- Email: [email protected]
Spontaneous Endometriosis in a Mandrill (Mandrillus sphinx)
J. Comp. Path. 2012, Vol. 147, 386e390
Available online at www.sciencedirect.com
www.elsevier.com/locate/jcpa
DISEASE IN WILDLIFE OR EXOTIC SPECIES
Spontaneous Endometriosis in a Mandrill (Mandrillus sphinx) S. Nakamura*, K. Ochiai*, A. Ochi*, M. Ito†, T. Kamiya† and H. Yamamoto† * Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University and † Sapporo Maruyama Zoo, Sapporo, Japan
Summary A 25-year-old female mandrill (Mandrillus sphinx) died after exhibiting weakness and recumbency with serosanguineous ascites. Gross findings included haemoperitoneum and multifocal to diffuse serosal thickening with petechiae and ecchymoses throughout the peritoneum. The uterus was covered entirely with large blood clots and was adherent to the ovaries and pelvic wall. Microscopical and immunohistochemical examination revealed extra- and intra-uterine growth of ectopic endometrial tissue with marked fibrosis. The ectopic endometrial tissues predominantly consisted of stromal cells expressing CD10 and progesterone receptor and variably-sized glands lined by the epithelium with occasional slight expression of oestrogen receptor a. A diagnosis of endometriosis was made. This is the first report of naturally occurring endometriosis in a mandrill. Ó 2012 Elsevier Ltd. All rights reserved. Keywords: CD10; endometriosis; mandrill; progesterone receptor
Endometriosis is a common disease in women and is defined as the ectopic growth of endometrial tissue, which generally includes both endometrial gland and stromal components. Spontaneously arising endometriosis has also been reported in non-human primates and apes that have true menstrual cycles, including cercopithecine monkeys (Schmidt and Hartfiel, 1978; Cary et al., 1982; Binhazim et al., 1989; Story and Kennedy, 2004) and a gorilla (Dore and Lagace, 1985). The disease is common in macaques (MacKenzie, 1975; Cary et al., 1982; Fanton and Hubbard, 1983; Chin, 1994; Hadfield et al., 1997; Zondervan et al., 2004; Mattison et al., 2007) and baboons (Folse and Stout, 1978; D’Hooghe et al., 1991; Shalev et al., 1992) and up to 25% of the population in colonies of captive macaques may be affected (Hadfield et al., 1997); however, no case of endometriosis has been previously reported in the genus Mandrillus. Few studies of this disease in non-human primates have applied immunohistochemistry (IHC) to the lesions, although
Correspondence to: K. Ochiai (e-mail: [email protected]). 0021-9975/$ - see front matter doi:10.1016/j.jcpa.2012.01.004
it is known that oestrogen receptor (OR), progesterone receptor (PR) and CD10 can be useful immunohistochemical markers for detecting human ectopic endometrial tissues (Jones et al., 1995; Fujishita et al., 1997). This report describes the pathological and immunohistochemical features of severe endometriosis in a mandrill. A 25-year-old captive-born female mandrill (Mandrillus sphinx) was kept in a zoological garden. There was no significant history of disease except for an episode of forelimb trauma. The animal had previously had four live births, but all of the offsprings had died on the day of parturition. The most recent birth had been in 1997 when the mandrill was 14 years old. After this parturition, she had not become pregnant again despite several matings. In October 2008, the mandrill was found weak and recumbent with haemoperitoneum and precordial subcutaneous oedema. Haematological and serum biochemical examinations revealed severe anaemia (haematocrit 17.5%, reference interval 36e40%; Peinado et al., 1996) and increased concentration of serum lactate dehydrogenase (1389 IU/l, reference interval 136e349 IU/l). Ó 2012 Elsevier Ltd. All rights reserved.
Endometriosis in a Mandrill
Cardiomegaly and pulmonary oedema were suspected on radiographic examination. Supportive measures with removal of ascites fluid were performed, but the cutaneous oedema and ascites recurred the next day. Although a selection of medicines to support cardiorespiratory function was also given, the mandrill was found dead on the following day. On necropsy examination, the carcass was in poor nutritional condition with no appreciable autolysis and minimal body fat stores. The oral mucosa and conjunctiva were pale. There was a locally extensive pressure sore with approximately 100 ml serosanguineous fluid located in the right precordial subcutis. On incision of the abdominal wall, there was approximately 100 ml of serosanguineous fluid. Each side of the thoracic cavity contained approximately 30 ml of serous pleural effusion and there was mild right ventricular dilation with mild hydropericardium. There was severe diffuse fibrotic thickening with petechial and ecchymotic haemorrhages of the parietal peritoneum, greater omentum, mesentery and the serosal surface of the abdominal viscera including the liver, spleen and gastrointestinal tract (Fig. 1). Mild to moderate adhesions between viscera were common. The pelvic cavity was occupied by a massive blood clot and the intrapelvic organs, including the uterus and ovaries, were entirely covered by the clot. The uterus was fused with the ovaries and the adjacent pelvic peritoneum by fibrotic tissue. Three discrete, rounded, smooth, firm, white to grey nodules, up to 1 cm in diameter, bulged from the serosal surface of the pelvic peritoneum. The cut surfaces of these nodules appeared as white to grey fibrous tissue. On sectioning the uterine body, white foci, 2 mm in diameter, were noted in the myometrium. The uterus and other organs, including the liver, spleen, kidneys, heart, lungs, gastrointestinal organs,
Fig. 1. Small intestine showing diffuse fibrous thickening of the serosa with petechial and ecchymotic haemorrhages.
387
urinary bladder and brain, were fixed in 20% neutral-buffered formalin and embedded in paraffin wax for microscopical examination. Sections (4 mm) were stained with haematoxylin and eosin (HE). IHC was performed on selected sections using the streptavidinebiotin (SAB)eperoxidase method with a commercial kit (Nichirei Corp., Tokyo, Japan). The primary antibodies were anti-human ORa (clone 1D5; diluted 1 in 35, DakoCytomation, Glostrup, Denmark), anti-human PR (clone PgR636; diluted 1 in 50, DakoCytomation), antiCD10 (clone 56C6; diluted 1 in 80, Novocastra Laboratories, Newcastle, UK) and anti-human a-smooth muscle actin (clone 1A4; undiluted, DakoCytomation). The reaction products were visualized by reacting with 3, 30 -diaminobenzidine (DAB). Microscopically, the serosal lesions in the abdominal and pelvic cavity, including the nodules in the pelvic peritoneum, were mainly composed of fibrous connective tissue containing dilated blood vessels and multifocal proliferation of round to slightly spindle-shaped cells (Fig. 2). The spindle-shaped cells had round to oval nuclei and indistinct cytoplasm, similar to endometrial stromal cells (Fig. 3). They occasionally showed granular cytoplasm. Additionally, various-sized ectopic glands lined by simple columnar epithelium were rarely observed. There were scattered mild to moderate multifocal haemorrhages with haemosiderin-laden macrophages. The smooth muscle of the gastrointestinal wall adjacent to the serosal lesions was hyperplastic. In contrast, aberrant smooth muscle fascicles were occasionally observed in the nests of stromal-like cells in the omentum. These cellular components, including fibroblasts, endothelial cells, stromal-like cells and glandular epithelium, showed no cellular or nuclear
Fig. 2. Ectopic endometrial tissue (arrowheads) in the omentum adjacent to the stomach (left of the figure). HE. Bar, 500 mm.
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Fig. 3. Ectopic endometrial tissue in the omentum. Ectopic glands are lined by simple columnar epithelium with periglandular endometrial stromal-like cells. Note smooth muscle fascicles in the nest of stromal-like cells (arrowheads). HE. Bar, 40 mm. Inset: the endometrial stromal-like cells express CD10. IHC. Bar, 30 mm.
atypia, and mitoses were infrequent. In the uterus, the endometrium was composed of a basal layer and ectopic endometrial tissue, consisting of glands and stroma, was observed in the myometrial foci corresponding to the gross lesions. The endometrial glandular epithelium and stromal cells in these foci had a normal histological appearance. The right and left ovaries contained occasional small glandular structures with stromal-like cells. There was multifocal fat necrosis with a macrophage-dominated inflammatory reaction in the adipose tissue of the affected mesentery and omentum. Immunohistochemically, the stromal-like cells proliferating outside the uterus, as well as normal and ectopic endometrial stromal cells within the uterus, expressed PR and CD10 (Fig. 3). The epithelium of the ectopic glands and normal endometrial glands showed slight expression of ORa. The ectopic tissues had similar immunoreactivity to the uterine endometrial glands and stroma. The smooth muscle fascicles in the nests of stromal-like cells, which were located apart from the gastrointestinal muscular layers, expressed a-smooth muscle actin, suggesting smooth muscle metaplasia of stromal-like cells (Fig. 4). Diffuse centrilobular congestion with hepatocyte degeneration and necrosis was noted in the liver. Steroid receptors, including ORa and PR, are immunohistochemically detectable in normal and malignant human endometrium (Mylonas et al., 2009). Antibodies against CD10 (or common acute lymphoblastic leukaemia antigen; CALLA) are now available for routine IHC of human haematopoietic neoplasms, and CD10 immunoreactivity is also useful
Fig. 4. Aberrant smooth muscle fascicles in the nest of endometrial stromal-like cells express a-SMA. IHC. Bar, 20 mm.
in confirming the endometrial nature of stromal cells outside the uterus because immunoreactivity is maintained in normal and neoplastic endometrial stromal cells as well as endometriotic stromal cells (Sumathi and McCluggage, 2002). Thus, the present findings indicate extra- and intra-uterine growth of the endometrium and the pathological features were consistent with those of human endometriosis (Clement et al., 1999; Clement, 2007). The marked secondary fibrosis of the peritoneum indicates that this was a chronic process. The necropsy findings, including intraabdominal serosanguineous fluid, serosal haemorrhage, intrapelvic blood clot, precordial subcutaneous oedema and chronic hepatic congestion, all suggest that the animal died of hypovolaemic shock secondary to severe endometriosis. Clinical signs associated with endometriosis in women include dysmenorrhoea, dyspareunia, pelvic pain, interference with intestinal and urinary bladder function and reduced fertility (Clement et al., 1999; Ellenson and Pirog, 2009). The most likely affected organs are the ovaries, uterine ligaments, rectovaginal septum and pelvic peritoneum. The gross lesions include red-brown (chocolate-coloured) cysts on the serosal surface of pelvic and abdominal organs, clear cysts and adhesions between visceral organs. Affected non-human primates show irregular vaginal bleeding or heavy menses, with recumbency, anorexia, grimacing, decreased grooming, restlessness and vocalization, suggesting pain (Hompes and Mijatovic, 2007; Mattison et al., 2007). The gross and microscopical lesions in macaques are similar to those in women (Zondervan et al., 2004; Mattison et al., 2007). The current case lacked cystic gross lesions and the extrauterine endometrial tissue, especially the endometrial glands, was microscopically obscured by marked secondary fibrosis. Compared with the distribution of
Endometriosis in a Mandrill
endometriosis previously reported in non-human primates, this case was considered to be among the most severe. The mandrill may have been suffering from endometriosis since the time of the last parturition at 14 years of age and thereafter become infertile. The extra-uterine lesions in the current case were characterized by the proliferation of endometrial stromal cells; however, close microscopical examination revealed a small number of endometrial glands in the extra-uterine foci. The smooth muscle metaplasia of stromal cells and reactive hyperplasia of smooth muscle in the gastrointestinal tract were also diagnostic clues. The metaplastic change is most common in ovarian endometriosis in women and is explained by the myofibroblastic potential of endometrial stromal cells (Clement, 2007). On the other hand, reactive smooth muscle proliferation more commonly occurs in endometriosis and may involve the smooth muscle of pelvic ligaments and the wall of the bowel and bladder (Clement, 2007). In addition to the morphological findings, expression of PR and CD10 was useful to confirm the ectopic proliferation of endometrial stromal cells in this mandrill (Jones et al., 1995; Fujishita et al., 1997; Clement, 2007). Two potential explanations are proposed for the origin of ectopic endometrial tissue (Ellenson and Pirog, 2009). Firstly, the metastatic theory suggests that retrograde menstruation through the fallopian tubes occurs regularly, even in normal women, and could mediate the spread of endometrial tissue to the peritoneal cavity. This theory can explain the spread of endometriosis to distant sites, including lungs and lymph nodes, via haematogenous and lymphatic metastases. Secondly, the metaplastic theory suggests that the endometrium could arise directly from the coelomic epithelium. Although the underlying mechanism of the metastatic theory has still not been established, this theory is most widely accepted. In the current case, the lesions were too severe to examine the development of the disease, but there was no discrepancy between our findings and the metastatic theory. In summary, the current case was considered to be severe endometriosis in a menstruating nonhuman primate. The immunohistochemical markers PR and CD10 appear useful in diagnosing endometriosis in mandrills. This report presents the first case of spontaneously occurring endometriosis in a mandrill.
References Binhazim AA, Tarara RP, Suleman MA (1989) Spontaneous external endometriosis in a De Brazza’s monkey. Journal of Comparative Pathology, 101, 471e474.
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Cary CJ, Peter GK, Schiffer SP (1982) A case report and review of endometriosis in nonhuman primates. Laboratory Animal Science, 32, 426. Chin SC (1994) Endometriosis and pyometra in a Taiwan rhesus (Macaca cyclopis). Journal of the Chinese Society of Veterinary Science, 20, 58e64. Clement PB (2007) The pathology of endometriosis. Advances in Anatomic Pathology, 14, 241e260. Clement PB, Young RH, Scully RE (1999) The peritoneum. In: Diagnostic Surgical Pathology, 3rd Edit., Vol. 2, SS Sternberg, Ed., Lippincott Williams and Wilkins, Philadelphia, pp. 2427e2432. D’Hooghe TM, Bambra CS, Cornillie FJ, Isahakia M, Koninckx PR (1991) Prevalence and laparoscopic appearance of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus). Biology of Reproduction, 45, 411e416. Dore M, Lagace A (1985) Spontaneous external endometriosis in a gorilla (Gorilla gorilla). Canadian Veterinary Journal, 26, 347e349. Ellenson LH, Pirog EC (2009) The female genital tract. In: Pathologic Basis of Disease, 8th Edit., V Kumer, AK Abbas, N Fausto, JC Aster, Eds., Saunders Elsevier, Philadelphia, pp. 1028e1029. Fanton JW, Hubbard GB (1983) Spontaneous endometriosis in a cynomolgus monkey (Macaca fascicularis). Laboratory Animal Science, 33, 597e599. Folse DS, Stout LC (1978) Endometriosis in a baboon (Papio doguera). Laboratory Animal Science, 28, 217e219. Fujishita A, Chavez RO, Nakane PK, Yamabe T, Koji T et al. (1997) Expression of estrogen and progesterone receptors in endometrium and peritoneal endometriosis: an immunohistochemical and in-situ hybridization study. Fertility and Sterility, 67, 856e864. Hadfield RM, Yudkin PL, Coe CL, Scheffer J, Uno H et al. (1997) Risk factors for endometriosis in the rhesus monkey (Macaca mulatta): a case-control study. Human Reproduction Update, 3, 109e115. Hompes PG, Mijatovic V (2007) Endometriosis e the way forward. Gynecological Endocrinology, 23, 5e12. Jones RK, Bulmer JN, Searle RF (1995) Immunohistochemical characterization of proliferation, oestrogen receptor and progesterone receptor expression in endometriosis: comparison of eutopic and ectopic endometrium with normal cycling endometrium. Human Reproduction, 10, 3272e3279. MacKenzie WF (1975) Endometriosis. American Journal of Pathology, 80, 341e344. Mattison JA, Ottinger MA, Powell D, Longo DL, Ingram DK (2007) Endometriosis: clinical monitoring and treatment procedures in rhesus monkeys. Journal of Medical Primatology, 36, 391e398. Mylonas I, Makovitzky J, Friese K, Jeschke U (2009) Immunohistochemical labelling of steroid receptors in normal and malignant human endometrium. Acta Histochemica, 111, 349e359. Peinado VI, Celdran JF, Viscor G, Palomeque J (1996) Hematology and serum chemistry in the whitecrowned mangabey (Cercocebus torquatus lunulatus) and
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in the mandrill (Mandrillus sphinx). Journal of Medical Primatology, 25, 282e286. Schmidt RE, Hartfiel DA (1978) Endometriosis in a graycheeked mangabey (Cercocebus albigena). Journal of Zoo Animal Medicine, 9, 42e45. Shalev M, Ciurea D, Deligdisch L (1992) Endometriosis and stromal tumor in a baboon (Papio hamadryas). Laboratory Animal Science, 42, 204e208. Story L, Kennedy S (2004) Animal studies in endometriosis: a review. ILAR Journal, 45, 132e138. Sumathi VP, McCluggage WG (2002) CD10 is useful in demonstrating endometrial stroma at ectopic sites and
in confirming a diagnosis of endometriosis. Journal of Clinical Pathology, 55, 391e392. Zondervan KT, Weeks DE, Colman R, Cardon LR, Hadfield R et al. (2004) Familial aggregation of endometriosis in a large pedigree of rhesus macaques. Human Reproduction, 19, 448e455.
May 7th, 2011 ½ Received, Accepted, January 5th, 2012
Available online at www.sciencedirect.com
www.elsevier.com/locate/jcpa
DISEASE IN WILDLIFE OR EXOTIC SPECIES
Spontaneous Endometriosis in a Mandrill (Mandrillus sphinx) S. Nakamura*, K. Ochiai*, A. Ochi*, M. Ito†, T. Kamiya† and H. Yamamoto† * Laboratory of Comparative Pathology, Graduate School of Veterinary Medicine, Hokkaido University and † Sapporo Maruyama Zoo, Sapporo, Japan
Summary A 25-year-old female mandrill (Mandrillus sphinx) died after exhibiting weakness and recumbency with serosanguineous ascites. Gross findings included haemoperitoneum and multifocal to diffuse serosal thickening with petechiae and ecchymoses throughout the peritoneum. The uterus was covered entirely with large blood clots and was adherent to the ovaries and pelvic wall. Microscopical and immunohistochemical examination revealed extra- and intra-uterine growth of ectopic endometrial tissue with marked fibrosis. The ectopic endometrial tissues predominantly consisted of stromal cells expressing CD10 and progesterone receptor and variably-sized glands lined by the epithelium with occasional slight expression of oestrogen receptor a. A diagnosis of endometriosis was made. This is the first report of naturally occurring endometriosis in a mandrill. Ó 2012 Elsevier Ltd. All rights reserved. Keywords: CD10; endometriosis; mandrill; progesterone receptor
Endometriosis is a common disease in women and is defined as the ectopic growth of endometrial tissue, which generally includes both endometrial gland and stromal components. Spontaneously arising endometriosis has also been reported in non-human primates and apes that have true menstrual cycles, including cercopithecine monkeys (Schmidt and Hartfiel, 1978; Cary et al., 1982; Binhazim et al., 1989; Story and Kennedy, 2004) and a gorilla (Dore and Lagace, 1985). The disease is common in macaques (MacKenzie, 1975; Cary et al., 1982; Fanton and Hubbard, 1983; Chin, 1994; Hadfield et al., 1997; Zondervan et al., 2004; Mattison et al., 2007) and baboons (Folse and Stout, 1978; D’Hooghe et al., 1991; Shalev et al., 1992) and up to 25% of the population in colonies of captive macaques may be affected (Hadfield et al., 1997); however, no case of endometriosis has been previously reported in the genus Mandrillus. Few studies of this disease in non-human primates have applied immunohistochemistry (IHC) to the lesions, although
Correspondence to: K. Ochiai (e-mail: [email protected]). 0021-9975/$ - see front matter doi:10.1016/j.jcpa.2012.01.004
it is known that oestrogen receptor (OR), progesterone receptor (PR) and CD10 can be useful immunohistochemical markers for detecting human ectopic endometrial tissues (Jones et al., 1995; Fujishita et al., 1997). This report describes the pathological and immunohistochemical features of severe endometriosis in a mandrill. A 25-year-old captive-born female mandrill (Mandrillus sphinx) was kept in a zoological garden. There was no significant history of disease except for an episode of forelimb trauma. The animal had previously had four live births, but all of the offsprings had died on the day of parturition. The most recent birth had been in 1997 when the mandrill was 14 years old. After this parturition, she had not become pregnant again despite several matings. In October 2008, the mandrill was found weak and recumbent with haemoperitoneum and precordial subcutaneous oedema. Haematological and serum biochemical examinations revealed severe anaemia (haematocrit 17.5%, reference interval 36e40%; Peinado et al., 1996) and increased concentration of serum lactate dehydrogenase (1389 IU/l, reference interval 136e349 IU/l). Ó 2012 Elsevier Ltd. All rights reserved.
Endometriosis in a Mandrill
Cardiomegaly and pulmonary oedema were suspected on radiographic examination. Supportive measures with removal of ascites fluid were performed, but the cutaneous oedema and ascites recurred the next day. Although a selection of medicines to support cardiorespiratory function was also given, the mandrill was found dead on the following day. On necropsy examination, the carcass was in poor nutritional condition with no appreciable autolysis and minimal body fat stores. The oral mucosa and conjunctiva were pale. There was a locally extensive pressure sore with approximately 100 ml serosanguineous fluid located in the right precordial subcutis. On incision of the abdominal wall, there was approximately 100 ml of serosanguineous fluid. Each side of the thoracic cavity contained approximately 30 ml of serous pleural effusion and there was mild right ventricular dilation with mild hydropericardium. There was severe diffuse fibrotic thickening with petechial and ecchymotic haemorrhages of the parietal peritoneum, greater omentum, mesentery and the serosal surface of the abdominal viscera including the liver, spleen and gastrointestinal tract (Fig. 1). Mild to moderate adhesions between viscera were common. The pelvic cavity was occupied by a massive blood clot and the intrapelvic organs, including the uterus and ovaries, were entirely covered by the clot. The uterus was fused with the ovaries and the adjacent pelvic peritoneum by fibrotic tissue. Three discrete, rounded, smooth, firm, white to grey nodules, up to 1 cm in diameter, bulged from the serosal surface of the pelvic peritoneum. The cut surfaces of these nodules appeared as white to grey fibrous tissue. On sectioning the uterine body, white foci, 2 mm in diameter, were noted in the myometrium. The uterus and other organs, including the liver, spleen, kidneys, heart, lungs, gastrointestinal organs,
Fig. 1. Small intestine showing diffuse fibrous thickening of the serosa with petechial and ecchymotic haemorrhages.
387
urinary bladder and brain, were fixed in 20% neutral-buffered formalin and embedded in paraffin wax for microscopical examination. Sections (4 mm) were stained with haematoxylin and eosin (HE). IHC was performed on selected sections using the streptavidinebiotin (SAB)eperoxidase method with a commercial kit (Nichirei Corp., Tokyo, Japan). The primary antibodies were anti-human ORa (clone 1D5; diluted 1 in 35, DakoCytomation, Glostrup, Denmark), anti-human PR (clone PgR636; diluted 1 in 50, DakoCytomation), antiCD10 (clone 56C6; diluted 1 in 80, Novocastra Laboratories, Newcastle, UK) and anti-human a-smooth muscle actin (clone 1A4; undiluted, DakoCytomation). The reaction products were visualized by reacting with 3, 30 -diaminobenzidine (DAB). Microscopically, the serosal lesions in the abdominal and pelvic cavity, including the nodules in the pelvic peritoneum, were mainly composed of fibrous connective tissue containing dilated blood vessels and multifocal proliferation of round to slightly spindle-shaped cells (Fig. 2). The spindle-shaped cells had round to oval nuclei and indistinct cytoplasm, similar to endometrial stromal cells (Fig. 3). They occasionally showed granular cytoplasm. Additionally, various-sized ectopic glands lined by simple columnar epithelium were rarely observed. There were scattered mild to moderate multifocal haemorrhages with haemosiderin-laden macrophages. The smooth muscle of the gastrointestinal wall adjacent to the serosal lesions was hyperplastic. In contrast, aberrant smooth muscle fascicles were occasionally observed in the nests of stromal-like cells in the omentum. These cellular components, including fibroblasts, endothelial cells, stromal-like cells and glandular epithelium, showed no cellular or nuclear
Fig. 2. Ectopic endometrial tissue (arrowheads) in the omentum adjacent to the stomach (left of the figure). HE. Bar, 500 mm.
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Fig. 3. Ectopic endometrial tissue in the omentum. Ectopic glands are lined by simple columnar epithelium with periglandular endometrial stromal-like cells. Note smooth muscle fascicles in the nest of stromal-like cells (arrowheads). HE. Bar, 40 mm. Inset: the endometrial stromal-like cells express CD10. IHC. Bar, 30 mm.
atypia, and mitoses were infrequent. In the uterus, the endometrium was composed of a basal layer and ectopic endometrial tissue, consisting of glands and stroma, was observed in the myometrial foci corresponding to the gross lesions. The endometrial glandular epithelium and stromal cells in these foci had a normal histological appearance. The right and left ovaries contained occasional small glandular structures with stromal-like cells. There was multifocal fat necrosis with a macrophage-dominated inflammatory reaction in the adipose tissue of the affected mesentery and omentum. Immunohistochemically, the stromal-like cells proliferating outside the uterus, as well as normal and ectopic endometrial stromal cells within the uterus, expressed PR and CD10 (Fig. 3). The epithelium of the ectopic glands and normal endometrial glands showed slight expression of ORa. The ectopic tissues had similar immunoreactivity to the uterine endometrial glands and stroma. The smooth muscle fascicles in the nests of stromal-like cells, which were located apart from the gastrointestinal muscular layers, expressed a-smooth muscle actin, suggesting smooth muscle metaplasia of stromal-like cells (Fig. 4). Diffuse centrilobular congestion with hepatocyte degeneration and necrosis was noted in the liver. Steroid receptors, including ORa and PR, are immunohistochemically detectable in normal and malignant human endometrium (Mylonas et al., 2009). Antibodies against CD10 (or common acute lymphoblastic leukaemia antigen; CALLA) are now available for routine IHC of human haematopoietic neoplasms, and CD10 immunoreactivity is also useful
Fig. 4. Aberrant smooth muscle fascicles in the nest of endometrial stromal-like cells express a-SMA. IHC. Bar, 20 mm.
in confirming the endometrial nature of stromal cells outside the uterus because immunoreactivity is maintained in normal and neoplastic endometrial stromal cells as well as endometriotic stromal cells (Sumathi and McCluggage, 2002). Thus, the present findings indicate extra- and intra-uterine growth of the endometrium and the pathological features were consistent with those of human endometriosis (Clement et al., 1999; Clement, 2007). The marked secondary fibrosis of the peritoneum indicates that this was a chronic process. The necropsy findings, including intraabdominal serosanguineous fluid, serosal haemorrhage, intrapelvic blood clot, precordial subcutaneous oedema and chronic hepatic congestion, all suggest that the animal died of hypovolaemic shock secondary to severe endometriosis. Clinical signs associated with endometriosis in women include dysmenorrhoea, dyspareunia, pelvic pain, interference with intestinal and urinary bladder function and reduced fertility (Clement et al., 1999; Ellenson and Pirog, 2009). The most likely affected organs are the ovaries, uterine ligaments, rectovaginal septum and pelvic peritoneum. The gross lesions include red-brown (chocolate-coloured) cysts on the serosal surface of pelvic and abdominal organs, clear cysts and adhesions between visceral organs. Affected non-human primates show irregular vaginal bleeding or heavy menses, with recumbency, anorexia, grimacing, decreased grooming, restlessness and vocalization, suggesting pain (Hompes and Mijatovic, 2007; Mattison et al., 2007). The gross and microscopical lesions in macaques are similar to those in women (Zondervan et al., 2004; Mattison et al., 2007). The current case lacked cystic gross lesions and the extrauterine endometrial tissue, especially the endometrial glands, was microscopically obscured by marked secondary fibrosis. Compared with the distribution of
Endometriosis in a Mandrill
endometriosis previously reported in non-human primates, this case was considered to be among the most severe. The mandrill may have been suffering from endometriosis since the time of the last parturition at 14 years of age and thereafter become infertile. The extra-uterine lesions in the current case were characterized by the proliferation of endometrial stromal cells; however, close microscopical examination revealed a small number of endometrial glands in the extra-uterine foci. The smooth muscle metaplasia of stromal cells and reactive hyperplasia of smooth muscle in the gastrointestinal tract were also diagnostic clues. The metaplastic change is most common in ovarian endometriosis in women and is explained by the myofibroblastic potential of endometrial stromal cells (Clement, 2007). On the other hand, reactive smooth muscle proliferation more commonly occurs in endometriosis and may involve the smooth muscle of pelvic ligaments and the wall of the bowel and bladder (Clement, 2007). In addition to the morphological findings, expression of PR and CD10 was useful to confirm the ectopic proliferation of endometrial stromal cells in this mandrill (Jones et al., 1995; Fujishita et al., 1997; Clement, 2007). Two potential explanations are proposed for the origin of ectopic endometrial tissue (Ellenson and Pirog, 2009). Firstly, the metastatic theory suggests that retrograde menstruation through the fallopian tubes occurs regularly, even in normal women, and could mediate the spread of endometrial tissue to the peritoneal cavity. This theory can explain the spread of endometriosis to distant sites, including lungs and lymph nodes, via haematogenous and lymphatic metastases. Secondly, the metaplastic theory suggests that the endometrium could arise directly from the coelomic epithelium. Although the underlying mechanism of the metastatic theory has still not been established, this theory is most widely accepted. In the current case, the lesions were too severe to examine the development of the disease, but there was no discrepancy between our findings and the metastatic theory. In summary, the current case was considered to be severe endometriosis in a menstruating nonhuman primate. The immunohistochemical markers PR and CD10 appear useful in diagnosing endometriosis in mandrills. This report presents the first case of spontaneously occurring endometriosis in a mandrill.
References Binhazim AA, Tarara RP, Suleman MA (1989) Spontaneous external endometriosis in a De Brazza’s monkey. Journal of Comparative Pathology, 101, 471e474.
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May 7th, 2011 ½ Received, Accepted, January 5th, 2012