JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

January 2025

R-M05

 

Slide A: Signalment (JPC #1414004): A female rhesus monkey (Macaca mulatta)

 

HISTORY: This monkey had a poor appetite for several months. 

 

HISTOPATHOLOGIC DESCRIPTION: Colon with mesocolon and mesocolonic lymph node: Markedly expanding the colonic muscularis layers up to 12 mm, primarily affecting the tunica adventitia, tunica muscularis, and submucosa, and extending into the mesocolon are multifocal, unencapsulated, infiltrative islands of tortuous, variably ectatic endometrial glands surrounded by abundant, densely cellular endometrial stroma. Endometrial glands are lined by simple to pseudostratified columnar, ciliated epithelium with a moderate amount of pale eosinophilic cytoplasm and prominent basilar vacuolation. Nuclei are oval with finely stippled chromatin and exhibit regular palisading. Endometrial glands rarely contain moderate numbers of macrophages, neutrophils, erythrocytes, and cellular debris. The endometrial stroma is composed of spindle cells with indistinct cell borders, scant eosinophilic, fibrillar cytoplasm, and an oval to elongate nucleus with finely stippled chromatin. Endometrial stroma within the mesocolonic adipose tissue surrounds a focus of hemorrhage, polymerized fibrin, degenerate neutrophils, and necrotic debris bound by haphazardly arranged reactive fibroblasts and collagen. The mesocolonic lymph node contains increased histiocytes within the paracortical and medullary sinuses, which often demonstrate erythrophagocytosis (draining hemorrhage).

 

MORPHOLOGIC DIAGNOSIS: Colon and mesocolon: Endometriosis, rhesus macaque (Macaca mulatta), nonhuman primate.

 

CONDITION: Endometriosis

 

Slide B: Signalment (JPC #1850940): A 9-year-old female Siamese cat

 

HISTORY: This cat had intermittent vomiting. 

 

HISTOPATHOLOGIC DESCRIPTION: Uterus: Diffusely the inner circular layer of the myometrium is thickened up to 1.5 cm by islands of endometrial glands and endometrial stromal elements (adenomyosis), which disrupt and replace smooth muscle bundles. The glandular epithelium occasionally forms papillary fronds and ectatic lumina often contain variable amounts of eosinophilic homogenous material (secretory product) admixed with cellular debris and moderate numbers of neutrophils and macrophages. The uterine lumen contains a large dense aggregate of degenerate neutrophils admixed with necrotic debris and sloughed epithelial cells (pyometra). The endometrium is multifocally thickened up to two times normal by mildly hyperplastic, ectatic, and tortuous endometrial glands (cystic endometrial hyperplasia). There is multifocal squamous metaplasia of the endometrial epithelium and glandular epithelium with scattered intracellular edema. There are rare lymphocytes, plasma cells, and neutrophils within the uterine stroma.

 

MORPHOLOGIC DIAGNOSIS: Uterus: Adenomyosis, with multifocal cystic endometrial hyperplasia, and suppurative endometritis (pyometra), Siamese, feline.

 

CONDITION: Uterine adenomyosis

 

GENERAL DISCUSSION: 

• Both endometriosis and uterine adenomyosis are non-neoplastic, estrogen-dependent, hyperplastic lesions of endometrial elements; animals may be simultaneously affected by both conditions 
• Uterine Adenomyosis

• Defined by the presence of endometrial tissue within the uterine wall (myometrium)
• Generally minimal effect in animals that don’t menstruate
• Uncommon; reported in dogs, cattle, cats, nonhuman primates, and humans

• Endometriosis

• Defined by the presence of “ectopic” endometrial tissue at a site outside of the uterus
• The most common reproductive disorder in menstruating OWM; baboons > macaques > mangabeys, and rarely chimpanzees and common marmosets (Kirejczyk, Vet Pathol. 2021); reported most commonly in rhesus following cesarean section or other pelvic surgery
• >30% or more of sexually mature rhesus and cynomolgus macaques affected in some colonies; incidence increases with age and a genetic predisposition may exist; hysterotomy and long term estrogen treatment increase risk
• Exposure to estrogen required for development; pregnancy is considered to have protective effects against progression
• Commonly affected locations in animals are ovary, mesometrium, peritoneum, and peritoneal surgical scars

 

PATHOGENESIS: 

• Uterine Adenomyosis: Possible pathogeneses

• Pressure induced migration: Due to pregnancy or pyometra
• Malformation: For example, cows with segmental aplasia or as a malformation of the tips of the uterine horns
• Hyperplastic overgrowth: Likely secondary to abnormal hormonal stimulation; e.g. bitches with cystic endometrial hyperplasia, primates with abnormal growth activity of the endometrium 

• Endometriosis: 3 major theories for the proposed development of endometriosis

• Metastatic: Endometrial tissue is implanted at abnormal locations; possible mechanisms include retrograde menstruation through fallopian tubes, post-surgical seeding, and hematogenous and/or lymphatic spread
• Metaplastic: Endometrium could arise directly from coelomic epithelium (mesothelium of pelvis or abdomen), from which the mullerian ducts and ultimately the endometrium itself originate during embryonic development
• Induction hypothesis: Unidentified substances released from shed endometrium cause undifferentiated mesenchyme to form endometrial tissues

• Following implantation, ectopic endometrial tissue responds to cyclic hormonal stimulation like normal endometrium > decidualization and hemorrhage > fibrosis and adhesion formation

 

TYPICAL CLINICAL FINDINGS:

• May be asymptomatic
• Uterine Adenomyosis

• Irregular and heavy menses (menometrorrhagia), dysmenorrhea, and pelvic pain 

• Endometriosis: 

• Pain and infertility; dysmenorrhea is associated with but not thought to be caused by endometriosis 

• Anorexia, depression, absence of feces, anemia, peritonitis
• Often occurs within laparotomy scars in rhesus macaques

• Potential sequelae include ureter blockage and compromise of the gastrointestinal tract lumen

 

TYPICAL GROSS FINDINGS: 

• Uterine Adenomyosis: Lesions range from diffuse symmetrical uterine enlargement to focal, nodular, asymmetrical uterine enlargement; on cross section cystic spaces are filled with clear to purulent fluid
• Endometriosis:

• Solid nodules or cysts of variable size and number filled with red to brown fluid (“endometriomas” or "chocolate cysts") adhered to serosal or peritoneal surfaces; may progress to large, solid, fibrous masses with only a few blood-filled cysts or spaces
• Cysts may be associated with extensive fibrosis and form adhesions to neighboring organs
• Located anywhere but usually in pelvic region of abdominal cavity (ovaries, colon, bladder, ureters); extraperitoneal locations may include the lungs
• Most common gross presentation: Purple to yellow-brown nodules on or beneath the serosa, may be associated with hemorrhage as these rests are responsive to sex hormones and "menstruate"

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Uterine Adenomyosis: Invasion of myometrium by uterine glands +/- stroma; glands immature, normal or hyperplastic
• Endometriosis: Varying proportions of uterine endometrial glands, uterine stroma, and/or hemorrhage/hemosiderin-laden macrophages 
• Variably shaped and sized uterine glands lined by endometrial epithelium surrounded by spindle cell stroma; some cases in humans may have only stroma (no glands)
• Marked fibrosis may obscure diagnosis

 

ADDITIONAL DIAGNOSTIC TESTS:

• Laparoscopy is the gold standard for diagnosis
• Immunohistochemical markers CD10 and progesterone receptor can detect human ectopic endometrial tissues
• Serum Cancer antigen 125 (CA125) – elevated levels are correlated with presence of endometriosis in NHPs and humans
• Longitudinal MRI screening

 

DIFFERENTIAL DIAGNOSIS:

Gross differential diagnosis for uterine wall lesions and/or serosa of abdominal viscera:

• Endometriosis

• Oesophagostomum sp. larvae
• Mesothelioma
• Carcinomatosis
• Sarcoma – for gland-poor endometriosis

Histologic differential diagnosis:

• Uterine Adenomyosis
• Physiologic progestational endometrial hyperplasia
• Uterine adenocarcinoma
• Cystic endometrial hyperplasia +/- pyometra
• Endometriosis
• Uterine adenocarcinoma 
• Other carcinomas 
• Retroperitoneal fibromatosis 

 

COMPARATIVE PATHOLOGY: 

Adenomyosis in other species:

• Adenomyosis of the epididymis (mesonephric duct): diverticula of the epididymis epithelium or deferent duct protrude through the muscular wall; hyperestrogenism can be an inciting cause; associated sperm granulomas; affects any species 
• Uterine adenomyosis:

• Apes: Reported in all apes; one of the most common lesions in the female reproductive system of chimpanzees 
• Mice: Rare; glandular invasion of myometrium that often extends to the serosa
• Reported in southern three-banded armadillos
• Non-domestic felids: More severe in lions than tigers; only reported in conjunction with endometrial hyperplasia

Endometriosis in other species:

 

REFERENCES:

1. Agnew D, Nofs S, Delaney MA, Rothenburger JL. Xenartha, erinacoemorpha, some afrotheria, and phloidota. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:523. 
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:104.
3. Camus MS, Allison RW, Miller D. Female Reproductive Tract. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:432-433. 
4. Carlson AK, Ramsay EC, Sun X, Chaffins D, Sula M-JM. Endometrial hyperplasia and pyometra in captive lions (Panthera leo) and tigers (Panthera tigris). Vet Pathol. 2022;59(6):1003-1011.
5. Cline JM, Brignolo L, Ford EW. Urogenital system. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases, Vol. 2. 2nd ed. Waltham, MA: Academic Press; 2012:510-514.
6. Foster RA, Premanandan C. Female reproductive system and mammae. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1282.
7. Kirejczyk S, Pinelli C, Gonzalez O, Kumar S, Dick E Jr, Gumber S. Urogenital Lesions in Nonhuman Primates at 2 National Primate Research Centers. Vet Pathol. 2021;58(1):147-160.
8. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:381. 
9. Matz-Rensing K, Lowenstine LJ. New world and old world monkeys. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:348-349. 
10. Miller AD. Neoplasia and proliferative disorders of nonhuman primates. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases, Vol. 2. 2nd ed. Waltham, MA: Academic Press; 2012:345-346.
11. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, Palmer’s Pathology of Domestic Animals. Vol 3. Philadelphia, PA: Elsevier Saunders; 2016:385.
12. 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; 2022:454.

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