AFIP SYSTEMIC PATHOLOGY

 

JPC SYSTEMIC PATHOLOGY

REPRODUCTIVE SYSTEM

January 2019

R-M05

 

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

 

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

 

HISTOPATHOLOGIC DESCRIPTION: Colon with adjacent mesentery and lymph node: Transmurally disrupting and markedly expanding the wall of the colon up to 12 mm, primarily affecting the tunica muscularis and submucosa, and extending into the mesentery are multiple, unencapsulated, infiltrative islands of tortuous endometrial glands surrounded by abundant, densely cellular endometrial stroma. The 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. 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. Rarely glands contain moderate numbers of macrophages, neutrophils, erythrocytes, and cellular debris. Endometrial stroma within the mesenteric adipose tissue surrounds a focus of hemorrhage, degenerate neutrophils and necrotic debris and is bound by haphazardly arranged reactive fibroblasts and collagen. The mesenteric lymph node contains increased histiocytes within the paracortical and medullary sinuses, which often demonstrate erythrophagocytosis (draining hemorrhage).

 

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

 

CONDITION: Endometriosis

 

Signalment Slide B (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 epithelium of glands 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: Adenomyosis

 

GENERAL DISCUSSION:

·      Both endometriosis and adenomyosis are non-neoplastic, estrogen-dependent, hyperplastic lesions of endometrial elements; recent studies in humans suggest endometriosis may give rise to carcinoma

·      Adenomyosis

o   Uncommon; reported in dogs, cattle, cats, nonhuman primates, and humans

o   Refers to endometrial stroma and/or glands within the myometrium of the uterine wall

·      Endometriosis

o   Reported in humans, Old World monkeys, and apes (rhesus, pig-tailed, cynomolgus macaques, African green monkeys, DeBrazza’s monkeys, baboons); in macaque species, reported most commonly in rhesus following cesarean section or other pelvic surgery

o   Endometrial glands or stroma are explanted to abnormal locations within and outside the uterus; common 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

o   Responds to cyclic hormonal stimulation as normal endometrium

 

PATHOGENESIS:

·         Adenomyosis: 2 possible pathogeneses

o    Malformation: For example, cows with segmental aplasia or as a malformation of the tips of the uterine horns

o    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

o   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

o   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

o   Induction hypothesis: Unidentified substances released from shed endometrium cause undifferentiated mesenchyme to form endometrial tissues

·       Profound activation of inflammatory cascade; i.e. PGE2, IL-1β, TNF, IL-6 and -8, NGF, VEGF, MCP-1, MMPs, TIMPs, TGFβ play a key role; 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 and because this growth factor can inhibit natural killer activity, induce angiogenesis and proliferation of endometrial stromal cells, it promotes 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

·         Endometriosis: Pain and infertility; dysmenorrhea is associated with but not thought to be caused by endometriosis; occasionally generalized illness with anemia and/or peritonitis

·         Endometriosis often occurs within laparotomy scars in the rhesus macaque

·         Possible sequelae of endometriosis include blockage of ureters and compromise of the gastrointestinal tract lumen

 

TYPICAL GROSS FINDINGS:

·         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:

o   Solid nodules or cysts of variable size and number filled with red to brown fluid ("chocolate cysts")

o   Located anywhere but usually in abdominal cavity

o   May be associated with extensive adhesions; can progress to large, solid, fibrous masses with only a few blood-filled cysts or spaces

o   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:

·         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

·         Marked fibrosis may obscure diagnosis

·         Immunohistochemical markers CD10 and progesterone receptor can detect human ectopic endometrial tissues

 

DIFFERENTIAL DIAGNOSIS:

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

·         Endometriosis

·         Oesophagostomum sp. larvae

·         Mesothelioma

·         Carcinomatosis

Histologic differential diagnosis:

·         Adenomyosis

o   Physiologic progestational endometrial hyperplasia

o   Uterine adenocarcinoma

o   Cystic endometrial hyperplasia +/- pyometra

·         Endometriosis

o   Uterine adenocarcinoma

o   Other carcinomas

o   Retroperitoneal fibromatosis

 

COMPARATIVE PATHOLOGY:

·         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

·         Recent reports of uterine adenomyosis in southern three-banded armadillos and a rock hyrax

·         Endometriosis in humans affects 1 in 10 women of reproductive age and is identical to the disease in non-human primates; recently a baboon endometriosis model has been proposed for study of the role of exogenous and endogenous estradiol

 

REFERENCES:

1.    Assaf BT, Miller AD. Pleural endometriosis in an aged rhesus macaque: a histopathologic and immunohistochemical study. Vet Pathol. 2012; 49(4):636-641.

2.    Baskin GB, Smith SM, Marx PA. Endometrial hyperplasia, polyps, and adenomyosis associated with unopposed estrogen in rhesus monkeys (Macaca mulatta). Vet Pathol. 2002; (39):572-575.

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.    Dick EJ Jr, Hubbard GB, Martin LJ, Leland MM. Record review of baboons with histologically confirmed endometriosis in a large established colony. J Med Primatol. 2003; (32):39-47.

5.    Ellenson LH, Pirog EC: The female genital tract. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran: Pathologic basis of disease. 9th ed. Philadelphia, PA: Saunders; 2015: 1010-1011.

6.    Fanton JW, Hubbard GB, Wood DH. Endometriosis: Clinical and pathologic findings in 70 rhesus monkeys. Am J Vet Res. 1986. 47:1537-154.

7.    Fazleabas AT, Brudney A, Gurates B, Chai D, Bulun S. A modified baboon model for endometriosis. Ann N Y Acad Sci. 2002;955:308-317.

8.    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.

9.    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.

10. 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.

11. Marrow J, Viner T, Thompson R, Boedeker N. Uterine adenomyosis in southern three-banded armadillos. J Zoo and Wildl Med. 2013; 44(4):1018-1026.

12. Nakamura S, OchiaiaK, Ochi A, Ito M, Kamiya T, Yamamoto H. Spontaneous endometriosis in a Mandrill. J Comp Path. 2012;147:386-390.

13. 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.

14. Shalev M, Ciurea D, Deligdisch L. Endometriosis and stromal tumor in a baboon. Lab Anim Sci. 1992; 42:204-208,

15. Sotnikova NY, Antsiferova YS, Posiseeva LV, Shishkov DN, Posiseev DV, Filippova ES. Mechanisms regulating invasiveness and growth of endometriosis lesions in rat experimental model and in humans. Fertil Steril. 2010; 93(8):2701-5.


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