JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
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 markedly expanded up to 8mm thick 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 thin 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 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 at the superficial aspect by columnar to cuboidal epithelial cells.  The deepest zone, in contact with the myometrium, is composed of scant relatively normal uterine stroma surrounding numerous endometrial glands that are tortuous, dilated up to 400um, lined by attenuated to cuboidal to occasionally hyperplastic epithelial cells, and contain 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
• 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
• Previously this lesion may have been termed “dediduoma”, but this term is discouraged
• There is an association between PEH and pyometra in dogs

PATHOGENESIS:

• Pseudopregnancy: visual stimuli or presence of surrogate neonates à hyperprolactinemia à mammary development, lactation, maternal behavior, uterine changes (PEH and mucometra)
• PEH: 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

TYPICAL CLINICAL FINDINGS:

• Overtly pseudopregnant dogs have increased serum prolactin and/or increased sensitivity to prolactin

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 in PEH 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 through 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 (e.g. granulosa cell tumor) or exogenous (e.g. estrogenic plants) estrogenic stimulation
  • Subinvolution of placental sites (R-M03): Variably occlusive post-partum coagulum of amorphous eosinophilic necrotic debris, fibrin, hemorrhage, and regenerating endometrium with persistent syncytial trophoblasts

COMPARATIVE PATHOLOGY:

Other types of endometrial hyperplasia in veterinary species:  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 a 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 and vulvar swelling
• Mare: Endometrial hyperplasia is rare
• Rabbit: A recent study of female rabbit reproductive tracts found endometrial hyperplasia (typically glandular-cystic) as the 2nd most common lesion after uterine adenocarcinoma, both of which had increasing incidence with age (Bertram, J Comp Pathol. 2018)
• Four-toed hedgehog: A recent study of female four-toed hedgehogs with clinical signs of uterine disease identified endometrial hyperplasia in 32%, uterine neoplasia in 54% (neoplasms were of unique types), and endometrial polyps in 14% (Chambers, Vet Pathol. 2018)
• Guinea pigs: Tumors and tumor-like lesions of the guinea pig reproductive system are rare and/or underreported; a recent study describes endometrial glandular-cystic hyperplasia in 8 of 83 guinea pigs with nodular lesions of the female reproductive tract, and benign lesions outnumbered malignant lesions in the study (Laik-Schandelmaier, J Comp Pathol. 2017); another study  reports that pet guinea pigs tend to develop cystic endometrial hyperplasia and uterine neoplasia, possibly secondary to cystic rete ovarii (common in guinea pigs), hormone dysregulation, and/or age (Veiga-Parga, J Vet Diagn Invest. 2016)
• Chimpanzees: Cystic endometrial hyperplasia is reported, but is much less common than other uterine changes in aging chimpanzees such as leiomyoma, adenomyosis, and endometrial atrophy (Chaffee, Vet Pathol. 2016)

Estrogenic plants: 

• Plants include: Subterranean clover (Trifolium subterraneum), red clover (Trifolium pretense), alfalfa (Medicago sativa), barrel medic (Medicago truncatula)
• 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. Bertram CA, Muller K, Klopfleisch R. Genital tract pathology in female pet rabbits (Oryctolagus cuniculus): a retrospective study of 854 necropsy examinations and 152 biopsy samples.  J Comp Pathol. 2018;164:17-26.
2. Chaffee BK, Beck AP, Owston MA, et. al. Spontaneous reproductive tract lesions in aged captive chimpanzees.  Vet Pathol.  2016;53(2):425-435.
3. Chambers JK, Shiga T, Takimoto H, et. al. Proliferative lesions of the endometrium of 50 four-toed hedgehogs (Atelerix albiventris).  Vet Pathol.  2018;55(4):562-571.
4. Foster RA. Female reproductive system and mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016: 1166-1167, 1189.
5. Laik-Schandelmaier C, Klopfleisch R, Schoniger S, Weiffenbach G, Staudacher M, Aupperle H. Spontaneously arising tumours and tumour-like lesions of the cervix and uterus in 83 pet guinea pigs (Cavia porcellus).  J Comp Pathol. 2017;156(4):339-351.
6. Santana CH, Santos DO, Trindade LM, Moreira LG, Paixão TA, Santos RL. Association of Pseudoplacentational Endometrial Hyperplasia and Pyometra in Dogs. J Comp Pathol. 2020:180:79-85.
7. 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.
8. Veiga-Parge T, La Perle KMD, Newman SJ. Spontaneous reproductive pathology in female guinea pigs.  J Vet Diagn Invest.  2016;28(6):656-661.

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