils) within the chorion or amnion (or both) of the extraplacental membranes or chorionic plate (maternal inflammatory response [MIR]), with or without acute inflammatory cell extravasation from the umbilical cord vasculature or chorionic plate vessels (fetal inflammatory response [FIR])
Essential features
  • Acute chorioamnionitis is due to a maternal (with or without accompanying fetal) inflammatory response
  • Fetal inflammatory response (inflammatory cell extravasation from umbilical or chorionic plate vessels) is associated with longer term and more severe infections
  • Commonly associated with ascending bacterial or fungal cervicovaginal flora infecting the amniotic fluid
  • Uncommonly associated with hematogenously disseminated bacteria (e.g., Listeria)
  • Associated with risk of neonatal sepsis and poor neonatal outcomes especially when there is a fetal inflammatory response
Terminology
  • Histologic chorioamnionitis
  • Necrotizing chorioamnionitis
  • Chorionitis
  • Subchorionitis
  • Umbilical vein vasculitis
  • Umbilical artery vasculitis
  • Fetal vasculitis
ICD coding
  • ICD-10:
    • O41.12 - chorioamnionitis
    • O41.121 - chorioamnionitis, first trimester
    • O41.122 - chorioamnionitis, second trimester
    • O41.123 - chorioamnionitis, third trimester
    • O41.129 - chorioamnionitis, unspecified trimester
Epidemiology
Sites
  • Extraplacental membranes: chorion or amnion (MIR)
  • Umbilical cord: vein or arteries (FIR)
  • Chorionic plate: chorion or amnion (MIR) and vessels (FIR)
Pathophysiology
  • Amniotic fluid infection by ascending cervicovaginal flora (common) or hematogenously or postprocedurally infecting organisms (uncommon) causes activation of material and fetal inflammatory responses
  • In the maternal inflammatory response, maternal neutrophils migrate from the decidual circulation into the extraplacental decidua, chorion and amnion, or the intervillous circulation into the chorionic plate and overlying amnion
  • In the fetal inflammatory response, fetal neutrophils extravasate from fetal vessels in the umbilical cord or chorionic plate and migrate toward the amniotic fluid (amniotropic)
  • Release of cytokines and other inflammatory mediators can lead to rupture of membrane or onset of labor
  • Reference: Pediatr Res 2022;91:289
Etiology
  • Amniotic fluid infection is typically polymicrobial, often involving 2 or more organisms from vaginal or enteric flora; single pathogens may be seen in hematogenously disseminated infections or when 1 organism in a polymicrobial infection outcompetes the others
  • Organisms that are commonly isolated from amniotic fluid infections include (J Infect Dis 1988;157:113):
    • Ureaplasma urealyticum and Mycoplasma hominis (Clin Infect Dis 1993;17:S100)
    • Gram negative anaerobic vaginal flora (e.g., Bacteroides spp., Gardnerella sp.)
    • Group B Streptococcus
    • Peptostreptococcus spp.
    • Escherichia coli
    • Enterococci
    • Fusobacterium spp.
Clinical features
Diagnosis
  • Clinical diagnosis (Obstet Gynecol 2016;127:426, J Perinat Med 2016;44:23):
    • Clinical chorioamnionitis (or intrauterine inflammation or infection) is diagnosed by a combination of physical examination findings and laboratory results
    • Isolated maternal fever:
      • Clinically documented fever ≥ 39.0 °C once or ≥ 38.0 °C (oral) twice
    • Suspected intrauterine inflammation or infection:
      • Fever (as above), plus 1 or more of the following:
        • Fetal tachycardia (greater than 160 beats per minute for 10 minutes or longer)
        • Elevated maternal white blood count (> 15,000 per mm3; in the absence of corticosteroids)
        • Purulent fluid from the cervical os
    • Confirmed intrauterine inflammation or infection:
      • Suspected intrauterine inflammation or infection findings, plus:
        • Positive amniotic fluid Gram stain or culture
        • Low amniotic fluid glucose (e.g., ≤ 14 mg/dL)
        • Elevated amniotic fluid white cell count (> 30 cells/mm3; in the absence of red blood cells indicating blood contamination)
        • Histopathologic evidence of acute chorioamnionitis
Laboratory
  • Positive:
    • Amniotic fluid Gram stain
    • Amniotic fluid culture
    • Placental tissue culture
    • Fetal tissue culture (e.g., lung tissue) in cases of fetal demise
    • Placental tissue (fresh or FFPE) molecular testing (e.g., PCR)
    • Neonatal blood cultures within day 1 of life
Prognostic factors
Case reports
Treatment
Gross description
  • Dull, opaque membranes with yellow-green discoloration and cloudy amniotic fluid, possibly with purulent exudate
  • Can be grossly normal
  • Acute marginal hemorrhage in preterm deliveries (ISRN Obstet Gynecol 2012;2012:856971)
  • Multifocal umbilical cord surface microabscesses in C. albicans infections (APMIS 2018;126:570)
Gross images

Contributed by Drucilla J. Roberts, M.D.

Patchy surface, plaque-like lesions

Yellow / cloudy fetal surface of placenta

Microscopic (histologic) description
  • Acute chorioamnionitis should be staged and graded based on MIR and FIR (Arch Pathol Lab Med 2016;140:698, Roberts: Atlas of Placental Pathology, 2021)
  • MIR stage (location):
    • Stage 0 (preacute chorioamnionitis): neutrophils in the subchorial intervillous space beneath the chorionic plate (subchorionitis)
    • Stage 1 (early): neutrophils in chorion laeve of the extraplacental membranes (chorionitis)
    • Stage 2 (intermediate): neutrophils within chorionic or amnionic mesoderm
    • Stage 3 (advanced): stage 2, plus necrosis of amnionic epithelium or neutrophil necrosis
  • MIR grade (severity):
    • Grade 1 (mild to moderate): anything less than severe, as described below
    • Grade 2 (severe): confluent neutrophils or > 3 foci of > 200 neutrophils
  • FIR stage:
    • Stage 1 (early): fetal inflammatory cells within chorionic plate vessel walls (fetal vasculitis) or umbilical vein vessel wall (umbilical vein vasculitis)
    • Stage 2 (intermediate): fetal inflammatory cells within umbilical arteries (umbilical artery vasculitis) or vein
    • Stage 3 (advanced): necrotizing funisitis (perivascular bands of necrotic Wharton jelly containing dense neutrophils)
  • FIR grade:
    • Grade 1 (mild to moderate): anything less than severe, as described below
    • Grade 2 (severe): confluent fetal inflammatory cells with attenuation / degeneration of smooth muscle
  • Accompanying findings:
    • Acute intervillositis: aggregates of neutrophils in the intervillous space; often due to Listeria monocytogenes
    • Peripheral funisitis: wedge-like foci of neutrophils with necrosis at the periphery of the umbilical cord; often due to Candida
Microscopic (histologic) images

Contributed by Drucilla J. Roberts, M.D. and AFIP

MIR stages and grades

FIR stages and grades

Umbilical cord with surface abscess

GMS stain showing invasive fungal hyphae

Virtual slides

Images hosted on other servers:

17 week placenta with stage 2 grade 2 MIR

24 week gestation with clinical suspicion for acute chorioamnionitis with umbilical cord microabscesses

Positive stains
  • GMS (Candida species or most bacteria)
  • PASD (Candida species)
  • Gram (most bacteria)
Sample pathology report
  • Singleton placenta, delivery:
    • Acute chorioamnionitis (maternal stage X; grade X) with fetal vascular involvement (fetal stage X; grade X)
Differential diagnosis
  • Chronic chorioamnionitis:
    • Mononuclear infiltrate in the chorion laeve or chorion and amnion
    • Often associated with villitis of unknown etiology
    • Thought to be a host versus graft-like reaction
    • Has a recurrence risk
  • Meconium histiocytic infiltrate:
    • Meconium pigment within histiocytes in the membranes
    • Often accompanies acute chorioamnionitis
  • Acute inflammation in the space between the amnion and chorion:
    • Inflammation is not within the soft tissue or epithelium but in the space between the 2 membranes
    • Often associated with vernix caseosa or loose meconium
    • Not true acute chorioamnionitis unless the inflammatory cells are within tissue
  • Acute deciduitis:
    • Acute inflammation retained only within the decidua capsularis or parietalis, not in the chorion laeve epithelium
    • Feature of labor, not infection
Board review style question #1

A yellow / green discolored and cloudy placenta shows which of the following histologies of the membranes and umbilical cord?

  1. Stage 0 grade 1 acute chorioamnionitis, maternal inflammatory response with a fetal inflammatory response stage 1 grade 1
  2. Stage 1 grade 1 acute chorioamnionitis, maternal inflammatory response with a fetal inflammatory response stage 2 grade 1
  3. Stage 2 grade 2 acute chorioamnionitis, maternal inflammatory response with a fetal inflammatory response stage 2 grade 1
  4. Stage 3 grade 2 acute chorioamnionitis, maternal inflammatory response with a fetal inflammatory response stage 2 grade 2
Board review style answer #1
C. Stage 2 grade 2 acute chorioamnionitis, maternal inflammatory response with a fetal inflammatory response stage 2 grade 1

Comment here

Reference: Acute chorioamnionitis
Board review style question #2

This umbilical cord shows patchy white / yellow lesions on the surface. What is the most likely diagnosis?

  1. Candidal funisitis
  2. Fusobacterial funisitis
  3. Meconium myonecrosis
  4. Syphilitic funisitis
Board review style answer #2
A. Candidal funisitis

Comment here

Reference: Acute chorioamnionitis

Acute villitis and intervillositis
Definition / general
  • Acute inflammation, maternal or fetal, in the chorionic villi or intervillous space
Essential features
  • Infectious process characterized by a predominantly leukocytic villous infiltrate, which can be either maternal (usually) or fetal (rarely) in origin
  • Can be macroscopically identified when abscesses are present but is usually a microscopic finding
  • Abscesses and acute villitis are critical values and should be called into the obstetric and neonatal providers
  • Most cases of acute villitis are bacterial in origin, although syphilis and tuberculosis can also present with acute villitis
ICD coding
  • ICD-10: O43.893 - other placental disorders, third trimester
Epidemiology
  • Pregnant women, generally preterm, with sepsis
  • Fetus associated with pregnant women with sepsis
Sites
Pathophysiology
  • Maternal infection leading to sepsis and hematogenously infecting the placenta
  • Fetal sepsis can occur following placental infection
Etiology
  • Exposure to infectious organisms leading to sepsis, including pneumonia, gastroenteritis, chorioamnionitis, oral or skin infections, etc.
  • Common causational organisms include Listeria monocytogenes, GBS and E. coli
Diagnosis
  • Histopathologic sections of the placental parenchyma
Laboratory
  • Cultures positive for infectious organisms
Prognostic factors
Case reports
  • 25 year old Korean woman, nullipara, presents at 36 5/7 weeks gestational age with fever and was treated with broad spectrum antibiotics, delivering by emergent cesarean section at 37 2/7 weeks gestational age; listeriosis (Obstet Gynecol Sci 2018;61:688)
  • 34 year old woman, primigravida, presents at 29 6/7 weeks with decreased fetal movement and delivers a stillbirth; listeriosis (Obstet Gynecol Sci 2018;61:688)
  • 36 year old woman, gravida 2, para 0, at 21 3/7 weeks gestation, with fever and intrauterine fetal demise; group B strep (Pediatr Dev Pathol 2016;19:165)
  • 41 year old woman, gravida 2, para 1, with a history of substance use disorder, has a complicated twin pregnancy, presenting at 17 2/7 weeks with fever and gastrointestinal symptoms; Bacillus cereus (Pediatr Dev Pathol 2021 Mar 17 [Epub ahead of print])
  • Nulliparous woman with sepsis delivers at 24 4/7 weeks gestational age; intravascular organisms - Escherichia coli (Pediatr Dev Pathol 2021;24:246)
Treatment
  • Antibiotics as specific to the source for both mother and if surviving, infant
Gross description
  • Acute villitis without abscesses or acute chorioamnionitis is not grossly evident
  • Acute villitis with abscesses can present grossly as yellow-white soft masses of varying sizes in the parenchyma
Microscopic (histologic) description
  • Common:
    • Multifocal neutrophilic infiltrate within chorionic villi, usually subtrophoblastic
    • Affected villi usually in clusters
    • Marked intervillous neutrophilic infiltrate, filling the intervillous space
  • Uncommon:
    • Mixed inflammatory infiltrate within the chorionic villi
    • Abscess formation in the parenchyma associated with villous necrosis
    • Intravascular organisms in the placental vasculature
  • Associated features:
Microscopic (histologic) images

Contributed by Drucilla J. Roberts, M.D.
Acute villitis and intervillositis

Acute villitis and intervillositis

Mixed acute and chronic villitis

Mixed acute and chronic villitis

Microabscess in  a term placenta

Microabscess in a term placenta

Intravascular organisms and acute villitis

Intravascular organisms and acute villitis

Positive stains
  • Tissue Gram stain, e.g. Brown-Hopps
  • Spirochete stain if syphilis is a candidate organism - immunohistochemistry or silver stain (Steiner)
  • AFB if tuberculosis is a candidate infection
Sample pathology report
  • Placenta:
    • Mature placenta (535 g, approximately the 50th percentile by weight for 40 weeks gestational age)
    • Acute villitis with macro and microscopic abscesses (see comment 1)
    • Acute chorioamnionitis (maternal stage 2; grade 2) with fetal vascular involvement (fetal stage 2; grade 1) (see comment 2)
    • Comment 1: Multiple abscesses are present throughout the placental parenchyma associated with acute villitis and villous necrosis. A Brown-Hopps stain is positive for rare gram variable rods in these foci and in the amniotic epithelium. These features are most consistent with listerial placentitis. Pediatrician notified of these findings by pathologist as a critical value on date and time.
    • Comment 2: Key to diagnostic category as per R.W. Redline et al. (Pediatr Dev Pathol 2003;6:435)
Differential diagnosis
  • Villitis of unknown etiology (VUE):
    • Typically a lymphohistiocytic villitis
    • Term multigravidas most commonly affected
    • Focal, multifocal, rarely diffuse
    • Often a maternal floor / basal predominance
    • Infectious organisms absent
    • Has a small but definite recurrence risk
    • Associated with perinatal morbidity, e.g. fetal growth restriction, neurological injury
  • Intervillositis associated with a placental infarct:
    • Limited necroinflammatory debris between villi
    • Usually but not always present in recent placental infarcts
  • Infectious chronic villitis:
Board review style question #1

A 29 year old woman, gravida 2, para 1 now 2, delivers at term with fever, nausea and vomiting. She has a history of eating processed meats. The placenta is delivered and shows multiple gray-yellow soft parenchyma masses, yellow cloudy membranes and has a fruity odor. Histologically, the masses are abscesses associated with acute villitis and villous necrosis. The most likely diagnosis is

  1. Cytomegalovirus placentitis
  2. Group B strep infection
  3. Listerial placentitis
  4. Syphilitic placentitis
  5. Villitis of unknown etiology
Board review style answer #1
C. Listerial placentitis

Comment Here

Reference: Acute villitis and intervillositis
Board review style question #2

A 31 year old woman, gravida 3, para 2, presents with an intrauterine fetal demise at 18 weeks gestational age. She is induced and delivers vaginally. The male fetus is externally unremarkable and autopsy / fetopsy consent was denied. A small noncloudy placenta was examined histologically and showed acute villitis with intravascular cocci. Which of the following is true?

  1. Bacteria are contaminants from the vaginal delivery
  2. Culturing the placenta is not possible, as this was a vaginal delivery
  3. Findings suggest an ascending infection in utero
  4. Most likely diagnosis is group B strep fetal sepsis and the clinician should be notified as a critical value, as there is a risk of maternal morbidity
Board review style answer #2
D. Most likely diagnosis is group B strep fetal sepsis and the clinician should be notified as a critical value, as there is a risk of maternal morbidity

Comment Here

Reference: Acute villitis and intervillositis

Amnion nodosum
Definition / general
  • Nodules of fetal skin, hair and fat found on the amnion
Essential features
  • Deposition of fetal squames as nodules of surface of amnion
  • Associated with severe prolonged oligohydramnios, anhydramnios
Terminology
  • Vernix granuloma
Sites
  • Amnion of the chorionic disc, placental membranes or umbilical cord
Pathophysiology
Etiology
  • Result of deficient amniotic fluid over a prolonged period of time
Clinical features
Diagnosis
  • Gross and histopathologic examination
Case reports
Gross description
  • Multiple firm, circumscribed, round to ovoid, raised, shiny, yellow nodules visible on the amniotic surface (Arch Pathol Lab Med 2007;131:1829)
  • 1 - 5 mm in diameter
Microscopic (histologic) description
  • Composed of varying proportions of squamous cells (occasionally keratinized), fat and hair embedded in degenerative amorphous acidophilic debris (Arch Pathol Lab Med 2007;131:1829)
Microscopic (histologic) images

Contributed by Caroline Simon, M.D.

Fetal squamous cells in amnion

Positive stains
  • Fetal skin cells within the amnion nodosum will stain positive for keratins
Electron microscopy description
  • Nodules are composed mostly of closely packed bundles of fibrillary material of high electron density and cellular elements of various kinds (Arch Pathol 1974;98:39)
  • Basement membrane of amnion epithelium is usually present under the nodules
Sample pathology report
  • Placenta, delivered:
    • Third trimester placenta 330 grams (tenth to twenty fifth percentile)
    • Umbilical cord: unremarkable 3 vessel cord
    • Fetal membranes and maternal decidua: amnion nodosum
    • Placental disc: villous maturation appropriate for gestational age; intervillous thrombus
Differential diagnosis
  • Squamous metaplasia:
    • Grossly typically more plaque-like, patchy and hydrophobic
    • Microscopically keratinizing metaplasia of the amnion
  • Chorion nodosum (Pediatr Dev Pathol 2006;9:353):
    • Similar nodules
    • Develop on the chorion
    • Associated with early amnion rupture / amniotic bands
Board review style question #1

The lesion in the image above is found in the placenta. What is the diagnosis?

  1. Acute chorioamnionitis
  2. Amnion nodosum
  3. Chorion nodosum
  4. Squamous metaplasia
Board review style answer #1
B. Amnion nodosum

Comment Here

Reference: Amnion nodosum
Board review style question #2
Amnion nodosum is most commonly associated with which congenital anomaly / malformation?

  1. Renal agenesis
  2. Tracheoesophageal fistula
  3. Trisomy 18
  4. Ventricular septal defect
Board review style answer #2
A. Renal agenesis

Comment Here

Reference: Amnion nodosum

Amnionic web and amniotic band syndrome
Definition / general
Amniotic web:
  • Small portion of amniotic membrane can be present extending from the base of the umbilical cord and spanning the angle made by the fetal surface and the umbilical cord insertion

Amniotic web and rupture:
  • Sporadic rupture of the amniotic sac; theories of pathogenesis vary
  • Amniotic rupture is associated with amniotic band syndrome (Am J Surg Pathol 1984;8:117), in which strips of amniotic epithelium wrap around fetal surfaces and cause amputations, necrosis and deformations
  • Craniofacial defects and limb abnormalities are the most common results
  • Early rupture is associated with more severe fetal defects
Terminology
  • Amnion is the single layer of cuboidal to columnar cells that lines the entire amniotic cavity, including the fetal surface of the placenta and the umbilical cord
  • Amniotic web should be distinguished from an amniotic band, which is a congenital amniotic malformation that can result in serious constriction or entrapment of fetal parts (amniotic band syndrome or amniotic rupture sequence)
Epidemiology
  • Uncommon finding, present in < 1% of uncomplicated live births
Pathophysiology
  • Amnion (and its underlying thin layer of amniotic mesoderm) is only loosely adherent to the adjacent chorion
  • This incompletely anchored nature of the amnion allows for incomplete investment of the acute angle made by the umbilical cord insertion and fetal surface
Clinical features
  • Generally an incidental finding with no clinical significance
  • Potential restriction of umbilical cord movement or constriction of vascular flow may be seen due to traction
Gross description
Amniotic web:
  • Translucent, delicate, sail-like portion of amnion spans the distance between a short segment of umbilical cord and the adjacent fetal surface
  • Retraction of the amnion can cause the umbilical cord to become tethered or anchored closely to the fetal surface

Amniotic band and rupture:
  • Fetal surface may appear rough
  • Residual strips of amnion may be seen but are usually overlooked
Gross images

Images hosted on other servers:
Missing Image

Limited movement at the cord base

Missing Image

Near term placenta

Microscopic (histologic) description
Amniotic band and rupture:
  • Vernix granulomas in separated amniotic mesenchyme and in denuded mesenchyme of chorionic plates confirm antepartum amniotic rupture
  • Biopsies of maternal placental bed may show 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 (Arch Pathol Lab Med 1997;121:167)
  • In prolonged amniotic leakage, may see subchorionic squames or subchorionic foreign body reaction (Arch Pathol Lab Med 1986;110:47)
Differential diagnosis
  • Amniotic bands vs. webs: amniotic bands consist of sheets or thicker strands / bands of amnion that can be found tethering any portion of the umbilical cord (not just its insertion site) or spanning between any portion of placenta and developing fetus

Anatomy & histology-placenta & umbilical cord
Definition / general
  • Placenta: fetomaternal organ (derived from the Greek word plakoús, which translates as flat cake) that provides gas exchange, nourishment and protection to the fetus
    • Also has excretory and endocrine functions; numerous hormones, such as human chorionic gonadotropin (hCG), progesterone, estrone, estradiol, estriol and human placental lactogen (hPL), are secreted by the placenta
  • Umbilical cord: anatomic tubular structure that physically connects the developing intrauterine fetus to the placenta, which is anchored to the maternal uterine wall; it is the cable that links the fetus to the placenta
Essential features
  • Umbilical cord is the conduit by which oxygenated, nutrient rich blood from the mother (via the intervening placenta) reaches the fetus and deoxygenated, nutrient poor blood from the fetus is returned back to the mother
Terminology
  • Umbilicus (or navel) is the attachment site of the umbilical cord to the fetus
  • 2 umbilical arteries in the umbilical cord return deoxygenated blood to the mother
  • 1 umbilical vein in the umbilical cord carries oxygenated blood to the fetus
  • Wharton jelly, in which the 2 umbilical arteries and single umbilical vein are embedded, is a hydrated extracellular matrix gel composed of open chain polysaccharides distributed in a fine network of microfibrils; it provides turgor regulation and protection to the umbilical cord
Diagrams / tables

Images hosted on other servers:
Views from the fetal (umbilical cord and chorionic plate) and maternal (decidua basalis) surfaces

Views from fetal and maternal surfaces

Clinical features
  • Umbilical cord
    • Derived from the allantois and yolk sac during the fifth week of fetal development
    • Fetoplacental circulation (connection) develops when allantoic vessels establish continuity with the developing villi of the placenta
    • Allantoic duct remnant is seen in ~15% of umbilical cords
    • Omphalomesenteric duct remnant is seen in ~1.5% of umbilical cords
    • 2 umbilical veins are initially present but one atrophies during the second month of pregnancy
    • 2 umbilical arteries, in the vast majority of deliveries (96%), anastomose with 1.5 cm of the placental insertion site
Gross description
  • Components of the placenta
    • Disc
      • Oval to circular in shape and devoid any accessory or succenturiate lobes
      • Composed of fetal portion (chorionic plate) and maternal portion (basal plate)
      • Weight of the trimmed disc is one of the critical measurements of placentas
      • Placental weight and fetoplacental ratio should be compared with values expected for gestational age
      • Divided into cotyledons from primary stem villi and lobules from secondary stem villi
      • Average weight at term: 510 g
    • Chorionic plate
      • Usually oval and consists of tan-white tissue overlying the villous parenchyma on the fetal side of the placenta
    • Basal plate (maternal surface)
      • Has slight gray-tan smooth to pebbled appearance at term
    • Membranes
      • Grossly, normal membranes are thin, tan-pink and semitranslucent; the amnion is clear and glistening while the chorion is thick and can have slight roughness to it, though it is mostly smooth
      • Normal placental insertion into the placental disc is marginate
      • Circummarginate insertion is a variation with no clinical significance
      • Circumvallation is an extrachorial placenta with a raised margin
      • Chorionic plate is smaller than the basal plate
      • Misalignment causes hematoma retention in the placental margin
      • Associated with poor pregnancy outcome (Obstet Gynecol Int 2014;2014:986230)
    • Umbilical cord
      • Twisted cable that connects the fetus to the placenta and is composed of Wharton jelly covered by a layer of amnion, 2 muscularized umbilical arteries carrying deoxygenated blood away from the fetus to the placenta and a single large, thin walled vein carrying oxygenated blood from the placenta to the fetus
      • Pearly white with smooth and glistening surface on gross examination; no surface nodules, ulcerations or deep grooves
      • Insertion on the placenta is normally centrally located by midgestation but may become more eccentric as gestation proceeds
      • Long cords (> 70 cm, with > 95 cm considered extremely long) are associated with knots and fetal entanglements (Pediatr Dev Pathol 2001;4:144)
      • A short cord (≥ 45 cm) is associated with adverse pregnancy outcomes (Clin Exp Obstet Gynecol 2017;44:216)
      • Most cords have a left coil, with an average of 2 coils per 10 cm; the normal range of coiling is 1 - 3 coils per 10 cm
        • Coils are different from twists; twists can be untwisted but coils cannot be uncoiled
      • Coiling direction is identified by holding the cord perpendicular to the ground and looking at the coils; if the coils go up towards the left (like the left line of the letter V), then that is a leftward coil
      • Pseudoknots are normal variations that have no clinical significance; they are vascular tortuosities (ectatic umbilical vein) that may form a mass-like lesion covered in Wharton jelly
Gross images

Contributed by Marta Cohen, M.D.

Fetal surface

Maternal surface

Microscopic (histologic) description
Chorionic plate (fetal surface)
  • Covered by a layer of amnion and chorion
  • Accumulation of fibrin beneath the chorionic plate is a common finding at term and is visible as tan-white plaques
  • Primary stem villi protrude perpendicularly downward from the chorionic plate
  • Microscopically, the chorionic plate and stem villi, both primary and secondary, are composed of dense collagenized connective tissue surrounding thick walled arteries and veins

Basal plate (maternal surface)
  • Consists of fibrin, extravillous trophoblast cells, decidua basalis and maternal blood vessels
  • Endometrial spiral arteries undergo physiological transformation characterized by lumen dilation, extravillous trophoblast invasion of the endothelial lining and fibrinoid replacement of the muscular and elastic tissue of the arterial wall (J Perinat Med 2006;34:447)
  • Therefore, maternal spiral arteries transform from high resistance, low capacitance to low resistance, high capacitance vessels
  • Maternal veins generally run parallel to the basal plate and are less conspicuous
  • Contour of the basal plate is coarsely folded, forming clefts known as placental septa that protrude into the parenchyma and can extend as far as the fetal surface
  • Insertion site of the anchoring villi into maternal endometrium
  • Invasive intermediate trophoblasts are seen here

Membranes
  • Composed of amnion, intermediate or spongy layer (reticular zone that represents remnants of the coelomic cavity), chorion laeve and chorion frondosum
  • Membrane layers adhere together but can be peeled apart with minimal effort
  • Amnion: innermost covering of amniotic cavity that is closest to the fetus; thin, avascular layer composed of cuboidal to low columnar epithelial cells that rest on a thin basement membrane with underlying thin band of loose connective tissue (spindled to stellate mesenchymal cells)
    • May show squamous metaplasia (plaques of keratinizing, stratified squamous epithelium), especially near umbilical cord insertion
    • Present as small gray nodules of 3 - 4 mm in diameter and should be distinguished from amnion nodosum
    • Squamous metaplasia is a normal variant (seen in nearly 50% of term placentas), while amnion nodosum is pathological and is strongly associated with longstanding oligohydramnios
  • Intermediate or spongy layer: potential space between the amnion and chorion, which results from incomplete fusion of amnionic and chorionic mesoderm during early pregnancy; this intermediate layer is composed of loosely arranged bundles of collagen fibers with a few scattered fibroblasts, separated by a communicating system of clefts and allows the membranes to slide against each other
  • Chorion: connective tissue membrane containing fetal vessels, internal to amnion, external to villi
  • Membranous chorion (chorion laeve): formed by the collapse of the intervillous space during development; composed of mononuclear, sometimes vacuolated, extravillous trophoblast and scattered atrophic chorionic villi
  • Decidual chorion (chorion frondosum): located in the placenta proper; it eventually fuses with the parietal decidua, thereby obliterating the uterine cavity (Front Bioeng Biotechnol 2020;8:610544)

Umbilical cord
  • 2 umbilical arteries have slightly thicker, double layered muscular walls without an elastic layer (Fetal Pediatr Pathol 2005;24:297)
  • Single umbilical vein has a thinner muscular wall containing a subintimal elastic layer
  • Intervening Wharton jelly contains loose ground substance, a fine network of microfibrils and scattered nucleated cells (predominantly macrophages, myofibroblasts and mast cells)
  • Umbilical cord is surfaced by a single layer of amnion, which is continuous with the surface of the placenta and the fetal skin
  • A single umbilical artery is present in ~1% of cases
  • Vessels branch out over the fetal surface to form the villous tree

Placental villi
  • Comprised of capillaries, fetal macrophages (Hofbauer cells) and perivascular fibroblasts without associated collagen; the surrounding trophoblast bilayer consists of an outer syncytiotrophoblast layer and inner cytotrophoblast layer
  • Site of gas exchange, metabolic and endocrine activities
  • Dual blood supply from both the fetal and maternal circulations
  • Villous trees are made up of ~40 major primary stem villi, each measuring 0.2 - 1.5 mm in diameter, which protrude perpendicularly downward from the chorionic plate; contain arteries, veins, fibrous stroma and capillaries
  • Primary villi separate into 4 - 8 secondary stem villi, which travel parallel to the chorionic plate
  • These secondary stem villi further divide into tertiary stem villi, which form the placental lobules and insert into the basal plate
  • Villi types evolve during pregnancy: immature intermediate villi are dominant in early pregnancy; mature intermediate branch into terminal villi represent the main exchange area of the third trimester placenta

Cytotrophoblast cells
  • Present in early gestation; differentiates into villous or extravillous trophoblast and forms syncytiotrophoblasts by fusing on villous surface
  • During early pregnancy, this layer is nearly complete but later in gestation it becomes discontinuous and is inconspicuous in term placenta
  • Cuboidal, polyhedral or ovoid cells with well demarcated cell borders and large, lightly staining nuclei containing finely dispersed chromatin
  • Cytoplasm is usually clear to slightly granular and somewhat basophilic
  • Mitotic figures are occasionally found

Extravillous (X cells) or intermediate trophoblast cells
  • Old literature described extravillous trophoblast as intermediate trophoblast, as the morphology appeared intermediate between cytotrophoblast and syncytiotrophoblast
  • Infiltrate decidua and myometrium of placental site, invade and replace spiral arteries of the basal plate to establish maternal - fetal circulation and keep vessels patent (Cell Mol Life Sci 2019;76:3479)
  • Form trophoblastic shell
  • Secrete parathyroid hormone (PTH) related protein
  • Located in the basal plate, septa and chorion laeve; morphology varies by location
  • In the basal plate, they are enlarged polyhedral to spindle cells with abundant amphophilic and vacuolated cytoplasmic and large, hyperchromatic nuclei; may resemble adjacent decidua
  • In myometrium, they are more spindled and resemble adjacent smooth muscle cells; may fuse to become multinucleated cells

Intraplacental trophoblast islands
  • Form the inner layer of the villous trophoblastic mantle and play an important role in maintaining the structural integrity of the villi
  • Serve as a source from which implantation site and chorionic type intermediate trophoblast cells are derived
  • Larger than cytotrophoblasts, mononucleate, polygonal, abundant pale to clear cytoplasm, distinct cell borders and single nuclei
  • Frequently, the islands contain villous remnants with perivillous fibrin

Syncytiotrophoblast cells
  • Single, continuous, normally uninterrupted layer that extends over the surfaces of all villous trees and chorionic villi as well as over parts of the inner surfaces of chorionic and basal plates
  • Synthesize and secrete hCG, hPL
  • Multinucleated giant cells with abundant homogeneous to finely granular, somewhat basophilic cytoplasm, often with multiple intracytoplasmic vacuoles and small dense pyknotic nuclei with moderately dense chromatin

Hofbauer cells
  • Fetal macrophages located in villous stroma
  • 10 - 35 μm in diameter
  • Present from 18 days postconception and throughout gestation
  • 4 subtypes according to differences in the expression of major histocompatibility complex (MHC) type II complement receptors, lectins, lipopolysaccharide coreceptor (CD14) and CD68 (Anal Quant Cytopathol Histpathol 2013;35:283)
  • Round to ovoid cells with eccentric nuclei and granular cytoplasm with many vacuoles containing flocculent material and occasional osmiophilic bodies
  • Their most important function is the immunological defense of the fetus and the prevention of vertical transmission of pathogens
Microscopic (histologic) images

Contributed by Marta Cohen, M.D.

Peripheral membranes

Umbilical cord

Basal plate

Chorionic plate


Placental villi

Immature villi

Extravillous trophoblast

Islands of extravillous trophoblast

Positive stains
Negative stains
Electron microscopy description
  • Syncytiotrophoblast cells: vacuoles are due to dilated endoplasmic reticulum and lacunae from plasma membrane infoldings
Board review style question #1

Placenta product of a concealed pregnancy is submitted for assessment of the gestational age. The trimmed placental weight is 51 grams. The histology shows a prevalence of intermediate immature villi with presence of extravillous (intermediate) trophoblast. What is the most likely gestational age of the placenta?

  1. 12 weeks
  2. 26 weeks
  3. 36 weeks
  4. 40 weeks
  5. 42 weeks
Board review style answer #1
A. 12 weeks gestation. Immature intermediate villi are dominant in early pregnancy (first trimester). The presence of extravillous trophoblast invades the uterus during implantation. Answers B - E are incorrect because these features would likely not be present by the gestational age listed.

Comment Here

Reference: Anatomy & histology-placenta & umbilical cord
Board review style question #2
In which placental compartment is the Wharton jelly present?

  1. Basal plate
  2. Chorionic plate
  3. Membranes
  4. Umbilical cord
  5. Villi
Board review style answer #2
D. Umbilical cord. Intervening Wharton jelly contains loose ground substance, a fine network of microfibrils and scattered nucleated cells (predominantly macrophages, myofibroblasts and mast cells). Answers A - C and E are incorrect because Wharton jelly is not present in these placental compartments.

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Reference: Anatomy & histology-placenta & umbilical cord

Blighted ovum / anembryonic gestation
Definition / general
  • Failure of development or early embryonic demise with persistent trophoblast development, leading to an anembryonic gestation
Microscopic (histologic) description
  • Villous stromal edema without central cistern formation or trophoblastic hyperplasia
  • Features of karyotypic abnormalities may be present
  • 52% are trisomic (smaller villi without cisterns), 20% are triploid (resemble partial moles with focal trophoblastic invaginations, cisterns, irregular surfaces and dysmorphic features) and 15% are XO and 6% are tetraploid
  • Before week 8, aneuploidy is most common with embryonic growth disorganization

Chorangioma
Definition / general
  • Well demarcated placental mass composed of capillaries, stromal cells and surrounding trophoblast arising in a stem villus
Essential features
  • Well circumscribed nodule(s) formed by proliferation of capillaries in a stem villus
  • Most are asymptomatic and microscopic
  • When large (> 4 cm), can cause fetal hemodynamic complications
Terminology
  • Placental hemangioma
  • Fibroangiomyxoma
ICD coding
  • ICD-10: 043.89 - other placental disorders
Epidemiology
  • Most common in multiple gestation pregnancies or pregnancies complicated by preeclampsia
  • Most common placental tumor (in 0.5 - 1% of all placentas) (Fetal Pediatr Pathol 2010;29:199)
Sites
  • Placenta
Pathophysiology
  • Likely a hamartoma but may be a reactive process due to hypoxia
Etiology
Clinical features
  • Most are small, incidental and asymptomatic
  • Large (> 4 cm) chorangiomas are associated with intrauterine growth restriction (IUGR), polyhydramnios, preterm delivery, arteriovenous shunting (and fetal cardiomegaly or heart failure), hydrops, fetal thrombocytopenia and maternal mirror syndrome (J Perinat Med 2014;42:273, Indian Pediatr 1996;33:520)
Diagnosis
  • Most are incidental and microscopic, rarely evident grossly as masses at the chorionic plate
  • If large enough, diagnosis can be made antenatally by imaging
Radiology description
  • Well circumscribed hypoechoic mass(es) by ultrasound imaging, vascular by color Doppler imaging or MRI
Radiology images

Contributed by Bryann Bromley, M.D.
Transabdominal ultrasound

Transabdominal ultrasound

Color Doppler

Color Doppler

Prognostic factors
  • Most small chorangiomas have no clinical relevance
  • Large chorangiomas (> 4 cm) may be associated with perinatal morbidity and even mortality due to hemodynamic stresses on the fetus (see Clinical features)
Case reports
Treatment
  • Careful monitoring for the development of hydrops if large
  • Symptomatic treatment (intrauterine transfusions, amniodrainage)
  • Interventions in rare cases (alcohol injection, microcoil embolization, endoscopic laser coagulation and interstitial laser therapy)
  • Reference: Fetal Pediatr Pathol 2010;29:199
Gross description
  • Single or multiple well circumscribed spherical / oval masses if large enough to be grossly identifiable
  • Subchorionic or marginal
  • Red-brown, fleshy
  • Firm and tan-brown, if infarcted
  • Range: 1 - 10 cm; most < 4 cm
  • Reference: Fetal Pediatr Pathol 2010;29:199
Gross images

Contributed by Baris Boyraz, M.D., Ph.D. and Drucilla J. Roberts, M.D.
Typical chorangioma

Typical chorangioma

Infarcted large chorangioma

Infarcted large chorangioma

Large chorangioma

Large chorangioma

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Baris Boyraz, M.D., Ph.D. and Drucilla J. Roberts, M.D.
Well circumscribed mass

Well circumscribed mass

Capillary proliferation and surrounding stroma

Capillary proliferation and surrounding stroma

Cellular chorangioma

Cellular chorangioma

Trophoblast hyperplasia

Trophoblast hyperplasia

Positive stains
Molecular / cytogenetics description
Sample pathology report
  • Placenta, term vaginal delivery:
    • Mature placenta (530 g, ~50th percentile for 40 weeks gestational age); patchy villous edema; chorangioma (2 cm) (see comment)
    • Comment: These are benign, usually incidental, placental masses, likely hamartomas, of no clinical significance when < 4 cm, as is this one. Some have noted an association with infantile hemangiomas; clinical correlation is necessary.
Differential diagnosis
Board review style question #1

Which of the following is the most likely diagnosis of this well circumscribed placental mass near the chorionic plate?

  1. Chorangioma
  2. Inflammatory myofibroblastic tumor
  3. Intervillous thrombus
  4. Leiomyoma
  5. Placental infarct
Board review style answer #1
A. Chorangioma. Chorangiomas are likely hamartomas of the placental stem villi forming vascular masses nearly always peripheral and adjacent to the chorionic plate. They are well demarcated, firm masses when grossly identifiable and most are incidental and microscopic. Leiomyomas from the uterus can be adherent to the basal plate of the placenta and are extremely rare masses, extraneous to the placental parenchyma. Placental infarcts are typically firm and gritty triangular or rectangular masses at the maternal floor (not the chorionic plate). Intervillous thrombi are laminated irregularly shaped red or white soft masses anywhere in the placenta. Placental associated inflammatory myofibroblastic tumors are also unusual extrinsic masses that can be attached to the placenta basal plate or membranes.

Comment Here

Reference: Chorangioma
Board review style question #2
What are complications associated with chorangioma?

  1. Fetal and maternal hydrops
  2. Malignant transformation
  3. Maternal visceral hemangiomas
  4. Obstructed labor and delivery
Board review style answer #2
A. Fetal and maternal hydrops. Vascular steal and heart failure due to fetal perfusion of a large chorangioma can lead to fetal hydrops. Maternal mirror syndrome is a rare but serious complication of hydrops fetalis. Malignant transformation does not occur in chorangiomas; if malignancy occurs, the diagnosis is likely an intraplacental choriocarcinoma, which can have associated hypervascular villi. Visceral hemangiomas in the mother are not associated with chorangiomas but fetal / neonatal hemangiomas of the skin have been reported. Chorangiomas rarely reach a size which could complicate delivery.

Comment Here

Reference: Chorangioma

Chorangiomatosis
Definition / general
  • Nonexpansile proliferation of anastomosing capillaries at the periphery of stem villi or immature intermediate villi
  • Closely related to chorangiosis and chorangioma and associated with advanced maternal age, extreme prematurity and multiple gestation; it is less common in those of African American ancestry (Hum Pathol 2000;31:945)
Essential features
  • Also called multifocal chorangiomatosis and multifocal diffuse chorangiomatosis
  • No gross findings; therefore, radiologic detection on antenatal evaluation is not possible
  • 2 subgroups: patchy (multiple foci, occupying < 10x microscopic field) and extensive (multiple foci with at least one > 4x microscopic field)
  • Fetal growth restriction, congenital malformation and adverse fetal outcomes associated with more extensive lesions
Terminology
  • Multifocal chorangiomatosis and multifocal diffuse chorangiomatosis
ICD coding
  • ICD-10: O43.813 - placental infarction, third trimester
Epidemiology
  • Maternal factors associated with multifocal chorangiomatosis include advanced maternal age and multiparity; it is less common in those of African American ancestry
  • Fetal outcomes can include growth restriction, congenital anomalies and stillbirth
Pathophysiology
  • Rare disorder without a clearly defined etiology or pathophysiology
  • Suspected to be due to fetal developmental anomalies or abnormal fetal blood flow
Diagnosis
  • Diagnosis is made on histologic evaluation of the placenta as there are no radiologic or grossly evident findings
Prognostic factors
  • Patchy multifocal chorangiomatosis has been associated with fetal growth restriction and prematurity
  • Extensive multifocal chorangiomatosis has been associated with macrosomia, congenital anomalies and stillbirth
Case reports
Microscopic (histologic) description
  • Anastomosing vascular proliferation along the edges of stem vessels and immature intermediate villi comprised of capillaries surrounded by pericytes and small, muscularized arterioles
  • Often with coexistent chorangiosis
  • 2 subtypes
    • Patchy: multiple foci occupying < 10x microscopic field
    • Extensive: multiple, more diffuse foci with at least one > 4x microscopic field
  • Reference: Hum Pathol 2000;31:945
Microscopic (histologic) images

Contributed by Shahrazad Saab, M.D.
Term placenta with intrauterine growth restriction

Term placenta with intrauterine growth restriction

Term placenta with delayed villous maturation Term placenta with delayed villous maturation

Term placenta with delayed villous maturation

Twin placentas (34 weeks gestational age) with fetal growth restriction of both fetuses Twin placentas (34 weeks gestational age) with fetal growth restriction of both fetuses

Twin placentas (34 weeks gestational age) with fetal growth restriction of both fetuses

Term placenta with severe fetal growth restriction

Term placenta with severe fetal growth restriction

Sample pathology report
  • Placenta:
    • Chorangiosis and multifocal chorangiomatosis
    • Immature (early third trimester) placenta, 256 g
Differential diagnosis
  • Chorangioma:
    • Benign, well circumscribed, nodular capillary proliferation
  • Localized chorangiomatosis:
    • Chorangioma that has spread to involve several contiguous primary stem villi (wandering chorangioma)
Board review style question #1

Which of the following describes the lesion shown above?

  1. A capillary proliferation localized to a group of contiguous primary stem villi
  2. A localized capillary proliferation which when > 3 cm can result in polyhydramnios and intrauterine growth restriction
  3. Enlarged villi with irregular contours, increased stroma, trophoblast inclusions and irregularly distributed arterioles, venules and capillaries
  4. Foci of excessive capillary proliferation present at the edges of stem and intermediate villi that can be associated with advanced maternal age, preterm birth and multiparty
  5. Multifocal or diffuse increase in villous diameter with increased stromal cellularity and the presence of nonperipheral villous capillaries
Board review style answer #1
D. Foci of excessive capillary proliferation present at the edges of stem and intermediate villi that can be associated with advanced maternal age, preterm birth and multiparty. Answer A is incorrect because it describes localized chorangiomatosis (wandering chorangioma). Answer B is incorrect since it describes a giant chorangioma, which has a high prevalence of poor fetal outcomes related to polyhydramnios, intrauterine growth restriction, cardiomegaly, high output heart failure and fetal hydrops. Answer C is incorrect because it describes dysmorphic villi. Answer E is incorrect because it describes immature villi.

Comment Here

Reference: Chorangiomatosis
Board review style question #2
Which of the following is true about multifocal chorangiomatosis?

  1. Can be categorized as patchy or extensive
  2. Can be seen in placentas of mothers living at high altitudes
  3. Localized, nodular capillary proliferation
  4. Placentas are enlarged with segmentally abnormal proximal villi showing stromal overgrowth and vascular abnormalities affecting small and large villous vessels
Board review style answer #2
A. Can be categorized as patchy or extensive. Answer B is incorrect because it describes chorangiosis. Answer D is incorrect because it describes placental mesenchymal dysplasia. Answer C is incorrect because it describes chorangioma.

Comment Here

Reference: Chorangiomatosis

Chorangiosis
Definition / general
Essential features
  • Terminal villous vascular hyperplasia resulting from longstanding low grade hypoxia in the placental tissue or fetal side hypoperfusion
ICD coding
  • ICD-10: O43.89 - other placental disorders
Epidemiology
Sites
  • Terminal chorionic villi of the placenta
Pathophysiology
  • Growth factor promotion of angiogenesis in response to long standing placental hypoperfusion or chronic low grade tissue hypoxia
  • Chronic hypoperfusion and tissue hypoxemia may lead to an excessive villous neoangiogenesis and to a high proliferative activity of connective tissue, probably mediated by growth factors (VEGF, bFGF and PDGF) (Gynecol Obstet Invest 2012;73:141)
Etiology
  • Higher incidence in maternal pathological conditions associated with hypoxemia
  • Incidence is higher:
  • Also associated with placental pathology, such as single umbilical artery, placental abruption, amnion nodosum, villitis and umbilical cord anomalies (e.g. long umbilical cord)
Clinical features
Diagnosis
  • Altshuler criteria: > 10 capillaries in at least 10 terminal villi in ≥ 10 noninfarcted areas in at least 3 low power fields of the placenta (Arch Pathol Lab Med 1984;108:71)
  • Normal villi rarely have > 5 capillaries / villous
Prognostic factors
Case reports
Gross description
  • No distinct gross abnormalities
  • Placenta may be heavy and boggy
  • Other placental findings may include: single umbilical artery and other umbilical cord anomalies, retroplacental hematoma (abruptio placentae) (Gynecol Obstet Invest 2012;73:141)
Microscopic (histologic) description
  • > 10 capillaries in > 10 terminal villi in at least 10 different noninfarcted areas in 3 low power fields of the placenta = diffuse chorangiosis
  • Focal chorangiosis with similar morbidity associations as diffuse (Pediatr Dev Pathol 2019;22:406)
  • Capillaries have distinct basement membranes but are not surrounded by a continuous layer of pericytes or associated with stromal fibrosis
  • May be associated with delayed villous maturation, chorangioma(s), villitis of unknown etiology, fetal vascular malperfusion
  • Must distinguish from villous vascular congestion (vessels appear prominent but are normal in number), chorangiomatosis and chorangioma(s)
Microscopic (histologic) images

Contributed by Drucilla J. Roberts, M.D.

Term placenta showing chorangiosis

Positive stains
Sample pathology report
  • Placenta:
    • Heavy, slightly immature placenta (650 g fresh, trimmed; > 90th percentile for 39 weeks gestational age)
    • Long umbilical cord (85 cm, expect 50 - 70 cm at term)
    • Chorangiosis, diffuse (see comment)
    • Comment: Chorangiosis, when diffuse, is a rare finding associated with in utero hypoxia.
Differential diagnosis
  • Chorangioma:
    • Nodular lesion composed entirely of capillary vascular channels with surrounding trophoblasts
    • Analogous to hemangiomas occurring elsewhere
  • Chorangiomatosis:
    • Heterogeneous and less well defined lesion with intermediate features between chorangioma and chorangiosis
    • Hyperplastic capillaries surround larger vessels in central cores of stem and intermediate villi
    • Increased number of perivascular bundles of reticulin fibers and pericytes
    • Smooth muscle actin positive in pericytes
  • Congestion:
    • Prominent capillaries in the villi but there is no numerical increase in the number of capillaries
Board review style question #1

This placenta from a primigravida living in Nepal shows what feature?

  1. Chorangioma
  2. Chorangiomatosis
  3. Chorangiosis
  4. Normal placenta villi
  5. Villous edema
Board review style answer #1
C. Chorangiosis

Comment Here

Reference: Chorangiosis
Board review style question #2

Chorangiosis (see figure) is associated with which of these clinical histories?

  1. CMV placentitis
  2. High altitude pregnancies
  3. Intrauterine fetal demise
  4. Maternal depression
  5. Small for gestational age fetus
Board review style answer #2
B. High altitude pregnancies

Comment Here

Reference: Chorangiosis

Choriocarcinoma
Definition / general
  • Aggressive form of gestational trophoblastic neoplasia composed of syncytiotrophoblast, cytotrophoblast and intermediate trophoblast
Essential features
  • Triphasic neoplasm (syncytiotrophoblast, cytotrophoblast and intermediate trophoblast components)
  • Arises from previous pregnancies, more commonly after complete hydatidiform mole
  • Aggressive behavior
  • Serum human chorionic gonadotropin (hCG) is a reliable tumor marker
  • High cure rates with chemotherapy
ICD coding
  • ICD-O: 9100/3 - Choriocarcinoma, NOS
  • ICD-10: C58 - Malignant neoplasm of placenta
  • ICD-11: 2C75 & XH8PK7 - Malignant neoplasms of placenta and choriocarcinoma, NOS
Epidemiology
Sites
Etiology
Clinical features
  • Vaginal bleeding is the most common symptom
  • Can also present initially with metastatic disease, especially after nonmolar pregnancies, in the lungs (dyspnea, hemoptysis), lower genital tract (violet nodules located in the vulva, vagina or cervix), liver (abnormal liver function, intraabdominal hemorrhage) and brain (neurologic symptoms, e.g. convulsion, altered mental status)
Diagnosis
Laboratory
  • Markedly elevated hCG is a reliable marker of the disease
  • hCG levels reflect the tumor burden, therefore, they are used for diagnosis, follow up, evaluation of therapy response and screening of recurrences (Int J Gynaecol Obstet 2018;143:79, Lancet 2010;376:717)
Radiology description
Radiology images

Contributed by Lawrence Hsu Lin, M.D., Ph.D. and Deborah DeLair, M.D.
Ultrasound of uterine choriocarcinoma Ultrasound of uterine choriocarcinoma

Ultrasound of uterine choriocarcinoma

CXR with lung metastases

CXR with lung metastases

CT scan with lung metastases

CT scan with lung metastases

CT scan with brain metastases

CT scan with brain metastases

MRI scan with brain metastases

MRI scan with brain metastases

Prognostic factors
  • WHO prognostic scoring system (includes age, antecedent pregnancy, interval between diagnosis and index pregnancy, hCG levels, largest tumor size, location and number of metastasis, chemoresistance) (Int J Gynaecol Obstet 2018;143:79):
    • Low risk: ≤ 6
    • High risk: ≥ 7
    • Ultra high risk: > 12
  • FIGO anatomic staging (Int J Gynaecol Obstet 2018;143:79):
    • I: confined to uterine corpus
    • II: extending to adnexa and vagina
    • III: extending to lung
    • IV: other metastatic sites
  • Prognostic factors of poorer outcome:
    • Older age
    • Arising from nonmolar pregnancy
    • Long interval between index pregnancy and diagnosis
    • Markedly elevated hCG
    • Large tumor burden
    • Metastasis to brain and liver
    • Chemoresistance

WHO scoring system based on prognostic factors
0 1 2 4
Age, years < 40 ≥ 40 - -
Antecedent pregnancy Mole Abortion Term -
Interval months from index pregnancy, months < 4 4 - 6 7 - 12 > 12
Pretreatment serum hCG (mIU/mL) < 103 103 - 104 104 - 105 > 105
Largest tumor size (including uterus), cm < 3 3 - 4 ≥ 5 -
Site of metastases Lung Spleen, kidney Gastrointestinal Liver, brain
Number of metastases - 1 - 4 5 - 8 > 8
Previous failed chemotherapy - - Single drug ≥ 2 drugs
Case reports
Treatment
  • Chemotherapy (Int J Gynaecol Obstet 2018;143:79)
    • Choice of chemotherapy is based on the FIGO / WHO prognostic score (Int J Gynaecol Obstet 2018;143:79)
      • Low risk: single agent, including methotrexate and actinomycin D
      • High risk: multi agent, including etoposide, methotrexate, actinomycin, cyclophosphamide, vincristine (EMA-CO); etoposide, cisplatin - etoposide, methotrexate, actinomycin (EP-EMA); paclitaxel, etoposide - paclitaxel, cisplatin (TE / TP)
  • Surgery only performed in selected cases (older age, chemoresistance, uterine rupture by tumor, life threatening hemorrhage)
  • Radiotherapy is controversial; some centers use radiotherapy for brain metastatic disease (Int J Gynaecol Obstet 2018;143:79)
Gross description
  • Dark red, solid, friable tumor, with areas of hemorrhage and necrosis
  • Intraplacental choriocarcinoma can be a subtle lesion grossly and is commonly mistaken for placental infarct
  • Most common location: endomyometrium
Gross images

Contributed by Lawrence Hsu Lin, M.D., Ph.D. and Deborah DeLair, M.D.
Uterine tumor

Uterine tumor

Large uterine tumor

Large uterine tumor

Cervical involvement

Cervical involvement

Tubal tumor

Tubal tumor



Images hosted on other servers:
Intraplacental tumor

Intraplacental tumor

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Regina Schultz, M.D., Ph.D. and Tatyana Zinger, D.O.
Solid tumor without chorionic villi

Solid tumor without chorionic villi

Triphasic neoplasm

Triphasic neoplasm

Increased mitotic activity

Increased mitotic activity

Intraplacental choriocarcinoma Intraplacental choriocarcinoma

Intraplacental choriocarcinoma

Virtual slides

Images hosted on other servers:
21 year old at 40 weeks with Zika exposure

21 year old at 40 weeks with Zika exposure

Cytology description
  • Not routinely performed
  • Clusters of cohesive atypical epithelioid cells
Electron microscopy description
  • Not routinely performed
  • Rare reports showing triphasic population: syncytiotrophoblasts, cytotrophoblasts and intermediate trophoblast
  • Syncytiotrophoblasts:
    • Complex cells with multiple, irregular and convoluted nuclei and dense and abundant cytoplasm containing dilated endoplasmic reticulum, Golgi apparatus, lysosomes and tonofilaments
    • Syncytiotrophoblast cell membranes often contain numerous microvilli
  • Cytotrophoblasts:
    • Closely spaced epithelial cells with single, large nucleus
    • Relatively simple cytoplasm with small amount of organelles and glycogen
  • Intermediate trophoblasts: intermediate sized mononuclear cells with moderately complex cytoplasm containing organelles
Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:
STR analysis of gestational choriocarcinoma

STR analysis of gestational choriocarcinoma

STR analysis of nongestational choriocarcinoma

STR analysis of nongestational choriocarcinoma

Sample pathology report
  • Uterus, total hysterectomy:
    • Choriocarcinoma (see comment)
    • Comment: The specimen shows a highly mitotically active neoplasm arising in the endomyometrium. There is a triphasic population of atypical cells composed of syncytiotrophoblast, cytotrophoblast and intermediate trophoblast. Immunohistochemical stains show reactivity for hCG (diffuse), p63 (focal) and hPL (focal). The previous history of complete hydatidiform mole is noted, favoring the diagnosis of gestational choriocarcinoma
Differential diagnosis
  • Placental site trophoblastic tumor:
    • Composed of implantation type intermediate trophoblast, characterized by a single population of mononuclear cells with eosinophilic and amphophilic cytoplasm
    • Diffusely positive for hPL and Mel-CAM; focal positivity for hCG
  • Epithelioid trophoblastic tumor:
    • Composed of chorionic type intermediate trophoblast, characterized by a single population of mononuclear cells with eosinophilic to clear cytoplasm
    • Diffusely positive for p63; focal positivity for hCG, Mel-CAM, hPL
  • Invasive mole / hydatidiform mole / early pregnancy loss:
    • Presence of villi indicates invasive mole, molar pregnancy or early pregnancy loss
    • Nuclear atypia can be present in invasive mole, molar pregnancy and early pregnancy loss; however, extensive marked cytologic atypia favors choriocarcinoma
    • Differential diagnosis can be challenging, especially when tissue is scant; diagnosis of atypical trophoblastic proliferation can be rendered, as some cases of early choriocarcinoma cannot be histologically differentiated from atypical proliferations associated with invasive mole, hydatidiform mole or early pregnancy loss
  • Nongestational choriocarcinoma:
    • Morphologically and immunohistochemically identical to gestational choriocarcinoma
    • Prepuberal ovarian tumor favors nongestational choriocarcinoma
    • Postmenopausal mixed endometrial tumor with nontrophoblastic carcinomatous components and extrauterine tumors without uterine primary favor nongestational choriocarcinoma
    • Definite diagnosis can be reached after STR analysis; nongestational choriocarcinoma has identical alleles to the patient's and absence of partner's alleles
Board review style question #1

Which of the following serum markers is markedly elevated in the tumor above?

  1. CA125
  2. CA19-9
  3. CEA
  4. hCG
  5. hPL
Board review style answer #1
D. hCG

Comment Here

Reference: Choriocarcinoma
Board review style question #2
Which is the best tool to differentiate gestational from nongestational choriocarcinoma?

  1. Copy number analysis
  2. Immunohistochemistry
  3. Microsatellite instability status
  4. Short tandem repeat analysis
  5. Tumor mutational burden analysis
Board review style answer #2
D. Short tandem repeat analysis

Comment Here

Reference: Choriocarcinoma

Chorionic cysts
Definition / general
  • Fluid filled spaces in the placental membranes, beneath the chorionic plate or within cell islands or septa
  • May be associated with chronic uterine hypoxia (Pediatr Dev Pathol 2011;14:1)
Etiology
  • Thought to be due to ischemia and degeneration
Gross description
  • When visible grossly, cysts are usually small ( < 3 cm) and bulge into the amnionic cavity from the fetal surface
  • Differential diagnosis of grossly visible cysts includes partial moles
Microscopic (histologic) description
  • Spaces filled with eosinophilic proteinaceous material and lined by extravillous trophoblastic cells

Chronic deciduitis
Definition / general
  • Abnormal infiltration of small lymphocytes and plasma cells in the decidualized endometrium
  • May be associated with preterm labor
Etiology
  • Presence of plasma cells is a sign of stimulation, possibly by microorganisms, autoantigens or fetal alloantigens
Microscopic (histologic) description
  • Infiltrate of small lymphocytes and plasma cells in the decidua
  • Diffuse lymphocytic infiltrate without plasma cells is also acceptable (Hum Pathol 2000;31:292)

Chronic histiocytic intervillositis
Definition / general
Gross description
  • Small placenta
Microscopic (histologic) description
  • Diffuse infiltrate of histiocytes within intervillous space with villous fibrinoid deposits
  • Other associated lesions may include atherosis, acute chorioamnionitis and rarely chronic villitis
  • Malaria: associated with abundant fibrin, black pigment, occasional neutrophils and parasite laden red blood cells
Positive stains
  • CD68 (histiocytic marker)
Negative stains
  • hCG (may be present in syncytiotrophoblasts but marked reduction compared to usual)

Chronic lymphocytic villitis
Definition / general
  • Chronic inflammatory cells within stroma of chorionic villi
  • No causative organism
  • Infiltrating cells have been shown to be maternal T cells, suggesting that this is an immune mediated disease
  • Associated with fetal growth restriction, premature delivery and stillbirth (more common with recurrent disease)
  • Seen in 3 - 5% of placentas with greater incidence (25%) in small for gestational age newborns
Grading
  • Focal (low grade): small clusters of villi ( < 10) on a single slide
  • Multifocal (low grade): small clusters of involved villi ( < 10) on multiple slides
  • Patchy (high grade): larger clusters of villi ( > 10) on multiple slides
  • Diffuse (high grade): large clusters of villi ( > 10) on all slides
Microscopic (histologic) description
  • Lymphocytes and macrophages within the villous stroma, sometimes with granulomas and giant cells
  • May be accompanied by chronic deciduitis with plasma cells, chronic chorioamniotis, perivillous fibrin, avascular villi and rarely with chronic intervillositis

Circummarginate placenta
Definition / general
  • Insertion of the membranes away from the placenta without a distinct ridge at the point of insertion
  • More common in multigravid pregnancies
Gross description
  • Like circumvallate placentas, the point of membrane insertion is inside the edge of the disc
  • However, no firm ridge at the site of insertion is present
  • Margin is thin and flat

Circumvallate placenta
Definition / general
  • Insertion of the membranes away from the peripheral edge due to a folding / rolling of the chorion on itself
  • Portion of extrachorial disc is present at the edge
  • Associated with low birth weight and multigravid pregnancies
Etiology
  • Usually attributed to marginal hemorrhage
Gross description
  • Membranes insert away from the peripheral margin
  • Firm ridge at the site of insertion is usually present
  • If cysts and other gross aberrations present, may be associated with fetal and maternal abnormalities
Gross images

Images hosted on other servers:

Double back membranes


Complete hydatidiform mole
Definition / general
  • Complete hydatidiform mole is a gestational trophoblastic disease characterized by diffuse hydropic enlargement and trophoblastic proliferation of the chorionic villi
Essential features
  • Proliferative disorder of the placenta, resulting in villous hydrops and trophoblastic hyperplasia without embryonic development
  • Diploid paternal only genome
  • Ultrasonography shows characteristic snowstorm appearance
  • Patients typically present with abnormal ultrasound, vaginal bleeding or a missed abortion
  • Trophoblastic neoplasia (invasive mole or choriocarcinoma) follows complete mole in 15 - 20% of cases
Terminology
  • Molar pregnancy, complete mole
ICD coding
  • ICD-10: O01.9 - hydatidiform mole, unspecified
Epidemiology
Sites
  • Placenta
Pathophysiology
  • A complete mole occurs when an empty ovum is fertilized by a sperm
  • About 80% of complete hydatidiform moles are 46XX, which originate from duplication of the chromosomes of a haploid sperm; the other 20% are 46XY; all the chromosomes are paternally derived
  • Although all chromosomes are paternally derived, mitochondrial DNA remains maternal in origin
  • Maternal recessive mutations in NLRP7 (75%) and KHDC3L (5%) are associated with familial biparental recurrent hydatidiform mole (Mod Pathol 2018;31:1116)
Etiology
  • Abnormal gametogenesis and fertilization
Diagrams / tables

Contributed by Rachelle Mendoza, M.D. and Raavi Gupta, M.D.

Karyotypes of complete mole

Clinical features
  • Abnormal vaginal bleeding ("prune juice" appearance) during the first trimester
  • Ovarian theca lutein cysts > 6 cm in diameter
  • The uterus is typically significantly enlarged for gestational age
  • Elevated human chorionic gonadotropin level for gestational age
  • Early onset of medical complications, such as pregnancy induced hypertension, hyperthyroidism and hyperemesis gravidarum
  • Reference: Am J Obstet Gynecol 2010;203:531
Diagnosis
  • Pelvic ultrasound
  • Dilation and curettage / evacuation
Laboratory
  • Elevated serum quantitative human chorionic gonadotropin (hCG) level, typically greater than 100,000 international units (IU)
  • Elevated thyroid panel (if signs and symptoms of hyperthyroidism present)
  • Elevated liver function tests and proteinuria (if preeclampsia is suspected)
  • Anemia and thrombocytopenia in complete blood count (CBC)
  • Reference: Am J Obstet Gynecol 2010;203:531
Radiology description
  • Pelvic ultrasound shows:
    • Heterogeneous, hyperechoic mass in the uterine cavity with multiple anechoic spaces ("snowstorm appearance")
    • Absence of embryo or fetus
    • Absence of amniotic fluid
    • Ovarian theca lutein cyst
    • Reference: Radiographics 2017;37:681
Radiology images

Images hosted on other servers:

Ultrasound image of complete mole

Prognostic factors
  • 1% recurrence risk (Hum Reprod 2015;30:2055)
    • After a molar pregnancy, the risk of a second complete mole rises to 1 - 2%; after two molar pregnancies, the risk of a third mole is 15 - 20%, which is not decreased by having a different partner (Gynecol Oncol 1999;75:224)
  • 15 - 20% risk of progressing to gestational trophoblastic neoplasia; 10 - 15% invasive mole, 2 - 3% choriocarcinoma (Gynecol Oncol 2009;112:654)
  • 50% of choriocarcinoma cases arise from complete mole (Am J Obstet Gynecol 2010;203:531)
  • Progression risk is higher:
    • Signs of trophoblastic proliferation (uterine size greater than gestational age, serum hCG levels > 100,000 milli-international units/mL, ovarian theca lutein cysts > 6 cm in diameter)
    • Age > 40 years
    • Dispermic complete mole
Case reports
  • 33 year old woman with a history of sudden onset of right iliac fossa pain and mild vaginal bleeding following 8 weeks amenorrhea and a positive pregnancy test (BMJ Case Rep 2018;2018:bcr2018225545)
  • 34 year old Japanese woman who was pregnant with a hydatidiform mole and two coexisting fetuses (J Med Case Rep 2019;13:256)
  • 42 year old primigravida woman with multiple metastatic gestational trophoblastic disease after a twin pregnancy with complete hydatidiform mole and coexisting fetus, following assisted reproductive technology (Taiwan J Obstet Gynecol 2018;57:588)
Treatment
  • Uterine evacuation of gestational tissue (mechanical dilation of the cervix, followed by electric suction aspiration and then sharp curettage to help assure complete evacuation of molar tissue)
    • Medication only methods of uterine evacuation (misoprostol, mifepristone, oxytocin) should NOT be used (Gynecol Oncol 2000;78:309)
  • Postevacuation serial serum quantitative hCG measurements, every 1 - 2 weeks until 3 consecutive tests are normal, followed by hCG measurement at 3 month intervals for 6 months
  • Hysterectomy
  • Prophylactic chemotherapy
    • Methotrexate and actinomycin D
Gross description
  • Bulky, bloody tissue with hydropic changes in all villi, which appear as semitransparent vesicles of variable size
  • Classically described as a "bunch of grapes", the individual vesicles measure anywhere from 1 to 30 mm in diameter and the total weight is usually over 200 g
  • Normal placental structures or fetal parts are absent
  • Early complete moles may not have gross evidence of abnormal villi
  • Reference: APMIS 2018;126:647
Gross images

Images hosted on other servers:
Complete mole

Complete mole

Microscopic (histologic) description
  • Diffuse, villous enlargement with marked hydropic changes
  • Cistern formation and marked trophoblastic hyperplasia usually in a circumferential pattern
  • Remarkable cytologic atypia is almost always present
  • Mitoses are common
  • Presence of exaggerated placental site
  • Distended core of the villus is traversed by widely separated, broken strands of fibrillar material (cistern formation)
  • Stromal changes of molar villi, which include stromal mucin and stromal nuclear debris (apoptosis), appear very early and represent a diagnostic clue
  • Reference: APMIS 2018;126:647
Microscopic (histologic) images

Contributed by Rachelle Mendoza, M.D. and Raavi Gupta, M.D.
Hydropic villi

Hydropic villi

Trophoblastic proliferation

Trophoblastic proliferation

Cistern formation

Cistern formation

Trophoblastic proliferation and atypia

Trophoblastic proliferation and atypia

p57 immunostain

p57 immunostain

Positive stains
  • p53 positive (85%, compared with 60.9% in partial moles)
  • hCG, PLAP and hPL
Negative stains
  • p57 negative in villous cytotrophoblast and stromal cells
    • Paternally imprinted maternally expressed gene
    • Complete mole does not have maternal genes and is p57-
    • Requires internal positive control in maternal decidua and intervillous trophoblasts
    • Rare cases of recurrent complete mole may be biparental (p57+), resulting from mutations of maternal NLRP7 or KHDC3L, shutting down the entire maternal imprinting gene expression
  • Reference: Mod Pathol 2014;27:238
Molecular / cytogenetics description
  • Karyotyping - 46XX (80%) with homozygous chromosome polymorphisms or 46XY (20%) androgenetic diploidy
  • Flow cytometric DNA analysis will show a single peak to denote androgenetic diploidy
  • Ploidy FISH - 2 fluorescent signals of androgenetic diploid alleles must be present in > 70% of villous trophoblastic cells
  • Genotyping of short tandem repeats / DNA microsatellites will show no maternal alleles and two homozygous (monospermic) or heterozygous (dispermic) paternal alleles
  • Mutational analysis may show biallelic NLRP7 or KHDC3L mutations in cases of recurrent complete mole
  • References: Mod Pathol 2014;27:238, Arch Pathol Lab Med 2013;137:55, Am J Hum Genet 2011;89:451
Molecular / cytogenetics images

Images hosted on other servers:

Electrophoretogram
of short tandem
repeats

Complete hydatidiform mole

Complete mole FISH using polymorphic deletion probe

Videos

Complete hydatidiform mole histopathology

Sample pathology report
  • Endometrium, curettage:
    • Complete hydatidiform mole (see comment)
    • Comment: Histologic sections show hydropic villi with marked circumferential trophoblastic proliferation and atypia. An exaggerated placental site is also present. p57 immunohistochemical stain shows absent staining in villous cytotrophoblastic and stromal cells, supporting the diagnosis.
Differential diagnosis
  • Partial hydatidiform mole:
    • Fetal or embryonic tissue may be present
    • Chorionic villi with focal edema, scalloping and prominent stromal trophoblastic inclusions
    • Functioning villous circulation
    • Focal trophoblastic hyperplasia and minimal atypia
    • p57 is positive in villous stromal and cytotrophoblast cells
    • Cytogenetic studies show diandric triploidy (69XXX, 69XXY)
  • Hydropic abortus:
    • Polarized trophoblastic proliferation
    • No trophoblast atypia
    • Only mildly enlarged and edematous villi, occasionally cistern formation
    • Biparental diploidy
  • Abnormal villous morphology, possibly related to other genetic abnormalities (e.g., trisomy):
    • Irregular villous outlines with patchy villous hydropic change
    • Complex karyotype (trisomy with combined monosomy, quadriploidy) (Diagn Pathol 2016;11:20)
  • Placental mesenchymal dysplasia:
    • Fetus is present, may have normal growth
    • Absence of trophoblastic proliferation
Board review style question #1

A 24 year old woman presents with vaginal bleeding during the 14th week of pregnancy. She reports intractable nausea. Serum beta human chorionic gonadotropin (beta hCG) levels are markedly elevated at 1,780,000 mIU/ml. Ultrasound assessment reveals no visible fetus but a snowstorm pattern is noted by the radiologist. Curettage reveals 510 grams of bloody granular and friable tissue with numerous small vesicles, which contain clear, colorless fluid. No fetal parts are seen grossly. Representative histologic section is as shown above with circumferential trophoblastic proliferation and cistern formation. Which of the following is true about this condition?

  1. Abnormal karyotype may arise from endoreplication of paternal chromosome
  2. Immunostaining for p57 should be negative in decidual tissue and syncytiotrophoblasts
  3. Typical genetic profile is diandric triploidy
  4. This results from fertilization of a haploid ovum with two haploid sperm cells
Board review style answer #1
A. Abnormal karyotype may arise from endoreplication of paternal chromosome

Comment Here

Reference: Complete hydatidiform mole
Board review style question #2
The most common karyotype for complete mole is

  1. 45XX
  2. 46XX
  3. 46XY
  4. 69XXY
Board review style answer #2

COVID-19 placentitis
Definition / general
  • Pattern of injury associated with transplacental maternal - fetal transmission of SARS-CoV-2
  • Chronic histiocytic intervillositis with trophoblast necrosis in placentas with documented viral infection by SARS-CoV-2
Essential features
  • Vast majority of placentas from mothers infected by SARS-CoV-2 show no specific gross of histologic findings regardless of maternal symptom severity or bulk detection of virus in the placenta
  • COVID-19 placentitis occurs in 1 - 3% of placentas of infected mothers and is associated with transplacental maternal - fetal transmission of SARS-CoV-2
  • Data is inconsistent regarding association of other patterns of placental injury (maternal or fetal vascular malperfusion) with maternal COVID infection, regardless of documented virus in the placenta
ICD coding
  • ICD-10:
    • O41.1410 - placentitis, first trimester
    • O41.1420 - placentitis, second trimester
    • O41.1430 - placentitis, third trimester
Epidemiology
Sites
  • Placenta
Pathophysiology
  • Pregnancies affected by COVID infection fall into 3 categories:
    • Group 1: infected placentas with infected neonates (vertical transmission)
    • Group 2: uninfected placentas from mothers with recent (< 14 days) COVID infection
    • Group 3: uninfected placentas from mothers with remote COVID infection
  • COVID placentitis occurs only in a subset of group 1
  • Main placental cell type supporting viral replication is the syncytiotrophoblast
  • Infection requires expression of the viral receptor angiotensin converting enzyme receptor 2 (ACE2) and the TMPRSS2 protease
  • Placentitis may arise due to direct cytotoxicity by active viral replication in the syncytiotrophoblast or immune mediated damage secondary to inflammatory / cytokine response to COVID-19 infection
  • Other patterns of injury:
    • Fetal vascular malperfusion (fetal thrombosis) may be more frequent among the acute SARS-CoV-2 (group 2) as compared to the nonacute SARS-CoV-2 group (53.8% versus 18.8%; P = 0.002) (Am J Surg Pathol 2022;46:51)
      • Overall, the literature does not provide strong support
    • Maternal SARS-CoV-2 infection early in gestation (group 3) may be associated with pregnancy complications related to implantation, such as preeclampsia and stillbirth, and histologic lesions of maternal vascular malperfusion (BJOG 2020;127:1374, Eur J Obstet Gynecol Reprod Biol 2020;252:559, Am J Obstet Gynecol MFM 2020;2:100107)
      • Evidence for maternal malperfusion is controversial:
        • Infection has been demonstrated in vitro in trophoblastic stem cells suggesting the possibility of preimplantation effects of infection and that the viral receptor ACE2 is required for normal decidualization and implantation
        • However, the overall literature supports only a weak association (Front Immunol 2021;12:685919)
        • In one study, the frequency of maternal vascular malperfusion did not differ by timing of infection (30.8% recent versus 29.7% remote; P > 0.99) (Am J Surg Pathol 2022;46:51)
    • Other currently unsupported theories of a placental role in pregnancy complications during COVID infection include:
      • Placenta might serve as a viral reservoir after clinical recovery in the respiratory tract, leading to chronic placental injury or maternal inflammatory state as manifested by maternal hypertension (Fetal Diagn Ther 2021 Nov 18 [Epub ahead of print])
      • Altered renin angiotensin signaling
        • ACE2, the viral receptor, is expressed in a soluble form shed by the placenta in third trimester via cleavage by ADAM17 enzyme
        • This shedding is increased in women with COVID-19 infection and theoretical systemic effects on blood pressure or renal function (bioRxiv 2021 Nov 22 [Preprint])
Etiology
  • No known risk factors for placental viral spread and COVID placentitis among women with SARS-CoV-2 infection
  • Lesions of maternal vascular malperfusion, gestational hypertension, preeclampsia and stillbirth may be more frequently detected in mothers with COVID infection due to the similarity in risk factors for these lesions and severe viral illness
Laboratory
  • Documentation of maternal SARS-CoV2 is an indication for placental examination but is not required for the diagnosis of COVID placentitis
Prognostic factors
  • Cases of fetal transmission are almost always associated with COVID-19 placentitis; however, specificity and sensitivity of COVID placentitis for fetal infection and poor clinical outcome is low (Arch Pathol Lab Med 2021;145:1341)
Case reports
  • 23 year old woman, gravida 1, at 35 + 2 weeks gestation delivered on day 3 of admission for moderately severe COVID and category III fetal heart rate tracing (Nat Commun 2020;11:3572)
  • 28 year old woman, gravida 4 para 3, with fetal demise of diamniotic twin pregnancy at 13 weeks and moderate symptomatic COVID (24 hour admission) (J Med Virol 2021;93:4480)
  • 29 and 34 year old women with decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation and leading to brain injury (Viruses 2021;13:2517)
  • 30 year old woman, gravida 2 para 1, with dichorionic diamniotic twins and gestational diabetes mellitus and asymptomatic COVID on screening nasal swab at 22 weeks gestation (Eur J Clin Microbiol Infect Dis 2020;39:2441)
  • 35 year old woman in second trimester with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption (J Clin Invest 2020;130:4947)
  • 37 year old woman, gravida 4 para 3, at 34 weeks gestation with large for gestational age female infant due to diabetes and obesity (Pediatr Infect Dis J 2020;39:e265)
Treatment
  • Viral testing and close monitoring of newborns is indicated
Gross description
  • Placentas affected by COVID placentitis often show tan-yellow, firm areas that involve a significant percentage (often > 50%) of the placental parenchyma, similar to the appearance seen in massive perivillous fibrin deposition
Gross images

Contributed by Sanjita Ravishankar, M.D.
Pale consolidation of disc Pale consolidation of disc

Pale consolidation of disc

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Sanjita Ravishankar, M.D.
Perivillous fibrin deposition and intervillous thrombus

Perivillous fibrin deposition and intervillous thrombus

Perivillous fibrin deposition and trophoblast necrosis

Perivillous fibrin deposition and trophoblast necrosis

Perivillous fibrin deposition and chronic intervillositis Perivillous fibrin deposition and chronic intervillositis

Perivillous fibrin deposition and chronic intervillositis

Chronic intervillositis and trophoblast necrosis

Chronic intervillositis and trophoblast necrosis


Syncytiotrophoblast are IHC positive for COVID-19 capsid protein

COVID-19 capsid protein

Positive stains
  • Immunohistochemistry may be used for detection of viral infection but diagnosis of COVID placentitis also requires the histologic pattern (Am J Obstet Gynecol 2021;225:593.e1)
  • Positive immunohistochemistry for COVID-19 is supportive but is not necessary for the diagnosis of COVID placentitis in the presence of the characteristic histologic findings
Electron microscopy description
Molecular / cytogenetics description
  • Placental infection may be detected using in situ hybridization with antisense probe (detects replication) or a sense probe (detects viral messenger RNA) or immunohistochemistry to detect viral nucleocapsid or spike proteins (least specific)
    • Not preferred are bulk viral RNA load in placental homogenates or electron microscopy
    • See examples in Case reports
  • Graded classification for the likelihood of placental infection (definitive, probable, possible and unlikely) was proposed at an NIH consensus conference (Am J Obstet Gynecol 2021;225:593.e1)
    • Definitive: evidence of active replicating virus with location in the placental tissues
    • Probable: evidence of viral RNA or protein located in placental tissues
    • Possible: evidence of viral RNA in placental homogenates or viral-like particles by electron microscopy in placental tissues
    • Unlikely: no evidence of any of the above
    • No testing: testing not done
Sample pathology report
  • Placenta:
    • Diffuse acute and chronic intervillositis with associated perivillous fibrin deposition and trophoblast necrosis, consistent with COVID-19 placentitis
Differential diagnosis
  • Chronic histiocytic intervillositis:
    • Diffuse histiocytic infiltrate in intervillous space with variable perivillous fibrin
    • Lacks prominent trophoblast necrosis
    • Usually small placenta and intrauterine growth restriction (IUGR) rather than acute maternal viral syndrome
    • IHC for SARS-CoV-2 is negative; no evidence of malaria
  • Placental infarction:
    • Aggregated necrotic villi; may be associated with hematoma
    • Intervillous histiocytes are not prominent as in COVID placentitis
    • Gross lesions are typically circumscribed and varying in age (red, yellow); COVID placentitis is more diffuse and poorly circumscribed
Additional references
Board review style question #1
A placenta was delivered to a mother with recent hospital admission for COVID pneumonia. The minimal diagnostic features required for COVID placentitis are

  1. Chronic histiocytic intervillositis and trophoblast necrosis and documentation of recent maternal infection via nasal swab
  2. Chronic villitis of uncertain etiology (VUE) with documented placental infection by SARS-CoV-2 by ISH
  3. Evidence of maternal vascular malperfusion and preeclampsia and documentation of recent maternal infection via nasal swab
  4. Fetal vascular malperfusion with documented placental infection by SARS-CoV-2 by ISH
Board review style answer #1
A. Chronic histiocytic intervillositis and trophoblast necrosis and documentation of recent maternal infection via nasal swab

Comment Here

Reference: COVID-19 placentitis
Board review style question #2
Which is the best predictor of fetal / neonatal SARS-CoV-2?

  1. Chronic histiocytic intervillositis and trophoblast necrosis in placentas with documented placental infection by SARS-CoV-2 by ISH
  2. Fetal demise in the setting of maternal COVID infection
  3. High grade chronic villitis of uncertain etiology (VUE) in a mother with severe clinical COVID viral syndrome
  4. Maternal infection with a severe clinical viral syndrome
Board review style answer #2
A. Chronic histiocytic intervillositis and trophoblast necrosis in placentas with documented placental infection by SARS-CoV-2 by ISH

Comment Here

Reference: COVID-19 placentitis
Board review style question #3

The findings depicted in this image are

  1. Chronic histiocytic intervillositis and trophoblast necrosis (COVID placentitis)
  2. Chronic villitis of uncertain etiology (VUE)
  3. Fetal vascular malperfusion; villous sclerosis and stem vessel thrombosis
  4. Maternal vascular malperfusion; infarction and accelerated maturation
Board review style answer #3
A. Chronic histiocytic intervillositis and trophoblast necrosis (COVID placentitis)

Comment Here

Reference: COVID-19 placentitis

Decidual arteriopathy
Definition / general
  • Pattern of injury to maternal vessels of the decidua that occurs in late pregnancy
  • Features thickening or fibrinoid necrosis of the vessel wall, endothelial swelling and detachment, loose collection of perivascular lymphocytes
Essential features
  • Closely associated with preeclampsia and fetal growth restriction
  • 2 forms: early / hypertrophic type and advanced / severe type with fibrinoid necrosis
  • Alteration is independent of endovascular trophoblast and is best seen away from the placental bed in the membrane roll
  • Likely caused by excess antiangiogenic proteins secreted by trophoblast
Terminology
  • Decidual arteriopathy
  • Decidual vasculopathy
ICD coding
  • ICD-10:
    • O43.109 - malformation of placenta, unspecified, unspecified trimester
    • O36.5190 - maternal care for known or suspected placental insufficiency, unspecified trimester, not applicable or unspecified
Sites
  • Decidua along the placental membranes
Pathophysiology
  • Represents chronic endothelial injury and remodeling in maternal vessels, usually in the setting of preeclampsia or growth restriction with maternal vascular malperfusion
  • Early lesions (hypertrophic type) show mural thickening due to continuous endothelial damage and repair
  • Endothelial damage is caused by trophoblastic secretion of circulating soluble antiangiogenic factors that accumulate in the amniotic fluid, such as soluble fms-like tyrosine kinase (sFLT) and soluble endoglin (sENG), in response to oxidative and hypoxic stress; local inflammatory cytokines such as interferon (INF) gamma may also play a role
  • Independent of trophoblast conversion of spiral arterioles in the implantation site
    • Although both processes are associated with maternal vascular malperfusion, decidual arteriopathy is not a failure of physiologic transformation of spiral arteries
    • Failure of physiologic transformation of spiral arteries involves direct contact between endovascular trophoblast in the implantation site
    • Decidual arteriopathy is a paracrine effect in the decidua of the free membranes (Am J Obstet Gynecol 2017;216:287.e1)
  • Decidual arteriopathy is not a form of hypertension related vascular remodeling; wall thickening in early lesions of decidual arteriopathy is accompanied by loss of smooth muscle (loss of desmin staining) rather than hypertrophy as seen in chronic hypertension
  • Form of hypertrophic decidual arteriopathy has been noted in patients with chronic hypertension unrelated to preeclampsia or growth restriction; such lesions do not seem to progress to acute atherosis
Etiology
Diagnosis
  • Histologic examination of the membranes
Gross description
  • Sections of membrane roll should be taken in areas of preserved decidua (roughened surface of the membranes)
  • Affected vessels may appear prominent on transillumination of the membranes
Microscopic (histologic) description
  • 2 forms: hypertrophic decidual arteriopathy (HDA) and severe decidual arteriopathy with fibrinoid necrosis (SDA)
  • Hypertrophic decidual arteriopathy:
    • Small arteries with thickened walls, swollen endothelial cells that detach into the lumen and a sparse collection of perivascular lymphocytes
  • Severe decidual arteriopathy:
    • Characterized by fibrinoid necrosis of vessel wall (amorphous eosinophilic vessel wall)
    • With or without foamy macrophages (atherosis)
  • Reference: Placenta 2016;42:37
Microscopic (histologic) images

Contributed by Jonathan L. Hecht, M.D., Ph.D.
Normal decidual vessel at 37 weeks

Normal decidual vessel at 37 weeks

Normal muscular decidual arteriole at 8 weeks

Normal muscular
decidual arteriole
at 8 weeks

Normal muscular decidual arteriole at 8 weeks (CD34)

Normal muscular
decidual arteriole
at 8 weeks (CD34)

Hypertrophic decidual arteriopathy

Hypertrophic decidual arteriopathy

Hypertrophic decidual arteriopathy (CD34)

Hypertrophic decidual arteriopathy (CD34)

Severe decidual arteriopathy

Severe decidual arteriopathy



Contributed by Yan Lemeshev, M.D.
Atherosis with fibrinoid necrosis

Atherosis with fibrinoid necrosis

Immunofluorescence description
  • Immunofluorescence is not used for clinical diagnosis
  • Characteristic staining pattern is endovascular deposition of immunoglobulin, complement and perivascular leakage of fibrin
  • Atherosis with deposition of IgM and C3 resembles vascular lesions in transplant rejection, suggesting maternal antifetal rejection (Placenta 1983;4 Spec No:489)
    • However, this pattern can also be seen in the context of diabetes and chronic hypertension due to local intravascular coagulation (Am J Obstet Gynecol 1981;141:773)
Positive stains
Negative stains
Videos

Placental lesions

Sample pathology report
  • Singleton placenta at _ weeks gestational age; _ g (_ percentile):
    • Membranes with decidual arteriopathy
Differential diagnosis
  • Normal muscular decidual arteries:
    • Thick muscular walls
    • Lack endothelial disruption and perivascular lymphocytes
    • Highlighted with desmin
Board review style question #1

A 34 year old woman who is pregnant with her third child and has 2 children (G3P2002) presents at 39 weeks for delivery. Histologic examination of the membrane roll reveals small arteries with detached endothelial cells and a perivascular lymphocytic infiltrate. Which immunohistochemical stain would best highlight the fragmentation of smooth muscle within the vessel walls?

  1. Caldesmon
  2. Desmin
  3. MyoD1
  4. Myogenin
  5. Smooth muscle actin
Board review style answer #1
B. Desmin

Comment Here

Reference: Decidual arteriopathy
Board review style question #2
32 year old G3P1102 presents at 39 weeks for delivery. Histologic examination of the membrane roll reveals small arteries with detached endothelial cells and a perivascular lymphocytic infiltrate. Which predisposing factor is this mother most likely to have?

  1. Gestational hypertension
  2. Increased exercise during pregnancy
  3. Infection during pregnancy
  4. Low body weight
Board review style answer #2
A. Gestational hypertension

Comment Here

Reference: Decidual arteriopathy

Distal villous hyperplasia (villous dysmaturity / delayed villous maturation)
Definition / general
  • Abnormal villous maturation associated with diabetes
  • Neonatal hepatitis should be suspected if pigment laden Hofbauer cells are present
Gross description
  • Placenta is usually large for gestational age
Microscopic (histologic) description
  • Terminal villi may be hypervascular and edematous with reduced numbers of syncytial knots
  • Trophoblast lacks normal syncytiotrophoblast

Early first trimester pregnancy loss
Definition / general
  • Early pregnancy loss (EPL) refers to an early, spontaneous, previable pregnancy loss that occurs before 14 weeks gestation
Essential features
  • Early first trimester pregnancy loss is a common event and may be recurrent
  • Abnormal karyotype occurs in approximately 50% of cases
  • Distinction of prominent villous edema (hydropic villous degeneration) from molar gestation is important
Terminology
  • Early pregnancy loss
  • Spontaneous abortion
  • Missed abortion
  • 2 subgroups, depending on timing of occurrence (J Clin Pathol 1981;34:819):
    • Embryonic (< 10 weeks)
    • Fetal (> 10 weeks)
  • Spontaneous / missed abortion refers to a nonviable intrauterine pregnancy that often results in passage of placental tissue without an embryo
  • Induced abortion refers to termination of pregnancy by artificial means:
    • Nonsurgical (medical abortion; e.g., misoprostol)
    • Vacuum aspiration
    • Dilation and curettage (D&C)
    • Dilation and evacuation (D&E)
ICD coding
  • ICD-10:
    • O02.1 - missed abortion
    • O03.4 - incomplete spontaneous abortion without complication
Epidemiology
Pathophysiology
  • Intrinsically abnormal gestation leading to spontaneous loss
  • Maternal or environmental factors affecting an otherwise normal gestation
Etiology
  • Abnormal karyotype detected in approximately 50% of spontaneous EPL; highest in embryonic (< 10 weeks gestational age) losses, with up to 70% in losses occurring prior to 6 weeks (Ultrasound Obstet Gynecol 2015;45:89)
    • Lethal trisomies - 30%: trisomy 16 accounts for 30% of all trisomies
    • Monosomy X - 10%
    • Triploidy - 2%
  • Other etiologies:
    • Maternal factors: physiologic or structural conditions (e.g., intrauterine scarring or abnormal septation, masses involving the uterine wall) or active disease process (e.g., autoimmune disorders, endocrinopathy, thrombophilia) (Nat Rev Dis Primers 2020;6:98)
    • Teratogen exposure
    • Infection (septic abortion)
Clinical features
  • Spontaneous passage of blood or tissue (Obstet Gynecol 2009;114:860)
  • May be incidentally discovered without associated contractions or vaginal bleeding
  • Conceptus with abnormal karyotype can manifest as abnormally low levels of human chorionic gonadotrophin (hCG)
  • Failure to develop a yolk sac, fetal pole or reduced chorionic sac diameter
  • Absent cardiac activity
  • Blighted ovum: often indicates pre-embryonic loss; gestational sac is identified but without developing embryonic structures (StatPearls: Anembryonic Pregnancy [Accessed 17 January 2022])
Diagnosis
  • Diagnosis may be confirmed by serology (hCG levels), ultrasound findings and microscopic tissue analysis
Laboratory
  • Inappropriately low hCG levels for gestational age
Radiology description
Prognostic factors
Case reports
Treatment
  • Surgical removal of products of conception by D&C, D&E or vacuum aspiration (Rev Obstet Gynecol 2011;4:5)
  • Labor induction by misoprostol (prostaglandin E1 analog)
  • Watchful waiting for complete expulsion of products of conception
  • Treatment of underlying disease (etiology specific management) for recurrent EPL
Gross description
  • Specimen often consists of fragments of placental tissue (chorionic villi, membranes / gestational sac that may be intact or disrupted and decidua)
  • Despite identification of embryo or fetus on ultrasound, an embryo is often not identified / recognized in surgical specimens (J Clin Pathol 1981;34:819)
Gross images

Contributed by Kathleen Sirois, PA (ASCP)
Missed abortion at 9 weeks gestation

Missed abortion at 9 weeks gestation

Chorionic villi in saline

Chorionic villi in saline

Microscopic (histologic) description
  • Removed or passed products of conception may contain:
    • Early first trimester chorionic sac (< 8 weeks): thin chorion and scant villi that are sparsely or nonvascularized
    • Villous trophoblast is bilayered (mononuclear cytotrophoblast inner layer and multinucleated syncytiotrophoblast outer later) and circumferential with occasional polarized trophoblast protrusions
    • Mid first trimester chorionic sac (8 - 10 weeks): may exhibit recognizable amnion, early stromal collagenization of chorion and proximal villi and increased volume of distal villi with distinct capillaries
    • Later first trimester chorionic sac (> 10 weeks): may exhibit loose fusion of amnion and chorion, a more collagenized chorion and stem villi, more distinct walls of fetal vessels and numerous villi with increasing demarcation between proximal and distal branches
    • Spectrum of villous changes in immature chorionic villi following embryonic death (Placenta 2005;26:114):
      • Cellular debris within villous vessels - earliest change
      • Villous edema with myxoid stromal degeneration - may be confused with molar gestation
      • Collagenized avascular villi (villous sclerosis / fibrosis)
      • Villous edema and sclerosis / fibrosis often coexist
      • Other findings: prominent perivillous fibrin with prolonged retention or in medical abortions, otherwise pathologic
    • Spectrum of villous morphology in nonmolar abnormal karyotype (Hum Pathol 1995;26:201):
      • Dysmorphic appearance (lacks sensitivity and specificity): highly irregular villous shapes / outlines, occasional trophoblastic inclusions
    • Gestational / decidualized endometrium:
      • Not uncommon to see inflammatory cells, especially lymphocytes but not plasma cells (plasma cells are pathologic)
      • Variable amount of decidual necrosis with inflammatory debris
    • Placental implantation site:
      • Extravillous trophoblast (EVT) within decidualized endometrium, visible maternal vascular remodeling, fibrinoid material in decidua, EVT within vascular wall or within vessel lumens
      • Confirms intrauterine pregnancy even in the absence of chorionic villi
      • Be careful with interpreting rare villi or syncytiotrophoblast in the absence of implantation site as this could indicate, although rarely, villous migration from a tubal pregnancy
  • Other recognizable pathologies (intervillous / maternal space should be empty; if material is present, rule out these pathologies) (Hum Reprod 2007;22:313):
    • Chronic histiocytic intervillositis (Malays J Pathol 2020;42:439)
    • Massive perivillous fibrin deposition (look for extravillous trophoblast proliferation; otherwise, increased fibrin may be seen with embryonic demise secondary to prolonged retention in utero or secondary to medical abortions)
    • Infectious etiologies: marked chronic lymphoplasmacytic or acute inflammation within the maternal vascular space or causing villitis (septic abortions - a critical value)
  • Reference: Fetal Pediatr Pathol 2018;37:191
Microscopic (histologic) images

Contributed by Chrystalle Katte Carreon, M.D. and Drucilla J. Roberts, M.D.
Products of conception specimen

Products of conception specimen

Missed abortion exhibiting villous edema

Missed abortion exhibiting villous edema

Missed abortion exhibiting villous sclerosis

Missed abortion exhibiting villous sclerosis

Caption

POC specimen with recognizable amnion


Placental implantation site

Placental implantation site

Septic abortion

Septic abortion

Aneuploid gestation

Aneuploid gestation

Normal p57 staining pattern

Normal p57 staining pattern

Cytology description
  • Although not routinely performed, cytologic analysis may, on some occasions, aid in the identification of rare trophoblast cells, which supports the clinical impression of intrauterine pregnancy
Cytology images

Contributed by Drucilla J. Roberts, M.D.
Blood with rare syncytiotrophoblast cells

Blood with rare
syncytiotrophoblast
cells

Videos

PathCast: products of conception by Dr. Vanda Torous

Sample pathology report
  • Products of conception, D&E:
    • Fragments of necrotic immature chorionic villi
    • Decidua with patchy necrosis and placental implantation site

  • Products of conception, spontaneously passed:
    • Necrotic, empty gestational sac
    • Necrotic decidua with placental implantation site

  • Uterine contents, D&E:
    • Decidualized endometrium
    • No chorionic villi or trophoblast present; entire specimen examined (see comment)
    • Comment: Pregnancy has not been confirmed and ectopic pregnancy cannot be excluded. Clinical correlation is necessary.
Differential diagnosis
  • Hydatidiform mole (Int J Gynaecol Obstet 2021;155:86, Hum Pathol 1998;29:505, Hum Pathol 1996;27:708):
    • Complete mole:
      • Gestational trophoblastic disease characterized by diffuse hydropic enlargement of chorionic villi with associated trophoblastic hyperplasia
        • Distinguishing features
          • Uniformly enlarged chorionic villi
          • Marked and often circumferential trophoblast proliferation, both cytotrophoblastic and syncytiotrophoblastic
          • Loss of the normal nuclear p57 staining in cytotrophoblasts and villous stromal cells; therefore, p57 immunostain is often helpful in distinguishing complete mole (absence of the normal pattern of staining in chorionic villi) versus edematous villi (normal pattern of staining with nuclear staining in villous cytotrophoblasts and stromal cells
    • Partial mole:
      • Gestational trophoblastic disease characterized by an admixture of normal and enlarged chorionic villi with irregular contours and mild trophoblastic hyperplasia
        • Distinguishing features
          • Chorionic villi of different sizes
          • Mild focal to circumferential, syncytiotrophoblastic hyperplasia
          • Scalloped villous outlines
          • Trophoblast inclusions
          • Excess tissue grossly
          • Retained normal p57 staining pattern; therefore, p57 immunostain will not distinguish a partial hydatidiform mole from a nonmolar gestation
          • Flow cytometry for ploidy analysis; partial hydatidiform moles are nearly always triploid (Mod Pathol 1995;8:775, Hum Pathol 2000;31:914)
      • Aneuploid nonmolar conceptions can be challenging to distinguish from a partial mole because of overlapping histomorphology but can be differentiated from a partial hydatidiform mole by carefully searching for partial mole features as described above
Board review style question #1
Which of the following is rarely present in early product of conception specimens?

  1. Decidualized / gestational endometrium
  2. Embryonic / fetal tissue
  3. Immature chorionic villi
  4. Placental implantation site
Board review style answer #1
B. Embryonic / fetal tissue. Despite frequent identification on ultrasound, embryo or fetus are often not recognized on product of conception specimens.

Comment Here

Reference: Early first trimester pregnancy loss
Board review style question #2

Which feature favors edematous villi over molar gestation?

  1. Absence of circumeferential trophoblastic proliferation
  2. Highly irregular villous shapes
  3. Trophoblast inclusions
  4. Uniformly vesicular and enlarged villi with circumferentially hyperplastic trophoblasts
Board review style answer #2
A. Absence of circumeferential trophoblastic proliferation. Circumferential trophoblastic proliferation should raise suspicion for molar pregnancy, particularly complete mole.

Comment Here

Reference: Early first trimester pregnancy loss

Ectopic pregnancy
Definition / general
  • Implantation of the embryo outside of the uterine cavity including within the tubes (90%), abdomen and the cornua of the uterus
  • Occurs in 1/150 pregnancies
  • Tubal pregnancies are the most common cause of hematosalpinx due to rupture which is a medical emergency and diagnosed with ultrasound, serum hCG and laparoscopy
  • Bleeding is sometimes due to placental separation without rupture
Etiology
  • 50% are associated with pelvic inflammatory disease or peritubal adhesions (due to appendicitis, endometriosis, surgery and leiomyomas)
Microscopic (histologic) description
  • Though not extensively studied, reports indicate a high prevalence of placenta accreta and percreta, to which tubal rupture is attributed
  • Placentas from abdominal pregnancies have been described as highly vascular with markedly diminished / absent decidua

Embryonic remnants
Definition / general
  • Vestigial structures representing extraembryonic ductal connections (the allantoic duct and the omphalomesenteric duct) in the primitive connecting (umbilical) stalk can be commonly seen in term placentas
Terminology
  • Yolk sac is an early embryonic structure, a portion of which will eventually be incorporated into the gut of the embryo; vitelline vessels supply the yolk sac and constitute the vitelline circulation
  • Allantois is the primitive extraembryonic urinary bladder and will eventually become the urachus, which connects the fetal bladder to the yolk sac; the allantoic duct originates as an outpouching of the yolk sac
  • Omphalomesenteric (vitelline) duct connects the midgut lumen with the yolk sac in the developing fetus
  • See diagram below
Epidemiology
  • Allantoic duct remnant is present in the proximal portion of 15% of umbilical cords
  • Omphalomesenteric duct remnant is present in about 1.5% of umbilical cords, often associated with remnants of vitelline vessels, seen in about 7% of umbilical cords
Pathophysiology / etiology
  • Allantoic duct usually regresses and is completely obliterated by 15 weeks gestation
    • Its persistence in the umbilical cord is common
    • Remnant (of the allantoic duct) between the umbilicus and the fetal urinary bladder persists as the medial umbilical ligament
  • Omphalomesenteric duct usually obliterates between 9 - 16 weeks gestation following gut rotation but can alternatively persist in term placentas
Diagrams / tables

Images hosted on other servers:
Clinical features
  • For allantoic duct remnants, usually no clinical significance
    • Rare cases of patent duct remnants can show urinary leakage from a clamped umbilical stump or cysts that may persist into adulthood
  • For omphalomesenteric duct remnants, usually no clinical significance
    • Rare cases of patent duct remnants can be symptomatic if direct communication is maintained with the fetal bowel or if ectopic gastric, pancreatic or intestinal mucosa stimulates tissue responses
    • Omphalomesenteric duct remnants have also been associated with intestinal atresia, Meckel diverticulum or intestinal protrusion into the umbilical cord through the duct
Case reports
Gross description
  • Typically no gross findings are evident (unless a rare cyst is present)
  • Yolk sac remnant: flat, gold nodule between the amnion and chorion of fetal surface or membranes
Gross images

Images hosted on other servers:

Yolk sac remmant

Microscopic (histologic) description
  • Allantoic duct remnants are usually located between the umbilical arteries of the proximal portion of the umbilical cord and are rarely accompanied by smooth muscle
    • Epithelium of the duct is cuboidal to flat and generally is of transitional type although mucin producing epithelium can be found
    • Small vessels around the periphery of the duct remnant may be occasionally seen
  • Omphalomesenteric duct remnants are also more common in the proximal umbilical cord but are present at the cord periphery and often have a smooth muscle wall
    • Epithelium of the duct is cuboidal to columnar with an intestinal phenotype
    • Rarely, mucosa resembling liver, pancreas, stomach or small intestine can be seen
    • Frequently, paired or clustered vitelline vessels (without muscular walls) will be associated with duct remnants
Microscopic (histologic) images

Images hosted on other servers:
Missing Image

Allantoic duct remnant

Missing Image Missing Image

Omphalomesenteric duct remnant


Epithelioid trophoblastic tumor
Definition / general
  • Epithelioid trophoblastic tumor (ETT) is a very rare gestational trophoblastic tumor derived from neoplastic chorionic type intermediate trophoblasts
Essential features
  • Histologic features include nodular and expansile growth pattern of nests and cords of relatively uniform tumor cells with distinct cell borders, moderate eosinophilic to clear cytoplasm and associated extracellular eosinophilic, hyaline-like material
  • Presence of decidualized stromal cells in the periphery is a useful diagnostic clue
  • Diffuse immunohistochemical expression of p63 with essentially negative human placental lactogen (HPL) can help differentiate from placental site trophoblastic tumor
ICD coding
  • ICD-10:
    • C58 - malignant neoplasm of placenta
    • D39.2 - neoplasm of uncertain behavior of placenta
Epidemiology
Sites
Etiology
Clinical features
Diagnosis
  • Imaging
  • Clinical laboratory
  • Histopathologic diagnosis on biopsy or resection specimen
Laboratory
Radiology description
  • On ultrasound, it may appear as lobulated, echolucent or echogenic mass with intratumoral, scattered, branching vascularity and turbulent blood flow on color flow Doppler (Ultrasound Obstet Gynecol 2010;36:249)
  • Metastatic lesions may appear as mildly enhancing nodules on CT scan with clear boundaries and less uniform echoes (J Med Case Rep 2020;14:178)
  • MRI shows heterogeneously enhancing tumor with moderate hypointense signal on T1
Radiology images

Images hosted on other servers:

Ultrasound with Doppler

Abdominal wall mass CT

MRI of uterine masses

Prognostic factors
Case reports
Treatment
  • Surgical resection is the definitive treatment
  • Multi agent chemotherapy after surgery in metastatic disease (J Cancer 2019;10:11):
    • FAEV (5-fluorouracil, actinomycin-D, etoposide and vincristine)
    • EMA / CO (etoposide, methotrexate, actinomycin-D / cyclophosphamide and vincristine)
    • EMA / EP (etoposide, methotrexate, actinomycin-D / etoposide and cisplatin)
  • Recent benefit seen with administration of PD-1 / PDL1 immune checkpoint inhibitors (i.e., pembrolizumab) (Gynecol Oncol Rep 2021;37:100819)
Clinical images

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Hysteroscopy

Hysteroscopy

Laparoscopic surgery

Laparoscopic surgery

Gross description
  • Tumor presents as an expansile mass with white yellowish fleshy, solid appearance on cut surface and invades the underlying stroma
  • Necrosis and hemorrhage may also be present
  • Ulceration and fistula formation is common
Gross images

Images hosted on other servers:
Expansile mass with fleshy, solid appearance

Expansile mass with fleshy, solid appearance

ETT involving uterine fundus

ETT involving uterine fundus

Necrotic and hemorrhagic mass

Frozen section description
  • Nests and cords of epithelioid cells with eosinophilic to clear cytoplasm, distinct cell borders, moderate cytologic atypia and frequent mitosis; set in a hyaline matrix
  • Associated with geographic necrosis, apoptotic cells, focal calcifications and scattered decidualized stromal cells in the periphery
  • May be mistaken for squamous cell carcinoma
Frozen section images

Contributed by Rachelle Mendoza, M.D.
Nests and cords of epithelioid cells

Nests and cords of epithelioid cells

Large areas of necrosis

Large areas of necrosis

Microscopic (histologic) description
  • Tumor shows nodular, expansile growth of relatively uniform, medium sized tumor cells arranged in nests, cords or large sheets
  • Tumor cells have a moderate amount of finely granular, eosinophilic to clear cytoplasm with distinct cell membrane and round nuclei with small nucleoli
  • Moderate nuclear atypia is seen in most of the tumors
  • Well circumscribed tumor border is characteristic; however, focal infiltrative peripheral areas are not uncommon
  • Occasional syncytiotrophoblastic cells may be present; unless they represent a substantial population, they do not warrant a diagnosis of choriocarcinoma
  • Extensive or geographic necrosis is often present
  • Eosinophilic hyaline-like material is characteristically present in the center of some tumor nests, simulating keratin formation
  • The mitotic count ranges from 0 - 9 per 10 high power fields but as high as 48 per 10 high power fields has been observed
  • Focal areas of placental site nodule, placental site trophoblastic tumor and choriocarcinoma can rarely be identified within the tumor
  • Unique histologic features:
    • Scattered decidualized benign stromal cells may be present at the tumor periphery
    • Calcification is common
    • ETT tumor cells frequently colonize the mucosal surface or glandular epithelium of the cervix and endometrium and can simulate high grade squamous intraepithelial lesion or squamous epithelium
  • Reference: Am J Surg Pathol 1998;22:1393, Arch Pathol Lab Med 2019;143:65
Microscopic (histologic) images

Contributed by Rachelle Mendoza, M.D. and Sonali Lanjewar, M.D., M.B.B.S.
Nests

Nests

Epithelioid tumor cells Epithelioid tumor cells

Epithelioid tumor cells

Extensive necrosis

Extensive necrosis

Decidualized stroma in periphery

Decidualized stroma in periphery

ETT with chorionic-type intermediate trophoblasts

ETT with chorionic type intermediate trophoblasts


ETT with chorionic-type intermediate trophoblasts ETT with chorionic-type intermediate trophoblasts ETT with chorionic-type intermediate trophoblasts

ETT with chorionic type intermediate trophoblasts

p63

p63

CK5/6

CK5/6

Ki67

Ki67

Positive stains
Molecular / cytogenetics description
Molecular / cytogenetics images

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DNA genotyping analysis

Sample pathology report
  • Uterus and cervix; hysterectomy:
    • Epithelioid trophoblastic tumor (3.6 cm) involving the lower uterine segment and upper endocervix (see comment)
    • Comment: The partially necrotic tumor shows expansile growth of epithelioid tumor cells with eosinophilic to clear cytoplasm, distinct cell membranes and moderate nuclear atypia. Mitotic activity is moderately increased (up to 6 per 10 high power fields). Scattered decidualized stroma is present in the periphery. The tumor invades 1.2 cm into a 1.8 cm thick myometrium and extends 1.1 cm into a 2.3 cm thick cervix. Immunohistochemical stains show the tumor is positive for AE1 / AE3, p63, HLA-G, inhibin and cyclin E, with increased Ki67 proliferation index (20%) and negative for HPL, hCG, ER and PR. The overall findings support the above diagnosis.
Differential diagnosis
  • Cervical squamous cell carcinoma:
    • Definitive squamous intraepithelial lesion, true keratin formation, cell bridges, not associated with decidualized stromal cells at the periphery
    • hCG is not increased
    • Negative for trophoblastic differentiation markers
  • Endometrioid carcinoma:
    • Negative for trophoblastic differentiation markers, negative for p63
    • Associated with mismatch repair protein loss
    • ER and PR+
  • Placental site nodule (PSN):
    • Single to multiple, well circumscribed nodules usually < 5 mm in size
    • Mitotic activity is very low (Ki67 proliferation index < 8%)
  • Atypical placental site nodule:
    • Larger size of the nodule than PSN (> 5 to 10 mm), increased cellularity, marked nuclear atypia, moderately increased mitotic activity and Ki67 proliferation index between 8% and 10%
    • May have cyclin E expression
  • Placental site trophoblastic tumor:
    • Infiltrative pattern of growth
    • Negative for p63 with diffuse HPL expression
  • Choriocarcinoma:
    • Diffusely hemorrhagic, marked cytologic atypia, dimorphic trophoblastic population
    • Diffuse expression for hCG and very high Ki67 proliferation index (> 70%)
Board review style question #1
Epithelioid trophoblastic tumor Epithelioid trophoblastic tumor Epithelioid trophoblastic tumor


A 35 year old gravida 2 para 1 woman presents with vaginal bleeding. On ultrasound, a 2.5 cm fungating lower uterine mass / upper endocervical is identified. The findings from the biopsy specimen are shown in the images above. The immunohistochemical stains show positive expression for p63, HLA-G and inhibin and negative expression for HPL, PLAP, hCG and p16. What is the most likely diagnosis?

  1. Choriocarcinoma
  2. Epithelioid trophoblastic tumor
  3. Placental site trophoblastic tumor
  4. Squamous cell carcinoma of the cervix
Board review style answer #1
B. Epithelioid trophoblastic tumor

Comment Here

Reference: Epithelioid trophoblastic tumor
Board review style question #2
Which of the following immunohistochemical stains can help differentiate placental site trophoblastic tumor from epithelioid trophoblastic tumor?

  1. CD10
  2. hCG
  3. HSD3B1
  4. p63
Board review style answer #2

Erythroblastosis
Definition / general
  • Nucleated fetal red blood cells (nRBCs) are common in preterm placentas but are an abnormal finding in placentas at term
Etiology
  • nRBCs reflect a response to fetal hypoxia or anemia due to a variety of causes including uteroplacental insufficiency, abruption, maternal diabetes, hemolytic disease of the newborn / ABO incompatibility, chronic fetomaternal transfusion, acute blood loss or chromosomal disorders
Microscopic (histologic) description
  • Red cells that are smaller than nonnucleated red cells and have round, basophilic nuclei with smooth nuclear surfaces, surrounded by a thin rim of eosinophilic cytoplasm
  • Number of cells per 10 HPF is counted
  • Grading: mild (cells are easily found in preterm placentae and are rare / occasional at term), moderate (cells easily found at all gestations) and severe (markedly increased cells at all gestations, with at least one in each HPF)
Microscopic (histologic) images

Images hosted on other servers:

Placental hydropic change accompanied by increased fetal erythroblasts and nucleated RBCs in fetal vessels in villi


Exaggerated placental site
Definition / general
  • Exuberant infiltration of the endometrium and myometrium by implantation site intermediate trophoblast
Essential features
  • Exaggeration of normal physiologic process, with infiltration of the endometrium and superficial third of myometrium by implantation site intermediate trophoblast
  • Can be associated with normal pregnancy or abortions, molar pregnancy and sometimes presents as postpartum bleeding
  • Ki67 labeling index is near 0%
  • Ki67 labeling index can be 0 - 5 % in exaggerated placental site (EPS) of molar pregnancies (Hum Pathol 1998;29:27)
ICD coding
  • ICD-10: O43.899 - other placental disorders, unspecified trimester
Epidemiology
Sites
  • Uterus
Pathophysiology
  • Exaggeration of normal physiologic process
  • Intermediate trophoblasts (IT) invade through endometrium into the superficial third of myometrium (Int J Gynecol Pathol 2001;20:31)
  • Normal structure of endometrial glands, myometrium and vessels is usually maintained
  • Ki67 indices of near zero indicate increased number of intermediate trophoblasts in EPS is not a result of de novo proliferation of IT in the implantation site (Hum Pathol 1998;29:27)
  • Increased Ki67 in molar pregnancy may be a spillover effect IT in the trophoblastic columns of hydatiform moles (Hum Pathol 1998;29:27)
  • Although histologically the same, increased Ki67 labelling index in complete molar implantation site represents related but different lesions (Hum Pathol 1998;29:27)
Clinical features
Diagnosis
  • Histologic examination
Radiology description
Prognostic factors
  • Excellent prognosis following curettage
Case reports
Treatment
Microscopic (histologic) description
  • Extensive infiltration of endometrium and myometrium by implantation site intermediate trophoblasts which are often multinucleate (Int J Gynecol Pathol 2001;20:31)
  • Endometrial glands and spiral arterioles can show invasion by trophoblasts
  • Smooth muscle cells of myometrium are separated by cords, nests and individual trophoblastic cells
  • Despite diffuse infiltration, there is not necrosis or mitoses
  • Trophoblastic cells share similar morphologic features of normal implantation site intermediate trophoblasts; these cells contain abundant eosinophilic cytoplasm with hyperchromatic and irregular nuclei (Int J Gynecol Pathol 2001;20:31)
  • Chorionic villi are morphologically unremarkable
Microscopic (histologic) images

Contributed by Raavi Gupta, M.D., Absia Jabbar, M.D. and Sonali Lanjewar, M.D., M.B.B.S.
Intermediate trophoblasts invading myometrium Intermediate trophoblasts invading myometrium Intermediate trophoblasts invading myometrium Intermediate trophoblasts invading myometrium Intermediate trophoblasts invading myometrium Intermediate trophoblasts invading myometrium

Intermediate trophoblasts invading myometrium

Virtual slides

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Exaggertated placental site

Exaggertated placental site

Positive stains
Negative stains
Sample pathology report
  • Uterus, endometrium, dilatation and curettage:
    • Exaggerated placental site
Differential diagnosis
Board review style question #1

Exaggerated placental site (shown in the image above) is characterized by which of the following features?

  1. Absence of villi
  2. Presence of necrosis and mitoses
  3. Proliferation of chorionic type intermediate trophoblasts with invasion of myometrium
  4. Proliferation of implantation type intermediate trophoblasts with invasion of myometrium
Board review style answer #1
D. Proliferation of implantation type intermediate trophoblasts with invasion of myometrium

Comment Here

Reference: Exaggerated placental site
Board review style question #2
Ki67 labeling index in exaggerated placental site is

  1. Near 0%
  2. Near 5%
  3. Near 15%
  4. Near 100%
Board review style answer #2

Fetal thrombotic vasculopathy
Definition / general
  • Thrombosis of fetal vessels results in fibrosis of downstream villi
  • Implies an increased risk for neurologic injury, growth restriction, oligohydramnios and renal / systemic thrombosis (Hum Pathol 1999;30:759)
  • Clinical abnormalities associated with 30%+ avascular villi (Hum Pathol 1995;26:80)
Etiology
  • May be associated with maternal diabetes, hypercoagulable disorders (Hum Pathol 2000;31:1036), maternal diabetes or perinatal liver disease
Gross description
  • Large thrombi of chorionic vessels may be visible
  • Areas of involvement may appear pale and firm
Microscopic (histologic) description
  • Occlusive thrombi in large stem vessels are accompanied by downstream changes including organization, septation, red cell extravasation, endothelial destruction, loss of vascularity and ultimately fibrosis
  • Trophoblastic basement membrane mineralization is common
  • Grading is based on the number of affected villi: focal (3 - 5 avascular villi), intermediate (6 - 19 villi) or large ( > 20 villi)
  • Massive or extensive involvement is defined as 25 - 50% affected parenchyma
  • Changes are similar to those seen in intrauterine fetal demise but are focal rather than diffuse
  • Associated pathologic findings may include meconium staining, villous chorangiosis and infarction
Microscopic (histologic) images

Contributed by Hillary Rose Elwood, M.D.

Sections demonstrate intravascular fibrin thrombi of skin / subcutis, not placenta; the patient was found to have antiphospholipid antibody syndrome


Fetal trisomies
Trisomy 13
  • Often abnormal placenta (small placental volume, reduced placental vascularization, a partial molar appearance, placental mesenchymal dysplasia) and preeclampsia (Taiwan J Obstet Gynecol 2009;48:3)
  • Also retinal dysplasia: retinal pigment epithelium within optic nerve or unilateral malformed eye not associated with other anomalies (such as persistent hyperplastic primary vitreous); histology shows series of straight branching tubes composed of abortive rod and cone layers (Arch Pathol Lab Med 1977;101:540)
Laboratory
  • Trisomy 21: elevated serum hcG and inhibin, reduced serum estradiol and AFP
  • Trisomy 18: low serum hcG, low AFP, low inhibin and low estradiol
Gross description
  • Single umbilical artery is more common in trisomic pregnancies
  • Early spontaneous abortions may show no fetal parts and an absent umbilical cord (Hum Pathol 1995;26:201)
Microscopic (histologic) description
  • Large hypovascular / avascular villi with irregular borders accompanied by normal appearing villi
  • Villous hydrops is also seen though less than in other abnormal karyotypes

Fetus in fetu
Definition / general
  • To our knowledge, FIF was originally described by Meckel in the 18th century
  • Subsequently, Willis described it as rare condition in which a malformed parasitic twin was found inside the body of its partner, usually in the abdominal cavity; Willis defined FIF in 1935 as a "mass containing a vertebral axis often associated with other organs or limbs around this axis" (Willis: The Borderland of Embryology and Pathology, 1962)
  • Presence of a vertebral axis in a fetiform mass has since been considered pathognomonic of FIF
  • Although several theories as to the pathogenesis of FIF had been proposed, the "twinning" theory has become accepted, as the mass is always found enclosed within a sac resembling the amniotic sac - in fact, the lining of the sac histologically resembles the amniotic membrane
  • Of late, Spencer has proposed that one or more of the following criteria needs to be present to label any fetiform mass as FIF: (1) the mass must be enclosed within a distinct sac, (2) it should be partially or completely covered by normal skin, (3) it should have grossly recognizable anatomic parts, (4) it should be attached to its host by only few relatively large blood vessels, (5) it should either be located immediately adjacent to one of the sites of attachments of conjoined twins or be associated with neural tube or the gastrointestinal tract (Clin Anat 2001;14:428)
Radiology images

Case #385

Radiograph showing
noncalcified
vertebral column

Epidemiology
  • Fetus-in-fetu (FIF) is an extremely rare pathological condition with an estimated incidence of 1 in 500,000 births
  • Less than 200 cases have been reported worldwide
Treatment
  • Surgical excision is curative, although the presence of immature elements indicates the need for close clinical, radiological and serological (AFP) followup
Case reports
Gross description
Case #385:
  • Mass measured 18 x 10 x 6 cm and weighed 910 g
  • External surface was sac-like and smooth, with partial skin covering the upper region
  • Vertical cut section showed solid and large cystic areas containing mucoid material
  • Upper segment of the mass contained hair, pultaceous (pulpy) material, scalp and brain substance
  • Middle segment showed vertebral column, cartilage, intestine and gray-white solid areas
  • Lower segment contained a cyst with a flattened wall and limb bud-like structures attached to the external aspect
Gross images

Case #385

Various images

Microscopic (histologic) description
Case #385:
  • Upper segment showed primitive brain parenchyma, cartilage and skin with adnexa and hair
  • Middle segment contained stomach, duodenum, small intestine, vertebral column, bone and bone marrow, pancreas, soft tissue, lymph nodes and adipose tissue
  • Lower segment contained a cyst wall with flattened lining and no adnexal structures
Microscopic (histologic) images

Case #385

Various images

Differential diagnosis
Other retroperitoneal masses such as:
  • Hydronephrosis
  • Neuroblastoma
  • Teratoma: main diagnostic challenge lies in differentiating FIF from retroperitoneal teratoma, which contains pluripotent cells without organogenesis or vertebral segmentation; this distinction is important as the latter can be associated with risk of malignancy; most important feature that has been used to distinguish between FIF and teratoma is the presence of the vertebral column
  • Wilms tumor

Furcate insertion
Definition / general
  • Grossly visible branching of the umbilical vessels before their insertion onto the placental surface
Terminology
Pathophysiology
  • Protective substance, known as Wharton jelly, which covers the umbilical cord is lost at the cord's insertion end
  • Cord displays less tubular integrity and the umbilical vessels divide or branch before reaching the placental surface
  • Umbilical vessels unsupported by Wharton jelly are more subject to shearing forces potentially causing rupture or hemorrhage
Etiology
  • There are no known causative factors
Clinical features
  • Usually, no clinical significance is associated with furcate insertion
  • Very rarely, fetal hemorrhage has been described
Radiology description
  • Furcate insertion can be detected on an ultrasound scan
Prognostic factors
  • Generally very good, unless the rare situation of hemorrhage from the unprotected portions of vessel occur
Case reports
Gross description
  • Umbilical vessels are seen to divide before reaching the placental surface, usually only involving the distal most 1 - 4 cm of the cord
  • Hemorrhage surrounding the vessels may very rarely indicate vascular rupture
Gross images

Images hosted on other servers:

Gross pathology of the placenta

Microscopic (histologic) description
  • Usually no significant microscopic changes are observed

Grossing
Definition / general
  • This topic describes how to gross specimens obtained from placental deliveries
  • Essential clinical history:
    • Placenta should always be grossed with knowledge and context of the clinical history
    • To improve efficiency, institutions may create a specific requisition sheet for placentas that contains this information
    • EMR systems are able to automatically populate the requisition from the patient’s chart, limiting the burden on both the clinician / nursing staff and pathologist
    • Gestational age at delivery
    • Maternal information: gravida (G) and para (P) status
    • Maternal history: presence of pregnancy related complications (pre-eclampsia, gestational hypertension, gestational diabetes, intrauterine growth restriction [IUGR], etc.) and prepregnancy disorders (chronic hypertension, pregestational diabetes, obesity, group B streptococci [GBS] status, etc.)
    • Clinical presentation and perinatal / labor course:
      • Examples: premature rupture of membranes (PROM), vaginal bleeding, maternal fever / clinical chorioamnionitis, nonreassuring fetal heart tracing, meconium stained fluid, etc.
    • Neonatal weight
    • Neonatal Apgar scores
    • Any additional findings or specific questions that the clinical team has about the placenta
  • Placental examination in the fresh state is highly preferable to formalin fixed specimens; however, not all institutions may be able to accommodate this preference
  • Note that placentas can stay in refrigeration for a relatively long period of time (1 week or more) without significant degradation of histology
  • See the Amsterdam consensus statement paper for additional information on placental grossing and sampling (Arch Pathol Lab Med 2016;140:698)
Procedure
  • Singleton placentas:
    • Remove the placenta from the container, including any detached segments of umbilical cord or blood clots that may be included
    • Wipe off excess blood and orient yourself to the major anatomic structures: the fetal surface, maternal surface, cord and membranes
    • Umbilical cord:
      • Measure the length of the umbilical cord
        • If there are detached segments of cord, measure each segment and provide an aggregate / total measurement
        • Long cords are > 70 cm
      • Measure the average diameter of the umbilical cord
        • Note any areas of stricture or thinning
      • Inspect the cord insertion and measure the distance to the closest margin
        • Abnormal cord insertions include peripheral (< 3.0 cm), marginal (< 0.5 cm), velamentous and furcate
      • Note the presence of any amniotic webs and whether they are tight or loose
      • Note the degree of coiling
        • Hypercoiled: greater than 3 - 4 coils/10 cm
        • Hypocoiled: less than 0 - 1 coils/10 cm
      • Identify the number of vessels: 2 versus 3
        • May need to look at multiple cross sections to determine, correlate with ultrasound imaging reports, if available
      • Inspect the entire length of the cord and describe any abnormalities
        • Hematomas, cysts / masses, rupture / defects, thrombi, surface nodules or plaques (classic finding in Candida funisitis), true knots
        • Note that false knots are clinically insignificant and do not need to be described
      • Remove the cord from the placenta at the insertion site
    • Extraplacental membranes:
      • Assess completeness of membranes
      • Locate the membrane rupture site and measure distance from the closest placental edge
      • Evaluate the color and opacity of the membranes
        • Normal: translucent
        • Green stained: meconium
        • Brown stained: hemosiderin
        • Opaque: chorioamnionitis
      • Assess the membrane insertion into the placental disc
        • Marginal (normal), circummarginate, circumvallate
      • If velamentous insertion, assess the intactness of the membranous vessels and describe any areas of disruption
      • After taking membrane rolls, remove the membranes from the placenta
    • Placental disc:
      • Measure the placenta in 3 dimensions
      • Weigh the placenta (most reference tables use the trimmed weight [i.e., the weight of the placenta after removal of the cord and membranes])
      • Assess the shape of the disc
        • Discoid, bilobed, multilobate, accessory lobes
        • Measure the size of any accessory lobes (may be multiple) and note their distance from the main placental disc and whether the connecting membranous vessels are intact
      • Assess the fetal surface
        • Color, opacity, subamniotic hemorrhage
        • Presence of squamous metaplasia (small white nodules that do not rub off; clinically insignificant), amnion nodosum (small white-yellow nodules that do rub off; clinically significant, associated with oligohydramnios)
        • Note any nodules, masses or cysts
        • Examine the fetal vessels for thrombi or disruption (particularly in abnormal cord insertions)
        • Note the amount of subchorionic fibrin deposition (optional)
          • Subchorionic fibrin is normal and does not necessarily need to be described or sampled unless extensive
      • Assess the maternal surface
        • Determine if the maternal surface is complete; are all cotyledons present?
          • Disrupted but appears complete; there is disruption of the surface but no missing tissue
          • Disrupted, possibly incomplete; there is disruption of the surface with missing tissue
            • In these cases, ink the junction of the intact and disrupted maternal surface and take additional sections of the junction (Mod Pathol 2020;33:2382)
          • Fragmented: there are portions of the placenta that are entirely detached from the main disc
        • Retroplacental blood clots:
          • Central or marginal?
          • Compression of underlying villous parenchyma
          • Firm lesions in underlying villous parenchyma
        • Areas of atrophy / thinning of the placental parenchyma
        • Palpate the entire placenta for firm areas; let your fingers do the walking
        • Serially section the placenta at 5 mm intervals
        • Assess the color of the villous parenchyma
          • Normal: dark red
          • Pale: may represent areas of avascular villi
        • Examine the cut surfaces carefully for lesions
          • Color, consistency, size in 3 dimensions, location relative to the fetal and maternal surface and placental margin
          • Single versus multiple lesions
          • Percentage of villous tissue with lesions involved
  • Multiple gestation placentas:
    • Dichorionic twins:
      • Separate with no dividing membrane: gross as 2 separate singletons
      • Separate with a dividing membrane: evaluate the dividing membrane as described below, then gross as 2 separate singletons
      • Fused with a dividing membrane: evaluate the dividing membrane as described below, then pull the 2 placentas apart and gross as 2 separate singletons
    • Monochorionic twins:
      • Gross as a single placenta as described below
    • Umbilical cord:
      • Determine if the cords are oriented with regard to which corresponds to twin A versus twin B (often done with cord clamps)
      • If the cords are not oriented, assign a random orientation for placenta A versus placenta B and maintain that orientation throughout the gross description and section code
    • Extraplacental membranes:
      • Monochorionic monoamniotic: no dividing membrane
      • Monochorionic diamniotic: dividing membrane consists of 2 layers of amnion, should be thin and translucent
      • Dichorionic diamniotic: dividing membrane consists of 2 layers of amnion and 2 fused chorions
      • If a dividing membrane is present, take a membrane roll of it
    • Placental disc:
      • Monochorionic twins:
        • Evaluate the percentage of vascular territory belonging to each twin
          • Keep in mind that the dividing membrane does not necessarily correspond to the vascular division
        • Can have clinically significant vascular anastomoses, which should be documented if possible
        • Inspect the fetal surface carefully for surface anastomoses between the 2 twins
          • Arteries pass over veins
          • Can have artery to artery, artery to vein or vein to vein anastomoses
        • Perform injection studies to evaluate for deep anastomoses (Pediatr Dev Pathol 2013;16:237)
          • Various techniques have been described, including ink, milk and air
          • Inject an artery / vein on 1 placenta and trace any flow that crosses into the vascular territory of the other placenta
      • Dichorionic twins:
        • Process as 2 separate singleton placentas
Sections to obtain
  • Singleton placentas:
    • Umbilical cord (1 block with 2 cross sections): 1 from the proximal one - third of the cord and 1 from the distal one - third of the cord
      • Additional sections of any lesions as needed
    • Membrane rolls (1 block with 2 cross sections):
      • Remove a sliver of the marginal placental parenchyma at the site of membrane attachment
      • Be sure to include the area of circummarginate or circumvallate membrane attachment in your section, if present
      • Grasp the sliver of parenchyma in smooth forceps and wrap the membranes around the forceps with the amnion on the outside
      • Cut a cross section of the roll to submit for histology
      • Create 2 separate membrane rolls, each with a single cross section submitted
    • Cord insertion site (1 block)
      • 1 full thickness section of the placental parenchyma at or adjacent to (if velamentous insertion) the cord insertion site
    • Placental parenchyma (2 blocks)
      • Full thickness sections of representative random placental parenchyma, taken from the central two - thirds of the placental disc
        • Do not sample the margin of the placenta unless it is to demonstrate a lesion
    • Abnormalities / lesions
      • 1 representative section of each type of lesion should be submitted; if multiple grossly identical lesions are identified, it is only necessary to submit 1 of them for histologic examination
        • Lesions that should be submitted include: infarcts, thrombi, masses, pale areas of parenchyma
        • Lesions that do not need to be submitted include: areas of atrophy, accessory lobes, subchorionic fibrin (unless extensive)
      • If the placenta is disrupted, possibly incomplete or fragmented, submit an additional block with at least 3 perpendicular cross sections of the basal plate only (not full thickness), adjacent to the area of disruption
        • The purpose of this block is to look for myometrial fibers that may be adherent to the basal plate
  • Multiple gestation placentas:
    • Same as singleton placentas, with the addition of the dividing membrane roll, which should be submitted as its own separate block
  • References: Placenta 2003;24:116, APMIS 2018;126:544
Tips
  • While placentas should be grossed fresh, sections may be difficult to cut to the appropriate thickness to allow for adequate fixation and processing
    • Place the membrane rolls and the sections of placental parenchyma in a cup of formalin and allow to fix for 1 - 2 hours before trimming, taking and submitting the final sections
  • If the placenta is too thick to fit a full thickness section in 1 cassette, submit 2 cassettes with the fetal surface (cord insertion site and 1 random section) and 1 with the maternal surface
  • If the completeness of the maternal surface is questionable, it is helpful to take a photograph for review at a later date, if needed
  • Photographing the fetal surface in monochorionic twin placentas can be helpful for subsequent evaluation for surface anastomoses; remember to wipe the blood off the surface before photographing
Gross description
  • Acute chorioamnionitis: opaque membranes or fetal surface with slight yellow discoloration
  • Candida funisitis: tan-white to tan-yellow plaques on the surface of the umbilical cord
  • Amnion nodosum: white-yellow or yellow-green nodules on the fetal surface, measuring up to X cm
  • Chorangioma: tan-red to tan-yellow well circumscribed nodule / mass, measuring XX cm, located at the cord insertion site / X cm from the margin
  • Chronic abruption: brown stained membranes, marginal retroplacental hematoma, circumvallate membrane insertion
  • Infarct / perivillous fibrin plaque: tan-white or tan-yellow firm lesion, measuring XX cm and located X cm from the margin
  • Intervillous thrombus: dark red lamellated lesion, measuring XX cm and located X cm from the margin
  • Massive perivillous fibrin deposition / maternal floor infarction: firm areas distributed throughout the placental parenchyma / along the basal plate, involving approximately X% of the placental parenchyma
  • Meconium staining: green stained membranes, umbilical cord or fetal surface
  • Retroplacental hematoma: maternal surface with central / marginal dark red blood clot, with or without indentation of the overlying placental parenchyma
Gross images

Contributed by Sanjita Ravishankar, M.D.

Accessory lobe

Bilobed placenta

Circumvallate membrane insertion

Squamous metaplasia

Amnion nodosum


Hypercoiled cord with meconium

Velamentous umbilical cord

Disrupted maternal surface

Avascular villi

Intervillous thrombus


Subchorionic fibrin

Large infarct

Artery to artery anastomosis

Dichorionic twin

Sample gross description report
  • Received fresh, labeled with the patient’s name and hospital number, is a placenta. The placental membranes are translucent and complete. The membrane insertion is marginal. The point of membrane rupture is 4.0 cm from the nearest margin. The umbilical cord is pale yellow, 40 cm in total length and inserts in the placenta, 5.0 cm from the margin. There are up to 2 coils per 10 cm. On cut section, the cord has 3 vessels and measures 1.0 x 1.4 cm. The placenta is discoid, 17 x 15 x 2.5 cm and weighs 420 g without cord or membranes. The fetal surface is blue-red and translucent. The maternal surface is complete. The cut surface is dark red and spongy. No gross abnormalities are noted. Representative sections are submitted in 5 cassettes.
  • Summary of cassettes:
    • A1: umbilical cord sections
    • A2: membrane rolls
    • A3: placental parenchyma, umbilical cord insertion site
    • A4 - A5: placental parenchyma
Diagrams / tables

Contributed by Sanjita Ravishankar, M.D.

Placenta requisition

Basal plate sections



Images hosted on other servers:

Placental shape abnormalities

Board review style question #1

Which of the following statements is true regarding appropriate gross handling of the placental finding depicted above?

  1. Clinically insignificant and does not need to be described
  2. Does not occur more than once in the same placenta
  3. Should be sampled as part of routine sections
  4. Status of the connecting vessels and distance from the main disc are important to describe
Board review style answer #1
D. Status of the connecting vessels and distance from the main disc are important to describe

Comment Here

Reference: Placenta - Grossing

Grossing-products of conception
Definition / general
  • This topic describes how to gross specimens obtained from products of conception specimens (dilation and curettage or dilation and evacuation with or without fetal parts)
  • Essential clinical history:
    • Gestational age
    • Ultrasound abnormalities
    • Presence / absence of a fetus / fetal pole
    • Abnormalities of beta hCG rise
    • Antenatal genetic testing results (i.e., noninvasive prenatal screening [NIPS])
  • Purpose of examination:
    • Identify chorionic villi or implantation site to confirm the presence of intrauterine pregnancy
      • If intrauterine pregnancy cannot be confirmed, this is a critical value and the clinician must be informed immediately, as there is risk for ectopic pregnancy
    • Evaluate villous morphology and identify abnormalities, including gestational trophoblastic disease (i.e., molar pregnancy)
    • If embryonic / fetal parts are identified, attempt to document:
      • Sex (if possible)
      • Whether growth is appropriate for gestational age
      • Any dysmorphic features or congenital anomalies
    • Collect fresh tissue for genetic / cytogenetic testing, if needed / requested
    • If procedure is being done for retained products of conception, evaluate for retained placental tissue or subinvolution of implantation site (see Placental site subinvolution)
  • References: Redline: Placental and Gestational Pathology Hardback, 1st Edition, 2018, Baergen: Manual of Pathology of the Human Placenta, 2nd Edition, 2011
Procedure
  • Remove all tissue from the specimen container and measure in aggregate
  • Separate blood clot from the soft tissue
  • Examine the soft tissue and separate the different types of tissue
    • Decidua: superficial part of the endometrium (maternal tissue)
      • Usually a pale gray-white color and often looks like a sheet
      • 1 side will be smooth while the other is rough
    • Implantation site: decidua that contains the area where the placenta implanted
      • Even if chorionic villi are absent, the presence of implantation site indicates an intrauterine pregnancy
      • Looks similar to decidua but is more yellow and somewhat firmer
    • Chorionic villi: placental tissue
      • Usually white or pink-white in color and has long finger-like projections
    • Membranes: placental tissue
      • Looks similar to membranes in mature placentas but thinner and more translucent
    • All of the above: may find an intact chorionic sac, which includes all of the above elements; may also contain umbilical cord, embryonic or fetal tissue
  • Measure the villous tissue in aggregate
  • Examine the villous tissue to determine if there is hydropic change or vesicles (see Gross images)
    • If vesicles are present, measure range of greatest dimension
  • If an embryo (< 8 weeks gestation, < 27 mm crown rump length) or fetal parts are identified:
    • Measure as many of the standard measurements as possible (crown to rump, crown to heel, head circumference, foot length)
    • Attempt to evaluate the external genitalia
      • Both male and female fetuses have an enlarged penile / clitoral swelling but females will have a vaginal orifice underneath, while males do not
    • Perform external and internal examination to evaluate for any anomalies
      • Correlation with prior ultrasound imaging can be very helpful
    • Submit sections, as considered appropriate by your institution's general practice
  • Reference: Obstet Gynecol 1986;67:79
Sections to obtain
Tips
Gross description
Gross images

Contributed by Sanjita Ravishankar, M.D.

Chorionic villi

Decidua

Decidua and chorionic villi

Complete mole with vesicles

Complete mole

Sample gross description report
  • Products of conception without chorionic villi:
    • Received (fresh, in formalin), labeled with the patient's name and hospital number and "[ ]", are multiple fragments of (pale red soft tissue, dark red-brown friable tissue) and clotted blood, aggregating to [__ x __ x __ cm]. Chorionic villi are not grossly identified. The specimen is entirely submitted in [__] cassettes.
  • Products of conception with chorionic villi:
    • Received (fresh, in formalin), labeled with the patient's name and hospital number and "[ ]", are multiple fragments of (pale red soft tissue, dark red-brown friable tissue) and clotted blood, aggregating to [__ x __ x __ cm]. Possible villous tissue is identified, measuring [__ x __ x __ cm]. A portion of the specimen is submitted for genetic analysis. Representative sections are submitted in 3 cassettes.
    • Summary of cassettes:
      • A1: possible villous tissue
      • A2: nonvillous tissue
      • A3: additional villous and nonvillous tissue
Board review style question #1

A products of conception specimen from a 41 year old woman has the gross appearance seen in the photo above. Which of the following structures is represented in the photo?

  1. Chorionic villi
  2. Decidua
  3. Fetal / embryonic tissue
  4. Implantation site
  5. Membranes
Board review style answer #1
A. Chorionic villi

Comment Here

Reference: Grossing-products of conception

Hematoma
Definition / general
  • Extravasation of blood from an umbilical vessel that subsequently accumulates in Wharton jelly
Terminology
  • Hematoma or hemorrhage should be distinguished from umbilical cord thrombosis, which can be seen in association with a cord hematoma
Epidemiology
  • Uncommon and estimated to occur in 1 per 5,000 - 13,000 deliveries
Sites
  • Hematomas typically occur at the fetal end of the umbilical cord
Etiology
  • Typically unknown but may be due to a ruptured umbilical vein varix (cystic vascular dilatation), trauma including therapeutic procedures (amniocentesis, cordocentesis, etc.) and cord abnormalities, such as traction occurring with short umbilical cords
Clinical features
  • Blood loss or compression of fetal vessels can lead to circulatory compromise, fetal distress and fetal death
  • Fetal mortality is estimated at 40 - 50% when umbilical cord hematoma is present
Diagnosis
Radiology description
  • Ultrasound can reveal cord expansion with a heteroechoic to hyperechoic mass or discordant umbilical artery Doppler waveforms
Case reports
Treatment
  • Induction of delivery can be undertaken if fetal compromise is present
Clinical images

Images hosted on other servers:
Missing Image

Rupture of umbilical vessels

Gross images

Images hosted on other servers:
Missing Image

Hematoma of umbilical cord, placenta was delivered by cesarean section, no traction or clamping of this segment of cord

Microscopic (histologic) description
  • Nonspecific and variable hemorrhage involving Wharton jelly
  • Less commonly, evidence of vascular disruption, cystic changes or aneurysmal dilatation

Hemorrhagic endovasculitis / vasculopathy
Definition / general
  • Endothelial injury with vascular necrosis
  • Existence as a separate lesion from fetal thrombotic vasculopathy (FTV) is debated by some
  • Associated with maternal hypertension, fetal neurologic injury, growth restriction, tissue hypoxia and increased perinatal morbidity / mortality
  • Etiology is unknown
Microscopic (histologic) description
  • Vascular wall injury with extravasated red cells, endothelial / medial hyperplasia, red cell fragmentation and hemosiderin deposition
  • Changes similar to intrauterine fetal demise but are focal rather than diffuse
  • May be accompanied by chronic villitis, chorionic vascular thrombosis, erythroblastosis, villous fibrosis, infarction and evidence of meconium exposure

Hepatocellular adenoma-like lesion of placenta
Definition / general
  • Extremely rare benign nontrophoblastic lesion (about 9 cases have been reported so far)
  • May represent a liver heterotopia or specialized monodermal teratoma (Am J Surg Pathol 1998;22:355)
Essential features
Sites
  • Usually presents as a subchorionic intervillous mass or in the villous parenchyma of the placenta
Pathophysiology
  • Exact pathophysiology of ectopic liver in the placenta is unknown
  • Hypothesized that aberrant migration or displacement of cells from the developing hepatic buds leads to ectopic liver formation
  • Groups of liver cells become entrapped in the foregut as the diaphragm closes (Pediatr Dev Pathol 2017 Jan 1 [Epub ahead of print])
  • It may represent a specialized monodermal teratoma in the placenta
Clinical features
  • Usually an incidental finding
Case reports
Gross description
  • Small (0.3 - 1.0 cm), well circumscribed tan to dark red nodules in the placental parenchyma
  • May be encapsulated
  • Without necrosis or hemorrhagic foci
  • Sometimes may not be grossly visible
Microscopic (histologic) description
  • Well circumscribed mass composed of semi distinct lobules of cords and nests of polygonal epithelial cells with pink and focally clear cytoplasm resembling fetal hepatocytes (Int J Gynecol Pathol 1998;17:241)
  • No portal tracts, bile ducts or central veins are identified
  • Extramedullary hematopoiesis is a constant feature
  • Lesional cells contain glycogen
  • No nuclear atypia, cellular pleomorphism or mitotic activity
  • No globular cytoplasmic inclusions, intracytoplasmic hyaline or bile pigment
Microscopic (histologic) images

Contributed by @RaulSGonzalezMD on Twitter
pathologyoutlines.com/topic/placentahepatocellularadenoma.html #pathology #liverpath (?) #pathtwitter #pathoutpic"
Contributed by @RaulSGonzalezMD on Twitter (see original post here)"> Hepatocellular adenoma-like lesion of placentapathologyoutlines.com/topic/placentahepatocellularadenoma.html #pathology #liverpath (?) #pathtwitter #pathoutpic"
Contributed by @RaulSGonzalezMD on Twitter (see original post here)"> Hepatocellular adenoma-like lesion of placentapathologyoutlines.com/topic/placentahepatocellularadenoma.html #pathology #liverpath (?) #pathtwitter #pathoutpic"
Contributed by @RaulSGonzalezMD on Twitter (see original post here)"> Hepatocellular adenoma-like lesion of placenta

Hepatocellular adenoma-like lesion of placenta

Positive stains
Negative stains
Electron microscopy description
  • Tumor cells contain numerous glycogen granules, diffusely scattered endoplasmic reticulum and multiple mitochondria
  • Cell membranes of adjacent cells are joined by desmosomes
  • Structures resembling bile canaliculi are found (Am J Surg Pathol 1986;10:436)
Differential diagnosis
  • Metastatic or primary hepatocellular carcinoma (reticulin stain shows increased plate thickness)
  • Heterotopic adrenocortical nodule, chorangioma and placental metastasis of maternal and fetal malignancies
Board review style question #1
    Which of the following is true?

  1. Hepatocellular adenoma of the placenta is a benign and extremely rare lesion.
  2. Histologically, it presents as a well circumscribed mass composed of nests and cords of epithelial cells resembling fetal hepatocytes.
  3. It may actually represent liver heterotopia or a specialized monodermal teratoma in placenta.
  4. All of the above.
Board review style answer #1

Hydatidiform mole
Definition / general
  • Abnormal placentas with variable trophoblastic proliferation and villous hydrops
Essential features
  • Proliferative disorder of the placenta resulting in villous hydrops and trophoblastic hyperplasia with or without embryonic development
  • Subdivided into complete and partial hydatidiform mole based on morphologic, cytogenetic and clinicopathological features
  • Maternal age and history of hydatidiform mole are the most important risk factors
  • Pelvic ultrasound shows characteristic snowstorm appearance
  • Combination of genotyping and p57 immunostaining is used for diagnosis
Terminology
  • Molar pregnancy
ICD coding
  • ICD-O:
    • 9100/0 - complete hydatidiform mole
    • 9103/0 - partial hydatidiform mole
Epidemiology
Sites
  • Uterus
  • Fallopian tube (ectopic)
Pathophysiology
  • Subdivided into complete and partial hydatidiform mole based on morphologic, cytogenetic and clinicopathological features
  • Complete hydatidiform mole:
    • Monospermic, homozygous complete hydatidiform mole (80 - 90%) results from 1 sperm fertilizing an empty oocyte with reduplication of its genome, leading to a diploid paternal only genome (Surg Pathol Clin 2022;15:197)
    • Dispermic, heterozygous complete hydatidiform mole (10 - 20%) results from 2 sperms fertilizing the same empty oocyte (Surg Pathol Clin 2022;15:197)
    • Tetraploid complete hydatidiform mole (rare) contains 4 haploid paternal chromosome sets (Am J Surg Pathol 2008;32:445)
    • An exceedingly small subset of complete hydatidiform moles (0.6 - 2.6% of all hydatidiform moles) are familial biparental complete moles that result from abnormal genomic imprinting of maternal effect genes (NALP7 / NLRP7 on chromosome 19q13.4, KHDC3L on chromosome 6q1) (Surg Pathol Clin 2022;15:197)
  • Partial hydatidiform mole:
    • These are diandric monogynic triploid gestations
    • Dispermic, heterozygous partial hydatidiform mole (> 95%) results from 2 sperms fertilizing an oocyte (Surg Pathol Clin 2022;15:197)
    • Monospermic, homozygous partial hydatidiform mole (less common) results from reduplication of a sperm's genome when it fertilizes an oocyte (Am J Surg Pathol 2008;32:445)
    • Rare cases of tetraploid partial hydatidiform moles have been reported (Surg Pathol Clin 2022;15:197)
Etiology
  • Presence of excess paternal genome
Clinical features
  • Patients typically present with symptoms consistent with early pregnancy or its complications
  • Common features: vaginal bleeding, pelvic pressure / pain, enlarged uterus, hyperemesis gravidarum
  • Less common or late features: anemia, vaginal passage of hydropic vessels; in complete hydatidiform mole, complications due to high human chorionic gonadotropin (hCG) levels include hyperthyroidism, theca lutein cysts, pulmonary embolization of trophoblast and early onset of preeclampsia
  • References: Int J Gynaecol Obstet 2015;131:S123, Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019
Diagnosis
  • Pelvic ultrasound
  • Dilation and curettage / uterine evacuation
Laboratory
  • High hCG levels (complete hydatidiform mole > partial hydatidiform mole)
Radiology description
  • Pelvic ultrasound:
    • Complete hydatidiform mole (Ultrasound Obstet Gynecol 2006;27:56):
      • Absent embryo
      • Absent amniotic fluid
      • Central heterogeneous mass with numerous anechoic spaces (also called snowstorm pattern)
      • Ovarian theca lutein cysts
    • Partial hydatidiform mole (Obstet Gynecol 1989;73:414):
      • Fetus may be identified but is often growth restricted
      • Amniotic fluid is present, typically low in volume
      • Placenta shows ≥ 1 abnormal finding(s) (snowstorm appearance, increased echogenicity of chorionic villi)
      • Increased transverse diameter of the gestational sac
      • Theca lutein cysts are usually absent
Radiology images

Images hosted on other servers:
Complete hydatidiform mole with cystic areas

Complete hydatidiform mole with cystic areas

Partial hydatidiform mole

Partial hydatidiform mole

Prognostic factors
  • Increased risk of persistent gestational trophoblastic disease (0.5 - 5% in partial hydatidiform mole, 15 - 20% in complete hydatidiform mole) (Lancet 2010;376:717)
  • Risk of persistent gestational trophoblastic disease is higher with heterozygous complete hydatidiform mole than with homozygous complete hydatidiform mole (Int J Gynecol Pathol 2016;35:134)
  • Risk of gestational choriocarcinoma is < 0.5% in partial hydatidiform mole and 2 - 3% in complete hydatidiform mole
Case reports
  • 21 year old woman with history of severe preeclampsia at 28 weeks gestation with ultrasound scans showing molar changes in the placenta with a viable fetus (J Med Case Rep 2018;12:140)
  • 24 year old gravida 2 para 1 woman who presented at 28 weeks gestation with severe preeclampsia and vulvar edema and ultrasound scan showing a live intrauterine pregnancy in addition to a large hydatidiform mole (Gynecol Oncol Rep 2019;31:100519)
  • 33 year old woman with a history of sudden onset of right iliac fossa pain and mild vaginal bleeding following 8 weeks of amenorrhea and a positive pregnancy test (BMJ Case Rep 2018;2018:bcr2018225545)
Treatment
  • Surgical removal of the molar pregnancy followed by surveillance of hCG levels to confirm disease resolution or to identify the development of gestational trophoblastic neoplasia
Gross description
  • Complete hydatidiform mole:
    • Well developed complete hydatidiform mole shows large specimen with villous hydrops (bunch of grapes)
    • Swollen villi may range from a few millimeters to as large as 3.0 cm in diameter (average: ~1.5 cm)
    • Very early complete hydatidiform mole may not show gross abnormalities
    • Fetal parts are absent, regardless of gestational age
  • Partial hydatidiform mole:
    • First trimester: unremarkable
    • Second trimester: focal fetal hydrops
    • Fetus may be present with developmental anomalies
  • Reference: Surg Pathol Clin 2022;15:197
Gross images

Images hosted on other servers:
Hydatidiform mole (left) and normal placenta (right)

Hydatidiform mole (left) and normal placenta (right)

Microscopic (histologic) description
  • Complete hydatidiform mole (well developed):
    • Diffuse villous enlargement and marked villous hydrops with cistern formation
    • Circumferential trophoblastic hyperplasia
    • Cytologic atypia of intermediate trophoblasts at the implantation site
    • Smooth villous contours but surface invaginations with trophoblastic pseudoinclusions may also occur
    • Absence of fetal vessels and fetal red blood cells
  • Complete hydatidiform mole (early):
    • No significant villous enlargement or hydrops
    • Polypoid, irregular villous shape
    • Hypercellular, myxoid villous stroma with apoptosis of primitive stellate cells
    • Labyrinthine network of villous stromal canaliculi
    • Focal hyperplasia of cytotrophoblasts and syncytiotrophoblasts on both villi and the undersurface of the chorionic plate
    • Atypical trophoblasts lining the villi and at the implantation site
    • Rare primitive fetal vessels and fetal red blood cells
  • Partial hydatidiform mole:
    • 2 villous populations seen: large hydropic and small fibrotic villi
    • Villous enlargement and hydrops with cistern formation
    • Scalloped villi with surface invaginations and trophoblastic pseudoinclusions
    • Prominent syncytiotrophoblastic knuckles
    • Minimal trophoblastic hyperplasia
    • Fetal vessels with nucleated red cells are usually present
    • Cytologic atypia is not significant
  • Reference: Surg Pathol Clin 2022;15:197
Microscopic (histologic) images

Contributed by Fahad N. Sheikh, M.D.
Hydropic villi

Hydropic villi

Cistern formation

Cistern formation

Circumferential trophoblastic proliferation

Circumferential trophoblastic proliferation

Trophoblastic proliferation and atypia

Trophoblastic proliferation and atypia

Partial mole with 2 populations of villi

Partial mole with 2 populations of villi

p57 immunostain

p57 immunostain

Virtual slides

Images hosted on other servers:
Partial hydatidiform mole

Partial hydatidiform mole

Complete hydatidiform more

Complete hydatidiform more

Positive stains
Negative stains
Molecular / cytogenetics description
  • Short tandem repeat (STR) DNA genotyping
    • Complete mole shows absence of maternal genetic contribution
    • Partial mole shows diandric triploidy
Sample pathology report
  • Uterine contents, removal:
    • Complete hydatidiform mole (see comment)
    • Comment: Immunohistochemical stain for p57 is negative in cytotrophoblasts and villous stromal cells. DNA ploidy shows a diploid content. The results support the diagnosis above.
Differential diagnosis
  • Nonmolar hydropic abortus:
    • Enlarged edematous villi with rare cistern formation
    • Polar trophoblastic proliferation is an important clue
    • No cytologic atypia
    • p57 positive in cytotrophoblasts and villous stromal cells
    • Molecular tests: biparental diploidy
  • Placental mesenchymal dysplasia:
  • Chromosomal trisomy syndromes:
    • Can display a range of morphologic features, which include dysmorphic villi, trophoblastic pseudoinclusions or cistern formation
    • Genetic testing is required to determine the abnormality
  • Choriocarcinoma:
    • Sheets of highly atypical biphasic population of trophoblastic cells with hemorrhage and necrosis
    • Invasion of surrounding tissue and vasculature
    • Typically, absence of villi is the rule, except in cases of choriocarcinomas arising in the setting of complete mole or in case of intraplacental choriocarcinoma
Board review style question #1
Which of the following is true regarding hydatidiform moles?

  1. Both partial and complete moles are most commonly monospermic and homozygous
  2. Heterozygous complete mole has a higher risk of postmolar gestational trophoblastic disease / neoplasia than homozygous complete mole
  3. Immunohistochemical staining for p57 is negative in partial and complete hydatidiform moles
  4. The typical genetic profile of a partial mole is digynic triploidy
Board review style answer #1
B. Heterozygous complete mole has a higher risk of postmolar gestational trophoblastic disease / neoplasia than homozygous complete mole. Immunostaining for p57 is positive in partial and negative in complete hydatidiform mole (C). Although complete moles are most commonly monospermic and homozygous, partial moles are more frequently dispermic and heterozygous (A) with diandric monogynic triploidy (D).

Comment Here

Reference: Hydatidiform mole
Board review style question #2

The image above shows products of conception in a 34 year old patient. Which of the following is true regarding this entity?

  1. Amniotic fluid is absent
  2. Can be associated with ovarian theca lutein cysts
  3. Can result from abnormal genomic imprinting of maternal KHDC3L gene
  4. Risk of choriocarcinoma is < 0.5%
Board review style answer #2
D. Risk of choriocarcinoma is < 0.5%. The image shows features of partial hydatidiform mole. Partial moles have a much lower risk of choriocarcinoma (< 0.5%) than complete moles (2 - 3%). Amniotic fluid is typically present in partial moles (A). Ovarian theca lutein cysts (B) and genomic imprinting of maternal KHDC3L gene (C) are commonly associated with complete moles, not partial moles.

Comment Here

Reference: Hydatidiform mole

Hydrops fetalis
Definition / general
  • Massive generalized fetal edema due to a variety of processes
Etiology
  • Immune related: hemolytic disease of the newborn, previously the most common cause of hydrops fetalis
  • Nonimmune related: chromosomal abnormalities, infection, congenital cardiac / other anomalies, anemia, metabolic disorders and fetal tumors
Gross description
  • Edematous placenta
Microscopic (histologic) description
  • Villous stromal edema with erythroblastosis (increased fetal nucleated red cells) and possibly intravillous hematopoiesis
  • No trophoblastic hyperplasia or cisterns (Hum Pathol 1985;16:785)
Microscopic (histologic) images

Images hosted on other servers:

Placental hydrops


Increased perivillous fibrin
Definition / general
  • Small amounts of fibrin are commonly scattered throughout the normal placenta
  • Diffusely increased amounts of perivillous fibrin involving stem and terminal villi and large enough to be grossly visible are a significant pathologic finding
  • Increased fibrin may impair gas exchange and lead to growth restriction, oligohydramnious, premature birth (Arch Pathol Lab Med 1994;118:698), neurologic impairment or fetal death
Gross description
  • Strands of pale, firm parenchyma
Microscopic (histologic) description
  • Abundant perivillous fibrin that obliterates the intervillous space with loss of the syncytiotrophoblast
  • Requires at least one area of full thickness involvement / entrapment of at least half of the villi on a single slide

Infarct
Definition / general
  • Placental parenchymal lesion comprised of villi that have undergone ischemic necrosis due to focally reduced placental (maternal) blood flow
Essential features
  • Ischemic necrosis of groups of villi due to maternal vascular malperfusion (focally reduced placental [maternal] blood flow)
  • Associated with preeclampsia / eclampsia and other gestational hypertensive disorders
  • Increasing number / total percentage of parenchymal involvement and central (versus peripheral / marginal) location are adverse prognostic indicators
  • Severe maternal vascular malperfusion is associated with a 10 - 25% recurrence risk
Terminology
  • Maternal vascular malperfusion, maternal vascular underperfusion, (utero)placental insufficiency, placental ischemia, placental hypoxia
ICD coding
  • ICD-10:
    • O43.811 - placental infarction, first trimester
    • O43.812 - placental infarction, second trimester
    • O43.813 - placental infarction, third trimester
    • O43.819 - placental infarction, unspecified trimester
Epidemiology
  • Pregnant women, often whose pregnancies are complicated by gestational hypertension / preeclampsia, intrauterine growth restriction, indicated or spontaneous preterm birth (APMIS 2018;126:551)
Sites
Pathophysiology
  • Aberrations of the normal uterine vasculature remodeling process lead to reduced vascular capacity or vascular occlusion, which in turn reduces placental (maternal) blood flow (APMIS 2018;126:551)
Etiology
  • Focally reduced placental (maternal) blood flow
Clinical features
Diagnosis
Prognostic factors
  • Severe maternal vascular malperfusion is associated with a 10 - 25% recurrence risk (Prenat Diagn 2016;36:953, APMIS 2018;126:551)
  • Increasing number / total percentage of parenchymal involvement and central (versus peripheral / marginal) location are adverse prognostic indicators (APMIS 2018;126:551)
    • Any infarct in a preterm placenta is considered significant
    • Infarct(s) involving > 5% of the nonmarginal parenchyma in a term placenta is considered significant
  • Small infarct(s) at term and especially when marginal may be of a different and nonconcerning etiology (normal wear and tear, relative hypoperfusion at the margin, etc.) (Arch Pathol Lab Med 2016;140:698)
Treatment
  • Specific therapies are not available; however, management / prevention includes optimization of maternal health (e.g. cardiovascular [blood pressure], glucose and weight management and exclusion of thrombophilias)
  • Aspirin (Am J Obstet Gynecol 2020 Aug 21 [Epub ahead of print])
  • Uterine artery Doppler or early third trimester placental evaluation by ultrasound
  • Early delivery in subsequent pregnancies
Gross description
  • Well delineated, polygonal parenchymal lesion, firmer than the surrounding parenchyma and variable in color, from red to tan-yellow
  • Color changes with age (recent = red; remote = tan-yellow)
  • Shape may be triangular and involve the maternal surface or rounded and intraparenchymal
  • Rounded and intraparenchymal infarcts often show central hemorrhage (infarction hematomas) and may represent intraplacental abruption
  • Reference: APMIS 2018;126:551
Gross images

Contributed by Athena Chen, M.D., Drucilla Roberts, M.D., Sarah Ferguson, PA (ASCP) and Justin Susterich, PA (ASCP)

Large, fairly acute infarct

Subacute infarct with hemorrhage

Remote infarct

Marginal infarct

Microscopic (histologic) description
  • Groups of villi (at least 5 but typically far more) showing ischemic necrosis (pyknosis followed by karyorrhexis and loss of nuclear staining of the villous trophoblast and then villous stromal cells) and collapse of the intervillous space
  • Well circumscribed / clearly demarcated from the surrounding parenchyma
  • Most are triangular and involve the maternal floor but infarction hematomas are rounded (spherical)
    • Infarction hematoma is diagnosed when the parenchyma contains a rounded focus of hemorrhage surrounded by infarcted villi (villi showing ischemic necrosis, at least 5 layers thick)
  • Reference: APMIS 2018;126:551
Microscopic (histologic) images

Contributed by Athena Chen, M.D.

Remote infarct

Subacute infarct

Villous necrosis

Early villous necrosis

Sample pathology report
  • For cases with multiple (2+) findings of maternal vascular malperfusion, the use of the below template is suggested (APMIS 2018;126:551):
  • Singleton placenta, (__ g, appropriate / small / large for gestational age of __ weeks), [delivery]:
    • Findings consistent with maternal vascular malperfusion:
      • Gross features:
        • Placental hypoplasia
        • Thin umbilical cord
      • Villous changes:
        • Villous infarct(s), acute / subacute / remote, __ cm in greatest dimension, occupying __% of the parenchyma
        • Retroplacental hematoma, acute / subacute / remote, __ cm in greatest dimension, occupying __% of the maternal surface
        • Accelerated villous maturation
        • Distal villous hypoplasia
      • Vascular lesions:
        • Decidual arteriopathy, hypertrophic type
        • Decidual arteriopathy, severe, with fibrinoid necrosis and acute atherosis
    • Other findings: __
Differential diagnosis
  • Focally increased perivillous fibrin deposition:
    • Grossly tan-yellow to tan-orange and may be of an appreciably different texture than an infarct
    • Microscopically composed of pink, acellular fibrinoid material in the intervillous space
  • Infarcted chorangioma:
    • Grossly rounded / roughly spherical lesion
    • Microscopically a stem villous vascular lesion composed of capillaries, stroma and trophoblast
  • Intervillous thrombus:
    • Grossly red to tan-yellow polygonal lesion in the intervillous space; may show lines of Zahn
    • Microscopically composed of blood or fibrin in the intervillous space, which mostly pushes aside the villous parenchyma (does not or only minimally affects the surrounding villi)
    • Scattered, rare infarcted / necrotic villi may be seen within the thrombus but if clustered or more than rare, consider the diagnosis of hemorrhage into a pre-existing infarct (hemorrhagic infarct)
Board review style question #1

It is generally accepted that any infarct in a preterm placenta is significant. In a term placenta, involvement of more than what percentage of the nonmarginal parenchyma is considered significant?

  1. 1%
  2. 5%
  3. 25%
  4. 50%
Board review style answer #1
B. 5%

Comment Here

Reference: Infarct
Board review style question #2

A placental infarct is an example (evidence) of what kind of lesion?

  1. Delayed villous maturation
  2. Fetal vascular malperfusion
  3. Maternal vascular malperfusion
  4. Villitis of unknown etiology
Board review style answer #2
C. Maternal vascular malperfusion

Comment Here

Reference: Infarct

Intrauterine fetal demise
Definition / general
  • Intrauterine fetal demise is the phrase used for fetal death in utero after the twentieth completed week of pregnancy; prior to that, miscarriage or spontaneous abortion is usually applied to circumstances of spontaneous fetal loss
Essential features
  • As pregnancy progresses, the causes of intrauterine fetal demise are increasingly likely to be extrinsic to the fetus
  • With fetal death, the placental fetal vascular tree begins to involute globally and in a temporally homogeneous manner
  • Fetal death due to fetal vascular malperfusion may be difficult to distinguish from passive postmortem fetal vascular involution, as both involve loss of placental fetal vascular integrity
  • Scant maternal inflammation within the extraplacental membranes may be due to nonviable antigen exposure rather than antemortem amniotic fluid infection
  • Stillbirth changes in umbilical and chorionic vasculature may mimic fetal vasculitis
Terminology
  • Before 20 completed gestation weeks: miscarriage, spontaneous abortion
  • After 20 completed gestation weeks: fetal death, intrauterine fetal demise (IUFD), stillbirth
ICD coding
  • ICD-10:
    • Z37 - outcome of delivery
      • Z37.1 - single stillbirth
      • Z37.3 - twins, one liveborn and one stillborn
      • Z37.4 - twins, both stillborn
      • Z37.6 - other multiple births, some liveborn
      • Z37.7 - other multiple births, all stillborn
    • O36 - maternal care for other fetal problems
      • O36.4 - maternal care for intrauterine death
      • O36.9 - maternal care for fetal problem, unspecified
Epidemiology
  • Intrauterine fetal demise can occur during maternal reproductive years or with assisted reproduction beyond menses
  • Stillbirth rates are highest in countries with limited health care resources
  • Stillbirth risk increases with advanced maternal age, high body mass index, low socioeconomic status, chronic illness, ingested toxins (smoking, alcohol, illicit substances), multifetal gestations
Sites
  • Normal: intrauterine
  • Abnormal: tubal, abdominopelvic
Pathophysiology
  • Intrauterine demise occurs when fetal cardiac output ceases, regardless of the inciting cause
Etiology
  • Sites of origin
    • Maternal: systemic disorders - hypertensive, diabetes, auto and other immune mediated, endocrine, hypercoagulability, malignancy
    • Uterine: abnormal uterine anatomy, previable delivery
    • Placental (not secondary to another primary underlying disorder): fetal vascular malperfusion (e.g., abnormal cord insertion, hypercoiling), fetal maternal hemorrhage, neoplasia (massive chorangioma, placental choriocarcinoma), multifetal complications, amniotic band umbilical cord constriction
    • Fetal: cardiac anomalies, multifetal gestation, mass lesions, neoplasia, genetic
    • Infectious: ascending, hematogenous, direct inoculation (e.g., amniocentesis)
    • Environmental / toxic: mechanical trauma, toxic exposure / ingestion (e.g., illicit drugs)
Clinical features
  • Silent stillbirth: maternal decreased fetal movement
  • Clinically apparent: uterine rigidity with or without vaginal bleeding due to placental abruption, fever, foul vaginal discharge
Diagnosis
  • Maternal: absent fetal heart tones on external fetal monitor, absent Doppler waveforms, absent cardiac activity of ultrasound, previable delivery
  • Fetal: previable delivery, Apgar scores 0 / 0 / 0 at delivery
Laboratory
  • Fetal maternal hemorrhage: positive Kleihauer-Betke
  • Pre and eclampsia: severe maternal hypertension, proteinuria, elevated liver enzymes, seizures, edema, headache, visual disturbances
  • Infection: positive cultures (bacterial, fungal), positive serology (viral, parasitic, autoimmune)
Radiology description
  • Diagnosis: absent cardiac activity on ultrasound
  • Ancillary information: evidence of causative process (e.g., placental abruption)
Prognostic factors
  • Recurrence risk is highest for unmodifiable or unmodified maternal diseases, heritable genetic causes, repeated toxic exposure
Treatment
  • Maternal
    • Treatment of potential sequelae associated with stillbirth (e.g., infection, trauma)
    • For potential future reproduction, treat underlying disorder as applicable (e.g., diabetes, hypertension, cervical incompetence)
  • Fetal
    • Not applicable
Clinical images

Contributed by Theonia K. Boyd, M.D.
Postmortem umbilical cord discoloration

Postmortem umbilical cord discoloration

Gross description
  • Nonspecific postmortem placental changes
    • Umbilical cord: ruddy brown discoloration
    • Extraplacental membranes: variable opacity, tan-brown discoloration
    • Fetal surface: variable opacity, tan-brown discoloration
    • Maternal surface: variably adherent blood clot without parenchymal compression
    • Cut surface: no specific changes
  • Selected specific changes
    • Umbilical cord
      • Ectatic dilated venous thrombosis
      • Green / tan meconium discoloration
      • Abnormal cord insertion, flat umbilical cord with nuchal / body wrapping
    • Extraplacental membranes
      • Green / tan meconium discoloration
      • Tan-white chorioamnionitis discoloration
    • Fetal surface
      • Green / tan meconium discoloration
      • Tan-white chorioamnionitis discoloration, chorionic vessel hypovolemia with fetal exsanguination
      • Ectatic thromboses chorionic vessels with fetal vascular malperfusion
    • Maternal surface
      • Tightly adherent retroplacental blood with abruption with or without underlying parenchymal compression and with or without infarction
    • Cut surface
      • Pallor with placental hydrops or fetal exsanguination
      • Rounded firm placental infarcts, variably red (recent) to white-tan (remote)
Gross images

Contributed by Theonia K. Boyd, M.D.
Umbilical cord and fetal surface discoloration

Umbilical cord and fetal surface discoloration

Formalin fixed stillbirth cord

Formalin fixed stillbirth cord

Microscopic (histologic) description
  • Nonspecific postmortem placental changes
    • Umbilical cord: umbilical myocyte elongation and pyknosis
    • Extraplacental membranes: bland maternal neutrophil migration with or without karyorrhexis
    • Fetal surface: chorionic myocyte elongation and pyknosis
    • Maternal surface: necrotizing decidual acute / chronic inflammation, variable retroplacental blood without overlying placental infarction
    • Cut surface
      • Fetal
        • Passive and global postmortem fetal vascular involution (progressively avascular villi and chorionic / stem vessel obliteration)
        • Note: muscular vessels (e.g., umbilical, chorionic, stem) with fibrin thrombi are never postmortem
        • Nucleated red blood cells with or without karyorrhexis
        • With or without meconium macrophages in extraplacental membranes, chorionic plate, umbilical cord stroma
      • Maternal: ischemic parenchymal changes with prolonged demise (increased syncytial knots, intervillous fibrin, parenchymal collapse)
  • Selected specific changes
    • Umbilical cord
      • Vasculitis with or without perivasculitis with intrauterine infection or meconium discharge
      • Meconium vascular necrosis with prolonged meconium exposure
      • Nucleated fetal red blood cells with infection, hypoxia, diabetes
      • Rarely umbilical thrombosis
    • Extraplacental membranes
      • Acute chorioamnionitis with intrauterine infection (with or without necrosis)
      • Meconium macrophages with or without particulate entrapped meconium
      • Decidual arteriopathy with hypertensive and autoimmune disorders
    • Fetal surface
      • Chorionic thrombosis with fetal vascular malperfusion
      • Massive subchorionic hematoma, chorionic vasculitis with or without perivasculitis with intrauterine infection
      • Chorionic meconium vascular necrosis
    • Maternal surface
      • Abruption with adherent retroplacental blood with or without overlying infarction, with or without basal intervillous extension and with or without intravillous hemorrhage
      • Decidual arteriopathy
    • Cut surface
      • Fetal vascular malperfusion
        • Clustered villous stromal vascular karyorrhesis or avascular villi
        • Stem vessel thrombosis orobliteration)
      • Maternal vascular malperfusion
        • Increased syncytial knots with or without aggregated terminal villi
        • Distal villous hypoplasia
        • Multifocal and temporally heterogenous infarction
      • Immune mediated
        • Massive perivillous fibrin
        • Noninfectious or infectious chronic villitis
        • Fetal hypovolemia and villous edema with anemia and exsanguination
      • Viral cytopathic effect, parasitic or spirochetal infection
      • Intervillous microabscesses with Listeria
      • Fetal intravascular bacteria with sepsis (rare)
  • Additional microscopic considerations
    • Without autopsy: compare microscopic placental changes to estimated time of intrauterine demise as determined clinically
    • With autopsy: compare microscopic placental changes by postmortem gross (skin maceration) and microscopic (visceral autolysis) changes to assist indiscriminating ante versus postmortem pathology
Microscopic (histologic) images

Contributed by Theonia K. Boyd, M.D.
Ischemic umbilical myocyte elongation

Ischemic umbilical myocyte elongation

Ischemic umbilical myocyte pyknosis

Ischemic umbilical myocyte pyknosis

Postmortem chorioamnionitis

Postmortem chorioamnionitis

Nucleated fetal red blood cells

Nucleated fetal red blood cells


Intravascular karyorrhexis

Intravascular karyorrhexis

Stem vessel obliteration Stem vessel obliteration

Stem vessel obliteration

Avascular villi

Avascular villi

Positive stains
  • Infectious organisms: bacterial, protozoal, viral special stains / immunohistochemistry (e.g., Toxoplasma)
  • Immune mediated disorder cell type immunohistochemistry if necessary (e.g., chronic histiocytic intervillositis)
Molecular / cytogenetics description
  • Parental, fetal and placental genetic disorders: whole chromosomes, translocations, single gene mutations, isodisomy
Sample pathology report
  • Placenta, stillbirth delivery at __/7 weeks gestation:
    • __ gram [small / heavy] placenta (__ grams expected; __percentile [if < tenth or > ninetieth percentile]; fetal / placental weight ratio __/1 (expected __/1) 
    • Intrauterine demise attributable to __ (list all clinical, gross and microscopic supporting evidence individually)
    • Additional findings (list additional information) (see comment)
    • Comment: Intrauterine demise in this case is attributable to ___. (Paragraph regarding relevant etiology, statistics, recurrence risk). This placenta accompanies fetal postmortem examination ___.
Differential diagnosis
  • Fetal vascular malperfusion (FVM) versus passive postmortem fetal vascular involution:
    • Features of FVM are geographically and temporally heterogeneous
    • Features of FVM precede fetal demise, if the time of fetal demise is discernible
    • Fetal muscular vessels with recent / organizing / organized / remote thrombosis containing fibrin are always antemortem
    • FVM is often accompanied by a known predisposing condition (e.g., umbilical hypercoiling, nuchal or body wrapped cord)
  • Maternal vascular malperfusion (MVM) versus postmortem altered maternal perfusion:
    • Features of MVM chronologically antedate the time of fetal demise if the latter is discernible
    • Tendency for multiple coexistent pathologies: infarcts, abruption, accelerated villous maturation, increased syncytial knots, increased perivillous fibrin
    • Decidual arteriopathy is antemortem only
    • MVM features usually seen in the latter half of pregnancy
    • Accompanied by placental and fetal growth restriction
  • Noninfectious chronic villitis (VUE) versus infectious villitis (lymphoplasmacytic inflammation with or without viral cytopathic effect [CMV / HSV]) / cytoplasmic tachyzoites (Toxoplasma):
    • VUE will be comprised solely of maternal lymphocytes and histiocytes
    • Maternal lymphocytes and histiocytes may be also present trafficking the intervillous space
    • Often accompanied by lymphoplasmacytic basal deciduitis
    • No viral cytopathic effect in villous stroma
    • No tachyzoites in villous stromal cells, amnion epithelium or Wharton jelly
    • No villous stromal hemosiderin on H&E
  • Amniotic fluid infection (AFI)
  • Maternal inflammation versus postmortem maternal membrane inflammatory response to nonviable antigen(s) exposure:
    • Maternal inflammatory response (MIR) with AFI can be of advanced grade and stage
    • Coexisting fetal inflammatory response (FIR) may be present
    • Coexisting acute subchorionitis (neutrophils beneath the chorionic plate) favors AFI
  • Fetal inflammation versus umbilical vascular ischemic myocyte pyknosis:
    • Fetal inflammatory response (FIR) will demonstrate nonpyknotic neutrophil nuclei with pale pink cytoplasm
    • FIR may extend to perivascular stroma in Wharton jelly or chorionic plate stroma
Board review style question #1

This is a placenta from a fetal demise at 28 weeks' gestation. What does the gross image above show?

  1. Abnormal umbilical cord insertion
  2. Amnion nodosum
  3. Heavy placenta
  4. Placental abruption
  5. Umbilical hypocoiling
Board review style answer #1
A. Abnormal umbilical cord insertion

Comment Here

Reference: Intrauterine fetal demise
Board review style question #2

This is a microscopic image from a placenta at 28 weeks' gestation. What is depicted in the image above?

  1. Acute subchorionitis
  2. Chorionic vasculitis
  3. Perivillous fibrin
  4. Postmortem fetal vascular involution
  5. Recent chorionic thrombosis
Board review style answer #2
E. Recent chorionic thrombosis

Comment Here

Reference: Intrauterine fetal demise
Board review style question #3

This is a microscopic image from a placenta at 28 weeks' gestation. What is depicted in the image above?

  1. Avascular villi due to fetal vascular malperfusion
  2. Avascular villi due to postmortem vascular involution
  3. Chronic villitis
  4. Massive perivillous fibrin
  5. Placental abruption
Board review style answer #3
A. Avascular villi due to fetal vascular malperfusion

Comment Here

Reference: Intrauterine fetal demise

Invasive hydatidiform mole
Definition / general
  • Invasive hydatidiform mole is a hydatidiform mole that has invaded the myometrium / uterine vessels or is present in extrauterine sites (metastatic hydatidiform mole)
Essential features
  • Most common form of persistent gestational trophoblastic disease after persistent hydatidiform mole
  • Defined as molar gestation invading the uterine wall, vessels or extrauterine sites
  • Extrauterine sites include vaginal / pelvic wall, lungs, vulva
  • Most commonly results from complete hydatidiform mole, presenting with persistently elevated human chorionic gonadotropin (hCG) after primary molar evacuation
  • Rarely diagnosed on imaging prior to evacuation
  • Chemotherapy is highly effective with a cure rate of > 80% (Int J Gynecol Pathol 2016;35:134)
Terminology
  • Invasive mole
ICD coding
  • ICD-O: 9100/1 - invasive hydatidiform mole
Epidemiology
Sites
Pathophysiology
  • Unknown at this time
Etiology
Clinical features
  • Vaginal bleeding with persistent serum human chorionic gonadotropin (hCG) after evacuation of a hydatidiform mole is the characteristic presentation (Rev Bras Ginecol Obstet 2015;37:42)
Diagnosis
  • Pelvic imaging but can rarely be diagnosed before evacuation
  • Uterine evacuation / resection
Laboratory
  • Persistently high hCG levels after evacuation of a hydatidiform mole
Radiology description
  • It is difficult to differentiate an invasive mole from other forms of gestational trophoblastic disease on imaging
  • Pelvic ultrasound
    • Echogenic vascular mass invading the myometrium
    • High velocity and low impedance flow on color Doppler interrogation
  • Pelvic magnetic resonance imaging (MRI)
    • Often appears as a poorly defined mass that deeply invades the myometrium
    • Complete or partial disruption of the junctional zone may also be seen
  • Reference: Radiopaedia: Invasive Mole [Accessed 12 May 2023]
Radiology images

Images hosted on other servers:
Ill defined lesion with solid and cystic areas

Ill defined lesion with solid and cystic areas

Case reports
  • 31 year old woman presented with abdominal pain and scanty vaginal bleeding 53 days postabortion (Front Surg 2022;8:798640)
  • 36 year old primigravida woman presented with vaginal bleeding and hCG elevation after removal of a complete hydatidiform mole (Am J Case Rep 2021;22:e931156)
  • 41 year old woman who had been pregnant 3 times, had 2 deliveries after 24 weeks gestation and had 1 abortion (G3P2Ab1) presented 2 months after curettage of molar pregnancy with vaginal bleeding and acute abdomen (J Reprod Infertil 2017;18:205)
Treatment
Gross description
Gross images

Images hosted on other servers:
Hydatidiform mole invading the cervix

Hydatidiform mole invading the cervix

Microscopic (histologic) description
  • Presence of molar villi with associated trophoblasts in the myometrium, uterine vessels or extrauterine sites is a diagnostic feature
  • Typically, the morphologic characteristics of complete (most common) or partial mole are seen in the invasive component; villi are usually less hydropic but can also show prominent hydropic changes with increased trophoblast hyperplasia
  • Metastatic hydatidiform moles are most commonly complete hydatidiform moles in extrauterine locations
  • Reference: Kurman: Blaustein Pathology of the Female Genital Tract, 7th Edition, 2019
Microscopic (histologic) images

Contributed by Sonali Lanjewar, M.D., M.B.B.S.
Villi invading myometrium Villi invading myometrium

Villi invading myometrium

Trophoblastic proliferation

Trophoblastic proliferation

Virtual slides

Images hosted on other servers:
Invasive hydatidiform mole

Invasive hydatidiform mole

Positive stains
  • Intact nuclear p57 expression in the villous cytotrophoblast and villous stromal cells in invasive hydatidiform moles associated with partial moles
Negative stains
  • Loss of nuclear p57 expression in the villous cytotrophoblast and villous stromal cells in invasive complete hydatidiform mole
Sample pathology report
  • Uterus, hysterectomy:
    • Invasive hydatidiform mole (see comment)
    • Comment: Chorionic villi are seen invading the myometrium.
Differential diagnosis
  • Choriocarcinoma:
    • Also presents with high hCG
    • Has more striking cytologic atypia and proliferation in addition to a biphasic pattern of atypical syncytiotrophoblasts and cytotrophoblasts
    • Lacks villi (except in the rare instance of gestational choriocarcinoma)
  • Placenta accreta:
    • Normal placenta with villous implants invading into the myometrium without an intervening decidual layer
    • Villi do not show hydropic changes and lack trophoblastic hyperplasia and atypia
    • Seen in term placenta whereas molar pregnancies are characteristically seen in first trimester
Board review style question #1

What is the most common site for metastatic invasive hydatidiform mole?

  1. Lungs
  2. Pelvis / vaginal wall
  3. Peritoneal cavity
  4. Vulva
Board review style answer #1
B. Pelvis / vaginal wall. The pelvis / vaginal wall is the most common site for metastatic hydatidiform moles. Answers D and A are incorrect because vulva and lungs are the next most common sites. Answer C is incorrect because metastatic invasive hydatidiform moles are not usually seen in the peritoneal cavity.

Comment Here

Reference: Invasive hydatidiform mole
Board review style question #2
Which of the following is true about invasive hydatidiform mole?

  1. Grossly presents as a mass-like lesion
  2. It is a rare type of persistent gestational trophoblastic disease
  3. Presents as a persistent elevation of hCG after primary evacuation of a hydatidiform mole
  4. They can usually be diagnosed by imaging prior to removal
Board review style answer #2
C. Presents as a persistent elevation of hCG after primary evacuation of a hydatidiform mole. In invasive / metastatic hydatidiform moles, hCG levels are persistently high despite the evacuation of the primary molar pregnancy. Answer A is incorrect because invasive hydatidiform moles present as an erosive, hemorrhagic lesion on gross examination. Answer B is incorrect because invasive hydatidiform moles are second only to primary hydatidiform moles in incidence. Answer D is incorrect because in most cases, imaging is not helpful in its diagnosis.

Comment Here

Reference: Invasive hydatidiform mole

Knots
Definition / general
  • Looping or interweaving of the umbilical cord that occurs during intrauterine growth of a fetus
Terminology
  • True knot is present when the umbilical cord loops upon itself and can be physically released / untied
  • Pseudoknot (false knot) is merely a varicosity or redundancy of an umbilical vessel (usually the vein) within the cord substance and cannot be physically released in an intact cord
Epidemiology
  • True knots occur in 1 per 2000 deliveries (0.5% of pregnancies)
  • Pseudoknots are very common and can be seen in a majority of pregnancies (especially small pseudoknots)
Pathophysiology
  • True knots probably develop early in pregnancy when intrauterine space is available for excessive fetal movement
  • As the fetus enlarges, a true knot may tighten or tightening may occur at delivery when the umbilical cord undergoes traction
  • Constriction or hematoma development may lead to fetal hypoxia, neurologic impairment or fetal demise
Etiology
  • True knots are associated with conditions that allow for increased fetal movement including multigravidae, long cord length, male fetuses, monoamnionic twins and increased amnionic fluid
Clinical features
  • Clinically significant circulatory compromise may often be associated with edema, congestion, constriction, hemorrhage or thrombosis
  • True knots (especially those that are tight) are associated with an overall mortality rate of 10%
  • Pseudoknots are currently viewed as having no clinical significance
Radiology description
  • Ultrasound examination can identify true knots and Doppler blood flow indices can be used to assess for cord constriction
Prognostic factors
  • Constriction of the umbilical cord at the knot, curling of the unknotted portion of cord and thrombosis in the cord are negative prognostic features
Case reports
Clinical images

Images hosted on other servers:
Missing Image

True knot in umbilical cord

Gross description
  • True knots demonstrate single or multiple / complex loops
  • Tightness of the knot, constriction or grooving of the umbilical cord, loss of Wharton jelly, cord congestion or hemorrhage and the diameter of the cord both proximal and distal to knot should all be noted
  • Mural thrombosis or complete obstruction of the umbilical vein or placental surface veins can be seen
  • With chronicity, the unknotted portion of cord may tend to curl
  • Pseudoknots show variable tortuosity of the cord and range from very small to several centimeters
Gross images

AFIP images
Missing Image

True knot with placental infarction



Images hosted on other servers:
Missing Image Missing Image

True knot

Missing Image

False knot

Microscopic (histologic) description
  • Changes are typically minimal unless evidence of significant hemorrhage or thrombosis is present
  • Veins may be thickened or contain mural "cushions," which are myxoid appearing, often fusiform shaped regions of intramural fibrin

Long cord
Definition / general
  • Umbilical cord length is variable and those considered as "long cords" are most commonly defined as an umbilical cord exceeding 80 cm in length
Terminology
  • Long cords have alternatively been defined as umbilical cords longer than 70 cm and 100 cm, in some reports
  • Normal cord length is typically 55 - 65 cm
Epidemiology
  • Umbilical cords 80 cm or greater occur in 3 - 7% of live births, while those 100 cm or greater occur in roughly 0.5% of live births
Pathophysiology
  • Fetal movement and cord traction are implicated in long cord development and fetuses with long cords show relative intrauterine hyperkinetic activity
  • Umbilical cords undergo most growth in length by 28 weeks and progressively slow thereafter
  • Genetics may influence cord length as long cords have been documented in subsequent pregnancies
Clinical features
  • Fetal factors include male sex and increased birth weight, with increased complications including cord entanglements, nuchal cords, nonreassuring fetal status during labor and fetal distress
  • Maternal factors implicate multiparity and also include delivery complications, such as umbilical cord prolapse (an obstetric emergency)
  • Associated placental findings include excess knotting (true knots), excessive cord coiling, cord constriction and thrombosis
Diagnosis
  • Cord length is most ideally assessed in the fresh placental specimen due to shrinkage associated with formalin fixation
  • Obstetrician can determine the most accurate cord length, as the pathologist typically does not receive the entire umbilical cord with the submitted placental specimen
Radiology description
  • Long cords can be detected during the prenatal period and be monitored by ultrasonography for adverse clinical sequelae
Case reports
Clinical images

Images hosted on other servers:
Missing Image

Wrapped around fetus

Gross description
  • Long umbilical cords can show edema, hemorrhage or thrombosis of umbilical or chorionic vessels
Gross images

Images hosted on other servers:
Missing Image Missing Image

Various images

Microscopic (histologic) description
  • Limited microscopic findings, unless an associated condition (as described above) is present

Marginal insertion
Definition / general
  • Generally refers to an umbilical cord insertion site located at or near the disc margin
Terminology
  • When directly at the disc margin (on the height or thickness dimensional aspect), the insertion is described as marginal or "battledore" (resembling a badminton racket)
  • When near the disc margin (on the width dimensional aspect), the insertion is described as peripheral or eccentric
Epidemiology
  • Marginal insertions occur in approximately 8% of singleton gestations
  • Occur in 20 - 30% of twin pregnancies, with higher incidences in monochorionic twins
Etiology
  • Developing placental disc demonstrates migrational tropism towards the uterine vascular supply
  • When the uterine vascular supply is asymmetric, the disc will migrate in relation to the relatively stationary umbilical cord, resulting in a cord insertion site that is no longer centrally located
  • Competition among twins for the uterine vascular supply can also result in asymmetric placental development and a marginally or peripherally located umbilical cord
Clinical features
  • Fetal growth restriction and the presence of a single umbilical artery (two vessel umbilical cord) are slightly increased with marginal insertions
  • Major chorionic vessels (that would normally insert on the disc more centrally) can instead transverse the adjacent membranes, are termed aberrant membrane vessels and are at risk for rupture
  • Marginal vessels are more likely to undergo twisting, occlusion or thrombosis
  • Discordant growth or fetal growth restriction may be seen with affected twin pregnancies
Case reports
Gross description
  • Umbilical cord insertion will occur at or near the disc margin
  • Aberrant membrane vessels may be present and may show evidence of rupture, hemorrhage or thrombosis
Gross images

Images hosted on other servers:
Missing Image

Marginal "battledore" insertion

Missing Image

Marginal insertion

Missing Image Missing Image Missing Image

Various images

Microscopic (histologic) description
  • Hemosiderin laden macrophages may be seen in the membranes or adjacent to vessels that have undergone rupture or thrombosis

Massive perivillous fibrin deposition
Definition / general
  • Massive deposition of intervillous fibrin that entrap the villi of the basal plate, extending to a thickness of at least 3 mm
  • May be accompanied by massive perivillous fibrin deposition
  • Associated with recurrent abortions / stillbirth, fetal growth restriction or neurologic impairment
  • Seen in 0.09 - 0.5% of placentas
Etiology
  • May be due to ischemic / infectious damage to deciduas basalis, including low maternal blood volume
  • Associated with acute chorioamnionitis (Hum Pathol 1985;16:823)
Gross description
  • Diffusely thick, stiff and pale basal plate
Microscopic (histologic) description
  • Thick ( > 0.3 cm) bands of fibrin with intermingled trophoblast cells involve the entire basal plate and may extend up into the intervillous space

Massive perivillous fibrin deposition / maternal floor infarction
Definition / general
  • Massive perivillous fibrin deposition (MPFD) involves extensive and smothering deposition of fibrin / fibrinoid material around chorionic villi within the placental parenchyma (maternal space), including at least 25% of intraparenchymal or basal villi
  • This entity results in the inability for maternal blood flow to reach the chorionic villi and thus, inhibition of oxygen exchange between maternal and fetal vascular spaces
Essential features
  • MPFD and maternal floor infarction (MFI) are related disorders caused by abundant fibrin deposition around chorionic villi, which results in obstructed perfusion; these diagnoses carry recurrence risk and should be reported as a critical value after diagnosis is confirmed
  • At least 25% of the placenta parenchyma (either intraparenchymal or involving basal villi) must be involved on at least one slide to make the diagnosis; gross evaluation of the placenta should be performed to aid in an accurate estimate of percent involvement
  • Leading theories for etiology: maternal thrombophilia, maternal allograft rejection, imbalanced antiangiogenic and proangiogenic factors and enteroviruses (coxsackievirus A) infection
  • Associated neonatal outcomes: neurocompromise, renal tubular dysplasia, cystic renal disease, long chain 3-hydroxyacyl-CoA dehydrogenase mutations, poor ossification of bones and death / stillbirth
  • Associated pregnancy complications: recurrent pregnancy loss, severe early onset fetal growth restriction, oligohydramnios and elevated maternal serum alpha fetoprotein (AFP)
Terminology
  • Maternal floor infarction (MFI)
  • Diffuse perivillous fibrin deposition
  • Diffuse perivillous fibrinoid deposition
ICD coding
  • ICD-10
    • O43.819 - placental infarction, unspecified trimester
    • O43.899 - other placental disorders, unspecified trimester
    • O43.89 - placental dysfunction
Epidemiology
Sites
  • Placenta: parenchyma or maternal floor (basal plate)
  • Products of conception (immature villi, e.g., from spontaneous abortions)
Pathophysiology
  • Pathophysiology is not well understood (see Etiology below)
Etiology
  • Though there is no clear, definitive etiology, 3 main hypotheses have been proposed (Roberts: Atlas of Placental Pathology, 2021):
    • Maternal thrombophilia
    • Maternal allograft rejection / immunologic (prevalence is increased with maternal autoimmune disorders as well)
    • Imbalance of proangiogenic and antiangiogenic factors
  • Additionally, MPFD has been seen in association with some placental infections (e.g., coxsackievirus A and SARS-CoV-2) (Pediatr Dev Pathol 2021;24:10)
  • A recent study associates excessively hypercoiled umbilical cords (at least 1 coil/cm) with MPFD / MFI (Pediatr Dev Pathol 2020;23:107)
Diagrams / tables
Not applicable
Clinical features
Diagnosis
  • Diagnostic criteria include the percentage of placental parenchyma involved and are determined by gross examination combined with histology
  • At least 25% parenchymal involvement is a borderline lesion
  • > 50% parenchymal involvement is a full case of MPFD
Laboratory
  • Early onset MPFD is associated with elevated maternal serum AFP, lover levels of placental growth factor (PlGF) and increased levels of soluble endoglin (sENG) and soluble vascular endothelial growth factor receptor (sVEGFR)
Radiology description
  • There are rare descriptions of the radiologic features of MPFD though the gross findings suggest that the imaging would be striking; there is a need for additional studies to be certain of this diagnosis via radiology alone
  • One report noted the placenta appearing dense by ultrasonography (J Obstet Gynaecol Can 2017;39:676)
  • One report described doppler ultrasound findings as cystic hypoechoic areas surrounded by echogenic tissue with very low blood flow in the setting of an enlarged placenta (Ultrasound Obstet Gynecol 2022;60:28)
Radiology images

Images hosted on other servers:
Ultrasound shows a thick and inhomogeneous placenta

Thick and inhomogeneous placenta

Prognostic factors
  • This is a serious diagnosis as it is associated with significant perinatal morbidity and mortality; the earlier the onset of the pathology, the worse the outcome and it seems clear that increased placental involvement is associated with increased morbidity and mortality
  • Fetal death can occur at any gestational age and neonatal deaths occur at high rates
  • In one study, the perinatal mortality rate was 40% (Eur J Obstet Gynecol Reprod Biol 2024;292:125)
  • Unfortunately, there are no favorable prognostic factors
Case reports
Treatment
Clinical images
  • Not relevant to this diagnosis
Gross description
  • Gross examination is critical in these cases to confirm the percentage of parenchyma involved
  • If one is hesitant to make the diagnosis based on histology alone, a look at the gross is enlightening and can be confirmatory
  • These placentas are typically strikingly firm with waxy, thick, tan-yellow to white bands of fibrin along the maternal floor and in the parenchyma
  • Often associated with chorionic cysts and cord anomalies: hypercoiled (> 4 coils per 10 cm) or single umbilical artery (Pediatr Dev Pathol 2021;24:10, Pediatr Dev Pathol 2020;23:107)
Gross images

Contributed by Bradley Quade, M.D., Ph.D.
Term placenta with MPFD

Term placenta with MPFD

Frozen section description
  • Not relevant to this diagnosis
Frozen section images
  • Not relevant to this diagnosis
Microscopic (histologic) description
  • Primary feature in diagnosing MPFD or MFI is choking of the chorionic villi by intervillous fibrin or fibrinoid deposition, resulting in obstruction of maternal blood flow for oxygen exchange with fetal vascular spaces
  • Fibrinous material is usually bright pink, homogeneous and acellular
  • There are 3 main categories of deposition (Roberts: Atlas of Placental Pathology, 2021)
    • Classic: fibrin encasing basal villi across the entire maternal floor with at least 3 mm thickness in at least 1 slide
    • Borderline: fibrin encasing 25 - 50% of chorionic villi in a transmural pattern of involvement in at least 1 slide
    • Transmural: fibrin encasing > 50% of chorionic villi in a transmural pattern of involvement in at least 1 slide
  • MPFD / MFI is often associated with inflammatory pathology, such as chronic villitis; however, this should be a small component of the involved region
Microscopic (histologic) images

Contributed by Lauren J. Ray, M.D.
Maternal floor infarction

Maternal floor infarction

Massive perivillous fibrin deposition Massive perivillous fibrin deposition Massive perivillous fibrin deposition

Massive perivillous fibrin deposition

Massive perivillous fibrin deposition Massive perivillous fibrin deposition

Massive perivillous fibrin deposition

Virtual slides
No information provided
Cytology description
  • Not relevant to this diagnosis
Cytology images
  • Not relevant to this diagnosis
Immunofluorescence description
  • Not relevant to this diagnosis
Immunofluorescence images
  • Not relevant to this diagnosis
Positive stains
  • Not relevant to this diagnosis
Negative stains
  • Not relevant to this diagnosis
Electron microscopy description
  • Not relevant to this diagnosis
Electron microscopy images
  • Not relevant to this diagnosis
Molecular / cytogenetics description
  • Not relevant to this diagnosis
Molecular / cytogenetics images
  • Not relevant to this diagnosis
Videos
No information provided
Sample pathology report
  • Placenta:
    • Massive perivillous fibrin deposition (MPFD) (see comment)
    • Comment: This is a rare but distinctive pathology of the placenta in which at least 25% of the parenchyma or the maternal floor villi or parenchyma are encased in dense fibrin / fibrinoid. The etiology is currently not clear but the pathology has been associated with certain infections (e.g., coxsackievirus A and SARS-CoV2), maternal thrombophilia and maternal autoimmune diseases. There is a definite recurrence risk in future pregnancies. Perinatal morbidity includes fetal growth restriction and death. It can occur at any stage of pregnancy. The pediatrician should be informed of this diagnosis. The patient may benefit from a maternal fetal medicine specialist consultation before any future pregnancies.
Differential diagnosis
Board review style question #1

Evaluation of a placenta demonstrates sections with the pathology shown above. Which of the following organ systems may be affected in this infant?

  1. Hematolymphoid
  2. Hepatobiliary
  3. Pulmonary
  4. Renal
  5. Vascular
Board review style answer #1
D. Renal is correct because associated neonatal outcomes of massive perivillous fibrin deposition can include neurocompromise, renal tubular dysplasia, cystic renal disease, long chain 3-hydroxyacyl-CoA dehydrogenase mutations, poor ossification of bones and death / stillbirth. Answers A, B, C and E are incorrect because these systems have not been associated with massive perivillous fibrin deposition / maternal floor infarction neonatal outcomes.

Comment Here

Reference: Massive perivillous fibrin deposition / maternal floor infarction
Board review style question #2
Gross evaluation of a placenta shows waxy, tan-white deposition, involving 60% of the parenchyma. Which of the following diagnoses is most appropriate?

  1. Massive perivillous fibrin deposition, borderline type
  2. Massive perivillous fibrin deposition, classic type
  3. Massive perivillous fibrin deposition, transmural type
  4. Maternal floor infarction
Board review style answer #2
C. Massive perivillous fibrin deposition, transmural type is correct because > 50% of the parenchyma is involved. Answers B and D are incorrect because these are the same entity and this is limited to the maternal floor (basal plate). Answer A is incorrect because this involves 25 - 50% of the parenchyma.

Comment Here

Reference: Massive perivillous fibrin deposition / maternal floor infarction

Maternal vascular malperfusion
Definition / general
Essential features
  • Conditions in which the functional capacity of the placenta is impaired due to altered maternal blood flow to the intervillous space
  • 2 patterns: global (small placenta with villous malformation: accelerated villous maturation or distal villous hypoplasia) and segmental (villous infarcts from occluded spiral arteries)
  • Gross features: infarction, infarction hematoma
  • Microscopic features: accelerated villous maturation, distal villous hypoplasia, syncytiotrophoblastic knots, decidual arteriopathy or acute atherosis
Terminology
ICD coding
  • ICD-10: O36.5190 - maternal care for known or suspected placental insufficiency, unspecified trimester, not applicable or unspecified
Epidemiology
Sites
  • Placenta
Pathophysiology
  • Global maternal vascular malperfusion:
    • Begins early in pregnancy with a high recurrence in subsequent pregnancy
    • Due to abnormal implantation with inadequate spiral artery remodeling, leading to erratic and heterogeneous blood flow (areas of underperfusion and areas of high velocity flow)
    • Severity determines the spectrum of disease from growth restriction to preeclampsia (see also: preeclampsia)
  • Segmental maternal vascular malperfusion:
    • Represents acute / intermittent events, associated with thrombophilia or abruption
  • Reference: Placenta 2009;30:473
Etiology
Clinical features
Diagnosis
Laboratory
Radiology description
Prognostic factors
  • Risk of recurrence for severe global maternal malperfusion: 10 - 25%
Case reports
Treatment
  • Close surveillance in subsequent pregnancy due to risk of recurrence (10 - 25%)
  • Consider acetylsalicylic acid (ASA) therapy and early third trimester placental ultrasound
  • Early delivery for growth restriction or poor uterine artery flow (J Obstet Gynaecol Can 2012;34:17)
  • Consider screening mother for diabetes, thrombophilia, metabolic syndrome
Gross description
  • Placenta that is small for gestational age (< tenth percentile of weight)
  • Infarction or infarction hematoma, located away from periphery of the disc and of significant size (any infarction in preterm or > 5% of the disc at term)
  • Thin umbilical cord (< 8 mm diameter near term), correlating with small disc
  • Reference: Placenta 2014;35:696
Gross images

Contributed by Jonathan L. Hecht, M.D., Ph.D.
Infarction Infarction

Infarction

Infarction hematoma Infarction hematoma

Infarction hematoma


Intraplacental hematoma

Intraplacental hematoma

Regression over old abruption Regression over old abruption

Regression over old abruption

Microscopic (histologic) description
  • Altered villous morphology (accelerated villous maturation):
    • Villi are small, thin and elongated with increased syncytial knots
    • Accelerated maturation should only be diagnosed based on examination of the villi adjacent to the maternal surface
    • Appearance of accelerated maturation is identical to the normal appearance of the placental region under the fetal surface; this subchorionic zone serves as a good internal control
  • Altered villous architecture (distal villous hypoplasia):
    • More easily recognized before 32 weeks of gestation as a paucity of villi in relation to the surrounding stem villi (increased space around the villi)
    • At lower power, this results in a prominence of large stem vessels all the way to the maternal surface
    • In second trimester, there is a loss of the normal gradient of larger immature villi to small mature villi as one scans from mid placenta to maternal surface
  • Syncytiotrophoblastic knots (aka Tenney-Parker change):
    • Increase in nuclear clumping and basophilia of the multinucleated cells on the terminal villi
    • Knots should generally only be reported if they are present in every 40x field (30% of the villi) or when prominent in a gestation under 36 weeks
    • Reference tables for syncytial knots are available (Pediatr Dev Pathol 2010;13:305)
  • Decidual arteriopathy
  • Acute atherosis: collection of intimal foam cells; best seen in the arteries in placental bed biopsies but may extend into the decidual arteries
  • Features often cited but not reproducible: islands of fibrin with extravillous trophoblasts; extensive increase in intervillous fibrin, chorion laeve pseudocyst; decidual necrosis
  • Reference: Placenta 2014;35:696
Microscopic (histologic) images

Contributed by Jonathan L. Hecht, M.D., Ph.D.
Decidual arteriopathy

Decidual arteriopathy

Infarction hematoma

Infarction hematoma

Infarction Infarction Infarction Infarction

Infarction


Trophoblast (fibrinoid) islands

Trophoblast (fibrinoid) islands

Distal villous hypoplasia Distal villous hypoplasia

Distal villous hypoplasia

Syncytial knots

Syncytial knots

Accelerated maturation

Accelerated maturation

Positive stains
  • sFLT1 expression increased in hypoxic villi (those with accelerated maturation and syncytial knots)
Videos

General approach to diagnostic reporting

Clinical relationship to neonatal encephalopathy

Sample pathology report
  • Singleton placenta at _ weeks gestational age; _ g (_ percentile):
    • Small placenta with features of maternal vascular malperfusion
    • Infarction, infarction-hematoma comprising _% of the disc
    • Thin umbilical cord
    • Accelerated villous maturation
    • Distal villous hypoplasia
    • Increased syncytiotrophoblastic knots
    • Membranes with decidual arteriopathy
Differential diagnosis
  • Incidental infarction:
    • Any infarction at the disc edge or infarction comprising < 5% of the disc at term
  • Features mimicking accelerated maturation:
    • Small, widely spaced, elongated villi with increased syncytial knots (normally seen under the fetal plate and in a patchy distribution near the maternal surface in the region of venous drainage)
Board review style question #1

A 34 year old woman who is pregnant with her third child and has 2 kids (G3P2002), with a history of gestational hypertension and diabetes, presents for delivery. Her placenta is sent for pathology. Gross examination reveals a placenta that is small for gestational age, with a 2.1 cm infarction within the central placenta (15% of placenta disc). What feature would be most expected on histopathologic examination?

  1. Chronic intervillositis
  2. Decreased syncytial knots
  3. Increased syncytial knots (Tenney-Parker changes)
  4. Maternal floor infarction
  5. Normal placenta
Board review style answer #1
C. Increased syncytial knots (Tenney-Parker changes)

Comment Here

Reference: Maternal vascular malperfusion
Board review style question #2
Accelerated maturation is a feature of maternal vascular malperfusion. What histologic feature is associated with it?

  1. Decidual arteriopathy
  2. Decreased syncytial knots
  3. High placental weight
  4. Villlous sclerosis
Board review style answer #2
A. Decidual arteriopathy

Comment Here

Reference: Maternal vascular malperfusion

Meconium staining
Definition / general
  • Meconium is the bile stained intestinal contents of the fetus that is normally expelled after birth
  • Intrauterine passage of meconium leads to characteristic macroscopic and microscopic changes in the placenta
  • Meconium passage is significantly associated with parameters of fetal distress
Essential features
  • More commonly seen in postterm pregnancies
  • Green, slimy membranes on gross examination
  • Characteristic microscopic findings include meconium laden macrophages, amnion edema and degenerative amniotic epithelium
ICD coding
  • ICD-10: P96.83 - meconium staining
  • ICD-11: KD38 - meconium staining
Epidemiology
  • Meconium stained amniotic fluid is present in 5 - 20% of deliveries
  • Frequency increases with increasing gestational age, reaching 31% in postterm pregnancies (Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019)
  • Meconium staining prior to 30 weeks gestation is exceptionally rare
  • Meconium staining occurs in many uncomplicated pregnancies; however, other predisposing factors may include maternal hypertension, obstetric cholestasis, multiple pregnancies, obstructed labor, etc. (Turk Patoloji Derg 2019;35:107)
Sites
  • Placenta: amnion, chorion, decidua and umbilical cord (longstanding exposure)
Pathophysiology
  • Meconium passage in newborn infants is a physiologic event that normally occurs within the first 24 - 48 hours after birth
    • Meconium may be discharged shortly before delivery
      • Also considered a normal physiologic event related to gastrointestinal maturation
      • In this case, meconium may coat the membranes, fetal surface or cord but does not stain them
  • Mechanism of intrauterine meconium passage is debated
    • Associated with increased motilin levels (Lancet 1979;2:968)
    • Controversy on its association with fetal distress
      • In utero hypoxia causes increased intestinal peristalsis and relaxed anal sphincter tone, resulting in meconium passage (Pediatr Clin North Am 1993;40:955)
      • Compression of the fetal head or umbilical cord (for example, in oligohydramnios) may cause a vagal response and meconium passage
  • Minimum of 4 - 6 hours is required between the passage of meconium into the amniotic fluid and the staining of the placenta or fetus (Am J Obstet Gynecol 1975;121:45)
Etiology
  • See Pathophysiology
  • Risk factors associated with meconium staining include
    • Obstetric factors
      • Prolonged labor, postterm pregnancy, low birth weight babies, oligohydramnios, intrauterine growth retardation and hypertensive disorders of pregnancy
    • Medical factors
      • Cholestasis of pregnancy and anemia
    • Sociodemographic and behavioral risk factors
Clinical features
  • Neonatal morbidity of all kinds has been significantly associated with meconium stained as compared to clear amniotic fluid (Kraus: Placental Pathology (Atlas of Nontumor Pathology), 1st Edition, 2005)
    • Associated with fetal acidemia, fetal hypoxia, clinical chorioamnionitis, low APGAR scores, higher rates of abnormal fetal heart tracings, etc. (Am J Obstet Gynecol 2023;228:S1158)
  • Meconium aspiration syndrome
    • Seen in 2 - 5% of deliveries with meconium stained amniotic fluid
    • Defined as respiratory distress that cannot be otherwise explained in term neonates with meconium stained amniotic fluid (Am J Obstet Gynecol 2023;228:S1158)
    • Pathogenesis
      1. Meconium may cause airway obstruction → atelectasis
      2. Chemical effect of meconium may result in surfactant inactivation
      3. Local inflammatory response (pneumonitis) to meconium can lead to decreased pulmonary function
  • Meconium associated umbilical cord vascular necrosis (Pediatr Dev Pathol 2016;19:315)
    • May be seen in cases of prolonged meconium exposure
    • Associated with vasocontraction and fetal hypoperfusion
    • May lead to adverse clinical outcomes and neurological impairments including cerebral palsy (Am J Obstet Gynecol 2005;192:452)
Diagnosis
  • Gross and microscopic examination of the placenta
Prognostic factors
  • Most cases have normal outcomes
  • Unfavorable prognostic factors
    • Longstanding exposure to meconium
    • Preterm birth (< 37 weeks)
    • Thick meconium stained amniotic fluid (Acta Obstet Gynecol Scand 2023;102:1092)
    • Other placental pathologies present (e.g., chorioamnionitis, fetal vascular malperfusion, extensive chronic villitis, etc.)
Case reports
Treatment
  • Intrapartum suctioning for infants with meconium stained amniotic fluid is no longer recommended
  • Resuscitation for infants with meconium stained fluid should follow the same principles as for those with clear fluid (Obstet Gynecol 2017;129:e33)
Gross description
  • Fetal membranes are green, glistening, slimy (due to the edema) and slippery
  • Dull and muddy brown, partially or completely stained throughout in chronic cases
Gross images

Contributed by Lucy Ma, M.D. and Joanna Chan, M.D.
Fetal chorionic plate

Fetal chorionic plate

Yellow-green staining

Yellow-green staining

Dull green staining

Dull green staining



Images hosted on other servers:
Green-black meconium

Green-black meconium

Microscopic (histologic) description
  • Meconium laden macrophages
    • Phagocytic cells with fine, brown-yellow colored cytoplasmic granules, often vacuolated
    • May be present in amnion, chorion, decidua and umbilical cord stroma (in chronic cases)
    • Meconium pigment intensity on H&E stained slides significantly diminishes following exposure to fluorescent lights (Arch Pathol Lab Med 2003;127:711)
  • Edema of the soft tissue plane between the amnion and chorion
  • Degenerative changes of amniotic epithelium
    • Vacuolization of cytoplasm
    • Heaping up of cells
    • Loss of cells and necrosis
  • Associated mild chorioamnionitis and umbilical phlebitis
    • Neutrophils in the amnion may be present as meconium promotes bacterial growth
    • Neutrophils in the wall of the umbilical vein
  • Meconium associated umbilical vascular necrosis
    • Prolonged exposure to meconium
    • Associated with meconium laden macrophages
    • Necrosis of individual fibers of umbilical vascular smooth muscle
      • Rounding of myocytes
      • Marked eosinophilic cytoplasm
      • Pyknosis or loss of nuclei
Microscopic (histologic) images

Contributed by Lucy Ma, M.D.
Amnion edema Amnion edema

Amnion edema

Degenerative changes of amnion epithelium Degenerative changes of amnion epithelium

Degenerative changes of amnion epithelium


Meconium laden macrophage Meconium laden macrophage Meconium laden macrophage

Meconium laden macrophages

Positive stains
  • Luna-Ishak (stains bile)
  • Zinc coproporphyrin I (ZnCP-I) immunohistochemistry (Placenta 2012;33:24)
Negative stains
Sample pathology report
  • Placenta, 40 weeks gestational age, vaginal delivery:
    • Third trimester placenta, 550 g (50 - 75th percentile for gestational age)
    • Fetal membranes with meconium laden macrophages
    • 3 vessel umbilical cord with no significant pathologic change
Differential diagnosis
  • Hemosiderin:
    • Red blood cell breakdown product
    • Seen in conditions associated with bleeding: circumvallate placentas, abruptio placentae, placental infarctions, erythroblastosis fetalis, thromboses, etc.
    • Brownish, rather than greenish tint
    • Larger, more refractile, yellow brownish granules
    • Prussian blue stain positive
    • Not associated with amnion edema or degenerative changes
  • Hematoidin:
    • Red blood cell breakdown product biochemically similar to unconjugated bilirubin
    • Golden brown crystalline pigment
    • Does not stain with Prussian blue (iron free pigment)
  • Lipofuscin:
Board review style question #1
A neonate and placenta are delivered vaginally at 40 weeks 4 days gestation. APGAR scores are 9/9. The placenta shows diffuse green staining of the membranes but is otherwise unremarkable. Microscopic examination of the fetal membranes would show which of the following changes?

  1. Cysts that contain secretions and are lined by extravillous trophoblasts within the chorion
  2. Diffuse infiltration of neutrophils in the amnion and chorion, including presence of microabscesses
  3. Macrophages demonstrating yellow-brown granular pigment, which stains positive on Prussian blue
  4. Vacuolization of the amniotic epithelium, heaping up of amniotic cells and edema of the amnion
Board review style answer #1
D. Vacuolization of the amniotic epithelium, heaping up of amniotic cells and edema of the amnion. Green staining of the fetal membranes generally refers to meconium staining and the amnion epithelial changes listed are characteristic degenerative changes associated with meconium staining. Answer B is incorrect because it depicts severe acute chorioamnionitis. Answer C is incorrect because the yellow-brown granular pigments that stain positive for Prussian blue are indicative of hemosiderin pigment rather than meconium. Answer A is incorrect because it describes a pseudocyst (or chorionic cyst).

Comment Here

Reference: Meconium staining
Board review style question #2

A 33 year old gravida 3 para 2 woman delivers a neonate at 39 weeks 6 days gestation. The pregnancy and delivery were uncomplicated. Gross examination of the placenta reveals a discoid placenta with a trimmed disc weight in the 75th percentile for gestational age, green stained slimy membranes and a left twisted umbilical cord with eccentric insertion. Microscopic findings of the fetal membranes are seen in the image above. Which of the following statements is true regarding this case?

  1. Antibiotic therapy is the standard of care
  2. It is predominantly associated with preterm births
  3. Most cases with this finding have normal neonatal outcomes
  4. There is a high likelihood of meconium aspiration syndrome
Board review style answer #2
C. Most cases with this finding have normal neonatal outcomes. The gross description supports the meconium staining of fetal membranes shown in the image. There does not appear to be any other lesion noted in the placenta and most cases with meconium staining have normal outcomes. Answer B is incorrect because meconium staining is more common in postterm, rather than preterm, births. Answer A is incorrect because antibiotic therapy may be the management for chorioamnionitis or other infectious lesions. Answer D is incorrect because only ~2 - 5% of cases with meconium staining are associated with meconium aspiration syndrome.

Comment Here

Reference: Meconium staining

Mesenchymal dysplasia
Definition / general
  • Rare disorder characterized by an enlarged, abnormal placenta due to overgrowth and vascular abnormalities
  • May be associated with fetal overgrowth syndromes, omphalocele or mosaicism
Case reports
Gross description
  • Bulky placenta with a "bed of yarn" appearance to the maternal surface
  • Large, dilated vessels on the chorionic plate that may be thrombosed or have aneurysms
  • Resembles a partial mole
Gross images

Contributed by Govindaswamy Koteeswaran, M.D.

Various images

Microscopic (histologic) description
  • Dilated thick walled chorionic plate vessels with fibromuscular hyperplasia
  • Stem villi are enlarged and hypervascular with hydropic stroma and central cisterns that may be lined by lymphatic endothelium (Placenta 2009;30:654) and are filled with gelatinous material
  • No trophoblastic hyperplasia is present
  • Intermediate villi show chorangiomatosis-like changes with abnormal vascular branching / dilatation
  • Terminal villi may be normal or immature
Microscopic (histologic) images

Contributed by Govindaswamy Koteeswaran, M.D.

Various images


Metastases
Definition / general
  • Metastatic involvement of placenta by maternal or fetal tumors
  • Placental metastases during pregnancy affect about 0.1% of pregnant women and most of them are of maternal origin, rarely of fetal origin (Cancer 1970;25:380)
  • Infrequent occurrence of this condition suggests that biological protective mechanisms may exist for the placento - fetal unit disrupted only by malignancies with particular invasive properties like melanoma (Singapore Med J 2008;49:e71)
  • Women presenting with maternal neoplasms metastatic to the placenta usually have widespread disease and poor prognosis (Fetal Pediatr Pathol 2017;36:465)
Essential features
  • Most common metastatic maternal tumors are melanoma (30%) (J Clin Oncol 2003;21:2179), breast carcinoma (14%), leukemia and lymphoma (15%), small cell carcinoma of lung (N Engl J Med 2002;346:1501) and gastric carcinoma (Oncol Lett 2014;8:2509)
  • Metastatic fetal tumors are very rare and include neuroblastoma (Int J Clin Exp Pathol 2014;7:8198), adenoid cystic carcinoma of trachea (Hum Pathol 1989;20:193), hepatoblastoma, melanoma and rhabdoid tumor
  • Fetal and maternal circulation is separated by trophoblast, connective tissue of the villus and the capillary wall (which prevents tumor spread from the placenta to the fetus in most cases); only when the tumor cells from the intervillous space invade into the villous capillaries can the metastases to fetus occur (Cancer 1970;25:380); spread to fetus more likely occurs in metastases with villous invasion and is rare in metastases confined to the intervillous space
Clinical features
  • Placental abruption with disseminated intravascular coagulation and fetal death can occur due to placental metastases in the intervillous space
  • Rarely, the mother may suffer from antepartum effects, such as sweating, flushing, palpitations and hypertension due to production of catecholamine by fetal neuroblastoma
Diagnosis
  • Meticulous histologic examination of the placenta is necessary in patients with previous diagnosis of malignancy and in those with fetal neoplasia detected antenatally
Radiology description
  • Nonspecific increased placental thickness
Case reports
Gross description
  • Placenta may appear bulky, pale and heavy
  • Tumor deposits are usually not macroscopically detectable (being identified mostly on histologic examination)
Microscopic (histologic) description
  • Multifocal clusters of malignant cells adjacent to intact villi
  • Metastases from maternal melanoma may show infiltration of villous stroma by malignant cells with Hofbauer cells containing melanin, even in the absence of villous invasion
  • Most cases of placental involvement are associated with minimal fetal complications but massive placental infiltration by maternal metastasis can lead to intrauterine fetal death (IUFD)
  • Presence of malignant cells in the intervillous space has been classified as placental metastasis although in reality the tumor cells remain within the maternal vascular space and in most cases do not truly invade placental tissue
  • Maternal leukemia with circulating malignant hematopoietic cells is associated with similar cells admixed within the intervillous space without true invasion (Ultrasound Obstet Gynecol 2009;33:235)
Microscopic (histologic) images

Images hosted on other servers:

Various images

Positive stains
  • Stains specific for the primary maternal or fetal malignancy
Board review style question #1
When is the risk of fetal metastasis by a maternal malignant tumor highest during pregnancy?

  1. When the placenta is normal microscopically
  2. When the tumor cells are present in the chorionic membranes
  3. When the tumor cells are seen in the intervillous space
  4. When the tumor cells invade into the chorionic villi
Board review style answer #1
D. When the tumor cells invade into the chorionic villi.

Comment Here

Reference: Metastases
Board review style question #2
Which maternal and fetal tumors, respectively, have been shown to have the highest proportion of placental metastases?

  1. Breast carcinoma and adenoid cystic carcinoma
  2. Gastric carcinoma and hepatoblastoma
  3. Leukemia and rhabdoid tumor
  4. Melanoma and neuroblastoma
Board review style answer #2
D. Melanoma and neuroblastoma.

Comment Here

Reference: Metastases

Nuchal cord
Definition / general
  • Umbilical cord that becomes wrapped around the baby's neck at some point during gestation
Terminology
  • Single nuchal cord is defined as an umbilical cord that loops once around the neck
  • Two nuchal cords (a double nuchal cord) occurs when two loops of umbilical cord are wrapped around the neck
  • Three nuchal cords (a triple nuchal cord) occurs when three loops of umbilical cord are wrapped around the neck
  • Nuchal cords can be qualitatively described as loose (no constriction) or as mildly, moderately or severely tight / constricting
Epidemiology
  • Increased risk in extremely long umbilical cords
  • Increased risk in twin or multiple gestations
  • Single nuchal cord is present in approximately 20% of term deliveries
  • Two nuchal cords and three nuchal cords occur in 2.5% and 0.5% of term deliveries, respectively
Pathophysiology
  • If the umbilical cord begins to constrict around the neck, vascular occlusion of the umbilical vessels and subsequent decreased venous return from the placenta can lead to asphyxia
  • In type A nuchal cord, the placental end of the umbilical cord crosses over the fetal end, allowing the ability for the nuchal cord to undo itself in time (an "unlocked" nuchal cord)
  • In a type B nuchal cord, the placental end of the umbilical cord crosses under the fetal end, negating the ability for the nuchal cord to undo itself in time (a "locked" nuchal cord)
Etiology
  • Fetal movement dynamics in utero can cause entanglement of the umbilical cord around fetal body parts, such as the fetal neck
Clinical features
  • Tight nuchal cord can compress the underlying fetal skin (the "divot" sign)
  • Nuchal cords are associated with fetal growth restriction, poorer long term neurologic outcomes, cerebral palsy, increased admissions to the intensive care unit, increased rate of cesarean delivery and fetal demise
Diagnosis
  • Prenatal or postnatal identification
Radiology description
  • Doppler ultrasound evaluation can identify a persistent structure wrapped around the fetal neck
Prognostic factors
  • Vast majority of single nuchal cords are not associated with adverse perinatal outcomes
  • Type B (locked pattern) nuchal cords have a greater significance in terms of clinical outcome
Clinical images

Images hosted on other servers:
Missing Image Missing Image

Nuchal cord

Gross description
  • Identify the number of loops around the neck and provide a qualitative assessment of constriction, if present (from obstetrics)
  • In excessively long umbilical cords, nuchal cords can coexist with true knots
  • Usually no gross abnormalities are present (after the umbilical cord and placenta have been received from obstetrics) but examine the cord for any associated abnormalities, such as hemorrhage, hematoma, thrombosis or stricture
Microscopic (histologic) description
  • Usually no significant histopathologic abnormality present unless accompanied by some type of secondary pathology

Partial hydatidiform mole
Definition / general
  • Gestational trophoblastic disease with abnormal chorionic villi (hydatidiform mole) characterized by a spectrum of villous populations ranging from normal to substantially enlarged, with irregular contours and mild, focal trophoblastic hyperplasia
Essential features
  • Hydatidiform mole resulting from fertilization of a normal egg by 2 spermatozoa or by 1 spermatozoa followed by duplication of the paternal chromosomal content
  • 2 discrete populations of villi (enlarged, hydropic villi and small, fibrotic villi), with the larger villi showing irregular scalloped borders and cistern formation
  • Typically has a diandric triploid genotype
  • Main differential diagnosis includes complete mole (p57-, diandric diploid genotype) and hydropic abortus (p57+, biparental diploid genotype)
  • Definitive diagnosis requires molecular testing for confirmation (essential diagnostic criterion in the 2020 WHO classification of female genital tumors)
Terminology
  • Partial molar pregnancy, partial / incomplete mole
ICD coding
  • ICD-O: 9103/0 - partial hydatidiform mole
  • ICD-11: JA02.1 & XH5325 - incomplete or partial hydatidiform mole & partial hydatidiform mole
Epidemiology
Sites
Pathophysiology
  • Most result from fertilization of a normal egg by 2 spermatozoa (dispermic, 99%)
  • Rarely from fertilization by 1 spermatozoa followed by duplication of the paternal chromosomal content (monospermic, 1%) (Mod Pathol 2014;27:238)
    • As a result, partial moles have a triploid genome, diandric and monogynic
  • Rare tetraploid partial moles have been reported, with 3 sets of paternal chromosomes and 1 set of maternal origin (Mod Pathol 2021;34:961, Int J Gynecol Pathol 2012;31:73)
Etiology
Diagrams / tables

Images hosted on other servers:

Algorithmic approach to diagnosis

Clinical features
Diagnosis
  • Combination of clinical, laboratory and imaging data raises the possibility of molar pregnancy
  • Poor interobserver agreement in differentiating between complete mole, incomplete mole and hydropic abortus when using histology alone, with discordance predominantly seen in partial mole versus hydropic abortus (Am J Surg Pathol 2012;36:443, Am J Surg Pathol 2012;36:1747, Am J Surg Pathol 2005;29:942)
  • Algorithmic approach, in conjunction with p57 immunohistochemistry, has been proposed by using morphological assessment to triage cases for genetic analysis
    • p57 negative cases with molar morphology would be diagnosed as complete hydatidiform moles without genotyping and all p57+ cases would be subjected to genotyping (Mod Pathol 2014;27:238)
  • Definitive diagnosis of partial mole requires molecular genotyping
Laboratory
Radiology description
  • Ultrasound but the sensitivity is low in the first trimester: routine pre-evacuation ultrasound examination identifies < 50% of hydatidiform moles before 14 weeks, with lower detection rate for partial moles (29%) compared with complete moles (79%) (Ultrasound Obstet Gynecol 2006;27:56)
  • Partial moles often present with minor cystic changes of the placenta or normal sonographic findings (J Clin Ultrasound 2017;45:72)
Radiology images

Images hosted on other servers:

Partial molar pregnancy

Prognostic factors
Case reports
Treatment
Gross description
Gross images

Images hosted on other servers:

Partial hydatidiform mole

Microscopic (histologic) description
  • Heterogeneity in villous size with 2 discrete populations (large, hydropic villi and small, fibrotic villi)
  • Enlarged villi are irregularly shaped with scalloped borders and secondary trophoblastic pseudoinclusions
  • Cistern formation can be seen in enlarged villi
  • Mild circumferential trophoblastic hyperplasia
  • Fetal parts and nucleated red blood cells can be present
  • Presence of at least 3 of the above histologic features of partial mole correlates with triploidy on FISH and flow cytometry analysis (Hum Pathol 2000;31:914, Int J Gynecol Pathol 2001;20:315)
Microscopic (histologic) images

Contributed by Aurelia Busca, M.D., Ph.D.
2 populations of villi 2 populations of villi

2 populations of villi

Edematous hydropic villi with pseudoinclusions

Edematous hydropic villi with pseudoinclusions

Hydropic villi with cistern formation

Hydropic villi with cistern formation

p57 nuclear staining p57 nuclear staining

p57 nuclear staining

Virtual slides

Images hosted on other servers:

Partial hydatidiform mole

Partial hydatidiform mole, p57

Positive stains
  • p57
    • Nuclear expression in at least 10% of villous stromal cells and cytotrophoblasts is considered positive
    • Requires internal positive control in maternal decidua and syncytiotrophoblast
    • Cannot distinguish partial mole from nonmolar specimens as both have maternal DNA (Hum Pathol 2005;36:180)
    • Rare cases of incomplete moles may lack p57 expression because of loss of the maternal copy of chromosome 11; genotypic analysis would confirm diandric triploidy (Mod Pathol 2021;34:961, Am J Surg Pathol 2011;35:1586)
Flow cytometry description
  • Cannot distinguish between maternal and paternal origin of genetic material
  • Triploid karyotype by flow cytometry is consistent with partial hydatidiform mole in conjunction with morphological features
  • Would require additional DNA testing to establish if triploidy is diandric versus digynic (Iran J Reprod Med 2015;13:269)
Molecular / cytogenetics description
  • Genotyping:
    • PCR amplification of short, tandem and repeat (STR) loci
    • Testing of both maternal decidua and villous tissue can identify diandric triploid genotype (Int J Gynecol Pathol 2011;30:101)
    • In a study of 158 partial moles, 155 were diandric triploid (83 cases XXY, 59 cases XXX, 13 cases XYY) and 3 were triandric tetraploid (2 cases XXYY and 1 case XXXY) (Mod Pathol 2014;27:238)
  • Fluorescence in situ hybridization (FISH):
    • Uses fluorescently labeled DNA probes targeting regions of various chromosomes, including X and Y
    • Can be used to determine sex chromosome and copy number
    • Cannot differentiate between maternal and paternal origins of genetic material (Prenat Diagn 2005;25:314, Hum Pathol 2000;31:914)
Videos

PathCast presentation on molar pregnancies and gestational trophoblastic

Sample pathology report
  • Uterus, curetting:
    • Partial hydatidiform mole (see comment)
    • Comment: Sections show immature chorionic villi with hydropic changes and cistern formation. There is focal noncircumferential trophoblast proliferation, without significant trophoblast atypia. No fetal parts are identified. By immunohistochemistry, there is retained p57 expression in villous stromal cells and cytotrophoblasts
    • Molecular testing shows the presence of diandric triploidy. The findings are consistent with partial hydatidiform mole
    • Note: If molecular testing results are unavailable at signout, issue a preliminary report followed by an addendum when available.
Differential diagnosis
  • Complete mole:
    • p57- and androgenetic diploidy by molecular testing
    • Early complete mole (less than 12 weeks):
      • No embryonic development
      • May have morphological overlap with incomplete mole, as molar features are not well developed (villi are smaller, cisterns and cavitation not well developed, some degree of trophoblastic proliferation and atypia)
    • Well developed complete mole:
      • No embryonic development
      • 1 population of villi with extensive hydrops, more trophoblastic hyperplasia and atypia
  • Hydropic spontaneous abortion:
    • Only mildly enlarged and edematous villi, occasional cistern formation
    • Tissue is usually less voluminous than partial mole
    • Biparental diploidy by molecular testing
  • Beckwith-Wiedemann syndrome:
    • Placenta often has gross abnormalities, including edema with enlarged villi and centrally cavitated stem villi
    • Scalloping and syncytiotrophoblastic hyperplasia should be absent
    • Diploid (Obstet Gynecol 1994;83:813)
  • Mosaic / chimeric conceptions:
    • Can exhibit a spectrum of morphologic alterations, some of which can suggest a hydatidiform mole
    • p57 is useful in identifying androgenetic tissue (which is p57-)
    • FISH and genotyping are required for full characterization (Int J Gynecol Pathol 2013;32:199)
  • Nonmolar placentas with cytogenetic abnormalities, such as trisomies:
    • Can show abnormal villi suggestive of an incomplete mole
    • Distinction on morphologic grounds alone is difficult and poorly reproducible
    • Would require genetic testing to identify the cytogenetic abnormality (J Mol Diagn 2010;12:525)
  • Twin gestation with complete mole and coexisting fetus:
    • Rare
    • Typically shows 2 villous populations, which may be mistaken for partial mole
    • Molar villi show typical features for complete mole: atypia, cavitation, marked trophoblastic proliferation
    • Fetus has a normal karyotype and is normally developed
    • p57 will be absent in the molar villi only (J Matern Fetal Neonatal Med 2007;20:175, J Ultrason 2017;17:299)
  • Placental mesenchymal dysplasia:
    • Rare and still poorly understood disorder
    • In 33% of cases, Beckwith-Wiedemann syndrome (associated with androgenetic and biparental mosaicism)
    • More commonly recognized in mature placentas; occasionally identified in early gestation POCs
    • Placentomegaly with changes in stem villi, including massive hydrops, cystic dilation and vesicle formation
    • Abnormally thick villous vessels with fibromuscular hypertrophy
    • Terminal villi appear normal
    • No trophoblastic hyperplasia or atypia
    • Placenta and fetus have a normal karyotype
    • Peculiar p57 pattern described in some cases, with retained staining in cytotrophoblast but loss in the villous stroma
    • References: Arch Pathol Lab Med 2014;138:1247, Surg Pathol Clin 2013;6:127
Board review style question #1
Partial hydatidiform mole Partial hydatidiform mole


Products of conception in a 30 year old patient. Which of the following statements is true for the entity depicted in the photos?

  1. It has exclusively paternal genetic material
  2. It has increased risk of persistent gestational trophoblastic disease and choriocarcinoma
  3. p57 immunohistochemistry can be used to differentiate it from complete hydatidiform mole
  4. p57 immunohistochemistry can be used to differentiate it from hydropic abortion
Board review style answer #1
C. p57 immunohistochemistry can be used to differentiate it from complete hydatidiform mole

Comment Here

Reference: Partial hydatidiform mole
Board review style question #2
What is the typical genetic profile of incomplete mole?

  1. Biparental diploidiy
  2. Diandric triploidy
  3. Digynic triploidy
  4. Triandric tetraploid
Board review style answer #2
B. Diandric triploidy

Comment Here

Reference: Partial hydatidiform mole

Placenta accreta, increta and percreta
Definition / general
  • Abnormal placental adherence to the uterine wall
    • Placenta accreta: villi implant on the myometrial surface without intervening decidua
    • Placenta increta: villi extend into the myometrium
    • Placenta percreta: villi penetrate the entire myometrial thickness and through the uterine serosa
Essential features
  • Patients with previous cesarean sections and placenta previa are at high risk for the development of abnormal placental implantation, which includes
    • Placenta accreta: villi implant on the myometrial surface without intervening decidua
    • Placenta increta: villi extend into the myometrium
    • Placenta percreta: villi penetrate the entire myometrial thickness and through the uterine serosa
Terminology
  • Placenta creta
  • Morbidly adherent placenta (MAP)
ICD coding
  • ICD-10:
    • O43.21 - Placenta accreta
    • O43.22 - Placenta increta
    • O43.23 - Placenta percreta
    • O43.2 - Morbidly adherent placenta
Epidemiology
Sites
  • In order of frequency: uterus, lower uterine segment and cervix
  • Placenta percreta may extend to bladder, ureters and bowel
Pathophysiology
Etiology
  • Previous cesarean sections (a greater number of cesarean sections means a greater risk for accreta) (Pediatr Dev Pathol 2017;20:387)
  • Placenta previa
  • Prior uterine instrumentation
  • Submucosal leiomyoma
  • Asherman syndrome (scar tissue within uterine cavity)
Diagrams / tables

Images hosted on other servers:
Placenta accreta, increta and percreta

Placenta accreta, increta and percreta

Clinical features
  • Severe peripartum hemorrhage can occur if the placenta cannot be separated from the uterus at delivery (J Matern Fetal Neonatal Med 2016;29:1795)
  • Massive peripartum hemorrhage may lead to disseminated intravascular coagulation (DIC) and shock
  • Placenta percreta may damage adjacent organs, including bladder, ureters and bowel
Diagnosis
  • Often suspected on prenatal imaging studies and operative findings
  • Diagnosis is made upon examination of the hysterectomy specimen
    • Histologic confirmation is required
  • On rare occasions, diagnosis of placenta accreta can be made on the delivered placenta
Radiology description
  • Ultrasound: loss of normal hypoechoic retroplacental zone, increased subplacental vascularity, abnormal interface between uterus and bladder, retroplacental myometrial thickness < 1 mm, multiple vascular lacunae within the placenta (J Matern Fetal Neonatal Med 2016;29:1795)
  • MRI may be helpful, particularly < 30 weeks gestation
  • Prenatal imaging is more sensitive at detecting severe cases of accreta and tends to not identify mild forms
Radiology images

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Ultrasound suspicious for placenta accreta

Ultrasound suspicious for placenta accreta

Ultrasound Doppler of placenta percreta

Ultrasound Doppler of placenta percreta

Ultrasound Doppler of placenta accreta

Ultrasound Doppler of placenta accreta

Prognostic factors
  • Delayed placental separation or manual removal increases the risk for accreta in future pregnancies
  • Presence of extensive myometrial fibers adherent to the basal plate in a delivered placenta has been shown to increase the risk of placenta accreta in subsequent pregnancies (BJOG 2016;123:2140)
Case reports
Treatment
  • Massive peripartum hemorrhage needs immediate treatment with blood transfusions and management of disseminated intravascular coagulation and shock
  • Emergent hysterectomy is required if bleeding cannot be controlled
  • Elective hysterectomy may be planned if imaging studies are concerning for severe forms of abnormal placental implantation
  • Conservative options include uterine artery ligation, balloon tamponade, uterotonics and hysteroscopic resection for mild forms (Am J Obstet Gynecol 2015;213:755)
Clinical images

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Intraoperative findings of placenta percreta

Intraoperative findings of placenta accreta

Gross description
  • Hysterectomy specimen:
    • With placenta in situ:
      • Placenta accreta: placenta adherent to the uterine wall; myometrium not thinned
      • Placenta increta: placenta extends into the uterine wall, usually in a blunt manner; myometrium thinned
      • Placenta percreta: placenta penetrates through the uterine or lower uterine segment wall; protruding placental tissue on external surface (should be inked) and adherent structures (bladder, bowel)
      • Note where the placenta is implanted (lower uterine segment implantation / placenta previa is common)
    • With separate placenta:
      • Placental implantation site may or may not be visible
      • Increased vascularity with ectatic vessels on superficial myometrium provide a clue for the placental implantation site
        • If visible, this area should be sampled
        • If not visible, check medical records for site of placental implantation and sample the area indicated
    • Refer to published guidelines on how to perform gross examination and sampling (Arch Gynecol Obstet 2016;293:951)
  • Delivered placenta:
    • Disruption of basal plate
    • Missing cotyledons in some cases
    • Higher yield of identifying adherent myometrial fibers microscopically by sampling the intact basal plate adjacent to disrupted areas
Gross images

Contributed by Fabiola Medeiros, M.D.
Placenta accreta

Placenta accreta

Placenta increta

Placenta increta

Placenta previa and percreta

Placenta previa and percreta

Placenta previa and percreta adherent to bladder

Placenta previa and percreta adherent to bladder

Disrupted manually removed placenta

Disrupted manually removed placenta

Microscopic (histologic) description
  • Diagnosis traditionally made on hysterectomy specimen
    • Placenta accreta:
      • Chorionic villi implant directly on the surface of the myometrium without intervening decidua
      • Fibrin and extravillous trophoblast (EVT) are often present between the villi and myometrial fibers, in which case a diagnosis of accreta should still be made, given that intervening decidua is not present
      • Differentiating decidual cells and extravillous trophoblastic cells may be difficult
      • Myometrium is not thinned
    • Placenta increta:
      • Chorionic villi identified within the myometrium
      • Fibrin and extravillous trophoblast can be present between the villi and myometrial fibers
      • Myometrium is thinned
      • Presence of extravillous trophoblast within the myometrium is not a diagnostic feature of placenta increta
    • Placenta percreta:
      • No residual myometrium
      • Ink present on villous tissue obtained from area suspicious for placenta percreta grossly
        • It is critical that invasion through the myometrial wall is identified in this area to exclude the possibility that the protruding placental tissue was displaced during surgery through the cesarean section incision
      • Villous tissue adjacent to adipocytes or in extrauterine structures, such as bladder, is seen in some cases and is diagnostic of percreta
  • Diagnosis uncommonly made on delivered placenta (occult placenta accreta)
    • Myometrial fibers attached to the basal plate with complete lack of intervening decidua between the myometrial fibers and the basal chorionic villi, with or without intervening fibrin / extravillous trophoblast (BJOG 2016;123:2140)
    • A staging system has been proposed but is not currently used in most practices (Placenta 2015;36:1419)
Microscopic (histologic) images

Contributed by Fabiola Medeiros, M.D.
Placenta accreta Placenta accreta

Placenta accreta

Trophoblastic versus decidual cells

Trophoblastic versus decidual cells

Placenta increta

Placenta increta

Placenta percreta

Placenta percreta

Occult placenta accreta

Occult placenta accreta

Virtual slides

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Placenta increta

Placenta increta

Cervical implantation of placenta

Cervical implantation of placenta

Positive stains
  • Immunohistochemistry is not required for diagnosis
  • Keratins and GATA3 are positive in extravillous trophoblast
  • Vimentin and CD10 are positive in decidual cells
Videos

Introduction to placenta accreta

Sample pathology report
  • Uterus and placenta, postcesarean supracervical hysterectomy:
    • Placenta accreta
    • Placental parenchyma, fetal membranes and trivascular cord with no significant histopathologic abnormalities
    • Myometrium and uterine serosa with no significant abnormalities
    • Endocervix with no significant abnormalities, no ectocervix identified
  • Uterus, cervix and placenta, postpartum total hysterectomy:
    • Placenta previa and percreta
    • Placenta adherent to serosa of urinary bladder but no involvement of bladder mucosa / muscular wall
    • Very preterm placenta (30 4/7 weeks), fetal membranes and trivascular umbilical cord
Differential diagnosis
  • Placenta protruding through the cesarean section defect versus placenta percreta:
    • Careful gross examination reveals that the protruding placental tissue is at the site of the cesarean section
    • Look for sutures at the site
    • Not true percreta
    • Correlate with operative note
  • Normally thinned myometrium at lower uterine segment versus placenta increta:
    • Compare the thickness of the lower uterine segment at the side suspicious for increta with the thickness of the lower uterine segment on the opposite side
    • If the myometrium of both sides has a similar thickness throughout, it is not increta
  • Physiologic invasion of extravillous trophoblast into the myometrium versus placenta accreta:
    • Extravillous trophoblast normally infiltrates the inner third of the myometrium and this is not accreta
    • In accreta, only extravillous trophoblast without decidual cells are present between villi and myometrium
  • Extravillous trophoblast versus decidual cells:
    • Both are large polygonal cells with abundant eosinophilic cytoplasm
    • Decidual cells have uniformly bland nuclei with smooth nuclear membranes, homogenous open chromatin and small nucleoli
    • Extravillous trophoblast cells have atypical nuclei with irregular nuclear membranes, variation in nuclear shape and size and often hyperchromatic or irregular chromatin
Board review style question #1

A 38 year old woman G3 P2 underwent a peripartum hysterectomy for life threatening uncontrollable vaginal bleeding. On gross examination, the placenta was in situ and the thickness of the myometrium was markedly decreased at the placental implantation site. The uterine serosa and lower uterine segment were grossly unremarkable. Microscopic examination revealed villi juxtaposed to myometrial fibers. What is the most appropriate diagnosis?

  1. Placenta accreta
  2. Placenta increta
  3. Placenta percreta
  4. Subinvolution of the placental site
  5. Uterine atony
Board review style answer #1
Board review style question #2
Which of the following is required for a diagnosis of placenta accreta?

  1. Absence of intervening decidua between villi and myometrium
  2. Invasive extravillous trophoblast into the myometrium
  3. Myometrial fibers adherent to the basal plate
  4. Placenta grossly adherent to the uterine wall
  5. Villous invasion through the myometrium and serosa
Board review style answer #2
A. Absence of intervening decidua between villi and myometrium

Comment Here

Reference: Placenta accreta, increta and percreta

Placenta previa
Definition / general
  • Implantation of the placenta in the lower uterine segment, partially or completely occluding the internal os
  • Important cause of late vaginal bleeding and emergent cesarean delivery
Etiology
  • Associated with a history of D&C, cesarean delivery and multiparity
Diagrams / tables

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Placenta previa

Gross description
  • Marginal hematomas may be present
  • In vaginal deliveries, point of membrane tear may be at the disc edge
Gross images

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Placenta previa


Placental development & hormones
Implantation
  • Blastocyst implants on postovulation day 6 - 7; by day 10, ovum is implanted in stroma
  • Trophoblasts proliferate and erode the maternal capillaries and venules to form the intervillous space
  • Extraembryonic mesoderm grows into the primary villi and capillary formation occurs
  • By 5 - 6 weeks, the villous vessels are formed
  • At 8 weeks, they contain nucleated red blood cells (nRBC) which diminish to 10% by 10 weeks and are absent at 12 weeks
First trimester
Implantation and arterial plugs:
  • Extravillous intermediate trophoblasts invade the endometrium while endovascular trophoblasts grow into arteries and form cellular plugs

Villous morphology:
  • Early mesenchymal villi are large (170 microns) with scant connective tissue, few Hofbauer cells, no thick walled vessels
  • They have a complete outer layer of syncytiotrophoblast and an inner cytotrophoblast layer
  • During mid trimester, they mature to immature intermediate villi which have loose stroma with many Hofbauer cells and a complete trophoblastic coat
  • Then transform to stem villi, which have denser stroma and thick walled vessels
  • This process continues through the second trimester

Microscopic (histologic) images:

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Chorionic villi covered
by cytotrophoblast and
syncytiotrophoblast

Second trimester
Implantation and vascular remodeling:
  • Invading trophoblasts extend into the myometrium while endovascular trophoblasts invade the arterial walls and destroy their endothelium and media, replacing them with fibrinoid material, creating a low pressure circulation

Villous morphology:
  • Mesenchymal villi give rise to mature intermediate villi, from which terminal villi sprout
  • Mature intermediate villi are large with loose stroma, capillaries, arterioles and venules
  • Terminal villi appear near the end of the trimester and are much smaller (70 microns) with denser stroma surrounded primarily by syncytiotrophoblasts and a thin cytotrophoblast layer that may have syncytial knots
  • Vessels are numerous (3 - 5 capillaries per villous) and in contact with the trophoblastic coat

Microscopic (histologic) images:

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"Syncytial knots" and pink fibrin

Third trimester
Villous morphology:
  • Mature intermediate and terminal villi are now more prevalent and smaller than second trimester with thin stroma
  • More have syncytial knots (approximately 30%) and vasculosyncytial membranes (fused fetal capillaries with syncytiotrophoblasts)
  • Trophoblastic inclusions are common

Microscopic (histologic) images:

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Vascularized chorionic villi and 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
Placental hormones
Steroid hormones: estrogens and progesterone
  • Trophoblasts synthesize estrogens and syncytiotrophoblasts synthesize progesterone, which maintains a noncontractile uterus and fosters development of an endometrium conducive to pregnancy
  • By the end of the first trimester, placental production of these hormones replaces the corpus luteum

Peptide hormones
Activin and inhibin:
  • Produced by trophoblast
  • Regulate hCG production

Cytokine growth factors (TGF-alpha, TGF-beta, EGF):
  • Produced by trophoblast
  • Stimulates proliferation of trophoblast and production of fibronectin

Human chorionic adrenocorticotropin (hACTH):
  • Small amounts produced
  • Believed to function similar to ACTH

Human chorionic gonadotropin (hCG) :
  • Glycoprotein similar in structure to pituitary LH
  • Synthesized primarily by the villous syncytiotrophoblast
  • Synthesis begins before implantation and is detectable 7 - 10 days after implantation, forming the basis for early pregnancy tests
  • Peak levels reached at 8 - 10 weeks
  • Maintains maternal corpus luteum that secretes progesterone and estrogens

Human chorionic thyrotropin (hCT):
  • Small amounts produced, probably by the syncytiotrophoblast
  • Believed to function 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) :
  • Polypeptide similar to growth hormone
  • Synthesized by the villous syncytiotrophoblast
  • First detectable by 4 weeks
  • Peak levels at end of third trimester
  • Acts as an insulin antagonist to influence 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 villous cytotrophoblast
  • 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

Placental edema (placental hydrops)
Definition / general
  • Accumulation of fluid in the placenta and umbilical cord
Etiology
  • Results from a variety of fetal or maternal factors, including erythroblastosis fetalis, hemolytic disease of the newborn, infection, cardiac anomalies, fetal anemia, hemorrhage, congenital anomalies, chromosomal disorders or tumors
Gross description
  • Placenta is enlarged and pale when edema is marked
  • Placental weight may be greater than expected for gestational age
Microscopic (histologic) description
  • Enlarged villi with edematous stroma and increased numbers of Hofbauer cells (macrophages)
  • Underlying cause of edema may be diagnosed based on other histologic findings

Placental site nodule
Definition / general
  • Placental site nodule (PSN) is a rare benign lesion of chorionic type intermediate trophoblast (Hum Pathol 1994;25:1295)
Essential features
  • Placental site nodules (or plaques) are composed of single to multiple, small (usually < 5 mm), well circumscribed nodular aggregates of intermediate trophoblastic cells embedded in a hyalinized stroma
  • Features favoring the diagnosis include its usually small size, circumscription, extensive hyalinization, degenerative appearance and mitotic inactivity
  • It represents the benign counterpart of epithelioid trophoblastic tumor (ETT)
  • Atypical placental site nodule (APSN) is a term assigned to placental site nodules with significant nuclear atypia or borderline proliferation index; APSN is considered a precursor to ETT
Terminology
  • Placental site plaques
ICD coding
  • ICD-10: O43.89 - other placental disorders
Epidemiology
Sites
Pathophysiology
  • Thought to arise from a noninvoluted placental site from remote gestations in the uterus; however, the morphologic and immunohistochemical features are more closely related to the intermediate trophoblast of chorion laeve (chorionic type intermediate trophoblast) than to the intermediate trophoblast of a placental site (implantation site intermediate trophoblastic cells) (Hum Pathol 1999;30:687, Int J Gynecol Pathol 2014;33:339)
  • Prior surgical interventions in the endometrium (or fallopian tubes in tubal pregnancy) have been linked to formation of placental site nodules; these surgical interventions (therapeutic abortions, cesarean sections) may disturb normal endometrial shedding, leading to abnormal involution of the placental site and subsequent placental site nodule formation (Int J Gynecol Pathol 2001;20:31, Am J Surg Pathol 1990;14:1001, Int J Gynecol Pathol 1994;13:191)
Etiology
Clinical features
  • Incidental findings in endometrial or endocervical curettings, cervical biopsies and hysterectomy of patients presenting with abnormal cervical smear (35%), metromenorrhagia, hypermenorrhea and dysmenorrhea (30%), recurrent spontaneous abortions (5%), retained products of conception (5%), postcoital bleeding (2.5%) and infertility (2.5%) (Hum Pathol 1999;30:687, Int J Gynecol Pathol 1994;13:191, Am J Surg Pathol 1990;14:1001)
Diagnosis
  • Endometrial or endocervical curettage
  • Hysterectomy
  • Salpingo-oophorectomy
Radiology description
  • Rarely, placental site nodules may cause uterine filling defects on hysterosalpingogram and sonohysterography (Fertil Steril 2005;83:213)
Radiology images

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Placental site nodule
hysterosalpingogram

Prognostic factors
  • Benign lesions; due to small size and circumscription, the lesions are usually removed in their entirety by the surgical procedure that led to their discovery
  • No local recurrence or progression to persistent gestational trophoblastic diseases has been documented in PSNs (Am J Surg Pathol 1998;22:1393)
  • However, intimate association of PSN with ETT has been reported and rare transformation of PSN into an ETT has been described (Histopathology 2008;53:601, Diagn Pathol 2013;8:85)
  • Behavior of atypical placental site nodules has not yet been fully elucidated
Case reports
Treatment
Gross description
  • Usually small, ranging from 1 to 14 mm (average 2.1 mm); occasionally, multiple and sizable (> 5 mm)
  • Appears as a yellow-white and necrotic appearing nodule in the endometrium or superficial myometrium when grossly visible
  • Reference: Hum Pathol 1999;30:687
Gross images

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PSN with PSTT / ETT

Microscopic (histologic) description
  • Well circumscribed, surrounded by a thin rim of chronic inflammatory cells and occasionally decidualized stroma
  • Typically composed of chorionic type intermediate trophoblast
    • Trophoblastic cells are arranged in a haphazard pattern, dispersed singly, in small clusters and cords or occasionally diffusely throughout the nodule
    • These cells occupy the outer portion of the nodules with a central hyalinized extracellular matrix
  • Cells vary in size; many have relatively small uniform nuclei and a few have large, irregular and hyperchromatic nuclei
    • Multinucleated cells are occasionally present
    • Cytoplasm of the larger trophoblastic cells is abundant and eosinophilic to amphophilic, whereas the smaller cells contain glycogen rich, clear cytoplasm
  • Mitotic figures are absent or rare
  • Although there are no criteria or quantitative measures for defining what is atypical, atypical placental site nodules usually contain more abundant lesional tissues and appear more cellular
    • Intermediate in size between placental site nodules and ETT
    • Higher cellularity, with trophoblastic cells arranged in more cohesive nests and cords
  • Reference: Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019
Microscopic (histologic) images

Contributed by Rachelle P. Mendoza, M.D.
PSN in endometrial sampling

PSN in endometrial sampling

PSN architecture

PSN architecture

PSN cellular morphology

PSN cellular morphology

PSN in cervical biopsy PSN in cervical biopsy

PSN in cervical biopsy

HLA-G / Ki67 dual immunostain

HLA-G / Ki67 dual immunostain

Virtual slides

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Placental site nodule, endometrium

Negative stains
Sample pathology report
  • Cervix, biopsy:
    • Fragment of endocervical tissue with placental site nodules (see comment)
    • Comment: The endocervical tissue fragments show small (2 - 3 mm in greatest diameter), well circumscribed nodules containing intermediate trophoblastic cells surrounding a core of eosinophilic, hyalinized acellular stroma. Mitotic figures and cellular atypia are not seen. The Ki67 proliferation index is < 1%. The cells are positive for PLAP, inhibin, p63, AE1 / AE3, EMA and only focally positive for HPL and CD146. They are negative for p16, beta hCG and mucin 4. These findings are consistent with placental site nodules.
Differential diagnosis
Board review style question #1

A 28 year old, para 2 woman presented with menorrhagia. Endometrial sampling was performed and a representative section of the lesion is shown above. No mitoses are seen. Which of the following immunohistochemical stains is expected to be expressed in this lesion?

  1. Beta hCG
  2. Cyclin E
  3. p16
  4. p63
Board review style answer #1
Board review style question #2
The typical immunophenotypic profile of placental site nodule is which of the following?

  1. p63-, inhibin-, cyclin E+
  2. p63-, inhibin+, cyclin E-
  3. p63-, inhibin+, cyclin E+
  4. p63+, inhibin+, cyclin E-
Board review style answer #2
D. p63+, inhibin+, cyclin E-

Comment Here

Reference: Placental site nodule

Placental site subinvolution
Definition / general
  • Delayed / incomplete sloughing of the modified spiral arteries in the superficial myometrium beneath the placental attachment site
  • Important cause of late postpartum bleeding
Etiology
  • May be due to deficiency in immunologic factors necessary for normal involution of uteroplacental arteries
Microscopic (histologic) description
  • Curettings show large, dilated vessels that lack a medial coat and are partially / completely thrombosed
  • Trophoblasts may be present

Placental site trophoblastic tumor
Definition / general
  • Placental site trophoblastic tumor (PSTT), a rare gestational trophoblastic disease (0.25 - 5% of all trophoblastic tumors), is a neoplastic proliferation of intermediate trophoblasts at placental implantation site (Hum Pathol 1991;22:847)
Essential features
  • Consists of aggregates or sheets of large, polyhedral to round, predominantly mononucleated cells composed of implantation site intermediate trophoblastic cells
  • Characteristic vascular invasion is often present, in which the tumor cells replace the wall of myometrial vessels
  • Tumor cells are positive for HPL, CD146 and HSD3B1 but only focally positive for hCG and negative for PLAP; Ki67 index is < 30%
  • Serum beta hCG levels are low (< 1,000 mIU/mL)
Terminology
  • Atypical choriocarcinoma, syncytioma, chorioepitheliosis, trophoblastic pseudotumor
ICD coding
  • ICD-O: 9104/1 - placental site trophoblastic tumor
  • ICD-11: 2C75.0 & XH1RM5 - malignant trophoblastic neoplasm of placenta and placental site trophoblastic tumor
Epidemiology
  • Patients are usually in the reproductive age group (mean: 31 years; range: 20 to 63 years)
Sites
Pathophysiology
  • Has been thought to develop as a result of neoplastic transformation of cytotrophoblastic cells; the transformed cells assume the differentiation toward implantation site intermediate trophoblast (Lancet Oncol 2007;8:642)
  • Duplication of paternal X chromosome is considered to cause abnormal genetic overdosing and plays a role in trophoblastic proliferation; 85% of PSTT have had a female antecedent gestation (Lab Invest 2000;80:965)
Etiology
  • Unknown
Diagrams / tables

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Origin of PSTT

Origin of PSTT

Clinical features
Diagnosis
  • Biopsy or hysterectomy specimen
Laboratory
Radiology description
  • On ultrasonography, a solid mass within the endometrial cavity or in the myometrium may be identified, with more or less prominent blood vessels on color Doppler imaging; in certain cases, ultrasound may reveal an enlarged uterus with a heterogeneous echotexture, echogenic foci and cystic areas of hemorrhage
  • On MRI, a frequent observation is the distortion of the junctional zone caused by a myometrial or endometrial mass, which is typically isointense to normal myometrium on T1 weighted images and isointense to slightly hyperintense to the myometrium on T2 weighted images; a diffusely heterogeneous pattern of the uterus with loss of zonal anatomy is also observed
  • Reference: J Radiol Case Rep 2015;9:14
Radiology images

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Uterine ultrasound

Uterine ultrasound

Pelvic MRI

Pelvic MRI

Uterine MRI

Uterine MRI

Prognostic factors
  • Poor prognostic factors include
    • Tumor cells with clear cytoplasm, deep myometrial invasion, large tumor size, necrosis and high mitotic count (> 2.5 mitoses/mm², equating to > 5 mitoses/10 high power fields of 0.5 mm in diameter and 0.2 mm² in area) (Gynecol Oncol 2006;100:511)
    • Advanced stage, ≥ 48 months since antecedent pregnancy, age > 40 years and the presence of tumor cells with clear cytoplasm are independent predictors of a worse prognosis (Gynecol Oncol 2006;100:511)
Case reports
Treatment
Gross description
Gross images

Contributed by Jonathan Keow, M.D., Ph.D., M.Sc.
Anterior endomyometrium with exophytic mass

Anterior endomyometrium with exophytic mass

Cross sections of anterior endomyometrium

Cross sections of anterior endomyometrium

Cross section of posterior endomyometrium

Cross section of posterior endomyometrium

Opened hysterectomy specimen

Opened hysterectomy specimen



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Uterus with PSTT

Uterus with PSTT

Microscopic (histologic) description
  • Infiltrative growth pattern consisting of aggregates or sheets of large, polyhedral to round, predominantly mononucleated cells composed of implantation site intermediate trophoblastic cells
  • Scattered multinucleated implantation site trophoblastic cells are common
  • Tumor cells often aggregate into confluent sheets; however, at the periphery the trophoblast cells invade singly or in cords and nests, characteristically infiltrating the myometrium by separating individual muscle fibers and groups of fibers
  • Vascular invasion is often present, in which the tumor cells replace the wall of myometrial vessels; these transformed blood vessels are unique among all human solid tumors and are diagnostic for PSTT
  • Cytologically, the cells have an abundant amphophilic (and occasionally eosinophilic or clear) cytoplasm; nuclei are pleomorphic and nuclear atypia is generally pronounced, with frequent, large, convoluted nuclei and marked hyperchromasia
  • Most tumors have a low mitotic count, with 1 - 2 mitoses/mm² (equating to 2 - 4 mitoses/10 high power fields of 0.5 mm in diameter and 0.2 mm² in area) (Gynecol Oncol 2006;100:511, Int J Gynecol Pathol 2001;20:31, Clin Obstet Gynecol 1984;27:248)
  • Decidua or an Arias-Stella reaction may be present in the adjacent, uninvolved endometrium; villi are almost never identified
  • Necrosis may be present
  • Reference: Kurman: Blaustein's Pathology of the Female Genital Tract, 7th Edition, 2019
Microscopic (histologic) images

Contributed by Rachelle Mendoza, M.D.
Infiltrative pattern with necrosis

Infiltrative pattern with necrosis

Tumor cells

Cell morphology

Vascular invasion

Vascular invasion

Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Uterus, cervix, total hysterectomy:
    • Placental site trophoblastic tumor (see comment)
    • Comment: The tumor is a polypoid, nodular mass infiltrating into the myometrium. It is composed mostly of mononucleated eosinophilic polygonal cells with admixed multinucleated cells, morphologically similar to intermediate trophoblastic cells. The tumor cells infiltrate in between the myometrial fibers and invades the myometrial vessel walls. Areas of tumor necrosis are identified comprising about 20% of the specimen. Mitotic activity is 1 - 2/mm² and the Ki67 index is approximately 15%. The tumor cells stain positively with HPL, MUC4 and CD146, focally positive for hCG and AE1 / AE3 and were negative for p63, p16, HMB45, S100, SMA and inhibin.
Differential diagnosis
  • Exaggerated placental site (EPS):
    • Exuberant infiltration of implantation site intermediate trophoblastic
    • Microscopic, lacks mitotic activity (Ki67 ~0%) and composed of intermediate trophoblastic cells separated by masses of hyaline
    • Usually admixed with decidua and chorionic villi and contains large numbers of multinucleated trophoblastic cells
  • Epithelioid trophoblastic tumor (ETT):
    • Grows in expansile nodular fashion, with presence of fibrillary hyaline material, extensive geographic necrosis, calcification and absence of vascular invasion
    • Positive for p63, PLAP and inhibin
  • Choriocarcinoma:
    • Comprised of trimorphic proliferation of syncytiotrophoblast, cytotrophoblast and intermediate trophoblast
    • Strong and diffuse beta hCG expression
    • Markedly elevated serum beta hCG (1,000 mIU/mL to 1,000,000 mIU/mL)
    • Increased Ki67 (> 40%)
  • Squamous cell carcinoma (SCC) of the cervix:
    • More cellular atypia with basaloid features (high nuclear to cytoplasmic ratio, nuclear hyperchromasia)
    • Positive for p16 and HPV ISH
    • Negative for HPL, CD146, MUC4, HSD3B1
    • Very elevated Ki67 index
  • Poorly differentiated carcinoma:
    • May show glandular differentiation and some variant epithelial differentiation (squamous, tubal)
  • Epithelioid smooth muscle tumors:
    • Characterized by fascicular morphologic pattern
    • Positive for SMA, desmin
    • Negative for HPL, CD146, HSD3B1
  • Metastatic melanoma:
    • Large nucleoli
    • Diffusely positive for melanoma markers (HMB45, melanA, S100)
Additional references
Board review style question #1

A 31 year old woman, gravida 2, para 1, presents with profuse vaginal bleeding. Prior to this, the patient had amenorrhea for about 12 weeks with uterine enlargment. Ultrasound reveals a 10 - 12 week enlarged uterus with a 4 cm polypoid endomyometrial mass. There was no intrauterine pregnancy. Serum beta hCG is < 1,000 mIU/mL. On H&E sections of the endometrial sample, the tumor shows an infiltrative growth pattern consisting of aggregates or sheets of large, polyhedral to round, predominantly mononucleated cells (representative section is shown above). Vascular invasion is present, replacing the wall of myometrial vessels. The proliferation index (Ki67) is < 30%. What is the most likely diagnosis?

  1. Choriocarcinoma
  2. Epithelioid trophoblastic tumor
  3. Placental site nodule
  4. Placental site trophoblastic tumor
Board review style answer #1
D. Placental site trophoblastic tumor

Comment Here

Reference: Placental site trophoblastic tumor
Board review style question #2
Characteristic histological features helpful in differentiating placental site trophoblastic tumor from most other neoplasms are

  1. Ability to replace and re-epithelialize the endocervical / endometrial surface epithelium
  2. Invasion and replacement of myometrial vessel walls
  3. Presence of distinct neoplastic components (triphasic tumor)
  4. Presence of extensive geographic necrosis and expression of p63
Board review style answer #2
B. Invasion and replacement of myometrial vessel walls

Comment Here

Reference: Placental site trophoblastic tumor

Prolapsed umbilical cord
Definition / general
  • Cord prolapse occurs when the umbilical cord is expelled with or prior to the fetus during the fetal presentation process
Epidemiology
  • Approximately 0.4 - 0.5% of deliveries are complicated by cord prolapse
Pathophysiology
  • Lack of fetal engagement within the uterus may create a space or gap that allows the umbilical cord to slip pass the fetus and into the birth canal
  • Umbilical cord can become markedly compressed when delivered with or before the fetus
  • Umbilical cord vascular occlusion and decreased placental venous return can severely limit fetal oxygenation capacity
Etiology
  • Spontaneous or artificial rupture of membranes are a major cause
  • Other risk factors include those that perturb the appropriate filling of the pelvic space (engagement) by the fetus: an abnormal fetal lie / position, prematurity or low birth weight fetus, polyhydramnios, multiple gestation pregnancy, multiparity
  • Umbilical cord abnormalities, such as a long umbilical cord, are also a risk factor
Diagrams / tables

Images hosted on other servers:

Schematic
representation
of cord prolapse
preceding delivery

Clinical features
  • Umbilical cord prolapse is an obstetrical emergency and is associated with perinatal mortality in 5 - 15% of cases
Diagnosis
  • Sudden decreases in fetal heart rate
  • Moderate to severe variable decelerations on fetal heart tracing
  • A portion of umbilical cord may be detected on vaginal examination
  • Antenatal ultrasound may show cord herniation into the lower uterine segment / cervical canal
Case reports
Treatment
  • Emergent cesarean section to prevent neurologic consequences or fetal death
Gross description
  • Usually no gross abnormality is seen unless complicated by another pathologic process, such as vascular thrombosis
  • If prolonged, the affected portion of prolapsed umbilical cord may appear dusky
Microscopic (histologic) description
  • Usually no microscopic abnormality is appreciated (unless complicated by another pathologic process)

Retroplacental hematoma with intraplacental extension (placental abruption)
Definition / general
  • Loss of maternal vascular integrity, resulting in accumulation of maternal blood between the maternal surface of the placenta and the uterine wall after 20 weeks gestation and before delivery of the fetus / infant
Essential features
  • Premature separation of the placenta from the uterine wall by maternal blood; strongly associated with maternal hypertensive disorders of pregnancy and maternal vascular malperfusion of the placenta
  • 3 main categories: classic acute abruption, acute marginal abruption and chronic abruption
  • Gross features: retroplacental hematoma (acute) / brown membrane staining and circumvallate membrane insertion (chronic)
  • Microscopic features: intravillous hemorrhage, hematoma with underlying infarction (acute) / chorioamniotic hemosiderosis (chronic)
Terminology
  • Abruptio placentae
  • Acute / chronic abruption
  • Acute / chronic marginal abruption
  • Acute / chronic peripheral separation
ICD coding
  • ICD-10: O45 - premature separation of placenta
Epidemiology
Sites
  • Placenta
Pathophysiology
  • Acute abruption
    • Loss of maternal vascular integrity (assumed to be arterial - high pressure / flow) results in rapid, often massive hemorrhage and placental separation
  • Acute marginal abruption (Obstet Gynecol Surv 1988;43:577)
    • Predilection for venous bleeding at the margin of the placenta for unclear reasons
    • Venous disruption at the margin leads to hemorrhage that dissects both retromembranously and subchorionically
  • Chronic abruption
    • Maternal vascular disruption, usually marginal and venous, for an extended duration leads to accumulation of blood clots and blood breakdown products (fibrin, hemosiderin)
Etiology
  • Acute abruption: hypertension / hypertensive disorders of pregnancy (preeclampsia, etc.), smoking, cocaine abuse, trauma
  • Acute marginal abruption: acute chorioamnionitis
  • Chronic abruption: etiology is poorly understood; no clear risk factors are known
  • Reference: Obstet Gynecol 2006;108:1005
Clinical features
Diagnosis
  • Clinical and pathologic diagnosis do not necessarily correlate
    • Very acute abruptions may not have enough time to leave any placental evidence of their occurrence
    • Marginal abruptions are often concealed / clinically silent and are only identified on pathologic examination
  • Bloody amniotic fluid
  • Couvelaire uterus (N Engl J Med 2020;383:1973)
  • Consumptive coagulopathy on laboratory evaluation
Laboratory
  • Decreases in maternal fibrinogen, prothrombin, factors V and VIII and platelets
  • Elevation in maternal fibrin split products
  • Maternal hypofibrinogenemia
  • Reference: Int J Obstet Anesth 2011;20:135
Radiology description
Radiology images

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Ultrasound and CT appearance Ultrasound and CT appearance Ultrasound and CT appearance

Ultrasound and CT appearance

Prognostic factors
Case reports
Treatment
  • Mild: close observation of maternal stability and reassuring fetal status with preparedness for immediate delivery if either worsens
  • Moderate - severe: expedite delivery depending on severity and gestational age (Obstet Gynecol 2006;108:1005)
Gross description
  • Acute abruption: retroplacental hematoma (central or marginal), with indentation and compression of the surrounding parenchyma
  • Very acute abruption may have no gross abnormalities
  • Chronic abruption:
    • Circumvallate membrane insertion
    • Organizing marginal hematoma
    • Brown stained membranes (corresponds to hemosiderin deposition)
  • Reference: Eur J Obstet Gynecol Reprod Biol 2020;254:188
Gross images

Contributed by Sanjita Ravishankar, M.D.
Abruption with clot

Retroplacental hematoma

Clot removed

Clot removed

Marginal hematoma

Marginal hematoma

Cross section

Cross section

Chronic abruption

Chronic abruption



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Abruptio placenta with dark red retroplacental blood clot Abruptio placenta with dark red retroplacental blood clot

Abruptio placenta with dark red retroplacental blood clot

Microscopic (histologic) description
  • Acute abruption (Hum Pathol 2017;67:187)
    • Decidual or retroplacental hemorrhage / hematoma, with or without extension into the placental parenchyma (intraparenchymal extension)
    • Early or well developed infarction of the surrounding placental parenchyma
    • Intravillous hemorrhage / villous stromal hemorrhage - red blood cells leak from the villous capillaries and into villous stroma
  • Chronic abruption (Am J Clin Pathol 1999;111:804)
    • Diffuse chorioamniotic hemosiderosis - accumulation of hemosiderin laden macrophages in the free membranes or chorionic plate
      • May be confirmed with special stain for iron
    • Accumulation of organized clot or fibrin at the margin of the placenta
Microscopic (histologic) images

Contributed by Sanjita Ravishankar, M.D.
Hematoma and infarct

Hematoma and infarct

Hemorrhage and infarct

Hemorrhage and infarct

Hemorrhage Hemorrhage

Hemorrhage


Intravillous hemorrhage

Intravillous hemorrhage

Circumvallate membrane insertion

Circumvallate membrane insertion

Hemosiderin

Hemosiderin

Videos

Disseminated intravascular coagulation and placental abruption

Sample pathology report
  • Placenta:
    • (Immature / slightly immature / mature) placenta (_ g)
    • Findings consistent with acute abruption:
      • Recent marginal retroplacental hematoma with intraparenchymal extension
      • Underlying villous infarction
      • Intravillous hemorrhage
  • Placenta:
    • (Immature / slightly immature / mature) placenta (_ g)
    • Findings consistent with chronic marginal abruption:
      • Circumvallate membrane insertion
      • Remote marginal retroplacental hematoma
      • Diffuse chorioamniotic hemosiderosis
Differential diagnosis
  • Nonadherent or loosely adhered retroplacental blood clot:
    • Easily peeled off the maternal surface - more likely to represent nonpathologic clot
  • Parenchymal atrophy or container artifact:
    • Areas that may appear grossly similar to parenchymal compression / indentation but are actually areas of atrophy or artifact from the specimen container (especially postfixation)
    • Look for gross evidence of infarction or congestion in the area; if in doubt, describe and submit a section
  • Villous congestion:
    • Look closely at high power to see if the red blood cells are still within the capillary spaces or are in the stroma itself
Additional references
Board review style question #1

A 35 year old woman at 25 weeks gestation presents with vaginal bleeding and nonreassuring fetal heart tracings and undergoes an urgent cesarean section. Gross examination of the placenta demonstrates a large retroplacental hematoma with indentation (see image above). What finding might you expect to see microscopically?

  1. Chronic villitis
  2. Delayed villous maturation
  3. Maternal floor infarction
  4. Villous stromal vascular karyorrhexis
  5. Villous infarction
Board review style answer #1
Board review style question #2
A 24 year old woman at 23 weeks gestation presents with intrauterine fetal demise. Pathologic examination of the placenta demonstrates a small placenta with foci of intravillous hemorrhage. What clinical syndrome is the mother likely to have?

  1. Cholestasis of pregnancy
  2. Gestational diabetes
  3. Maternal fever
  4. Placenta previa
  5. Preeclampsia
Board review style answer #2

Short cord
Definition / general
  • Decrease in the absolute length of the umbilical cord
Essential features
  • Variably defined but short umbilical cords measure less than 35 cm in absolute length
  • Usually best measured at the time of delivery, as the umbilical cord tends to slightly shrink in the few hours following delivery and a small portion of the umbilical cord is left attached to the infant following delivery
  • The length of the umbilical cord received for pathologic evaluation must always be recorded; nonetheless, the diagnosis of short cord can only be made if the absolute length is known (measured at the time of delivery)
Terminology
  • Absolute length of the umbilical cord can vary from its functional length, such as when additional pathology limits the length of the physical cord (as seen with umbilical knots, nuchal cords, cord entanglements, etc.)
Epidemiology
  • Incidence is 1 - 2% when using < 35 cm as a cutoff; incidence is < 1% when using < 32 cm as a cutoff
Etiology
  • Uncertain but a propensity for shorter cords (or cord length in general) in some patients suggest a genetic etiology
Pathogenesis
  • Not well understood, although fetal movement may stimulate elongation of the cord - fetuses with decreased intrauterine movement tend to possess shorter cords, such as long standing oligohydramnios
Clinical features
  • The following complications can be seen with short umbilical cords, mostly due to increased traction on the placenta during delivery:
    • Placental abruption
    • Cord rupture
    • Cord hemorrhage or hematoma
  • Other obstetric conditions include delayed second phase of labor, fetal distress, low Apgar scores and uterine inversion
  • Developmental defects in the fetal abdominal wall can also be associated with a short umbilical cord
Case reports
Gross description
  • Absolute / true length less than 35 cm; most accurately assessed at the time of delivery
  • Umbilical cord length must be always included in the gross / macroscopic description; however, the diagnosis of short cord can only be made if the absolute length is known by the pathologist
Gross images

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Short umbilical cord sequence (SUCS)

Microscopic (histologic) description
  • No significant histopathologic changes are associated with a short umbilical cord
Board review style question #1
All of the following are associated with short umbilical cords, except:

  1. A poorly understood etiology, although a genetic predisposition is possible
  2. Cord length is most accurately measured at the time of delivery
  3. Defined as an absolute cord length less than 35 cm
  4. Includes functionally shortened cords, such as with nuchal cords
  5. It increases the risk of traction phenomena on the placenta
Board review style answer #1
D. Includes functionally shortened cords, such as with nuchal cords

Comment Here

Reference: Short umbilical cord

Single umbilical artery and supernumerary vessels
Single umbilical artery
  • Two vessel cord (usually are 3 vessels) with a single artery and a single vein (a hypoplastic artery may be present)
  • Remaining artery may be a persistent vitelline artery in cases of caudal regression / synringomelia
  • Diagnosed in 1% of placentas, with higher rates occurring with congenital anomalies, perinatal death and fetal growth restriction
  • Also more common in maternal diabetes
  • No increased risk of postneonatal mortality
Supernumerary vessels
  • Four or more umbilical cord vessels due to an extra artery or vein
  • May be associated with fetal anomalies and maternal smoking
  • Thought to originate from persistent umbilical veins or vitelline vessels
  • Looping may cause artifactual supernumerary vessels and should be excluded on gross examination
Gross description
  • Evaluation of vessel number should be performed away from the disc due to the possibility of umbilical artery anastamoses / fusion in this location
  • Single umbilical artery associated with higher incidence of abnormal cord (velamentous) and membrane (circumvallate) insertion
Microscopic (histologic) images

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Two vessel umbilical cord


Small / large for gestational age
Small for gestational age
  • Placental weight that falls below the 10th percentile for gestational age
  • Also called low weight placenta
  • Due to a variety of causes, including:
    • Fetal factors: prematurity, fetal malformations or trisomy, small for date fetus, neonatal high hemoglobin or 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
Large for gestational age
  • Placenta weight > 90th percentile for estimated gestational age
  • Also called high weight placenta
  • Usually due to edema as a result of fetal or maternal factors
    • Fetal factors: acute antenatal hypoxia, including low Apgar scores, respiratory distress syndrome, neurologic abnormalities (may persist), hydrops / neonatal death (erythroblastosis fetalis, tumors or fetal renal vein thrombosis), chronic intrauterine infection, immunohemolytic anemia, fetomaternal hemorrhage and polyhydramnios (Hum Pathol 1987;18:387)
    • Maternal factors: diabetes, anemia, malnutrition, retroplacental hematoma and TORCH infections
  • Gross description: bulky, overweight placenta
  • Microscopic (histologic) description: may include extensive villous edema, chorangiosis and villous dysmaturity (distal villous hypoplasia)
Microscopic (histologic) description
  • Small for gestational age: evidence of placental hypoxia including terminal villous hypoplasia, chorangiosis or Tenney-Parker change

Specific infectious organisms
Bacteroides fragilis
  • Gram negative anaerobic bacillus that inhabits the gastrointestinal tract
  • Rare cause of chorioamnionitis and premature delivery (Arch Gynecol Obstet 1990;247:1)
  • Ascending infection from genitourinary tract
  • Microscopic (histologic) description: gram negative bacilli
  • Positive stains: immunofluorescent stains used to demonstrate small, safety pin-like organisms
Candida albicans
  • Fungal organism
  • Most common cause of acute chorioamnionitis with peripheral funisitis
  • Most cases are diagnosed in preterm deliveries
  • Gross description: well circumscribed, pale yellow plaques scattered over the surface of the umbilical cord
  • Microscopic (histologic) description: microabscesses containing yeast in subamniotic layer of umbilical cord (Hum Pathol 1983;14:984); chorioamnionitis or necrotizing funisitis may be present
Chlamydia psittaci (psittacosis)
  • 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, headache and abnormal liver enzymes
  • Microscopic (histologic) description: intense acute intervillositis, perivillous fibrin deposition with villous necrosis and large irregular basophilic intracytoplasmic inclusions within syncytiotrophoblast (Mod Pathol 1997;10:602)
Chlamydia trachomatis
  • Obligate intracellular bacterial causing genitourinary infections including chorioamnionitis, endometritis and salpingitis
  • Usually associated with preterm delivery, fetal conjunctivitis and less commonly with pneumonia
Cytomegalovirus (CMV)
  • DNA virus that causes 10% of chronic villitis cases; often no clinical symptoms (Hum Pathol 1994;25:815)
  • Fetal CMV infection is most severe in placentas with plasmacytic villitis and inclusion bodies (Arch Pathol Lab Med 1984;108:403)
  • Gross description: placenta may be large and edematous or small and fibrotic
  • Microscopic (histologic) description: lymphocytic or plasmacytic villitis with hyalinized villi and mineralization; Hofbauer cell (fetal macrophage) hyperplasia, rare intranuclear and cytoplasmic inclusions (Arch Pathol Lab Med 1992;116:21)
  • Immunohistochemistry helpful since histology often nonspecific (Hum Pathol 1992;23:1234)

Microscopic (histologic) images:

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Intranuclear inclusions

Congenital cytomegalovirus (CMV) infection

Coccidioidomycosis
Cryptococcus
  • Case reports: mother taking steroids for systemic lupus erythematosus (Arch Pathol Lab Med 1994;118:757), HIV+ mother with massive pulmonary embolus and disseminated infection; yeast cells in perivillous space (Hum Pathol 1989;20:920)
  • Gross description: white parenchymal nodules
  • Microscopic (histologic) description: intervillous and villous encapsulated budding yeasts; increased fetal macrophages; no chorioamnionitis or villitis
Fusobacterium
  • Gram negative anaerobic bacteria associated with periodontal disease, preterm birth and stillbirth
  • Microscopic (histologic) description: acute chorioamnionitis; meshworks of pleomorphic and filamentous bacteria that are difficult to detect with routine stains; use Warthin-Starry, Giemsa or Brown and Hopps stains
Haemophilus influenzae
  • Gram negative bacteria that causes antepartum and postpartum sepsis, premature delivery, neonatal meningitis and stillbirth
  • Microscopic (histologic) description: acute chorioamnionitis and umbilical vasculitis with short gram negative bacilli, highlighted by Brown and Hopps stain
Herpes simplex virus (HSV)
  • Rare, may be accompanied by necrotizing funisitis (HSV2) (Hum Pathol 1994;25:715)
  • Microscopic (histologic) description: chorioamnionitis and villous changes that range from bland villous necrosis to mild lymphocytic villitis, active chronic villitis and intervillositis with necrosis
    • Characteristic viral inclusions, villous fibrosis and calcification are present
    • Immunohistochemistry should be performed in suspicious cases without inclusions
  • Molecular / cytogenetics description: HSV infection of decidua capsularis (Arch Pathol Lab Med 1991;115:1141)
  • Differential diagnosis of necrotizing funisitis: syphilis
Human immunodefficiency virus (HIV)
  • Viral particles / antigens identified in placental Hofbauer cells, endothelium and trophoblasts by electron microscopy, immunohistochemistry and PCR (Hum Pathol 1992;23:411)
  • No specific histopathology; inflammatory findings due to secondary infection
Human papillomavirus (HPV)
  • More common in spontaneous abortion specimens than elective abortion specimens
  • Usually infects syncytiotrophoblasts (Hum Pathol 1998;29:170)
Listeria
  • Gram positive bacteria strongly associated with stillbirth, premature delivery and sepsis
  • Gross description: small white nodules (microabcesses) scattered throughout parenchyma
  • Microscopic (histologic) description: acute intervillositis with intervillous microabcesses; organisms identified with gram stain

Microscopic (histologic) images:

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Placental villitis
with a small
microabscess in
congenital infection

Malaria
  • Microscopic (histologic) description: active disease shows free and intraerythrocytic parasites in intervillous space with minimal amounts of coarse brown pigment
    • Chronic intervillositis with trophoblast basement membrane thickening and increased syncytial knots has been noted
    • In chronic infections, parasites coexist with pigment covered with fibrin
    • In inactive infections, only pigment is identified
  • 50% with parasites in placenta had no parasites in peripheral blood
  • Additional references: Am J Surg Pathol 1998;22:1006, Hum Pathol 2001;32:1022, Hum Pathol 2000;31:85
Measles
  • Case reports: monozygotic twins with maternal infection
    • 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 (Mod Pathol 2001;14:1300)
Mycobacterium tuberculosis
  • Microscopic (histologic) description: miliary tubercles in villi or perivillous fibrin with granulomatous or chronic deciduitis
Mycoplasma and Ureaplasma
  • Role of Ureaplasma urealyticum or Mycoplasma hominis is controversial but these organisms, often associated with bacterial vaginosis, are believed to play an important role in chorioamnionitis and possibly perinatal morbidity, including preterm delivery
Parvovirus B19
  • Destroys early RBCs (normoblasts), causing anemia and resultant fetal hydrops with marked erythroid hypoplasia of bone marrow and occasional giant erythroblasts
  • Fetuses may also develop myocarditis
  • Microscopic (histologic) description: increased fetal erythroblasts with intranuclear inclusions and villous edema
Syphilis (Treponema pallidum)
  • Often associated with stillbirth or early neonatal death
  • Umbilical cord often normal; 36% have necrotizing funisitis
  • Microscopic (histologic) description: immature, edematous villi with increased fetal erythroblasts, endarteritis and perivasculitis of stem vessels and lymphoplasmacytic villitis
    • Necrotizing funisitis or acute villitis have also been reported
    • May not have prominent plasma cells (Hum Pathol 1996;27:366, Hum Pathol 1993;24:779); associated with intravillous hemosiderin
    • Most cases with positive PCR have negative histology so do PCR of placental tissue if suspect syphilis
  • Positive stains: visualize spirochetes in cord using silver (Warthin-Starry or Steiner) stain and immunofluorescent stains (Hum Pathol 1995;26:784)
Toxoplasma
  • Microscopic (histologic) description: low grade chronic villitis and villous fibrosis with Hofbauer cell hyperplasia and endarteritis
    • Chronic intervillositis may be present
    • Cysts and free organisms are identified in the chorionic plate or amnion
Varicella zoster virus
  • Early infections (before 20 weeks) may result in fetal eye, skin, limb and neural developmental abnormalities
  • Later infections may result in neonatal varicella
  • Case reports: spontaneous abortion in first trimester (Hum Pathol 1998;29:94)
  • Microscopic (histologic) description: early infection associated with acute necrotizing villitis; later infection presents with lymphocytic villitis with giant cells and stromal fibrosis
    • Characteristic viral inclusions, villous fibrosis and calcification are present
    • Immunohistochemistry should be performed
  • Additional references: Hum Pathol 1996;27:191

Staging-GTD
AJCC / UICC TNM classification
Primary tumor (T):
  • TX: primary tumor cannot be assessed
  • T0: no evidence of primary tumor
  • T1 (I): tumor confined to uterus
  • T2 (II): tumor extends to other genital structures (ovary, tube, vagina and broad ligaments) by metastasis or direct extension

Regional lymph nodes:
  • No regional nodal designation (N classification) in the staging of gestational trophoblastic tumors
  • Nodal involvement is classified as metastatic M1b disease

Distant metastasis (M):
  • M0: no distant metastasis
  • M1: distant metastasis
  • M1a (III): lung metastasis
  • M1b (IV): all other distant metastasis (direct invasion or metastasis to nongenital structures)

TNM descriptors for special circumstances:
  • "m" suffix: multiple primary tumors in a single site (recorded in parentheses)
  • "y" prefix: classification performed during / after initial therapy
  • "r" prefix: recurrent tumor after documented disease free interval
  • "a" prefix: stage determined at autopsy
  • Residual tumor (R)
    • Rx: cannot be assessed
    • R0: no residual tumor
    • R1: microscopic residual tumor
    • R2: macroscopic residual tumor
Prognostic index scores
Factors and scoring:
  • Age: 0 if < 40, 1 if age 40 or more
  • Antecedent pregnancy: 0 if hydatidiform mole, 1 if abortion and 2 if term pregnancy
  • Interval months from index pregnancy: 0 if < 4 months, 1 if 4 - 6 months, 2 if 7 - 12 months and 4 if > 12 months
  • Pretreatment hCG: 0 if < 1,000, 1 if 1,000 - 9,999, 2 if 10,000 - 99,999 and 4 if 100,000 or more
  • Largest tumor size, including uterus: 0 if < 3 cm, 1 if 3 - 5 cm and 2 if > 5 cm
  • Site of metastases: 0 if lung, 1 if spleen or kidney, 2 if GI tract and 4 if brain or liver
  • Number of metastases identified: 1 if 1 - 4, 2 if 5 - 8 and 4 if > 8
  • Previous failed chemotherapy: 2 if single drug, 4 if 2+ drugs

  • Low risk: score of 6 or less (usually treat with single agent chemotherapy)
  • High risk: score of 7 or more (usually treat with combined, multiple agent chemotherapy)
2006 FIGO staging
Stage I tumor confined to the uterus:
  • IA stage I with low risk prognostic score
  • IB stage I with high risk prognostic score

Stage II tumor extends outside of the uterus, limited to the genital structures:
  • IIA stage II with low risk prognostic score
  • IIB stage II with high risk prognostic score

Stage III tumor extends to the lungs, with or without known genital tract involvement:
  • IIIA stage III with low risk prognostic score
  • IIIB stage III with high risk prognostic score

Stage IV tumor involves all other metastatic sites:
  • IVA stage IV with low risk prognostic score
  • IVB stage IV with high risk prognostic score
2006 FIGO stage groupings (TNM classification and risk category)
Stage I: T1 M0 unknown risk factors:
  • Stage IA: T1 M0 low risk
  • Stage IB: T1 M0 high risk

Stage II: T2 M0 unknown risk:
  • Stage IIA: T2 M0 low risk
  • Stage IIB: T2 M0 high risk

Stage III: any T M1a unknown risk:
  • Stage IIIA: any T M1a low risk
  • Stage IIIB: any T M1a high risk

Stage IV: any T M1b unknown risk:
  • Stage IVA: any T M1b low risk
  • Stage IVB: any T M1b high risk

Tenney Parker changes
Definition / general
  • Increased numbers of trophoblastic syncytial knots, often due to maternal hypertension or uteroplacental insufficiency
  • Often seen in association with terminal villous hypoplasia
Etiology
  • Inadequate maternal perfusion (diabetes, hypertension)
Microscopic (histologic) description
  • Increased syncytial knotting
  • Changes of hypertension / preeclampsia / decidual vasculopathy may be present in the decidua

Thin cord
Definition / general
  • Decrease in the cross sectional diameter of the umbilical cord
  • Also called thin cord syndrome
Essential features
  • Due to a reduction in the amount and fluid content of supportive Wharton jelly, the number of umbilical vessels present or a combination of both
  • Cord diameter < 1.0 cm (normal: 1.25 - 2.5 cm) at term or an umbilical cord cross sectional area (on ultrasound examination) < 10th percentile for gestational age
Terminology
  • Thin or lean umbilical cord should be distinguished from segmental thinning of an umbilical vessel, which is due to a paucity of the tunica media layer
Epidemiology
  • Present in up to 10% of term infants, in some series
Pathogenesis
  • Reduction in Wharton jelly can predispose to compression of the umbilical vessels
Etiology
  • Factors that determine the amount and content of Wharton jelly are poorly understood, although Wharton jelly typically increases until 32 weeks gestation and then slightly declines in fluid content thereafter
  • Reduction in the number of umbilical vessels is suggested to be due to atrophy of an umbilical artery
Clinical features
  • Associated with preeclampsia, intrauterine growth restriction and intrauterine fetal demise
  • Associated with fetal distress at the time of delivery (oligohydramnios, low Apgar scores and meconium stained amniotic fluid)
Case reports
Gross description
  • Umbilical cord diameter is measurably reduced
  • Lower coiling index (reduced number of spirals per unit length) may result in a hypocoiled gross appearance
Gross images

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Missing Image

Fig C: comparative image
of a thin umbilical cord
(bottom) with a normal
diameter umbilical cord

Microscopic (histologic) description
  • Decrease in Wharton jelly can be appreciated
  • Umbilical vein may be diminished in size, while umbilical arteries appear normal in histologic appearance
Board review style question #1
Which of the following best describes a thin umbilical cord?

  1. A cord diameter less than 2 cm at term is characteristic
  2. A reduction in the size of the tunica media layer
  3. Associated with preterm labor
  4. No change in the number of umbilical vessels
  5. Predisposes the umbilical vessels to compression effects
Board review style answer #1
E. Thin cord is due to a decrease in Wharton jelly or a decrease in the number of umbilical vessels, which can predispose the umbilical vessels to compression phenomena.

Comment Here

Reference: Thin umbilical cord

Thrombosis of fetal arteries
Definition / general
  • Thrombosis of fetal vessels results in fibrosis of downstream villi
  • Thrombi may also embolize to fetal organs, resulting in perinatal asphyxia and an increased risk of neurologic injury
  • More common in diabetic pregnancies, often associated with increased syncytial knots, fibrotic villi, Langhans cells and villous fibrinoid necrosis
Gross description
  • Triangular or hemispheric pale areas, seen better after formalin fixation or otherwise similar to remaining placenta
Microscopic (histologic) description
  • Occlusive thrombi in large stem vessels accompanied by downstream changes, including loss of vascularity and fibrosis

Torsion / hypercoiling
Definition / general
  • Normal umbilical cord has approximately 1 coil per 5 cm
  • Number of coils is related to fetal movement
  • Torsion / hypercoiling (> 2 coils per 5 cm) is associated with extremely long cords, twin gestation and cocaine; has increased risk of fetal growth restriction or death
  • Associated with fibrosis and loss of Wharton jelly (Arch Pathol Lab Med 2000;124:1352)
Gross images

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Torsion of umbilical cord


Toxemia of pregnancy (preeclampsia and eclampsia)
Definition / general
  • Preeclampsia is a pregnancy specific hypertensive disorder diagnosed by the presence of 3 main signs: hypertension, proteinuria and edema
  • Diagnosed after 20 weeks gestational age (GA) (usually begins at 32 weeks but may present earlier in patients with pre-existing kidney disease, hypertension or hydatidiform moles) (SAGE Open Med 2019;7:2050312119843700)
  • Current view of the clinical picture of preeclampsia and its convulsive form, eclampsia, deviates from using proteinuria as the sole indicator; other than the maternal hypertension (160/110 mmHg) at bed rest and proteinuria that are consistently detected in preeclampsia, hepatic functions could be impaired and manifest serologically as hepatic marker values that are twice normal (SAGE Open Med 2019;7:2050312119843700)
  • May lead to HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count) (SAGE Open Med 2019;7:2050312119843700)
    • This syndrome may cause cerebral hemorrhage and consequently maternal and fetal demise
Essential features
  • Thrombocytopenia, recalcitrant epigastric pain, progressive renal dysfunction, pulmonary edema; some cerebral and ophthalmic manifestations could be evident (SAGE Open Med 2019;7:2050312119843700)
  • Pregnancy toxemia is scaled into (SAGE Open Med 2019;7:2050312119843700)
    • Nonsevere hypertension / mild: systolic blood pressure (SBP) of 140 - 149/90 - 99 mmHg
    • Nonsevere hypertension / moderate: systolic blood pressure of 150 - 159/100 - 109 mmHg
    • Severe: systolic blood pressure of ≥ 160 mmHg
  • Categorized into the following, depending on the gestational age that hypertension is discovered (SAGE Open Med 2019;7:2050312119843700):
    • Chronic / pre-existing hypertension: before 20/52 gestational age
    • Gestational hypertension: later than 20/52 gestational age and disappears postpartum
    • Preeclampsia / eclampsia: later than 20/52 gestational age + at least 1 of the following:
      • Proteinuria
      • Maternal organ dysfunction (such as increased creatinine, increased liver enzymes, neurological complications, hematological complications)
      • Uteroplacental dysfunction (such as intrauterine growth restriction [IUGR] or stillbirth)
    • Chronic / pre-existing hypertension with superimposed preeclampsia / eclampsia: before 20/52 gestational age + preeclampsia or eclampsia
Terminology
  • Toxemia of pregnancy (preeclampsia and eclampsia)
  • Preeclampsia: pregnancy + hypertension, proteinuria and edema
  • Eclampsia: preeclampsia + convulsions
  • HELLP syndrome: hemolysis, elevated liver enzymes and low platelet count
ICD coding
  • ICD-10:
    • O14 - preeclampsia
      • O14.0 - mild to moderate preeclampsia
      • O14.1 - severe preeclampsia
      • O14.2 - HELLP syndrome
      • O14.9 - unspecified preeclampsia
    • O11 - pre-existing hypertension with preeclampsia
      • O11.1 - pre-existing hypertension with preeclampsia, first trimester
      • O11.2 - pre-existing hypertension with preeclampsia, second trimester
      • O11.3 - pre-existing hypertension with preeclampsia, third trimester
      • O11.4 - pre-existing hypertension with preeclampsia, complicating childbirth
      • O11.5 - pre-existing hypertension with preeclampsia, complicating the puerperium
      • O11.9 - pre-existing hypertension with preeclampsia, unspecified trimester
    • O15 - eclampsia
      • O15.0 - eclampsia complicating pregnancy
        • O15.00 - eclampsia complicating pregnancy, unspecified trimester
        • O15.02 - eclampsia complicating pregnancy, second trimester
        • O15.03 - eclampsia complicating pregnancy, third trimester
      • O15.1 - eclampsia complicating labor
      • O15.2 - eclampsia complicating the puerperium
      • O15.9 - eclampsia, unspecified as to time period
  • ICD-11:
    • JA20 - pre-existing hypertension complicating pregnancy, childbirth or the puerperium
    • JA21 - preeclampsia superimposed on chronic hypertension
    • JA24 - preeclampsia
    • JA25 - eclampsia
Epidemiology
Sites
  • Placenta, brain, vascular system
Pathophysiology
Etiology
  • Idiopathic
Diagrams / tables

Images hosted on other servers:

Diagnostic template:
maternal vascular
malperfusion

Clinical features
  • Hypertension
  • Proteinuria
  • Creatinine: ≥ 90 μmol/L
  • Increased alanine transaminase (ALT) or aspartate transaminase (AST): > 40 IU/L
  • Pain, abdominal: right upper quadrant / epigastric
  • Seizures (eclampsia)
  • Altered visual / mental status
  • Intrauterine growth restriction
  • Stillbirth
  • HELLP syndrome: hemolysis, elevated liver enzymes and low platelet count (< 150,000/μL) (SAGE Open Med 2019;7:2050312119843700)
  • Abruptio placenta with prolonged seizures, 20 - 50% (Fetal Matern Med Rev 2011;22:91)
Diagnosis
Laboratory
Case reports
  • 27 year old woman who presented with abducens nerve palsy immediately after the delivery with severe preeclampsia (Tunis Med 2018;96:76)
  • 28 year old, 33 + 4 weeks pregnant woman presented with severe preeclampsia and severe HELLP syndrome (BMC Nephrol 2020;21:204)
  • 30 year old Bangladeshi - Bengali woman in her 28th week of pregnancy presented with severe systemic hypertension, biventricular heart failure and preeclampsia (BMC Res Notes 2014;7:814)
  • 31 year old pregnant woman with a history of 2 pregnancy losses presented with preeclampsia and HELLP syndrome (BMC Pregnancy Childbirth 2018;18:191)
Treatment
  • Delivery of baby and placenta (most effective)
  • Corticosteroids (promote lung maturation of baby)
  • Antihypertensives (treat hypertension)
  • Anticonvulsants (magnesium sulfate, treat convulsions)
  • Reference: SAGE Open Med 2019;7:2050312119843700
Gross description
  • Placental hypoplasia:
    • Placental weight: < 10th percentile of gestational age
    • Thin umbilical cord (width: < 10th percentile for gestational age or < 8 mm at term)
  • Placental infarction:
    • Requires histologic confirmation / sampling
    • Location: central or marginal (away from periphery is more significant)
    • Also describe shape, color, consistency, size and percentage of infarcted parenchyma (significant percentage: any percentage preterm, > 5% at term)
    • Compared to normal parenchyma, the lesions are:
      • Demarcated slightly (new) to well (old)
      • Red (new) to tan (old)
      • Firmer consistency temporally
    • Shape is rectangular, polygonal, wedge or triangular with base at maternal surface
    • Rounded lesions represent intraparenchymal infarction hematomas / intraplacental abruption
  • Retroplacental hemorrhage / abruption
  • Reference: APMIS 2018;126:551
Gross images

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Focal placental infarction

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Extensive placental infarction

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Placental infarction, hematoma

Microscopic (histologic) description
  • Placental findings can be variable ranging from no pathologic features to three main categories of lesions: lesions consistent with maternal vascular malperfusion, lesions consistent with fetal vascular thrombo-occlusive disease, lesions consistent with amniotic fluid infection (Placenta 2005;26:S114)
  • Lesions consistent with maternal vascular malperfusion (Placenta 2014;35:696)
    • Altered villous morphology (accelerated villous maturation):
      • Small, thin, elongated villi with increased syncytial knots
      • Should only be diagnosed based on examination of the villi adjacent to the maternal surface
      • Morphology is identical to the normal appearance of the subchorionic zone which serves as an internal control
    • Altered villous architecture (distal villous hypoplasia) (Pediatr Dev Pathol 2016;19:31):
      • Paucity of villi in relation to the surrounding stem villi (increased space around the villi), leading to prominent large stem vessels all the way to the maternal surface at low power examination
      • Easier to recognize before 32 weeks of gestation
      • In second trimester, loss of the normal gradient of larger immature villi to small mature villi at scanning magnification from midplacenta to maternal surface
      • May be graded as:
        • 0: none
        • 1: mild to moderate (decreased density and sparseness of some distal villi, thinning of intermediate villi)
        • 2: severe (significantly decreased density and sparseness of distal villi, thinning of intermediate villi); best identified at x4 objective
    • Syncytiotrophoblastic knots (also known as Tenney-Parker change) (Pediatr Dev Pathol 2010;13:305):
      • Increased nuclear clumping and basophilia of the multinucleated cells on the terminal villi
      • Only reported when identified in every 40x field (30% of the villi) or when prominent under 36 weeks
    • Decidual vasculopathy (Placenta 2016;42:37):
      • Hypertrophic arteriopathy:
        • Small arteries with wall thickening, swelling and detachment of endothelial cells and a sparse perivascular lymphocytic infiltrate
      • Severe arteriopathy:
        • Fibrinoid necrosis of vascular walls (amorphous eosinophilic vessel wall)
    • Placental infarction (APMIS 2018;126:551):
      • Groups of villi (at least 5) with ischemic necrosis (pyknotic nuclei, followed by karyorrhectic nuclei and loss of nuclear staining of the villous trophoblast and then villous stromal cells) and collapse of the intervillous space
      • Infarcted areas are well circumscribed / clearly demarcated from the surrounding parenchyma
      • Most infarcted areas are triangular and involve the maternal floor
      • Infarction hematoma is a rounded (spherical) hemorrhage surrounded by infarcted villi
    • Acute atherosis:
      • Intimal foamy cells, usually seen in placental arteries but may extend into the decidual arteries
      • May be associated with uteroplacental thrombosis, infarction, abruption
    • Other features:
      • Laminar necrosis of basal plate or membranes
      • Diffuse decidual leukocytoclastic necrosis
      • Islands of fibrin with extravillous trophoblasts
      • Increase in intervillous fibrin
      • > 3% of villi with fibrinoid necrosis
      • Extravillous trophoblast cysts
      • Membrane chorionic microcysts
      • Proliferation of basal extravillous cytotrophoblasts and villous cytotrophoblasts
      • Increased multinucleate trophoblasts in decidua basalis
      • Intraluminal endovascular trophoblast in third trimester
      • Presence of fetal nucleated red blood cells in villous vessels
      • Thickened trophoblast basement membrane (highlighted by PAS stain)
      • Placental mesenchymal dysplasia
      • Chorangioma / localized or multifocal chorangiomatosis
      • Calcifications
      • Unconverted placental bed spiral arteries
      • Meconium effects
  • Lesions consistent with fetal vascular thrombo-occlusive disease:
    • Villous changes:
      • Early: villous stromal-vascular karyorrhexis
      • Late: hyalinized avascular villi
      • Severe: fetal thrombotic vasculopathy (average of > 15 affected villi/slide)
    • Vascular changes:
    • Inflammatory lesions:
      • Chronic villitis of unknown etiology with obliterative fetal vasculopathy
  • Lesions consistent with amniotic fluid infection:
    • Chorioamnionitis, maternal response:
      • Stage 1 early: acute subchorionitis / chorionitis
      • Stage 2 intermediate: acute chorioamnionitis
      • Stage 3 late: necrotizing or subacute chorioamnionitis
      • Severe: subchorionic microabscesses
    • Chorioamnionitis, fetal response:
      • Stage 1 early: umbilical phlebitis / chorionic vasculitis
      • Stage 2 intermediate: umbilical arteritis
      • Stage 3 late: concentric umbilical perivasculitis (necrotizing funisitis)
      • Severe: intense chorionic vasculitis with recent nonocclusive chorionic vessel thrombi
Microscopic (histologic) images

Contributed by Khaldoon Aljerian, M.D., M.H.Sc.

Decidual vasculopathy

Decidual vasculopathy thrombus

Retroplacental hemorrhage thrombus

Positive stains
Negative stains
Molecular / cytogenetics description
Videos

Categories of placental pathology
by Dr. Drucilla Roberts

Sample pathology report
  • Placenta and membranes, spontaneous vaginal delivery:
    • Maternal vascular malperfusion; consistent with toxemia of pregnancy (see comment)
    • Comment: Singleton placenta. Placental weight: < 5th percentile for gestational age. Evidence of maternal vascular malperfusion with villous changes: increased intervillous fibrinoid with calcifications, multifocal placental / villous infarction (40%). Implantation site shows evidence of maternal vascular malperfusion: increased placental site giant cells / immature intermediate trophoblasts, decidual arteriopathy. Retroplacental hematoma with intraplacental extension (abruptio placenta) with acute and chronic hemorrhage with hemosiderin laden macrophages. The retroplacental hemorrhage with villous infarction and maternal vascular malperfusion may be consistent with gestational hypertension and may have resulted in the low placental weight; this is consistent with toxemia of pregnancy. Clinical correlation required.
Differential diagnosis
  • Disc edge infarction:
    • Groups of villi confined to the (term) placental edge showing ischemic necrosis and villous agglutination
  • Infarction of < 5%, full term disc:
    • Less than 5% of the placental disc shows villi with ischemic necrosis and villous agglutination
  • Increased perivillous fibrin:
    • Abundant perivillous fibrin that obliterates the intervillous space with loss of the syncytiotrophoblast
    • Requires at least 1 area of full thickness involvement / entrapment of at least half of the villi on a single slide
  • Normal muscular decidual arteries:
    • Thick muscular walls
    • Lack endothelial disruption and perivascular lymphocytes
    • Highlighted with desmin
  • Features mimicking accelerated maturation:
    • Small, widely spaced, elongated villi with increased syncytial knots (normally seen under the fetal plate and in a patchy distribution near the maternal surface in the region of venous drainage)
Board review style question #1
Which disease is included in the definition of preeclampsia?

  1. Elevated liver function tests
  2. Hemolysis
  3. Hypertension
  4. Hypovolemic shock
  5. Low platelets
Board review style answer #1
Board review style question #2
Which diagnosis is related to toxemia of pregnancy and may lead to death by cerebral hemorrhage?

  1. Convulsions
  2. Disseminated intravascular coagulation
  3. HELLP syndrome
  4. High platelets
  5. Hypovolemic shock
Board review style answer #2
Board review style question #3

A 30 year old gravida 2 para 1 with gestational hypertension, edema and proteinuria with intrauterine growth restriction presents at term for spontaneous vaginal delivery (SVD). The placenta is small for the gestational age. Histological examination of the placental disc section reveals the above changes in the decidual arteries. Which complication should we be aware of?

  1. Convulsions
  2. Depression
  3. Diabetes
  4. High platelets
  5. Hypovolemic shock
Board review style answer #3

Twin - twin transfusion
Definition / general
  • Unbalanced flow of blood through arteriovenous anastomoses with worse clinical outcome if AV anastomoses without arterioarterial or venovenous anastomoses
  • Results in growth discrepancy and mortality, which is usually marked in second trimester
  • Both twins are at risk (70% mortality)
  • After death of donor twin, may get an acute reverse transfusion
Case reports
  • 22 year old pregnant woman with twins, one with oligohydramnios, one with polyhydramnios (Case of the Week #264)
Treatment
  • Serial amniocentesis; removal of a fetus
  • Surgical interruption of common vasculature
Gross description
  • Donor twin is anemic, small and pale with small organs
  • Recipient twin is large and plethoric with large organs; at risk for high output cardiac failure
Gross images

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Twin - twin transfusion

Anastomosis

Microscopic (histologic) description
  • Donor placentas have large edematous villi, small capillaries and numerous nucleated red blood cells
  • Recipient placenta has small, firm and mature villi with congested vessels

Twins
Definition / general
  • Multiple gestations are common and in recent times, more frequently encountered due to advances in assisted reproductive techniques
  • Twin pregnancies are higher risk than singletons with monochorionic twins having a significantly higher risk than dichorionic twins, making determination of chorionicity important for the clinical complications inherent to the type of placentation; examples include
    • Twin to twin transfusion syndrome (TTTS)
    • Fetal growth restriction
    • Twin anemia polycythemia sequence (TAPS)
    • Twin reversed arterial perfusion (TRAP)
    • Conjoined twins
Essential features
  • Chorionicity refers to the type of placentation and is not a reflection of zygosity
  • Zygosity refers to the type of conception and the degree of similarity of the genetic makeup of the zygotes from which twins develop
Terminology
  • Chorionicity and zygosity:
    • Dichorionic twin placentas can be monozygotic (derived from a single fertilized ovum with identical genotypes) or dizygotic (derived from 2 separate fertilized ova)
      • All dizygous twins are dichorionic and placentas can be fused or separate
      • Monozygous twins can result in dichorionic or monochorionic placentas
    • Monochorionic twin placentas are one placenta shared by twins who may have separate amnions (diamnionic) or a common amnion cavity (monoamnionic); they are predominantly monozygotic, though occasional dizygotic monochorionic twinning has been documented (Eur J Pediatr 2014;173:1249, J Obstet Gynaecol Res 2018;44:576)
ICD coding
  • ICD-10: O30.009 - twin pregnancy, unspecified number of placenta and unspecified number of amniotic sacs, unspecified trimester
Epidemiology
Pathophysiology
  • Mechanism for zygosity in twinning is not completely understood
  • Dizygotic (nonidentical) twins result from fertilization of separate ova by different sperm
  • Monozygotic (identical) twins arise from a single ovum fertilized by 1 sperm; the resultant zygote can undergo division and the timing of the division translates into the type of placentation:
    • Division within the first 3 days after fertilization (morula) usually results in dichorionic placentation (70% of monochorionic placentas)
    • Division 3 - 9 days after fertilization (blastocyst) results in monochorionic diamnionic placentation
    • Division 8 - 12 days after fertilization results in monochorionic monoamnionic placentation
    • Later splitting results in conjoined twins with monochorionic monoamnionic placentation
  • Reference: Darwish: Contemporary Gynecologic Practice, 2015
Diagrams / tables

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Placentation in monozygotic and dizygotic twins

Clinical features
Diagnosis
  • Determination of chorionicity is part of fetal surveillance throughout pregnancy
  • Gross evaluation of the placenta establishes chorionicity and can identify pathologies of the placenta, especially those unique to twin placentas
  • Determination of zygosity by the assumption that all monochorionic twins are monozygotic is unreliable as dizygotic monochorionic twinning has been documented
  • Reference: Am J Obstet Gynecol 2015;213:S91
Radiology description
  • Traditionally, transabdominal ultrasonographic studies in the second and third trimesters were able to determine chorionicity by demonstrating separate placentation, discordant fetal gender, identification of the twin peak sign (also known as the lambda sign) and thickness of the dividing fetal membrane; these are features of chorionic placentas
    • Zygosity could be determined in the setting of discordant fetal genders by ultrasonography
  • Chorionicity and amnionicity can be determined in the first trimester transvaginal ultrasound, ideally between 9 and 10 weeks of gestation (Am J Perinatol 2001;18:23)
Radiology images

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Dichorionic - diamniotic twins

Twin pregnancy with defect

Twin
oligohydramnios
- polyhydramnios
sequence

Cotwin demise

Prognostic factors
  • Twin pregnancies are higher risk than singletons with 4 fold higher perinatal mortality rates with some of the risk attributed to prematurity, fetal growth restriction and chromosomal abnormalities but also to complications directly related to complexities uniquely inherent to the type of chorionicity (Am J Obstet Gynecol 2015;213:S91, Am J Perinatol 2001;18:23)
  • Perinatal demise in twin pregnancies accounts for 12.6% of all perinatal mortality (Am J Perinatol 2001;18:23)
    • Chorionicity and perinatal mortality: 50% of monoamnionic twins, 26% of diamnionic monochorionic twins and 9% of dichorionic diamnionic twins
Case reports
  • 27 year old woman with monochorionic dizygotic, sex discordant twins resulting from spontaneous pregnancy with blood chimerism (J Matern Fetal Neonatal Med 2009;22:708)
  • 28 year old woman who became pregnant with twins with a partial hydatidiform mole and a coexistent live fetus; diagnostic and therapeutic dilemmas (Ginekol Pol 2020;91:589)
  • 30 year old woman who became pregnant with monochorionic diamnionic twins discordant for esophageal atresia, duodenal atresia, gastric perforation and hypoplastic left heart structures in 1 twin (J Med Case Rep 2017;11:64)
  • 34 year old woman who became pregnant with monochorionic dizygotic twins with sex discordance and confined blood chimerism (Eur J Pediatr 2014;173:1249)
  • 39 year old woman with fetal sex discordance in a monochorionic twin pregnancy following intracytoplasmic sperm injection (J Obstet Gynaecol Res 2018;44:576)
Gross description
  • Dichorionic twins:
    • Separate without dividing membrane: 2 separate placentas
    • Separate with dividing membrane consisting of 4 layers (2 amnions and 2 chorions)
    • Fused with a dividing membrane consisting of 3 or 4 layers (2 layers of amnion and 1 or 2 layers of chorion)
  • Monochorionic twins:
    • Monochronionic diamnionic: single placental disc with dividing membrane consisting of 2 layers (2 layers of amnion, no chorion)
    • Monochorionic monoamnionic: no dividing membrane
  • Reference: Darwish: Contemporary Gynecologic Practice, 2015
Gross images

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Dichorionic diamnionic twin placenta

Dichorionic diamnionic
and monochorionic
quadruplet placenta

Twin placenta - acardia

Monochorionic placentas

Microscopic (histologic) description
  • Dividing membrane in dichorionic placentas shows the separation of amnion layers by chorion layers which may be fused
  • Dividing membrane in monochorionic membranes shows juxtaposed amnion layers
Microscopic (histologic) images

Contributed by Shahrazad Saab, M.D.

Dichorionic diamnionic dividing membrane

Monochorionic diamnionic dividing membrane

Sample pathology report
  • Twin placentas, cesarean section:
    • Fused / separate dichorionic diamnionic twin placentas
      • Placenta A: mature placenta, 425 g, with no significant histopathologic abnormality
      • Placenta B: mature placenta, 420 g, with no significant histopathologic abnormality

  • Twin placentas, cesarean section:
    • Small, slightly immature (mid third trimester) monochorionic diamnionic twin placentas (300 g, less than third percentile for gestational age)
      • Placenta A:
        • Fetal vascular distribution: 60%
        • Single large focus of avascular villi
      • Placenta B:
        • Fetal vascular distribution: 40%
        • Fetal vascular malperfusion (velamentous insertion of hypercoiled umbilical cord with large foci of villous vascular and stromal karyorrhexis)
Board review style question #1

Which of the following is correct in reference to dichorionic twin placentas?

  1. All dichorionic twin placentas are dizygotic
  2. All dichorionic twin placentas are monozygotic
  3. Dichorionic placentas are never monozygotic
  4. Dichorionic placentas can be either dizygotic or monozygotic
Board review style answer #1
D. Dichorionic placentas can be either dizygotic or monozygotic (Am J Obstet Gynecol 2015;213:S91)

Comment Here

Reference: Twins
Board review style question #2
Which of the following is true regarding dividing membranes of twin placentas?

  1. Dichorionic twins cannot have separate placentas without a dividing membrane
  2. The dividing membranes of dichorionic diamnionic twin placentas are always comprised of 4 layers
  3. The dividing membranes of monochorionic diamnionic twin placentas can be comprised of 2 or 3 layers
  4. The dividing membranes of separate, fused dichorionic diamnionic twin placentas are comprised of 3 or 4 layers
Board review style answer #2
D. The dividing membranes of separate, fused dichorionic diamnionic twin placentas are comprised of 3 or 4 layers (Am J Obstet Gynecol 2015;213:S91)

Comment Here

Reference: Twins

Umbilical vasculitis and funisitis
Definition / general
  • Inflammation of the umbilical vessels (vasculitis) and cord substance (funisitis) occurs in response to many injuries and constitutes the fetal inflammatory response
Essential features
  • Umbilical vasculitis and funisitis represent a fetal response to injury
  • Vasculitis and funisitis are often microscopic findings but when the inflammatory response is severe, gross findings may also be evident
  • Microorganisms are often causative, although vasculitis and funisitis can be seen in a wide range of injury
  • Chorioamnionitis or meconium exposure are often associated conditions
Terminology
  • Specific diagnoses can define the location and extent of the general inflammatory process
    • Vasculitis: a general term defining inflammation of an umbilical vessel
    • Funisitis: inflammation within the cord substance / Wharton jelly
    • Arteritis: inflammation involving an umbilical artery
    • Phlebitis: inflammation involving the umbilical vein
    • Peripheral funisitis: inflammation located at the radial periphery or external surface of the umbilical cord and may be the primary observed histologic pattern
    • Necrotizing funisitis: established or longstanding infections demonstrating tissue necrosis, abundant inflammation and accumulation of cellular debris throughout the umbilical cord
ICD coding
  • ICD-10:
    • O41.1 - infection of amniotic sac and membranes
    • B37.8 - candidiasis of other sites
Epidemiology
  • Patients with documented microorganisms (e.g. herpes simplex virus, group B Streptococcus, Candida albicans, Treponema pallidum)
  • Patients with preterm labor, chorioamnionitis or meconium exposure
Sites
  • Progressive inflammatory infiltration that involves umbilical vein, umbilical arteries or umbilical cord substance (Wharton jelly)
Pathophysiology
  • Microorganisms gain access to the placenta or umbilical cord by ascension from the endocervical canal, by the maternal blood stream or by direct inoculation (such as from a diagnostic procedure)
  • Cytokines (IL8, interferon gamma, complement components, leukotriene B4) are released by endothelium, mast cells and macrophages in response, creating a chemoattractant chemical gradient for neutrophils
  • Chemical gradient may be augmented by certain peptides released by microorganisms
  • Activated neutrophils marginate against the vascular endothelium and transmigrate through the vascular wall into the connective tissue of Wharton jelly (for general funisitis and all forms of vasculitis)
  • Eventual precipitation of immune complexes (for necrotizing funisitis) as microbiologic antigens elicit a maternal antibody response through the transplacental passage of antibodies
  • Reference: Kumar: Robbins & Cotran - Pathologic Basis of Disease, 10th Edition, 2020
Etiology
  • Bacteria associated with intrauterine infection (group B Streptococcus, Escherichia coli, Fusobacterium or Bacteriodes species, Listeria monocytogenes)
  • Fungi (Candida species)
  • Less common causes include Actinomyces species, herpes simplex virus and Treponema pallidum (a classic causative agent of necrotizing funisitis)
  • Reference: Am J Obstet Gynecol 2015;213:S29
Clinical features
  • Typically seen in association with chorioamnionitis (maternal inflammatory response, including fever, tachycardia, leukocytosis or foul smelling amniotic fluid)
  • Minimal / mild inflammation (particularly mild phlebitis of the umbilical vein) can be associated with only meconium exposure
Diagnosis
  • Presence of any neutrophilic infiltrate involving the umbilical vein, umbilical arteries, cord substance (Wharton jelly) or peripheral umbilical cord
  • Qualifying the location and degree of inflammation is encouraged over the generic use of the term funisitis, historically used to inadequately describe the presence of any inflammation in any location
Laboratory
  • Positive documentation of intrapartum infection or maternal infectious status may be useful in some cases
Radiology description
  • Inflammation induced calcifications within Wharton jelly can be distributed to resemble a spiral barber's pole on maternal radiographs in some cases of necrotizing funisitis
Prognostic factors
  • Linked to increased incidence of interventional deliveries, low Apgar scores, clinical sepsis and admission to neonatal intensive care units (Virchows Arch 2016;468:503)
Case reports
Gross description
  • External surface of an involved umbilical cord is usually unremarkable
  • Peripheral funisitis may be seen as multiple small, white or yellow plaques on the surface of the umbilical cord (often associated with Candida infection)
  • Necrotizing funisitis on cut surface may appear as concentric perivascular rings resembling Ouchterlony immunodiffusion plates
  • Necrotizing funisitis may become calcified and appear chalky white or as a white linear spiral (barber's pole configuration)
  • Reference: Beargen: Manual of Pathology of the Human Placenta, 2nd Edition, 2011
Gross images

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Listeria monocytogenes

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Concentric waves of inflammation

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Barber's pole umbilical cord

Microscopic (histologic) description
  • Umbilical phlebitis is the presence of neutrophils in the wall of umbilical vein (stage 1: early; most common histologic finding)
  • Umbilical arteritis is the presence of neutrophils in the wall of 1 or both umbilical arteries (stage 2: intermediate)
  • Necrotizing funisitis typically shows 3 vessel panvasculitis, with degenerating neutrophilic and cellular debris present in the cord substance, sometimes arranged as concentric arcs (or waves) of necrosis (stage 3: late)
  • Peripheral funisitis displays epithelial necrosis and multiple microabscesses involving the periphery of the umbilical cord (and often Candida species can be documented)
  • Evidence of meconium exposure may be observed, possibly with meconium induced myocyte necrosis
  • Calcification of the immune complexes or cellular debris can be partially or entirely encircling the vessels, particularly with necrotizing funisitis
  • Reference: Kraus: Placental Pathology (AFIP Atlas of Nontumor Pathology), 1st Edition, 2005
Microscopic (histologic) images

Contributed by Paul J. Kowalski, M.D. (source: University of Toronto)
Panvasculitis and acute funisitis

Panvasculitis and acute funisitis

Peripheral microabscess

Peripheral microabscess

Candidal fungal elements

Candida fungal elements

Virtual slides

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Missing Image

Candida funisitis, H&E

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Candida funisitis, PAS

Positive stains
  • GMS / PAS: fungal etiologies, such as Candida species
  • Brown-Brenn Gram stain: for bacteria
  • Warthin-Starry or Steiner silver stains: spirochetes / syphilis
  • Treponema immunohistochemistry: syphilis
  • HSV immunohistochemistry: herpes
Sample pathology report
  • Placenta, third trimester, spontaneous passage:
    • Umbilical cord with panvasculitis, diffuse acute funisitis and peripheral microabscesses (see comment)
    • Comment: Colonization with organisms morphologically compatible with Candida species, confirmed by PAS special stain.
Differential diagnosis
  • Acute chorioamnionitis:
    • Often shows both panvasculitis and funisitis (stage 3)
    • Inflammation appears centered around vessels
    • Foul smelling specimens, with green tinged and slimy membranes
  • Intrauterine fetal demise:
    • Vasculitis and funisitis of any degree or distribution possible
    • General breakdown and inflammation of delicate membranes
Board review style question #1

A 32 year old with no prenatal care presents with premature rupture of membranes and delivers an infant at approximately 31 weeks with Apgars of 5 and 6 at 1 and 5 minutes. At delivery, a maternal fever of 101.5 °F and foul smelling amniotic fluid are identified. The placental surface and fetal membranes are green tinged and opaque. The umbilical cord reveals the features seen in the submitted image (PAS stain). Which of the following gross features would most likely be found on careful macroscopic examination of the umbilical cord?

  1. Excessive twisting
  2. Excessively long length
  3. Peripheral white plaque(s)
  4. True knot(s)
  5. Umbilical vein thrombosis
Board review style answer #1
C. Peripheral white plaque(s). While often no macroscopic lesions are seen in cases of mild-moderate umbilical vasculitis or funisitis, gross findings are evident in some circumstances. A common gross finding with funisitis is the presence of peripheral white, creamy or yellowish plaques / lesions, which are often due to infection by Candida species (which is present in the above image). Additionally, white concentric rings may be appreciated around umbilical vessels. This finding is usually associated with necrotizing funisitis and represents the accumulation of dying cells, cellular debris and associated immune complexes that aggregate as arcs around vessels (analogous to the precipitin arcs seen in an Ouchterlony immunodiffusion assay).

Comment Here

Reference: Umbilical vasculitis and funisitis
Board review style question #2
A 19 year old G1P0 delivers a healthy term infant with post due dates (40.5 weeks) and Apgars of 9 and 9 at 1 and 5 minutes. Meconium fluid is identified at delivery. Which of the following is the most likely histologic finding in the umbilical cord?

  1. Arteritis involving one or both umbilical arteries
  2. Concentric calcifications around umbilical vessels
  3. Necrotizing funisitis
  4. Phlebitis involving the umbilical vein
  5. 3 vessel vasculitis (panvasculitis)
Board review style answer #2
D. Phlebitis involving the umbilical vein. Mild phlebitis (inflammation specifically of the umbilical vein) is a relatively common finding with meconium in the amniotic fluid. Presumably, this is due to the early / developing fetal response toward an injurious agent (meconium).

Comment Here

Reference: Umbilical vasculitis and funisitis

Velamentous insertion
Definition / general
  • Insertion of umbilical cord into extraplacental membranes, with intramembranous portions of vessels exposed to possible trauma / rupture
  • Occurs in 1% of placentas
  • Associated with twin gestations, congenital malformations, maternal smoking and single umbilical arteries
  • Poses a risk for vascular compression, trauma and thrombosis with associated risks of fetal morbidity and mortality
Gross images

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Velamentous insertion of umbilical cord

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Recent Placenta Pathology books

Crum: 2017

Heller: 2015

IARC: 2020

Kraus: 2005

Nucci: 2020

Oliva: 2019

Roberts: 2021



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