JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
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)
• Starts as inflammation of endometrium that progress to 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 , 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 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 coli) impairs sensitivity of collecting tubular epithelial cells to ADH > isosthenuria or hyposthenuria, polyuria/polydypsia

TYPICAL CLINICAL FINDINGS:

• Depression, anorexia, vomiting, polyuria/polydipsia, gait abnormalities and lameness
• 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:
• coli and Proteus sp. produce thick, viscid, tenacious, opaque to brown material that has a characteristic fetid odor
• Staphylococcus 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:

• 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
• Inflammation composed of plasma cells with foci of lymphocytes in the stroma in all species
• 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

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, 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; the cat is an induced ovulator
• 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
• Doe: Pasteurella multocida and Staphylococcus aureus frequently isolated in pyometra or metritis
• Non-human primates: 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
• 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

REFERENCES:

1. Cline JM, Brignolo L, Ford EW. Rogenital System. In: Abee CR, Mansfield K, Tardif S, et al. Nonhuman primates in biomedical research: Vol 2.  San Diego, CA: Academic Press; 2012:514-515.
2. De Biase D, Costagliola A, Del Piero F, et al. Coxiella burnetti in Infertile Dairy Cattle With Chronic Endometritis. Vet Pathol. 2018;55(4):539-542.
3. Egan RJ. Re: “Coxiella burnetti in Infertile Dairy Cattle With Chronic Endometritis”. Vet Pathol. 2018 Dec 17:300985818819231. doi: 10.1177/0300985818819231. [Epub ahead of print]
4. Foster RA. Female Reproductive System and Mammae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1163-1164.
5. 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.
6. 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.

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