{"paper_id":"de4b5737-2761-47e7-ab48-fe6287268b71","body_text":"211\nUterine Adenomyosis in Beagle Dogs\nHak Soo Kim 1, 2 , Sang- Chul Kang 2,3 , Hu-Song Zhang 2 , Jin Seok Kang 4,5 , Jae-Hoon Kim 3 ,\nKap -Ho Kim 2 , Boo -Hyon Kang 2 and Byung-IL Y oon 1,5, *\n1 College of V eterinar y Medicine & Institute of V eterinar y Science, Kangwon National University , Chuncheon , K orea\n2 P reclinical R esearch Center , Chemon Inc., Y ongin , K orea\n3 College of V eterinar y Medicine, Jeju National University , Jeju, K orea\n4 Depar tment of Biomedical Laborator y Science, Namseoul University , Chonan , K orea\n5 P eer R eview W orking Group of P reclinical R esearch Center , Chemon Inc., Y ongin , K orea\nAdenomyosis is a nonneoplastic hyperplastic lesion, characterized by invagination of proliferating\nendometrial glands into myometrium. In dogs, uterine adenomyosis is relatively rare and it is important\nin T oxicologic P athology to differentiate other non-neoplastic and neoplastic lesions in uterus. In the\npresent study , we report two cases of adenomyosis in the female beagle dogs used for a chemical toxicity\ntest. Clinically , one out of the two female beagle dogs, 15 months of age, had vaginal bleeding for 2\nweeks and the other one, 11 months of age, showed swelling of vulva for a week. At necropsy , the weight\nof uterus was markedly increased to 27.9 g and 15.8 g, compared with the mean value (4.01 ± 2.37, n=6)\nof that of other normal dogs, respectively . The parameters of hematology and serum chemistry were\nranged normal in both of the dogs with enlarged uterus. F or differentiation of connective tissue with\nmuscle fibers, V an Gieson stain was also performed in the serial tissue sections. Histopathologically , the\nlesions of the enlarged uteruses were characterized by proliferating endometrial glands into myometrium,\nsurrounded by connective tissue. The endometrial glands were proliferating downward to myometrium or\nembedded in multiple clustered glands in deeper myometrium without compressing the adjacent muscle\nfibers. The gland epithelial cells are uniformly cuboidal shape with a dense and bottom-located nucleus.\nThese gross and histological findings were consistent with adenomyosis.\nK ey words: Adenomyosis, endometrial hyperplasia, beagle, uterus.\nReceived 6 May 2010; Revised version received 14 June 2010; Accepted 15 June 2010\nAdenomyosis is a nonneoplastic hyperplastic lesion,\ncharacterized by invagination of proliferating endometrial\nglands into myometrium. Adenomyosis can occur in many\nspecies including dogs, cats, rodents and non-human primates\n(T amada et al. , 2005; Bulman-Fleming , 2008; Hur et al .,\n2008; Schlafer and Gifford, 2008; Graham et al. , 2009). This\naltered change is relatively frequently found in the mouse\nand less frequently in the rat (Greaves, 1990). In dogs, uterine\nadenomyosis is relatively rare and usually found as an incidental\nlesion and it is important in T oxicologic P athology to\ndifferentiate other non-neoplastic and neoplastic lesions in\nuterus (Nielsen and K ennedy , 1990; MacLachlan and K ennedy ,\n2002). The invasive glands consist of uniform, normal\nappearing epithelial cells, surrounded by endometrial stroma,\nwithin the myometrium (Nielsen and K ennedy , 1990;\nMacLachlan and K ennedy , 2002; Schlafer and Gifford, 2008).\nThe glands may be small and have the appearance of an\nendometrial gland, or they may be multiple, or larger with\nmore proliferative endometrial epithelial cell lining (Schlafer\nand Gifford, 2008). In dogs, an extreme case of uterine\nadenomyosis may produce “ Swiss cheese ”  pattern in the\nuterine wall (Schlafer and Gifford, 2008).\nThe importance of uterine adenomyosis has not yet been\ndefined in terms of the safety assessment. Adenomyosis is\nclassified as T ype IIE response with cystic endometrial\nhyperplasia, squamous metaplasia, endometrial polyp and\nendometriosis, all associated with the estrogenic effects\n(Haschek and Rousseaux, 1998). However , its underlying\nmechanism is still unclear .\nIn the presents study , we report two cases of adenomyosis\n*Corresponding author: Byung -IL Y oon, College of V eterinary\nMedicine  & Institute of V eterinary Science, Kangwon National\nUniversity , 192-1 Hyoja- dong , Chuncheon, Gangwon 200-701,\nRepublic of K orea\nT el: +82-33-250-8679\nF ax: +82-33-244-2367\nE-mail: byoon@kangwon.ac.kr\nLab. A nim. Res. 2010: 26(2), 211-213\nCase Report\n\n212 Hak Soo Ki m et al.\nLab. A nim. Res. | June, 2010 | Vol. 26, No. 2\nspontaneously found in the beagle dog which has been\ncommonly used for preclinical safety assessment and discuss\nits clinical and histopathological characteristics, compared to\nother non-neoplastic and neoplastic lesions in uterus.\nClinically , one out of the two female beagle dogs, 15 months\nof age, had vaginal bleeding for 2 weeks and the other one,\n11 months of age, showed swelling of vulva for a week.\nAt necropsy , the uteri of the dogs were markedly enlarged\n(F igure 1A); the weight of uterus was increased to 27.9 g\nand 15.8 g , compared with the mean value (4.01 ± 2.37, n=6)\nof that of other normal dogs, respectively . The parameters\nof hematology and serum chemistry were ranged normal in\nboth of the dogs with enlarged uterus (data not shown). The\nenlarged uterus of each dog was fixed in 10% neutral buffered\nformalin and, after routine tissue processing , tissues sections\nwere prepared for hematoxylin and eosin stain and examined\nunder light microscope. F or differentiation of connective tissue\nwith muscle fibers, V an Gieson stain was also performed in\nthe serial tissue sections. Briefly , after deparaffinization and\nhydration, they were stained by W eigert’s hematoxylin and\nV an Gieson ’s solution for 10 min and 15 min, respectively .\nHistopathologically , the lesions of the enlarged uteruses were\ncharacterized by proliferating endometrial glands into\nmyometrium, surrounded by connective tissue (F igure 1B -\n1D). The endometrial glands were proliferating downward\nto myometrium or embedded in the multiple clustered glands\nin deeper myometrium without compressing the adjacent\nmuscle fibers (F igure 1C). The gland epithelial cells are\nuniformly cuboidal shape with a dense and bottom-located\nnucleus (F igure 1C). These gross and histological findings were\nconsistent with adenomyosis.\nDespite of some confusion in cases, adenomyosis may\nusually be differentiated from other non-neoplastic lesions\nsuch as endometriosis, cystic endometrial hyperplasia and\npseudo -plancentational endometrial hyperplasia and benign\nuterine tumors such as leiomyoma, in particular adenomyoma.\nEndometriosis is defined as the presence of endometrial tissue\nin locations distant to the uterus, usually in the peritoneal\ncavity (Leininger an d Jokinen, 1990). In ge neral, endometriosis\nhas the tissue resembling endometrium lying outside the\nendometrial cavity . Cystic endometrial hyperplasia is limited\nin endometrium and it can be induced by estrogen (T ype\nIIE response) or more frequently progesterone in the dog\n(T ype IIP response) (Nielsen and K ennedy , 1990). Cystic\nendometrial hyperplasia generally arises from endometrial\nglandular epithelium, but it also develops from villous folds\ncovered by luminal epithelium. Since this condition with\nexudates accumulation is frequently associated with\ninflammation and bacterial infection, it may progress to\ndevelopment of pyometra, namely cystic hyperplasia/\nFigure 1. Gross and microscopic findings of adenomy osis. The uteri of the dogs w ere markedly  enlarged (A). Note the proliferating\nendometrial glands into my ometrium (M) from endometrium (E, upper of line) (B). Some multiple clustered endometrial glands w ere\nalso found w ith being embedded in deeper my ometrium w ithout compressing the adj acent muscle fibers (C). The glandula r\nepithelial cells are uniformly  cuboidal shape w ithout cellular aty pia. The glands w ere surrounded by  connective tissue (deep re d in\nD). H&E st ain for B and C and V an Gieson st ain for D. Bars=100 µ m for C and D and 200 µ m for B. \n\nUterine adenomy osis in Beagle dogs 213\nLab. A nim. Res. | June, 2010 | Vol. 26, No. 2\npyometra complex (Schlafer and Gifford, 2008). Pseudo -\nplancentational endometrial hyperplasia is also a kind of\nendometrial hyperplasia, resembling maternal placental\ntissues. It has been known to occur primarily during the luteal\nphase of the cycle when the endometrium is highly sensitive\n(Schlafer and Gifford, 2008). However , the histological features,\nas they have the normal histology of the endometrium at\nplacentation sites in normal pregnancy , are very much different\nfrom adenomyosis (Schlafer and Gifford, 2008). Another\nconfusing lesion in uterus with adenomyosis is leiomyoma.\nBut unlike leiomyoma, adenomyosis has indistinct, poorly\ndelimited margins from the adjacent myometrium (Bergeron\net al ., 2006). In the present study , foci of adenomyosis were\nsurrounded by connective tissue and normal smooth muscle\ncells without compression. In human, adenomyoma which\nappear to be histologically very similar with adenomyosis is\ncharacterized by a circumscribed, nodular aggregate of smooth\nmuscle, endometrial glands and stroma (Bergeron et al ., 2006).\nHowever , in the domestic and experimental animals,\nadenomyoma has not been documented in the literature. \nIn terms of differential diagnosis based on the clinical\nsymptoms, it is difficult to differentiate those uterine lesions\ndescribed above. In this study , one dog had bleeding for\n2 weeks, although we were not sure if it is due to adenomyosis\nor not.\nThe cause(s) and mechanisms of adenomyosis are unclear ,\nbut it is most likely to originate from the deep part of the\nendometrial mucosa (Bergeron et al ., 2006). The lesions\nsupporting this hypothesis were also noted in the present\nstudy; the endometrial glands located in the deep part of\nendometrium invaded into myometrium with surrounding\nstroma. Indeed, it was found that estradiol receptor expression\nis greater in the adenomyotic foci than in the normal\nendometrium with an association with apoptosis -regulating\nbcl-2 gene product which reaches peak during the proliferative\nphase of the menstrual cycle (Otsuki et al ., 1994). Adenomyosis\nfrequently occurs with other estrogenic effects such as cystic\nendometrial hyperplasia, squamous metaplasia, endometrial\npolyp and endometriosis, suggesting that it is associated hyper -\nestrogenic states (Greaves, 1990). Another hypothesis is that\nadenomyosis may originate and develop through metaplasia\nfrom de novo ectopic intramyometrial endometrial tissue\nwhich is capable of differentiating both glands and stroma\n(Bergeron et al. , 2006).\nIn summary , in the present study , we first reported two\ncases of adenomyosis in the beagle dogs used for a preclinical\ntoxicity study in K orea. Adenomyosis is relatively rare in dogs\nand it need to be differentiated from other uterine non-\nneoplastic and neoplastic lesions in the safety and risk\nassessment.\nAcknowledgment\nThis study was partially supported by Institute of V eterinary\nScience of Kangwon National University\nReferences\nBergeron, C., Amant, F . and F erency , A. (2006) P athology and\nphysiopathology of adenomyosis. Best P ract. R es. Clin .\nObstet. Gynaecol. 20, 511-521.\nBulman-Fleming , J . (2008) A rare case of uterine adenomyosis in\na Siamese cat. Can . V et. J.  49, 709-712.\nGraham, K.J ., Hulst, F .A., V ogelnest, L., F raser , I.S. and Shilton,\nC.M. (2009) Uterine adenomyosis in an organ-utan (P ongo\nabelii/pygmaeus). Aust. V et. J.  87, 66-69.\nGreaves P . (1990) Histopathology of P reclinical T oxicity Studies:\nInterpretation and R elevance in Drug Safety Evaluation . 1st\ned., pp. 638-639, Elsevier , Amsterdam.\nHaschek, W .M. and Rousseaux, C.G. (1998) F undamentals of\nT oxicologic P athology .  1 st  ed., pp. 485-514, Academic Press,\nSan Diego. \nHur , H.M., Jung , J .Y ., Kang , S.C., P ark, D .S., Bae, J .H. and Kim,\nJ .H. (2008) Uterine adenomyosis in a cat. J. V et. Clin . 25, 19-\n22.\nLeininger , J .R. and Jokinen, M.P . (1990) P athology of the F ischer\nRa t . 1 st  ed., pp.  443-459, Academic Press, London.\nMacLachlan, N .J . and K ennedy , P .C. (2002) T umors in Domestic\nAnimals . 4 th  ed., pp. 547-573, Blackwell P ublishing , Ames. \nNielsen, S.W . and K ennedy , P .C. (1990) Tu m o r s  i n  D o m e s t i c\nAnimals . 3 rd  ed., pp.  479-517, University of California Press,\nLondon. \nOtsuki, Y ., Misaki, O ., Sugimoto, O ., et al. (1994) Cyclic bcl-2\ngene expression in human uterine endometrium during\nmenstrual cycle. Lancet  344, 28-29.\nSchlafer , D .H. and Gifford, A.T . (2008) Cystic endometrial\nhyperplasia, pseudo -plancentational endometrial hyperplasia,\nand other cystic conditions of the canine and feline uterus.\nTheriogenology  70, 349-358.\nT amada, H., Kawate, N ., Inaba, T ., K uwamura, M., maeda, M.,\nKajikawa, T . and Sawada, T . (2005) Adenomyosis with severe\ninflammation in the uterine cervix in a dog . Can . V et. J.  46,\n333-334.","source_license":"CC0","license_restricted":false}