JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

December 2024

R-B02

 

Signalment (JPC #1454646): A 13-year-old female dog 

 

HISTORY: This dog presented with a distended abdomen.

 

HISTOPATHOLOGIC DESCRIPTION: Uterus: The myometrium is circumferentially thinned secondary to marked luminal dilation. Diffusely filling the lumen, infiltrating the nearly diffusely ulcerated endometrium and underlying uterine stroma, and separating, surrounding, and filling endometrial glands are many viable and degenerate neutrophils, fewer epithelioid macrophages, lymphocytes, and plasma cells, hemorrhage, fibrin, edema, and eosinophilic cellular and karyorrhectic debris (necrosis). Endometrial glands are often ectatic and lined by attenuated to cuboidal epithelium or, occasionally, by tall columnar, pseudostratified epithelium with abundant eosinophilic foamy cytoplasm and vesiculate nuclei (progestational epithelium). Multifocally, glandular epithelium is disrupted and replaced by eosinophilic cellular and karyorrhectic debris (necrosis) and fibrin. Endometrial lymphatics are ectatic and blood vessels are congested. The deep endometrial stroma is edematous and contains moderate numbers of large foamy macrophages. 

 

MORPHOLOGIC DIAGNOSIS: Uterus: Endometritis, necrosuppurative, diffuse, moderate, with glandular ectasia, breed unspecified, canine.

 

ETIOLOGY: Bacterial infection of progesterone-primed endometrium

 

ETIOLOGIC DIAGNOSIS: Bacterial endometritis 

 

CONDITION: Pyometra

 

GENERAL DISCUSSION:

• Endometritis: Involvement of primarily uterine mucosa (endometrium: mucosa, glands, and endometrial stroma)

• Almost all uterine infections start as inflammation of endometrium that progresses to the myometrium, becoming metritis (i.e. inflammation of all layers of the uterine wall)

• Chronic endometritis: Characterized by productive fibrosis, lymphocytes, and plasma cells
• The most common isolate is Escherichia coli (fecal isolates and urinary tract pathogens); pyometra may also be caused by other normal vaginal microorganisms or urinary tract pathogens (Staphylococcus sp., Streptococcus sp., Klebsiella sp., Pseudomonas sp., Proteus sp., Hemophilus sp., Pasteurella sp., Serratia sp.)
• Pyometra: Acute or chronic suppurative infections with accumulation of purulent material in the uterine lumen

• Common in bitches and cows, less so in other species

• In bitches and queens, most frequently occurs weeks after estrus (during diestrus), with associated cystic endometrial hyperplasia (CEH) due to progesterone influence; associated with endometrial hyperplasia in bitches

• A 2020 article found that in dogs, CEH, pseudoplacentational endometrial hyperplasia, uterine inflammation, and pyometra are associated with diestrus, but endometritis IS NOT (Santana, J Comp Pathol. 2020)

• Extragenital lesions are also present due to toxemia and intermittent bacteremia in younger dogs is associated with estrogen administration for prevention of pregnancy (mismating injection)

 

PATHOGENESIS:

• Uterine susceptibility to infection is highest during the luteal phase of the estrous cycle
• Progesterone is the dominant hormone during diestrus and is an essential feature in the pathogenesis of pyometra
• Progesterone causes increased susceptibility to infection via:

• Increased endometrial growth and glandular secretion
• Continued closure of cervix
• Decreased migration of neutrophils to the uterus and reduced phagocytosis of uterine bacteria
• Secretion of progesterone-induced immunosuppressants
• Pyometra typically develops a few weeks after estrus in the bitch 
• The endometrial response to progesterone depends on estrogen priming in dogs and cats

• Recent evidence suggests that any appropriate stimulus to a progesterone-primed uterus can produce cystic endometrial hyperplasia (CEH); bacterial infection of the progesterone-primed uterus can cause both CEH and pyometra

• Cystic Endometrial Hyperplasia (CEH)

• Results in accumulation of endometrial excretions
• May involve a single gland, few glands, or entire surface
• May be due to prolonged estrogenic stimulation in some species

• Membranoproliferative glomerulonephritis from immune complex deposition may be a sequela
• Endometritis may also occur post-coitus in all species, but is typically mild
• Endotoxin (usually E. coli) impairs sensitivity of collecting tubular epithelial cells to ADH > isosthenuria or hyposthenuria, polyuria/polydypsia (nephrogenic diabetes insipidus)

 

TYPICAL CLINICAL FINDINGS:

• Depression, anorexia, vomiting, polyuria/polydipsia, gait abnormalities and lameness; mild endometritis may be subclinical
• Most pyometras are closed-cervix but if the cervix is open, there is a serosanguinous to mucopurulent discharge from the vagina
• Neutrophilia often with a left shift (may be degenerative with toxic changes), in pyometra

• In chronic cases, there is normocytic, normochromic, nonregenerative anemia
• Hyperproteinemia and hyperglobulinemia
• Hypoglycemia is possible with sepsis
• Isosthenuria or hyposthenuria

 

TYPICAL GROSS FINDINGS:

• Uterine enlargement
• Serosa is dark with congested vessels
• Uterine wall is friable; rupture may occur, with subsequent peritonitis
• Character of the purulent exudate varies with causative agent:

• E. coli and Proteus sp. produce thick, viscid, tenacious, opaque to brown material that has a characteristic fetid odor  
• Staphylococcus sp. and Streptococcus sp. produce a typically yellow purulent exudate

• Irregularly thickened mucosa with patchy areas of necrosis and ulceration
• Hyperplastic endometrium which contains small cysts and is dull white

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• If mild, may only see mild, diffuse neutrophilic inflammation with mild desquamation of the superficial epithelium
• The best indications of endometritis in all species are accumulations of plasma cells and foci of lymphocytes in the stroma
• Progestational changes to the endometrial epithelium in bitches:

• Enlarged, tall columnar, vacuolated cytoplasm, with pyknosis
• Pseudostratification or papillary proliferations

• In acute stage, numerous neutrophils in the lumen and infiltrating the epithelium and stroma
• Chronic infection may be accompanied by fibrosis, hyperplasia and squamous metaplasia of surface epithelium
• Variably cystic glands
• Non-uterine lesions (in bitch): Bone marrow depression, widespread extramedullary hematopoiesis, and immune complex glomerulonephropathy

 

ADDITIONAL DIAGNOSTIC TESTS:

• Culture 
• Radiographs/ultrasound
• Clinical Pathology

• Canine pyometra may cause a marked inflammatory neutrophilia (“leukemoid response”)
• Hyposthenuria or isosthenuria
• Pyometra or uterine stump flushing samples are characterized by a low number of endometrial epithelial cells often with degenerative changes; numerous nondegenerate and degenerate neutrophils, macrophages, and plasma cells; and abundant intracellular and free bacteria

 

DIFFERENTIAL DIAGNOSIS: 

For an enlarged uterus:

• Hydrometra or mucometra: Sterile fluid or mucus in the uterus that develops in association with endometrial hyperplasia
• Pregnancy
• Neoplasia

 

COMPARATIVE PATHOLOGY:

• Cow: Uterine disease associated with pyometra inhibits the synthesis and release of prostaglandin F2-alpha, the luteolytic factor, leading to persistence of the corpus luteum (CL) and high progesterone levels; pyometra usually occurs early postpartum or following a breeding-induced venereal infection

• Common agents include Streptococci, Staphylococci, coliforms, T. pyogenes, Pseudomonas, and T. foetus after breeding
• Other causes of metritis/endometritis: 

• Tuberculosis may cause miliary or diffuse caseating metritis/endometritis
• Coxiella burnetti may also cause severe chronic endometritis
• Endometritis may be associated with bovine herpesvirus 4

• Queen: Pyometra develops 2-5 weeks after estrus; approximately 50% of affected cats do not have a CL which is associated with pyometra development, and the association with endometrial hyperplasia is not clear; cats are induced ovulators
• Mare: Most mares continue to cycle during disease but estrous cycle length may be affected; will decrease fertility; pyometra in the mare rarely leads to systemic disease, and cystic endometrial hyperplasia is very uncommon in mares

• Most common after foaling and breeding 

• Taylorella equigenitalis (contagious equine metritis, R-B05): Venereal disease of mares that causes temporary infertility

• Recent reports of Chlamydia abortus in endometrial biopsies suggesting that C. abortus may be a cause of conception failure and abortion in horses (Ricard, J Vet Diagn Invest, 2024)

• Doe: Pasteurella multocida and Staphylococcus aureus frequently isolated in pyometra or metritis

• Recent report of Paeniclostridium-sordellii-associated peripartum metritis in goats (Gonzalez-Astudillo, Vet Pathol, 2024)

• Non-human primates: E. coli and coagulase-positive Staphylococcus sp. are the most common isolates
• Ewe: Uncommon; recent association with indwelling central venous catheter and Staphylococcus aureus
• Sow: Uncommon 
• Mice: Cystic endometrial hyperplasia is common in aged female mice and may be associated with secondary bacterial pyometra
• Rabbits: Acute, transmural, necrotizing metritis has been associated with peracute pasteurellosis during the perinatal period; affected does usually die within hours of showing clinical signs; more typical chronic suppurative metritis and pyometra also occur
• Zoo canids: Red wolves, maned wolves, African wild dogs, bat eared foxes, and others treated with melengestrol acetate, a contraceptive, are prone to development of uterine lesions including cystic endometrial hyperplasia, uterine mineralization, pyometra, and endometritis 
• Koalas: Chlamydia pecorum can cause pyometra and cystitis as part of larger systemic infections

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016: 104, 284-285.
2. Cline JM, Brignolo L, Ford EW. Rogenital System. In: Abee CR, Mansfield K, Tardif S, et al. Nonhuman primates in biomedical research: Diseases. Vol 2. San Diego, CA: Academic Press; 2012:514-515.
3. Foster RA, Premanandan C. Female Reproductive System and Mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:121279-1282.
4. Gonzalez-Astudillo V, Asin-Ros J, Moore J, Uzal FA, Navarro MA. Paeniclostridium sordellii-associated peripartum metritis in goats. Vet Pathol. 2023:60(1):69-74.
5. Higgins D, Rose K, Spratt D. Monotremes and Marsupials. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:469. 
6. 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.
7. Ricard RM, Wobeser B. Molecular detection of Chlamydia abortus in endometrial biopsies of mares from western Canada. J Vet Diag Invest. 2024:36(6):921-924.
8. 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.
9. Schlafer DH, Foster RA. Female Genital System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016: 387-393.
10. Solano-Gallego L, Masserdotti C. Chapter 13: Reproductive System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:460-461.
11. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Oxford UK: Blackwell Publishing; 2008: 74, 448, 451. 

 

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