JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

January 2025

R-M08 (NP)

 

Signalment (JPC #2118235): 2-year-old female Labrador retriever

 

HISTORY: This dog presented for routine spay a month after estrus. During surgery a 2.5 cm in diameter, firm, round structure was noted in the left uterine horn just cranial to the bifurcation. On cut section the mucosa was markedly thickened, firm, and hemorrhagic with luminal accumulation of small amounts of flocculent material.

 

HISTOPATHOLOGIC DESCRIPTION: Uterus: The endometrium is multifocally expanded up to 8mm by broad-based polypoid projections of endometrium that partially occlude the uterine lumen. These projections are composed of three distinctive zones. The most superficial zone is composed of long villous folds extending from the endometrial surface, often forming papillary projections, lined by simple columnar to pseudostratified epithelium with foamy, often vacuolated cytoplasm (progestational epithelium) and large vesiculate nuclei, supported by a fibrovascular core. The superficial aspect of the epithelium is multifocally either eroded or necrotic with accumulation of karyorrhectic debris and fibrin. There is luminal and intervillous accumulation of an amphophilic to eosinophilic mucoid material. The middle zone of the polypoid mass is composed of a band of loose fibrous connective tissue that is mildly to moderately expanded by clear space (edema) and lined columnar to cuboidal epithelial cells. The deepest zone, in contact with the myometrium, is composed of relatively normal uterine stroma surrounding numerous tortuous endometrial glands, dilated up to 400um, lined by attenuated to cuboidal to occasionally hyperplastic epithelial cells, and containing variable amounts of luminal amphophilic to eosinophilic secretory product. Cystic, hyperplastic endometrial glands multifocally extend into the myometrium (adenomyosis). There are multifocal perivascular lymphoid aggregates within the myometrium. 

 

MORPHOLOGIC DIAGNOSIS: Uterus, endometrium: Hyperplasia, pseudoplacentational, focally extensive, Labrador retriever, canine (Canis familiaris)

 

CONDITION SYNONYMS: Pseudoplacentational endometrial hyperplasia; localized endometrial hyperplasia of pseudopregnancy

 

GENERAL DISCUSSION:

• Pseudoplacentational endometrial hyperplasia (PEH) is an unusual but characteristic uterine change that occurs during pseudopregnancy in dogs
• Uterine lesion is characterized by endometrial hyperplasia with decidual changes of the superficial endometrial epithelium (resembles placental sites)
• Previously may have been termed “deciduoma”, but this term is discouraged

 

PATHOGENESIS: 

• Pathologenesis of PEH is unknown; can be induced by a variety of sterile substances (e.g. silk, autogenous tissue) in the lumen of the uterus during the luteal phase of the estrous cycle 
• Pseudopregnancy: Visual stimuli or presence of surrogate neonates à hyperprolactinemia à mammary development, lactation, maternal behavior, uterine changes (PEH and mucometra)
  1. Physiologic/covert pseudopregnancy occurs due to the prolonged luteal phase of estrus in female dogs
• Overt pseudopregnancy, an exaggeration of physiologic pseudopregnancy, occurs in part due to prolactin or its receptors; occurs especially in toy breeds, and is frequently associated with PEH
• Associated with pyometra, though causal relationship has not been established (Santana, Jour Comp Pathol 2020)
  1. Cystic endometrial hyperplasia not significantly associated with pyometra, as previously believed

 

TYPICAL CLINICAL FINDINGS:

 

TYPICAL GROSS FINDINGS: 

• Unopened uterus may have one or more ovoid distended areas that may resemble pregnancy sites
• The mucosa exhibits localized (zonary) proliferation of endometrial tissue resembling implantation sites

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Formation of structures that closely resemble placental sites, except there are no fetal components (i.e. fetal chorioallantoic villi with trophoblasts, etc.): characteristic segmental hyperplastic endometrium that may appear as a broad-based polypoid mass extending into the lumen or may form a continuous band of protruding tissue
• Endometrium is organized in 3 discrete layers: 

• Deep glandular zone: Contains many uniformly distended endometrial glands 
• Condensed connective tissue band: Lined by a folded layer of hyperplastic and hypertrophied endometrial epithelial cells
• Folded luminal epithelium junctional zone: Long villous folds extending from the endometrial surface that may contain accumulations of endometrial secretions

• The luminal surface is almost always necrotic

 

DIFFERENTIAL DIAGNOSIS: 

• Gross, unopened uterus with nodules: 

• Endometrial polyp: Pedunculated nodule with substantial connective tissue stroma and dilated glands; may protrude trough the vagina, and/or cause uterine prolapse
• Chronic pyometra (see R-B02)
• Leiomyoma
• Fetal mummification

• Histologic, endometrial hyperplastic lesions:

• Cystic endometrial hyperplasia: May be accompanied by pyometra or mucometra; marked distention of endometrial glands; in some species can be attributed to excessive and prolonged endogenous (granulosa cell tumor) or exogenous (estrogenic plants) estrogenic stimulation
• Subinvolution of placental sites: Variably occlusive post-partum coagulum of amorphous eosinophilic necrotic debris, fibrin, hemorrhage, and regenerating endometrium with decidual cells and syncytial trophoblasts

 

COMPARATIVE PATHOLOGY:

Endometrial hyperplasia: simple (non-cystic) endometrial hyperplasia can be overlooked grossly, cystic endometrial hyperplasia is often grossly noted

• Bitch, +/- queen: Cystic endometrial hyperplasia (CEH) is common in diestrus, or can be induced by estrogen priming followed by progesterone administration; bacteria are almost always present in uteri with CEH
• Ewe: Estrogens from plants (phytoestrogens), most likely subterranean clover (Trifolium subterraneum) and red clover (Trifolium pretense), cause mammary gland enlargement and endometrial hyperplasia including subcaruncular ~1cm diameter, clear fluid-filled cysts; endometrial hyperplasia à reduced fertility (“clover disease”), dystocia, and uterine hypotonicity à uterine prolapse; cervical changes include increased glandular development (appears more like uterus), reduced numbers of goblet cells, and reduced amount of stratified epithelium, associated with increased incidence of cervicitis
  • Current management practices have decreased the incidence of severe disease, with resultant increase of chronic insidious disease due to chronic/repeated ingestion of low levels of phytoestrogens, in which infertility tends to be permanent due to cervical changes (blunting of cervical folds, increased lamina propria stroma, increased endometrium-like glands, termed “estrogen-induced transdifferentiation”) à impaired sperm transport
• Cow: Estrogens from plants (likely those listed for ewes, and alfalfa), cystic Graffian follicles, and ovarian neoplasms (granulosa cell tumors) can cause endometrial hyperplasia
• Sow: Estrogenic mycotoxin zearalenone (from moldy feed) causes endometrial cysts
  • CEH can also develop in non-domestic suids, presumably due to prolonged endogenous or exogenous estrogen simulation (as in domestic pigs)
    • Cyst epithelium lacks vacuoles that are found with progesterone stimulation
• Mare: Endometrial hyperplasia is rare
• Rabbit: Cystic endometrial hyperplasia is relatively common; mucometra is a sporadic finding that can be unilateral or bilateral (since there is complete separation of uterine horns separate cervices) 
  • Second most common uterine lesion in rabbits (behind endometrial adenocarcinoma) in retrospective study of small pet mammals (Pazdzior-Czapula, J Comp Pathol 2024)
  • CEH is believed to be antecedent to uterine adenocarcinoma
•  Mice: Cystic endometrial hyperplasia is common in aged female mice
  • May be associated with bacterial pyometras (Klebisella oxytoca most commonly)
• Guinea pigs: Cystic endometrial hyperplasia (as well as mucometra, endometritis, and leiomyomas) may be associated with cystic rete ovarii
  • Deciduoma (non-neoplastic endometrial proliferative lesion with decidualized stroma) diagnosed in 6 of 71 guinea pigs in retrospective study of reproductive lesions of small pet mammals (Pazdzior-Czapula, J Comp Pathol 2024)
• Red wolves, African wild dogs: CEH and pyometra are common, with lesions similar to those in domestic dogs; use of synthetic progestogen contraceptives may increase the risk for severe CEH and mineralization
• Zoo felids: Endometrial hyperplasia occurs spontaneously, most commonly with the use of melengestrol acetate contraceptives and in older females; parity is associated with decreased risk
• Elephants: Endometrial hyperplasia is common in captive females, particularly older and nulliparous animals
• Seba’s short-tailed bat (Carollia perspicillata): proliferative endometrial lesions have been observed in zoo settings
• Non-human primates:
  • Endometrial glandular hyperplasia is induced by estrogen administration in macaques
  • Endometrial hyperplasia may be indicative of tumor-producing effect, or may be part of progression to neoplasia 
  • Endometrial polyps and polycystic ovary syndrome may also be associated with endometrial hyperplasia
  • Endometrial hyperplasia was diagnosed more frequently in Old World Monkeys compared to New World Monkeys (Kirejczyk, Vet Pathol 2021)

Estrogenic plants: Subterranean clover (Trifolium subterraneum), red clover (Trifolium pretense), alfalfa (Medicago sativa), Medicago truncatula (barrel medic)

• General discussion: Clovers usually contain estrogenic isoflavones, alfalfa and barrel medic contain estrogenic coumestans
• Pathogenesis: Phytoestrogens (isoflavones, coumestans) are metabolized in the rumen into more potent metabolites (e.g. in sheep, the isoflavone formononetin is converted to the potent estrogen equol) à estrogenic effects, e.g. bulbourethral gland enlargement (wethers), impaired fertility (especially ewes) due in large part to changes in the cervical mucus, dystocia (attributed to myometrial hypotonicity), endometrial hyperplasia, uterine prolapse, hydrometra, and pyometra

 

REFERENCES:

1. Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2nd ed. San Diego, CA: Elsevier; 2012:515-518.
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:62,104, 249,310,320.
3. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:486. 
4. Foster RA, Premanandan C. Female Reproductive System and Mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1266,1280-1282,1302-1303.
5. Keel MK, Terio KA, McAloose D. Canidae, Ursidae, and Ailuridae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:234.
6. Kirejczyk S, Pinelli C, Gonzalez O, Kumar S, Dick E, Gumber S. Urogenital Lesions in Nonhuman Primates at 2 National Primate Research Centers. Vet Pathol. 2021;58(1):147-160. 
7. Martinez MAJ, Gasper DJ, Mucino MCC, Terio KA. Suidae and Tayassuidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:208. 
8. Pazdzior-Czapula K, Mikiewicz M, Fiedorowicz J, Otrocka-Domagala I. Mammary and reproductive tract tumours and tumour-like lesions of 286 small pet mammals: a retrospective study. J Comp Pathol. 2024;213:46-58
9. Santana CH, Santos DO, Trindade LM, et al. Association of Pseudoplacentational Endometrial Hyperplasia and Pyometra in Dogs. J Comp Pathol. 2020;180:79-85.
10.  Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:383-385.
11. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:269.

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