JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
R-M01

SLIDE A: Signalment:  Adult female cat

HISTORY:  This cat was clinically normal and pregnant

HISTOPATHOLOGIC DESCRIPTION:  Uterus and placenta:  The uterus is complete with a perimetrium, myometrium, and endometrium.  Extending from the endometrium are maternal septa that interdigitate with the labyrinthine villar projections of the fetal chorioallantois. At the base of these interdigitations, the endometrium is composed of a deep glandular zone consisting of dilated uterine glands and cellular debris and the superficial junctional zone with terminal lamellae, maternal vessels, and glandular secretions.  Fetal tissues consist of the allantoic membrane, normal edematous allantochorionic connective tissue containing large vessels, and lamellae/villi lined by trophoblasts.  Multifocally, maternal vascular endothelium directly apposes fetal trophoblasts, separated by a thin acellular layer of stroma.  In an area of smooth placentation (chorion laeve), the fetal tissues are characterized by sparse to indistinguishable allantochorionic connective tissue and a chorionic epithelial layer consisting of columnar cells with basal nuclei.

MORPHOLOGIC DIAGNOSIS:  Uterus with placenta:  Essentially normal tissue, breed unspecified cat, feline.

SLIDE B: Signalment (JPC # 2879193-00):  Adult female horse

HISTORY:  This horse was clinically normal and pregnant.

HISTOPATHOLOGIC DESCRIPTION:  Uterus and placenta: The uterus is complete with a perimetrium, myometrium, and endometrium. The endometrium is composed of a glandular zone consisting of dilated uterine glands containing cellular debris separated by loosely arranged connective tissue. Extending from the endometrium are crypts formed by the interdigitation of chorioallantoic villi with the endometrium in a microcotyledonary arrangement, imparting a nodular appearance to the maternal-fetal interface. Fetal tissues include the allantoic epithelium (lining the allantoic cavity), edematous allantochorionic connective tissue containing large vessels, and fetal microcotyledons lined by trophoblastic epithelium that interdigitate with the maternal endometrium to form an epitheliochorial attachment.

MORPHOLOGIC DIAGNOSIS:  Uterus and placenta:  Essentially normal tissue, breed unspecified, equine.

SLIDE C: Signalment (JPC #4056477-00):  Adult, female, sheep

HISTOPATHOLOGIC DESCRIPTION:  Uterus and placenta:  Two sections are present, with one exhibiting a placentome and the other the intercotyledonary/intercaruncular space. In the placentome, the uterus is complete with a perimetrium, myometrium, and endometrium. The endometrium is composed of a glandular zone consisting of flattened uterine glands separated by loosely arranged connective tissue. The surface of the endometrium is forming crypts (caruncle) which interdigitate with the fetal chorionic villous projections (cotyledon) which together form the placentome. The chorionic villi are lined by trophoblastic epithelial cells that multifocally have lost cellular borders to form multinucleated syncytiotrophoblasts which contact the maternal endometrium to form an epitheliochorial attachment. Subjacent to the trophoblast epithelium is the edematous allantois connective tissue containing large vessels and areas of hemorrhage (marginal hematoma). The allantoic epithelium is indistinct. The intercaruncular uterus has attenuated or indistinct endometrium, flattened endometrial glands, and prominent myometrium. The intercotyledonary chorioallantois is thin with an edematous stroma lined by flattened chorionic epithelium (trophoblasts).

MORPHOLOGIC DIAGNOSIS:  Uterus, placenta and placentome:  Essentially normal tissue, breed unspecified, ovine

SLIDE D: Signalment (JPC # 4055712-00):  Adult female dog

HISTOPATHOLOGIC DESCRIPTION:  Placenta: The chorioallantois is present forming a labyrinthine or lamellar interconnecting network of trophoblast epithelial cells and multifocal multinucleated syncytiotrophoblasts often in direct apposition to maternal blood vessels which are lined by hypertrophic endothelial cells. There are multifocal areas of hemorrhage (stagnant maternal blood) with formation of hematoidan crystals, and maternal vessels are often congested. When apparent, the endometrial epithelium and connective tissue are replaced by necrotic cell debris and fibrin. Subjacent to the chorioallantoic trophoblastic epithelium, the allantois is edematous and contains numerous congested blood vessels.  The allantoic epithelium is flattened and attenuated or multifocally cuboidal.

MORPHOLOGIC DIAGNOSIS:  Placenta:  Essentially normal tissue, breed unspecified, canine.

SLIDE E: Signalment (JPC # 4070866-00):  7-year-old female paint horse

HISTORY:  This horse was diagnosed with peritonitis and pyrexia prior to necropsy

HISTOPATHOLOGIC DESCRIPTION: Uterus, endometrial cup: The endometrium is multifocally lost and endometrial glands are widely separated by numerous large, often elongated, specialized trophoblasts with abundant eosinophilic vacuolated cytoplasm and one or two vesiculate nuclei, each with a single prominent nucleolus. Trophoblasts are admixed with numerous lymphocytes and plasma cells with fewer macrophages, multinucleated giant cells, and neutrophils. Endometrial glands are often ectatic, lined by attenuated epithelium, and their lumina contain moderate to abundant homogenous eosinophilic material (secretory product) or sloughed cellular debris. Large vessels are congested and the lamina propria is edematous and contains dilated lymphatics. There are lymphocytes and plasma cells occasionally surrounding vessels in the lamina propria and myometrium. 

MORPHOLOGIC DIAGNOSIS:  Uterus, endometrial cup:  Essentially normal tissue, paint, equine.

SLIDE F: Signalment (JPC # 4124902):  < 12-month-old female mouse (breed unspecified)

HISTORY:  This mouse was in a cage with a male for breeding and there is no known history of experiments being conducted on either mouse; reportedly, this particular mouse strain (unknown breed/strain) is known to have a neural tube disorder. At morning rounds, the female mouse was found lying on her left side and/or rolling to the right. Reportedly, the male would come and lay on her; after which, she would start rolling from her stomach to her back around to her stomach. When lifted by the tail, she would spin around her tail in an uncoordinated manner and not exhibit normal righting behaviors or attempts to get away. She had an elevated and distressed breathing pattern. No overt signs of trauma were observed. Due to this animal’s debilitated condition, euthanasia (via CO2 with cervical dislocation) was elected.

HISTOPATHOLOGIC DESCRIPTION:  Ovary, uterus, and placenta:  The uterus is complete with a perimetrium, myometrium, and endometrium. There are 5 fetal cross sections within the bicornuate uterus. Each fetal attachment site is characterized by three layers: the decidua basalis, junctional zone, and labyrinth. The decidua basalis arises from the endometrium and is characterized by abundant vasculature and vacuolated decidual cells. Adjacent to the decidua basalis is the junctional zone with maternal venous drainage, trophoblast giant cells, and spongiotrophoblast cells. Trophoblast cells are often large and bizarrely shaped with multiple nuclei. Spongiotrophoblasts rarely contain phagocytozed erythrocytes or debris. The labrynthine zone is composed of closely apposed fetal and maternal blood channels, with trophoblasts in direct contact with maternal blood (hemochorial). There is a thin layer of overlying endometrial epithelium, the inverted yolk sac (fused with the chorion), and a thin, attenuated allantois. Some fetuses have prominent umbilicuses present in section and all fetuses contain developing endoderm, mesoderm, and ectoderm. Within the serosa of the uterus and vagina, there are multifocal perivascular aggregates of lymphocytes. The ovary is normal with few corpora lutea present. The cervix mucosal epithelium has abundant microvacuolated cytoplasm (progestational epithelium) and the lumen contains erythrocytes, fibrillar eosinophilic material, and few leukocytes. Just cranial to the cervix there is a focally extensive 3mm coagulum of necrotic cellular debris, trophoblasts, hemorrhage, fibrin, and edema that extends from the endometrial mucosa and protrudes into the uterine lumen (involuting placental site).

MORPHOLOGIC DIAGNOSIS:  Ovary, uterus, placenta:  Essentially normal tissue, breed unspecified, rodent

GENERAL DISCUSSION:

• The placenta provides fetal nutrition, respiration, and waste removal, synthesis of substances required by the fetus, enzyme production necessary for the uterine attachment, and hormone production (estrogen, relaxin, and progesterone) to maintain pregnancy
• Only eutherian mammals have a true placenta composed of fetal membranes (chorion, amnion, yolk sac, and allantois) and endometrium
• Metatherians (kangaroo and opossum [marsupials]) form a transitory yolk sac placenta that lacks intimate contact with the uterine mucosa
• Prototherians or monotremes (platypus and echidna) are egg layers
• Fetal membranes:
  • Yolk sac: This forms as an outpouching of the endodermal embryonic midgut and nourishes the embryo before the definitive placenta forms; the yolk sac then regresses; yolk sac endoderm is the source of primordial germ cells that later migrate to the fetal gonad
  • Somatopleure: Composed of the chorion and amnion
    • Chorion: This forms from somatic mesoderm in combination with trophoblasts and covers the entire conceptus; it is initially avascular until combination with the allantois provides vascularization
      • Frondose chorion: Surface forms projections that increase the surface area and come in contact with the maternal tissues
      • Smooth chorion: Areas without projections, area not in contact with maternal tissues
    • Amnion: Formed from ectoderm and covers the embryo
    • Ectodermal epithelium of amnion and chorion is initially squamous
      • Chorionic epithelium becomes cuboidal and forms the trophoblast
      • In some species, some trophoblast cells lose their cytoplasmic borders and form syncytia, termed syntrophoblasts; those that retain their cytoplasmic borders are termed cytotrophoblasts
  • Allantois: Forms as an evagination of the embryo hindgut
    • Expands to fill the extraembryonic coelom; fuses with the amnion to form the allantoamnion and with the chorion to form the allantochorion (or chorioallantois)
    • This fusion triggers vascularization of the amnion and chorion
    • Umbilical vessels form from allantoic splanchnic mesoderm, which serves as the origin of the fetal vessels of the placenta
    • In the ruminant and pig, the allantois incompletely fills the coelom and the amnion fuses with the chorion to form an amniochorion

CLASSIFICATION OF PLACENTATION:

Classification based upon the fetal extraembryonic membranes:

• Choriovitelline (yolk sac) placenta: Yolk sac wall (endoderm) fuses with the chorion (trophoblast and mesoderm) and then opposes the endometrium
  • Transitory and of little importance in domestic animals; definitive placenta of metatherian mammals
  • Mice, rats, rabbits, and guinea pigs have inverted yolk sac placentae with the yolk sac directly exposed to the uterine lumen; this is involved in fetal immunoprotection
• Allantochorionic placenta: Formed by fusion of the allantois and chorion mesoderms

Classification based upon the degree of uterine destruction:

• Nondeciduate placenta: Trophoblasts do not significantly invade or destroy the endometrium; at parturition there is virtually no loss of maternal tissue; most domestic animals are nondeciduate
• Deciduate placenta: Trophoblasts invade and destroy superficial endometrium, which responds by forming large, polygonal cells, called decidual cells, whose precise function is unknown; at parturition there is loss of maternal tissue and maternal hemorrhage; dogs and cats have mildly deciduate placentas; rodents and primates have fully deciduate placentas

Classification based upon the area of fetal-maternal attachment:

• Diffuse placentation: The chorionic villi are present over the entire surface of the endometrium (sow, mare, camel, llama)
• Cotyledonary placenta: Isolated tufts of branched chorionic villi (cotyledons) attach to preformed endometrial prominences (caruncles), together they form placentomes (cattle, sheep, goats)
• Zonary placenta: Chorionic projections occupy a ring‑like band extending transversely around the circumference of the fetus (carnivores, cats, dogs)
• Discoid placenta: One or two disk-shaped areas of the chorion are attached to the endometrial stroma (primate, rabbit, rodent)

Classification based upon the fetal-maternal interhemal barrier:

• There are a maximum of six layers of tissue separating fetal and maternal blood: (1) maternal capillary endothelium, (2) maternal connective tissue, (3) uterine epithelium, (4) chorionic epithelium (i.e. trophoblast), (5) allantochorionic connective tissue (mesenchyme), and (6) allantochorionic capillary endothelium
• Epitheliochorial placenta: All six layers present (sow, ruminant, horse)
• Syndesmochorial placenta: Five layers are present; the uterine epithelium is eroded; this type occurs focally in ruminants after the establishment of an epitheliochorial placenta and in pathological circumstances
• Endotheliochorial placenta: Uterine epithelium and connective tissue are eroded, leaving only four layers (carnivores)
• Hemochorial placenta: All maternal layers are eroded leaving trophoblasts in direct contact with maternal blood (primate, rabbit, rodent)

Configuration of maternal and fetal tissue interface:

• Folded:  Macroscopic undulations of fetal tissues (plicae) and microscopic ridges (rugae in pigs; lamellae in carnivores) interlock with corresponding infoldings (fossae) in the endometrium
• Villous:  Branched chorionic villous protrusions interdigitate with corresponding maternal crypts (horse, ruminant, human)
• Labyrinthine:  Trophoblasts form an intercommunicating network with maternal capillaries

Summary of placentation by species:

	Fetal/Maternal Attachment	Maternal/Fetal Interface	Uterine Destruction	Interhemal Barrier
Pig	Diffuse	Folded	Nondeciduate	Epitheliochorial
Horse	Diffuse	Villous	Nondeciduate	Epitheliochorial
Ruminant	Cotyledonary	Villous	Nondeciduate	Epitheliochorial
Carnivore	Zonary	Labyrinthine	Deciduate	Endotheliochorial
Primate	Discoid	Villous	Deciduate	Hemochorial
Rodent	Discoid	Labyrinthine	Deciduate	Hemochorial

Placental variations in individual species:

Pig: 

• Early in development the yolk sac is large, it regresses after day 20
• Trophoblast epithelium is columnar at the base of the folded ridges and becomes flattened at the tips; areola-gland complexes form over uterine gland openings
• Maternal areolae surround uterine glands; fetal areolae are associated structures composed of villi
• Uterine “milk” (histiotrophe) forms from degenerate cells and accumulates between uterine and fetal tissue

Horse: 

• Initially the conceptus is unattached to the uterus and is held in place only by increased uterine tone
• The allantochorion and adjacent uterine epithelium undergo specialized folding, forming microcotyledons over most of the placenta after day 60; spaces similar to areoli surround the microcotyledons opposite ducts of the endometrial glands
• Chorionic girdle: This refers to rapidly proliferating trophoblasts between the regressing yolk sac and the developing chorioallantois; trophoblasts become binucleate and invade the endometrium around day 37, destroying uterine endothelium and implanting in the stroma to form endometrial cups
• Endometrial cups: Scattered over the placental surface within the endometrium
  • Form from detachment and invasion of chorionic girdle trophoblasts into the uterine stroma of the pregnant mare
  • Up to 5 cm in diameter, discrete structures in the superficial endometrium composed of large, binucleate, eosinophilic, polyhedral cells, intermingled with uterine glands
  • Responsible for the production of equine chorionic gonadotropin (ECG), which stimulates development and stabilizes hormonal function of the corpora lutea and is found in the serum of mares between 40 and 120 days gestation
  • Peak hormone production occurs around 60 days gestation and degeneration and eventual sloughing begins around 75 days gestation
  • Lymphocytes and plasma cells are common at the periphery of the cups in early formation which progresses to diffuse mixed inflammation by the time regression occurs, and the fetal cells undergo necrosis with the necrotic cells eventually forming “chorioallantoic pouches” on the surface of the chorioallantois near where the umbilicus attaches

• Hippomanes are soft, dark brown masses that usually float free in the allantoic fluid or may be lodged in fetal membranes and consist of concentric rings of amorphous material composed of mostly mucoprotein and calcium phosphate from cellular debris
• Cervical star: No villi; cervical part of the placenta; most common site of mycotic placentitis

Ruminant: 

• Giant binucleate trophoblasts fuse with uterine epithelium and form trinucleate hybrid cells in which hormone-containing granules are transferred from fetus to dam
  • Secrete placental lactogen
• Although there are areas where the trophoblast is in contact with maternal connective tissue (i.e. syndesmochorial), in general, two layers of epithelium separate fetal and maternal blood
• Hematomas develop at the base of the chorionic villi because of erosion of maternal capillaries and extravasation of maternal blood later in gestation
  • Trophoblasts phagocytize the red blood cells and release iron
  • These areas are predisposed to bacterial infection during pregnancy
• Because of interdigitation of fetal villi in maternal crypts, fetal tissue may be retained within the caruncles after birth
• Trophoblastic epithelium at the base of villi is generally columnar and becomes cuboidal at the tips
• The epithelium of crypts is irregular, usually cuboidal, but in the sheep and goat, there are areas that are syncytial

Carnivores:

• Initially extensive choriovitelline placenta, which invades and erodes uterine tissue, then regresses
• Yolk sac persists through the pregnancy
• The definitive placenta is composed of three layers:
  • The labyrinthine layer
  • Junctional zone: Contains terminal lamellae, maternal vessels, and glandular secretions (enlarged in the canine)
  • Glandular zone: The deepest layer; contains dilated, secreting glands and decidual cells
  • Marginal hematomas occur randomly; processing of extravasated blood by trophoblasts produces green or brown meconium
  • Syncytiotrophoblasts constitute the majority of the trophoblastic layer

Anomalies and abnormalities of the placenta:

• Hydrops amnion (excessive amniotic fluid): Volumes 8-10 times normal often associated with fetal monsters and prolonged pregnancies
• Hydrops allantois (excessive allantoic fluid): Volumes 10-50 times normal
• Retained placenta: Usually caused by infections or uterine inertia/atony
• Adventitial placentation: Duplication or fusion of placentomes in ruminants because of inadequate fetal-maternal contact
• Amniotic plaques: Squamous epithelium, with or without keratinization, on the amnion internal surface, present mostly on the bovine umbilical stump
• Adenomatous dysplasia/hyperplasia of the chorion and/or allantois (R-N11): Horses
• Mineralization: Many species, little significance
• Allantoic calculus: Cow; homogenous mucoproteinaceous material attached to allantois or floating freely within the allantoic cavity
• Yolk sac remnants are often attached to the umbilicus in many species.
• Amorphous globosis: Frequently haired, solid mass attached to the umbilicus; may be a defective twin
• Freemartinism: Hypoplasia of the female genital tract when twinned with a male; ruminants; results from shared blood supply and shared hormones in utero (anti-Müllerian hormone)

REFERENCES:

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