Signalment:  

16-year-old, female, Rhesus Macaque (Macaca mulatta)The animal had been infected with Simian immunodeficiency virus (SIV) and was being treated with Depo Provera for endometriosis. The animal had a history of several episodes of dehydration despite adequate access to water. Previous bouts of dehydration had responded to fluid therapy. On the day of presentation, the animal was found down in the cage, hypothermic, dehydrated and weak with a distended abdomen. Intravenous fluid therapy, including IV dextrose, was initiated prior to the collection of blood.

Analyte	Value	Normal	Units
BUN	175_	5 - 25	mg/dL
Creatinine	4.4_	0.5 - 1.1	mg/dL
Total protein	4.7_	6 - 8.5	g/dL
Sodium	119_	145 - 152	mmol/L
Chloride	92_	105 - 115	mmol/L
Potassium	7.3_	3 - 4.5	mmol/L
Calcium	1.92_	2.1 - 2.55	mg/dL
Phosphorous	>12_	3 - 4.5	mg/dL
Glucose	470_	60 - 120	mg/dL
WBC	20.8_	5 13.5	K/uL
Polys - calc	18.7 _	1.6 7.4	K/uL
HCT	34	33 - 45	%

The serum chemical findings were consistent with chronic renal disease. The animal was euthanized after failing to respond to IV fluid therapy.

Gross Description:  

The animal was in lean body condition with adequate hydration. Multifocally within the abdomen, the omentum was attached loosely to the peritoneal wall. In between the loops of intestine and on the capsular surface of the kidneys, there were multifocal, small, white, fibrous adhesions. Within the caudal abdomen, surrounding and invading the body of the uterus and effacing the ovaries, and compressing the colon and bladder was a 3 x 3.5 x 6 cm³ cystic mass. The mass contained approximately 10ml of clear fluid and had an irregularly thickened, lobular inner surface. The lungs were congested with moderate edema and the kidneys were pale. No other significant lesions were noted in the heart, liver, spleen, gastrointestinal tract, or brain. 

Histopathologic Description:

Submitted sections were from the uterus, ovary, and oviduct. Multifocally, the serosal surfaces of these organs were irregularly expanded by a thick band of homogenous, eosinophilic material with numerous, widely spaced, 15 25um polygonal cells and few glands lined by cuboidal epithelium. The polygonal cells had distinct cell borders with ample, fibrillar cytoplasm. Nuclei were round oval, with reticular chromatin and a single nucleolus [decidualized stromal cells]. No mitotic figures were seen within the polygonal cells. In some sections, there were small lymphoid aggregates in the stroma. Some glands contained cellular and necrotic debris, but RBCs and hemosiderophages were not a common finding. Few sections contained small foci of mineralization. On some slides, the endometrium was expanded by similar decidualized stromal cells and ample eosinophilic stroma. 

Morphologic Diagnosis:  

Caudal abdominal mass: endometriosis with decidualized stromal cells.

Lab Results:  

The eosinophilic matrix was not birefringent with Congo red staining and few fibrils were seen with trichome stain. The polygonal cells failed to stain with macrophage [HAM56], muscle [Desmin], and epithelium [AE1/AE3] markers.

Condition:  

Endometriosis

Contributor Comment:  

AFIP confirmed the diagnosis of endometriosis with decidualized stromal cells. In addition to the uterus and ovaries, endometriosis affected the intestines, kidneys, colon, and bladder in this animal. Although endometriosis is not an unusual lesion in macaques, the presence of the large polygonal decidualized stromal cells with abundant eosinophilic, homogenous stroma was not a change we had commonly encountered. The endometriotic stromal cells we have seen in the past have been small, spindeloid, contained little to no cytoplasm, had spindle-shaped nuclei and were not widely separated by stroma. 

Endometriosis, the presence of endometrial tissue outside the uterus, is a progressive disease that occurs in women and old world primates, primarily during their reproductive years. ^5,10,12,17 Clinical signs associated with endometriosis include dysmenorrhea, dyspareunia, pelvic pain, interference with intestinal and urinary bladder function and reduced fertility.¹⁰ In rhesus, there may be similar signs with irregular vaginal bleeding or heavy menses and signs of pain include lying down in the cage, anorexia, grimacing, decreased grooming, restlessness, and vocalization.^5,10

On gross examination or laparotomy, endometriosis may have a varied appearance but is most easily recognized by red/brown [chocolate] cysts on the serosal surface of pelvic and abdominal organs. The cysts are endometriotic glands containing viable and degenerate RBCs and hemosiderophages.^5,15 Endometriotic lesions may also exist as clear cysts and variably-sized adhesions between organs.¹⁵ In women with endometriosis, the organs most likely affected (in descending order) are: ovaries, uterine ligaments, rectovaginal septum, pelvic peritoneum, as well as laparotomy scars.⁴ Endometriosis may also occur outside of the peritoneum and, rarely, in men.¹²

Endometriosis is definitively diagnosed by laparoscopic surgery to biopsy/remove suspected lesions with histologic examination of the samples. ¹¹ The diagnosis of endometriosis is based upon the presence of endometrial glands and stroma outside the uterus.^4,12 In women, stromal changes that may be associated with endometriosis are fibrosis, numerous small vessels, aggregates of foamy and pigmented [hemosiderin] macrophages, smooth muscle metaplasia, and myxoid change.3 Progestin treatment, which this macaque received, can cause decidual change in the endometrial stromal cells so that stromal cells appear large and polygonal rather than small and spindeloid. The appearance of endometriotic glands can range from normal-appearing glands lined by cuboidal epithelial cells to glands lined by flattened epithelium that may be mistaken for ectatic vessels.³ Hormone treatment, pregnancy, and menopause will change the appearance of both the stroma and the glands. For suspected cases of endometriosis, the immunohistochemical marker CD10, which stains both normal and endometriotic stromal cells, can be used to assist in making the diagnosis.³

Historically, endometriosis has been thought to develop and progress via one of three theoretical pathways:

1. Regurgitation/implantation: retrograde menstruation, the backflow of uterine contents, including epithelial cells, and debris through the fallopian tubes into the peritoneal cavity¹⁰, may cause endometriosis.⁴
2. Metaplasia: the peritoneum of the pelvis, which arises from the same embryonic coelomic epithelium as the endometrium, undergoes metaplastic change to develop into endometriosis.^4,8,12
3. Vascular or lymphatic dissemination: endometriotic tissue may be transported through pelvic veins and lymphatics to cause endometriosis in tissues distant from the uterus such as lungs and lymph nodes.⁴

The current understanding is that the first step in the pathogenesis of endometriosis is the regurgitation of endometrial contents into the peritoneal cavity. ² However, retrograde menstruation occurs in 76-90% of women, most of who never develop endometriosis.⁵ How the ectopic endometrial tissue develops into endometriosis is still being defined. Although the disease estrogen-dependent,⁵ the progression is likely multifactorial involving hormonal, immune, genetic and environmental influences.¹⁰ Significant factors associated with the development of endometriosis are: kinship with affected individuals; abdominal surgeries such as cesarean sections, fetal instrumentation, ovarian follicle aspirations and embryo transfers; age; and with environmental factors such as exposure to dioxin, polychlorinated biphenyls (PCBs) and ionizing radiation.^1,17 Additional risk factors for the development of endometriosis in humans are short menstrual cycle length, prolonged menses, low parity number and increased serum estrogen.¹⁵

Recent work using gene expression analysis to evaluate the uterine endometrium of women with endometriosis and those without the disease has identified numerous genes that are both up and down regulated in comparison to non affected women. In addition, the uterine endometrium of women with moderate/severe endometriosis is less sensitive to the effects of progesterone. In normal endometrium, progesterone has an antiproliferative effect and, after ovulation, leads to the onset of secretory phase and deciduization of stroma. In the endometrium of affected women, progesterone resistance leads to enhanced cellular survival, as well as decreased regulation of DNA synthesis and cellular mitosis.²

Nonprimate and primate animal models have been developed to study the genesis and progression of endometriosis. Endometriosis can be induced in rodents and rabbits by implanting autologous or human uterine tissue within the peritoneum. These models have been helpful in the study of early events involved in the attachment of endometrial stroma and glands after implantation into the abdomen. In addition, the influence of immune and inflammatory components in the development of endometriosis can be more easily studied in a sequential manner in smaller animal models. However, rodents and rabbits lack a true menstrual cycle and the endometriotic lesions they develop differ from those seen in women. ¹⁵

Endometriosis occurs spontaneously and can be induced in primates.¹⁵ In colonies of captive macaques, spontaneous endometriosis has been seen in up to 25% of the population.^10,17 Rhesus macaques have been most often studied and are a good model for human endometriosis in that their menstrual cycle is approximately 28 days long, with a 4 day menstrual bleeding period, they tend to develop the disease during their reproductive years, and have disease that progresses with time. In addition, the clinical signs, gross and histologic lesions in the macaques are similar to those seen in women. ^10,17

The treatment goals for endometriosis are to decrease pain, decrease the size of endometriotic lesions, remove associated obstructions, and restore fertility. ¹¹ Treatment may involve surgical removal of endometrial explants within the abdomen or medical treatment to cause the ectopic tissue to atrophy or both. Unfortunately, clinical signs may recur after surgery or after hormonal treatment is discontinued.^11,12 Medical therapies target the hypothalamic-pituitary-gonadal axis, by selective modulation of estrogenic and progestogenic pathways, by inhibiting angiogenesis, or by modulating inflammatory and immunological responses.^5,11 Depo Provera, a commonly used progestin-based treatment, will cause endometrial tissue to atrophy, but also may reduce bone density. Other hormone treatments include gonadotropin-releasing hormone agonists, progestogens, androgenic agonists, combined oral contraceptive therapy, and antiprogestogens may also lead to osteoporosis.¹¹ More recent therapies include selective progesterone-receptor modulators (SPRMs), selective estrogen-receptor modulators (SERMs) which reduce estrogen but have a bone-sparing effect, immunomodulatory drugs, angiogenesis inhibitors which may interfere with implantation and vascularization of ectopic implants, aromatase inhibitors (AIs) which decrease non-ovarian sources of estrogen, and statins which reduce the growth of endometrial stroma in vitro.⁵

Renal changes included multifocal, moderate chronic infarcts with mild chronic interstitial nephritis as well as moderate acute tubular necrosis with tubular proteinosis. Adverse renal effects from Depo Provera treatment have not been reported.¹³ Clinical veterinarians did not find a cause for the episodes of dehydration and no other animals in colony developed unexplained dehydration. A specific agent for the renal changes was not identified. No opportunistic infections or changes associated with SIV infection were seen in the other tissues of this animal. 

JPC Diagnosis:  

Ovary and uterus: Endometriosis, with decidualized stromal cells, Rhesus macaque (Macaca mulatta), nonhuman primate.

Conference Comment:  

The contributor gives an excellent overview of endometriosis.

Endometriosis is defined as endometrial glands or stroma explanted to abnormal locations within and outside the uterus.³ The explanted tissue responds to hormonal stimulation similar to normal endometrium.⁴ It has been reported in humans, old world monkeys, and apes.¹⁵ Key histologic features include endometrial glands, endometrial stroma, and pigment-containing histiocytes.

These features may vary depending on hormonal stimulation. In longstanding cases of endometriosis, the endometrial glands or endometrial stroma may be obscured by fibrosis or an infiltrate of histiocytes that contain hemosiderin, ceroid, or lipofuscin.³

Adenomyosis is endometrial stroma and/or glands within the myometrium of the uterine wall and has been reported in humans and domestic animals.^4,14

References:

1. Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, Propst AM: Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril 81:775-779, 2004
2. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC: Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148:38143326, 2007
3. Clement PB: The pathology of endometriosis: A survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol 14:241-260, 2007
4. Crum CP: The female genital tract. In: Robbins and Cotran Pathologic Basis of Disease, eds. Kumar V, Abbas, AK, Fausto N, 7th ed., pp. 1083-1084. Elsevier Saunders, Philadelphia, PA, 2005
5. Hompes PGA, Mijatovic V: Endometriosis: The way forward. Gynecol Endocrinol 23:5-12, 2007
6. Kang J, Chapdelaine P, Laberge PY, Fortier M: Functional characterization of prostaglandin transporter and terminal prostaglandin synthases during decidualization of human endometrial stromal cells. Hum Reprod 21:592-599, 2005
7. Klemmt PAB, Carver JG, Kennedy SH, Koninckx PR, Mardon HJ: Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. Fertil Steril 85:564-572, 2006
8. Lane B, Oxberry W, Mazella J, Tseng L: Decidualization of human endometrial stromal cells in vitro: effects of progestin and relaxin on the ultrastructure and production of decidual secretory proteins. Hum Reprod 9:259- 266, 1994
9. Mantena SR, Kannan A, Cheon YP, Li Q, Johnson PF, Bagchi IC, Bagchi MK: C/EBP_ is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc Natl Acad Sci USA 103:1870-1875, 2006
10. Mattison JA, Ottinger MA, Powell D, Longo DL, Ingram DK: Endometriosis: Clinical monitoring and treatment procedures in Rhesus monkeys. J Med Primatol, doi:10.1111/j.1600-0684.2006.00208.x, 2007
11. Mihalyi A, Simsa P, Mutinda KC, Meuleman C, Mwenda JM, DHooghe TM: Emerging drugs in endometriosis. Expert Opin Emerg Drugs 11:503-524, 2006
12. Olive DL, Schwartz LB: Endometriosis. N Engl J Med 328:1759-1769, 1993
13. Physicians Desk Reference. 61st ed., Thompson PDR, Montvale, NJ, 2007
14. Schlafer DH, Miller RB: Female genital system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 3, pp. 464- 465. Elsevier Limited, St. Louis, MO, 2007
15. Story L, Kennedy S: Animal studies in endometriosis: A review. ILAR J 45:132-138, 2004
16. Yang S, Fang Z, Suzuki T, Sasano H, Zhou J, Gurates B, Tamura M, Ferrer K, Bulun S: Regulation of Aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins (C/EBPs): decreased C/EBP_ in endometriosis is associated with overexpression of aromatase. J Clin Endocrinol Metab 87:2336-2345, 2002
17. Zondervan KT, Weeks DE, Colman R, Cardon LR, Hadfield R, Schleffler J, Trainor AG, Coe CL, Kemnitz JW, Kennedy SH: Familial aggregation of endometriosis in a large pedigree of Rhesus macaques. Hum Reprod 19:448- 455, 2004

A virtual slide is not available for this case.

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