JPC SYSTEMIC PATHOLOGY
REPRODUCTIVE SYSTEM
January 2022
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:  Transmurally disrupting and markedly expanding the colon wall up to 12 mm, primarily affecting the tunica adventitia, tunica muscularis, and submucosa, and extending into the mesocolon are multiple, 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 epithelial cells with a moderate amount of clear to pale eosinophilic cytoplasm and prominent basilar vacuolation.  Nuclei are anti-basilar and oval with finely stippled chromatin and frequently exhibit nuclear regimentation.  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, 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)
  • 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); in macaque species, 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
  • Commonly affected locations in animals are ovary, mesometrium, peritoneum, and peritoneal surgical scars; in humans, endometriosis occurs in the following sites, in descending order of frequency:

1. Ovaries
2. Uterine ligaments
3. Rectovaginal septum
4. Cul de sac
5. Pelvic peritoneum
6. Large and small bowel and appendix
7. Mucosa of the cervix, vagina, and fallopian tubes
8. Laparotomy scars

PATHOGENESIS: 

• Uterine Adenomyosis: 2 possible pathogeneses
  • 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 for implantation are 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 mÜllerian 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
• Profound activation of inflammatory cascade; PGE2, IL-1β, TNF, IL-6 and -8, NGF, VEGF, MCP-1, MMPs, TIMPs, and TGFβ play a key roles; in a rat model of endometriosis, matrix metalloproteinases (MMPs) 2 is increased with decreased expression of tissue inhibitor of metalloproteinases (TIMP-2); TGFβ is also increased and stimulates production of extracellular matrix proteins; TGFβ can also inhibit natural killer activity, induce angiogenesis, and induce proliferation of endometrial stromal cells, promoting endometriosis development
• Estrogen production by endometriotic stromal cells is markedly upregulated due to high levels of aromatase (steroidogenic enzyme) within endometriotic stromal cells; this enzyme is absent in normal endometrial stroma

TYPICAL CLINICAL FINDINGS:

• May be asymptomatic
• Uterine Adenomyosis
  • Irregular and heavy menses (menometrorrhagia), dysmenorrhea, and pelvic pain reported in humans
• Endometriosis:
  • Pain and infertility; dysmenorrhea is associated with but not thought to be caused by endometriosis; occasionally generalized illness with anemia and/or 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; 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: Nodules outside of the uterus containing at least 2 of the following 3 features:  Uterine glands, uterine stroma, and/or hemorrhage/hemosiderin-laden macrophages
• Variably shaped and sized uterine glands lined by endometrial epithelium surrounded by spindle cell stroma; glands and stroma occur in varying proportions
• Marked fibrosis may obscure diagnosis

ADDITIONAL DIAGNOSTIC TESTS:

• 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 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: Older animals, most often bulls and dogs; characterized by invasion of the muscle layer and stroma by epithelium; often associated sperm granulomas; may be associated with chronic estrogen stimulation
• Uterine adenomyosis:
  • Apes: reported in all apes, including wild mountain gorillas; one of the most common lesions in the female reproductive system of chimpanzees, in addition to ovarian atrophy, uterine leiomyoma, and endometria atrophy
  • Mice: rare; glandular invasion of myometrium that often extends to the serosa
  • Reported in southern three-banded armadillos and a rock hyrax
  • Humans: up to 20% of women affected

Endometriosis in other species:

• Non-human primates: any primate that menstruates (all OWM and few larger cebids) can develop endometriosis; very rarely reported in chimpanzees, gorillas, and orangutans
• Humans: affects 10-15% of women of reproductive age and is identical to the disease in non-human primates; recent studies in humans suggest endometriosis may give rise to carcinoma

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. 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.
4. Ellenson LH, Pirog EC: The female genital tract. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran: Pathologic basis of disease. 10th ed. Philadelphia, PA: Elsevier; 2021: 1004-1006.
5. Foster RA. Female reproductive system and mammae. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1167.
6. Holman HJ, Gailbreath K. Uterine adenomyosis and an endometrial polyp in a rock hyrax (Procavia capensis). J Zoo Wildl Med. 2016; 47(4):1114-1117.
7. Nishimoto-Kakiuchi A, Netsu S, Okabayashi S, et al. Spontaneous endometriosis in cynomolgus monkeys as a clinically relevant experimental model. Hum Reprod. 2018;33: 1228-1236.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.

Click the slide to view.

---