J Med Primatol doi:10.1111/jmp.12133
CASE REPORT
Nodular lymphoid hyperplasia of the colon in a vervet monkey (Cholorocebous aethiops) M.H. Hablolvarid Razi Vaccine and Serum Research Institute, Karaj, Iran
Keywords African green monkey – histopathology – immunohistochemistry Correspondence Mohammad Hassan Hablolvarid, Razi Vaccine and Serum Research Institute, Beheshti street, Karaj 3197619751, Iran. Tel.: +98 26 4570038-46; fax: +98 26 34552194; e-mail: [email protected] Accepted May 20, 2014.
Abstract Background Diffuse nodular lymphoid hyperplasia (DNLH) of gastrointestinal tract is regarded as a very rare disease in the adult population. It is characterized by presence of diffuse detectable small polypoid masses distributed in the small intestine, colon, or both. Methods A 6-year-old male in captivity suddenly died, due to myocardial infarction. During routine necropsy procedure, incidentally, numerous tan, sessile polyps, up to 0.2 cm were noticed in all segments of the colon. Results Histopathological and immunohistochemical examination revealed polypoid masses as nodular lymphoid hyperplasia (NLH), comparable with DNLH of the colon in human. Conclusions In this article, the author has tried to introduce some immunosuppresive (e.g., simian retrovirus type D (SRV), simian immunodeficiency virus (SIV)) and opportunistic viruses (e.g., lymphocryptovirus, c-herpesvirus, adenovirus), as well as, primary and opportunistic bacteria (e.g., Yersinia psedotuberculosis, and Helicobacter spp.) that may trigger benign reactive process, lymphoid hyperplasia, in non-human primates (NHPs) in captivity.
Introduction Lymphoid hyperplasia of the intestine is a benign reactive process also recognized as pseudolymphoma, lymphonodular hyperplasia [6]. It occurs in all age groups, but is best described in children [6, 7]. There are no definitions or valid criteria for when normal lymphoid tissue becomes hyperplastic or when hyperplasia becomes pathologic [22]. Lymphoid hyperplasia may be discovered incidentally at colonoscopy or in patients undergoing colectomy [6, 7]. Lymphoid hyperplasia of the gastrointestinal tract may be focal or rarely nodular encompassing long segments of the small and large intestine [2]. DNLH is a very uncommon disease of unidentified etiology. The characteristic of DNLH is the presence of numerous visible mucosal nodules in the small intestine, colon, or both. The presence of the lesions in the colon may mimic a variety of polyposis syndromes, and this may cause some problems in diagnosis and treatment [9, 14]. The main difficulty in the separation of gastrointestinal lymphomas from lymphoid hyperplasia concerns 498
marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) type that are dominated by small lymphocytes and that commonly are associated with germinal center formation [2]. Several causes of lymphoid hyperplasia have been postulated. Giardia lamblia is often present. In a small minority, immunodeficiencies underlie the hyperplasic state [7]. In children, lymphoid hyperplasia is often associated with viral infection [20]. Unless associated with other specific endoscopic or histologic lesions, lymphoid nodular hyperplasia is related to a condition of delay-type food hypersensitivity [15]. In this report, a case of NLH of the colon in a vervet monkey, comparable with DNLH in human, is described and discussed. Case presentation Human care guidelines The animal was treated in compliance with the guidelines of Animal Welfare Committee of the Research J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hablolvarid
Deputy of Razi vaccine and serum research institute, Karaj, Iran. A 6-year-old male vervet monkey suddenly died, in quarantine of Razi vaccine and serum research institute, Karaj, Iran. Gross and histopathologic examination revealed myocardial infarction as the cause of death. However, during routine necropsy procedure, numerous tan, sessile polyps, up to 0.2 cm, were noticed in all segments of colon (Fig. 1), as well as, very few numbers in cecum. Searches for parasites revealed no organisms. The animal was negative in tuberculin (TB) and SIV tests. Histological sections of the colon showed the polyps to be composed of multiple lymphoid follicles in the submucosa and lamina propria of the colonic mucosa. The follicles were discrete and contained prominent germinal centers surrounded by a mantle of small lymphocytes (Fig. 2). There were few tingible body macrophages in some of germinal centers. However, cytologically atypical cells were not present. Immunohistochemical (IHC) stains showed the follicles to be composed predominantly of B cells with CD20+ (CD20cy, clone L26; Dako, Glostrup, Denmark); CD10- (CD10, clone 56C6; Dako); and Cyclin D1- (Cycline D1, Clone 124; Dako) markers, mixed with few CD3-positive small T-cell lymphocyte (RTUCD3, Clone PSI; Novocastra, Newcastle, UK). CK20 was focally positive, only, in epithelial cell layer (Cytokeratin 20, Clone Ks20.8; Dako), and germinal center B cells were negative for Bcl-2 (BCL2 Oncoprotein, Clone 124; Dako). A diagnosis of NLH, comparable with DNLH of the colon, was made, based on morphologic and histological diagnosis and confirmation by IHC analysis.
Fig. 1 Colon of the vervet monkey. Nodular lymphoid hyperplasia. Multiple polypoid lesions on the surface of the colon are seen. J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Colonic nodular lymphoid hyperplasia
Fig. 2 Colon of the vervet monkey. Nodular lymphoid hyperplasia. A lymphoid follicle with active germinal center, located in the mucosa, is seen (H&E9 90).
Discussion DNLH has been reported in association with inflammatory bowel disease, variable immunodeficiency, bacterial overgrowth, recurrent giardiasis and rarely malignant, intestinal lymphoma. Helicobacter pylorus is also probably linked with duodenal DNLH. Although the etiology of DNLH in adults is unknown, in children, it may be related to food hypersensitivity and/or viral infections [14]. Lacono et al. [15] by examination of 245 children, for whom colonoscopy had been indicated, reported lymphoid nodular hyperplasia in pediatric patients is related to a condition of delayed-type food hypersensitivity, and presence of lymphoid nodular hyperplasia in the colon and/or terminal ileum is a frequent finding in symptomatic children undergoing colonoscopy, unless associated with other specific endoscopic or histologic lesions. Despite honing of the criteria to separate gastrointestinal lymphoid hyperplasia from lymphoma, gastrointestinal lymphoid hyperplasia remains a relatively common histologic alteration [2]. Various forms of reactive lymphoid hyperplasia clinically and pathologically mimic gastrointestinal lymphomas, such as gastric lymphoid hyperplasia and chronic lymphocytic gastritis [2]. The presence of the DNLH lesions in the colon may mimic a variety of polyposis syndromes, and this may cause some problems in diagnosis and treatment [9]. In the present case, the follicle-like structures showed variation in size and were composed of large cells surrounded by a thin rim of small, round lymphocytes. Mitotic activity was found to be quite low. Hence, it was quite difficult to give a confirmative diagnosis solely on the base of routine histopathologic examination; immunohistochemical investigations were 499
Colonic nodular lymphoid hyperplasia
performed to resolve the issue. The result was positive for CD20 upon entire follicles admixed with few CD3 small lymphocytes and negative for CD10, Bcl2, and cyclin D1. As it was mentioned earlier, the main difficulty in the separation of gastrointestinal lymphomas from lymphoid hyperplasia concerns MALT-type lymphoma. Immunophenotyping studies have shown that there is predominant population of CD20+ B cells, CD5-, CD10-, CD23- and Cyclin D1- with appreciable background population of T cells positive for CD3 in low-grade B-cell MALT-type lymphoma. However, in lymphoid hyperplasia, CD20 B cells confined to follicular and immediate perifollicular regions with the reminder of the cells being predominantly T cell. On the other hand, aberrant antigen expression, such as Bcl-2, is present in MALT-type lymphoma but absent, like as present case, in lymphoid hyperplasia [1, 18]. Staining for cytokeratin, CK20, revealed there were no lymphoepithelial lesions (epithelial infiltration by lymphoid cells) or scattered epithelial cell remnants [1]. These findings were consistent with the immunohistochemistry profile of present case and thus confirmed diagnosis of NLH of the colon. On the best knowledge of the author, there are few reports of gastrointestinal nodular lymphoid hyperplasia in NHPs. Chamanza et al. [5] in a retrospective study for determining the incidence and range of spontaneous pathology finding in 570 control cynomolgous monkeys (285 animals per sex) reported 16 cases (2.8%) of lymphoid hyperplasia in stomach. Miller et al. [19] reported diseases ranging from lymphoid hyperplasia to fatal lymphomas after inoculation with Epstein–Barr virus in cotton-top tamarins (Saguinus Oedipus). Chalifoux et al. [4] reported lymphoid hyperplasia as one of the findings in chronic colitis of marmosets. Pesker and Claros [21] described lymphoid hyperplasia with few giant cells in the intestine of squirrel monkeys, spontaneously, infected with Yersinia psedotuberculosis. However, this observation was not reported by Hablolvarid et al. [12] in the intestine of a spontaneously infected vervet monkey, with Yersina entrocolitica. Sakurai et al. [23] reported apparent severe hyperplasia in the lymphoid nodules of the colon and spleen of adenovirus serotype 5 (Ad 5) vector-injected cynomolgus monkeys. Cypess et al. [8] reported the morphological changes in the intestine of experimentally infected rhesus monkeys with Trichinella spiralis were essentially similar to those seen in humans, and a generalized lymphoid hyperplasia was not observed. Fox et al. reported debilitating, chronic diarrhea in six rhesus monkeys. Histologically, colonic tissues were characterized as chronic moderate to severe colitis and typhlitis with diffuse mononuclear 500
Hablolvarid
inflammation of lamina propria, reactive lymphoid hyperplasia and multifocal micro-abscesses. They described isolation of novel Helicobacter spp. from inflamed colons of the rhesus monkeys [10]. However, chronic idiopathic diffuse colitis is a well-recognized clinical and pathological entity in captive rhesus monkeys [10, 25]. Guzman et al. [11] reported an increase in incidence, severity, and distribution of lymphoid infiltrates in various organs in SRV positive animals. Lohman et al. in an experiment on infected rhesus monkeys with the highly attenuated or moderately attenuated molecular clones of SIV (SIVmac) reported they had minimal lymphoid hyperplasia. However, monkeys infected with the partially attenuated virus had moderate to marked lymphoid hyperplasia [16]. Viral opportunistic infection and cherpesvirus-induced lymphoid hyperplasia and lymphomas are more common than bacterial opportunistic infections in the context of experimental SIV-infected macaques [24]. Hutto et al. [13] reported a T-lymphocyte-depleting biopharmaceutical in cynomolgus macques that was associated with c-herpesvirusinduced B-cell hyperplasia and lymphoma. There are some reports of iatrogenic c-herpesvirus-associated lymphoid hyperplasia and lymphoma in humans (usually after transplantation) that have been associated with the use of various immunomodulators [3]. Experimental infection with rhesus monkey rhadinovirus (RRV) and lymphocryptovirus in immunocompetent macaques may be mildly symptomatic, RRV can induce mild febrile response and lymphoproliferative disorder, and lymphocryptovirus may induce B-cell hyperplasia and lymphadenopathy [17, 24]. In the present case, there was no history of diarrhea and colitis and the animal was negative in TB, SIV, and parasitological tests. However, capture and prolonged captivity of wild African green monkeys in single housing has been shown to result in high morbidity and mortality [27]. These animals are more susceptible to stress associated with immune suppression, when housed singly in captivity, and subsequent high frequency of infectious disease than other East African NHPs confined to laboratory housing [26, 27]. Although numerous viral, bacterial, and parasitic pathogens endemic in NHP populations remain clinically inapparent in immunocompetent animals and are in general mild and self-limiting [24], but, as it was mentioned earlier, some immunosuppresive (e.g., SRV, SIV) and opportunistic viruses (e.g., Lymphocryptovirus, c-herpesvirus, adenovirus), as well as, primary and opportunistic bacteria (e.g., yersinia psedotuberculosis, and Helicobacter spp.) may trigger benign reactive process, lymphoid hyperplasia, in NHPs in captivity. J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hablolvarid
Colonic nodular lymphoid hyperplasia
Conclusion DNLH is a rare but problematic disease, in humans, with respect to diagnosis and treatment. In this report, a case of NLH of the colon, comparable with DNLH, in a vervet monkey is described and discussed. The author has tried to introduce some immunosuppresive (e.g., SRV, SIV) and opportunistic viruses (e.g., lymphocryptovirus, c-herpesvirus, adenovirus), as well as, primary and opportunistic bacteria (e.g., yersinia
psedotuberculosis and Helicobacter spp.) that may trigger benign reactive process, lymphoid hyperplasia, in NHPs in captivity. Acknowledgment The author wishes to thank Mr. Mohammad Mahdi Gharaghozloyan for his technical assistance and thanks all staffs of the Department of Pathology of Razi Vaccine & Serum Research Institute, Karaj, Iran.
References 1 Bacon CM, Du NQ, Dogan A: Mucosa-associated by lymphoid tissue (MALT) lymphoma: a practical guide for pathologist. J Clin Pathol 2007; 60:361–72. 2 Burke JS: Lymphoproliferative disorders of the gastrointestinal Tract: a review and pragmatic guide to diagnosis. Arch Pathol Lab Med 2011; 135:1283–97. 3 Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K: Post transplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation 2005; 80:1233–43. 4 Chalifoux LV, Bronson RT, Escadajllo A, Mckenna S: An analysis of the association of gastroenteric lesions with chronic wasting syndrome of Marmosets. Vet Pathol 1982; 19(7 suppl):141–62. 5 Chamanza R, Marxfeld HA, Blanco AI, Taylor SW, Bradley AE: Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies. Toxicol Pathol 2010; 38:642–57. 6 Colon AR, DiPalma JS, Leftridge CA: Intestinal lymphonodular hyperplasia of childhood: patterns of presentation. J Clin Gastroenterol 1991; 13:163–6. 7 Cooper HS: Intestinal neoplasms. In: Diagnostic Surgical Pathology, Vol 2, 3rd ed. Sternberg (ed). Philadelphia: Lippincott Williams & Wilkins 1999; 1413–67.
8 Cypess RH, Lubinecki A, DeSeau V, Siebert JR: Observation on trichinosis in rhesus monkey. J Med Primatol 1977; 6:23–32. 9 Ersoy E, Gundogdu H, Ugras NS, Aktimur R: A case of diffuse nodular lymphoid hyperplasia. Turk J Gastrenterol 2008; 19:268–70. 10 Fox JG, Handt L, Silu X, Zeli S, Dewhirst FE, Paster BJ, Dangler CA, Lodge K, Motzel S, Kleein H: Novel Helicobcter species isolated from rhesus monkeys with chronic idiopathic colitis. J Med Microbiol 2001; 50:421–9. 11 Guzman RE, Kerlin RL, Zimmerman TE: Histologic lesions in cynomolgus monkeys (Macaca fascicularis) naturally infected with simian retrovirus type D: comparison of seropositive, virus-positive, and uninfected animals. Toxicol Pathol 1999; 27:672–7. 12 Hablolvarid MH, Sarbanan Z, Arefpajoohi R, Motamedi G: Yersinia enterocolitica infection in a vervet monkey (Cercopithecus aethiops) in Iran. Arch Razi Inst 2008; 63:53–7. 13 Hutto D, TenHoor C, Lane J, Bernier L, Quander R, Green J: B cell hyperplasia associated with immunosuppression in cynomolgus monkeys. Vet Pathol 2003; 40:624. 14 Koulaouzidis A, Madalinski M: Diffuse nodular lymphoid hyperplasia of the colon. Prz Gastroentrol 2012; 7:108–10. 15 Lacono G, Ravelli A, Di Pima L, Scallci C, Bolognini S, Chiappa S,
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Pirrone G, Licastri G, Carroccio A: Colonic lymphoid nodular hyperplasia in children: relationship to food hypersensitivity. Clin Gastroentol 2007; 5:361–6. Lohman BL, Mccheesney BM, Miller CJ, McGowan E, Joy SM, Van Rompay KK, Reay E, Antipa L, Pedersen NC, Marthas ML: A partially attenuated simian immunodeficiency virus induce host immunity that correlates with resistance to pathogenic virus challenge. J Virol 1994; 68:7021–9. Mansfield KG, Westmoreland SV, DeBakker CD, Czajak S, Lackner AA, Desrosiers RC: Experimental infection of rhesus and pig-tailed macaques with macaque rhadinoviruses. J Virol 1999; 73:10320–8. Manveen JK, Subramanyam RV, Harshaminder G, Madhu S, Narula R: Primary B-cell MALT lymphoma of the Palate: a case report and distinction from benign lymphoid hyperplasia (pseudolymphoma). J Oral Maxillofac Path 2012; 16:97–102. Miller G, Shope T, Coope D, Waters L, Pagano J, Bornkamm GW, Henle W: Lymphoma in cotton-top marmosets after inoculation with Epstein-Barr virus: tumor incidence, histologic spectrum antibody responses, demonstration of viral DNA, and characterization of viruses. J Exp Med 1977; 145:948– 67. Mukhopadhyay S, Harbol TL, Floyd FD, Sidhu JS: Polypoid nod-
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ular lymphoid hyperplasia of the terminal ileum. Arch Path Med 2004; 128:1186–1187. 21 Pesker R, Claros M: A spontaneous Yersinia pseudotuberculosis-infection in a monkey colony. Zentralbl Veterinarmed B 1992; 39:201–8. 22 Riddell RH, Petras RE, Williams GT, Sobin LH: Lymphoproliferative disorders of the intestines. In: Tumors of the Intestines. Riddell, Petras, Williams & Sobin (eds). Washington, DC: Armed Forces Institute of Pathology, 2003; 395– 430. Atlas of Tumor Pathology; 3rd series, fascicle 32. 23 Sakurai F, Nakamura S, Akitomo K, Shibata H, Terao K, Kawabata
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K, Hayakawa T, Mizuguchi H: Transduction properties of adenovirus serotype 35 vectors after intravenous administration into nonhuman primates. Mol Ther 2008; 16(4):726–33. 24 Sasseville VG, Diter WD: Impact of infections and normal flora in nonhuman primates on drug development. ILAR J 2008; 49: 179–90. 25 Sasseville VG: Gastrointestinal lesions and pathogens in Macaques and Marmosets. In: 62nd annual meeting of the American college of veterinary pathologist and 46th annual meeting of the American society for veterinary clinical
pathology, Nashville, TN, USA, 2011. 26 Suleman MA, Wango E, Farah IO, Hau J: Adrenal cortex and stomach lesions associated with stress in wild male African green monkeys (Cercopithecus aethiops) in the post-capture period. J Med Primatol 2000; 29:338–42. 27 Suleman MA, Yole D, Wango E, Sapolsky R, Kthome K, Carrison HE, Hau J: Peripheral blood lymphocyte immunocompetence in wild African green monkeys (Cercopithecus aethiops) and the effect of capture and confinement. In Vivo 1999; 13:25–7.
J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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CASE REPORT
Nodular lymphoid hyperplasia of the colon in a vervet monkey (Cholorocebous aethiops) M.H. Hablolvarid Razi Vaccine and Serum Research Institute, Karaj, Iran
Keywords African green monkey – histopathology – immunohistochemistry Correspondence Mohammad Hassan Hablolvarid, Razi Vaccine and Serum Research Institute, Beheshti street, Karaj 3197619751, Iran. Tel.: +98 26 4570038-46; fax: +98 26 34552194; e-mail: [email protected] Accepted May 20, 2014.
Abstract Background Diffuse nodular lymphoid hyperplasia (DNLH) of gastrointestinal tract is regarded as a very rare disease in the adult population. It is characterized by presence of diffuse detectable small polypoid masses distributed in the small intestine, colon, or both. Methods A 6-year-old male in captivity suddenly died, due to myocardial infarction. During routine necropsy procedure, incidentally, numerous tan, sessile polyps, up to 0.2 cm were noticed in all segments of the colon. Results Histopathological and immunohistochemical examination revealed polypoid masses as nodular lymphoid hyperplasia (NLH), comparable with DNLH of the colon in human. Conclusions In this article, the author has tried to introduce some immunosuppresive (e.g., simian retrovirus type D (SRV), simian immunodeficiency virus (SIV)) and opportunistic viruses (e.g., lymphocryptovirus, c-herpesvirus, adenovirus), as well as, primary and opportunistic bacteria (e.g., Yersinia psedotuberculosis, and Helicobacter spp.) that may trigger benign reactive process, lymphoid hyperplasia, in non-human primates (NHPs) in captivity.
Introduction Lymphoid hyperplasia of the intestine is a benign reactive process also recognized as pseudolymphoma, lymphonodular hyperplasia [6]. It occurs in all age groups, but is best described in children [6, 7]. There are no definitions or valid criteria for when normal lymphoid tissue becomes hyperplastic or when hyperplasia becomes pathologic [22]. Lymphoid hyperplasia may be discovered incidentally at colonoscopy or in patients undergoing colectomy [6, 7]. Lymphoid hyperplasia of the gastrointestinal tract may be focal or rarely nodular encompassing long segments of the small and large intestine [2]. DNLH is a very uncommon disease of unidentified etiology. The characteristic of DNLH is the presence of numerous visible mucosal nodules in the small intestine, colon, or both. The presence of the lesions in the colon may mimic a variety of polyposis syndromes, and this may cause some problems in diagnosis and treatment [9, 14]. The main difficulty in the separation of gastrointestinal lymphomas from lymphoid hyperplasia concerns 498
marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) type that are dominated by small lymphocytes and that commonly are associated with germinal center formation [2]. Several causes of lymphoid hyperplasia have been postulated. Giardia lamblia is often present. In a small minority, immunodeficiencies underlie the hyperplasic state [7]. In children, lymphoid hyperplasia is often associated with viral infection [20]. Unless associated with other specific endoscopic or histologic lesions, lymphoid nodular hyperplasia is related to a condition of delay-type food hypersensitivity [15]. In this report, a case of NLH of the colon in a vervet monkey, comparable with DNLH in human, is described and discussed. Case presentation Human care guidelines The animal was treated in compliance with the guidelines of Animal Welfare Committee of the Research J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hablolvarid
Deputy of Razi vaccine and serum research institute, Karaj, Iran. A 6-year-old male vervet monkey suddenly died, in quarantine of Razi vaccine and serum research institute, Karaj, Iran. Gross and histopathologic examination revealed myocardial infarction as the cause of death. However, during routine necropsy procedure, numerous tan, sessile polyps, up to 0.2 cm, were noticed in all segments of colon (Fig. 1), as well as, very few numbers in cecum. Searches for parasites revealed no organisms. The animal was negative in tuberculin (TB) and SIV tests. Histological sections of the colon showed the polyps to be composed of multiple lymphoid follicles in the submucosa and lamina propria of the colonic mucosa. The follicles were discrete and contained prominent germinal centers surrounded by a mantle of small lymphocytes (Fig. 2). There were few tingible body macrophages in some of germinal centers. However, cytologically atypical cells were not present. Immunohistochemical (IHC) stains showed the follicles to be composed predominantly of B cells with CD20+ (CD20cy, clone L26; Dako, Glostrup, Denmark); CD10- (CD10, clone 56C6; Dako); and Cyclin D1- (Cycline D1, Clone 124; Dako) markers, mixed with few CD3-positive small T-cell lymphocyte (RTUCD3, Clone PSI; Novocastra, Newcastle, UK). CK20 was focally positive, only, in epithelial cell layer (Cytokeratin 20, Clone Ks20.8; Dako), and germinal center B cells were negative for Bcl-2 (BCL2 Oncoprotein, Clone 124; Dako). A diagnosis of NLH, comparable with DNLH of the colon, was made, based on morphologic and histological diagnosis and confirmation by IHC analysis.
Fig. 1 Colon of the vervet monkey. Nodular lymphoid hyperplasia. Multiple polypoid lesions on the surface of the colon are seen. J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Colonic nodular lymphoid hyperplasia
Fig. 2 Colon of the vervet monkey. Nodular lymphoid hyperplasia. A lymphoid follicle with active germinal center, located in the mucosa, is seen (H&E9 90).
Discussion DNLH has been reported in association with inflammatory bowel disease, variable immunodeficiency, bacterial overgrowth, recurrent giardiasis and rarely malignant, intestinal lymphoma. Helicobacter pylorus is also probably linked with duodenal DNLH. Although the etiology of DNLH in adults is unknown, in children, it may be related to food hypersensitivity and/or viral infections [14]. Lacono et al. [15] by examination of 245 children, for whom colonoscopy had been indicated, reported lymphoid nodular hyperplasia in pediatric patients is related to a condition of delayed-type food hypersensitivity, and presence of lymphoid nodular hyperplasia in the colon and/or terminal ileum is a frequent finding in symptomatic children undergoing colonoscopy, unless associated with other specific endoscopic or histologic lesions. Despite honing of the criteria to separate gastrointestinal lymphoid hyperplasia from lymphoma, gastrointestinal lymphoid hyperplasia remains a relatively common histologic alteration [2]. Various forms of reactive lymphoid hyperplasia clinically and pathologically mimic gastrointestinal lymphomas, such as gastric lymphoid hyperplasia and chronic lymphocytic gastritis [2]. The presence of the DNLH lesions in the colon may mimic a variety of polyposis syndromes, and this may cause some problems in diagnosis and treatment [9]. In the present case, the follicle-like structures showed variation in size and were composed of large cells surrounded by a thin rim of small, round lymphocytes. Mitotic activity was found to be quite low. Hence, it was quite difficult to give a confirmative diagnosis solely on the base of routine histopathologic examination; immunohistochemical investigations were 499
Colonic nodular lymphoid hyperplasia
performed to resolve the issue. The result was positive for CD20 upon entire follicles admixed with few CD3 small lymphocytes and negative for CD10, Bcl2, and cyclin D1. As it was mentioned earlier, the main difficulty in the separation of gastrointestinal lymphomas from lymphoid hyperplasia concerns MALT-type lymphoma. Immunophenotyping studies have shown that there is predominant population of CD20+ B cells, CD5-, CD10-, CD23- and Cyclin D1- with appreciable background population of T cells positive for CD3 in low-grade B-cell MALT-type lymphoma. However, in lymphoid hyperplasia, CD20 B cells confined to follicular and immediate perifollicular regions with the reminder of the cells being predominantly T cell. On the other hand, aberrant antigen expression, such as Bcl-2, is present in MALT-type lymphoma but absent, like as present case, in lymphoid hyperplasia [1, 18]. Staining for cytokeratin, CK20, revealed there were no lymphoepithelial lesions (epithelial infiltration by lymphoid cells) or scattered epithelial cell remnants [1]. These findings were consistent with the immunohistochemistry profile of present case and thus confirmed diagnosis of NLH of the colon. On the best knowledge of the author, there are few reports of gastrointestinal nodular lymphoid hyperplasia in NHPs. Chamanza et al. [5] in a retrospective study for determining the incidence and range of spontaneous pathology finding in 570 control cynomolgous monkeys (285 animals per sex) reported 16 cases (2.8%) of lymphoid hyperplasia in stomach. Miller et al. [19] reported diseases ranging from lymphoid hyperplasia to fatal lymphomas after inoculation with Epstein–Barr virus in cotton-top tamarins (Saguinus Oedipus). Chalifoux et al. [4] reported lymphoid hyperplasia as one of the findings in chronic colitis of marmosets. Pesker and Claros [21] described lymphoid hyperplasia with few giant cells in the intestine of squirrel monkeys, spontaneously, infected with Yersinia psedotuberculosis. However, this observation was not reported by Hablolvarid et al. [12] in the intestine of a spontaneously infected vervet monkey, with Yersina entrocolitica. Sakurai et al. [23] reported apparent severe hyperplasia in the lymphoid nodules of the colon and spleen of adenovirus serotype 5 (Ad 5) vector-injected cynomolgus monkeys. Cypess et al. [8] reported the morphological changes in the intestine of experimentally infected rhesus monkeys with Trichinella spiralis were essentially similar to those seen in humans, and a generalized lymphoid hyperplasia was not observed. Fox et al. reported debilitating, chronic diarrhea in six rhesus monkeys. Histologically, colonic tissues were characterized as chronic moderate to severe colitis and typhlitis with diffuse mononuclear 500
Hablolvarid
inflammation of lamina propria, reactive lymphoid hyperplasia and multifocal micro-abscesses. They described isolation of novel Helicobacter spp. from inflamed colons of the rhesus monkeys [10]. However, chronic idiopathic diffuse colitis is a well-recognized clinical and pathological entity in captive rhesus monkeys [10, 25]. Guzman et al. [11] reported an increase in incidence, severity, and distribution of lymphoid infiltrates in various organs in SRV positive animals. Lohman et al. in an experiment on infected rhesus monkeys with the highly attenuated or moderately attenuated molecular clones of SIV (SIVmac) reported they had minimal lymphoid hyperplasia. However, monkeys infected with the partially attenuated virus had moderate to marked lymphoid hyperplasia [16]. Viral opportunistic infection and cherpesvirus-induced lymphoid hyperplasia and lymphomas are more common than bacterial opportunistic infections in the context of experimental SIV-infected macaques [24]. Hutto et al. [13] reported a T-lymphocyte-depleting biopharmaceutical in cynomolgus macques that was associated with c-herpesvirusinduced B-cell hyperplasia and lymphoma. There are some reports of iatrogenic c-herpesvirus-associated lymphoid hyperplasia and lymphoma in humans (usually after transplantation) that have been associated with the use of various immunomodulators [3]. Experimental infection with rhesus monkey rhadinovirus (RRV) and lymphocryptovirus in immunocompetent macaques may be mildly symptomatic, RRV can induce mild febrile response and lymphoproliferative disorder, and lymphocryptovirus may induce B-cell hyperplasia and lymphadenopathy [17, 24]. In the present case, there was no history of diarrhea and colitis and the animal was negative in TB, SIV, and parasitological tests. However, capture and prolonged captivity of wild African green monkeys in single housing has been shown to result in high morbidity and mortality [27]. These animals are more susceptible to stress associated with immune suppression, when housed singly in captivity, and subsequent high frequency of infectious disease than other East African NHPs confined to laboratory housing [26, 27]. Although numerous viral, bacterial, and parasitic pathogens endemic in NHP populations remain clinically inapparent in immunocompetent animals and are in general mild and self-limiting [24], but, as it was mentioned earlier, some immunosuppresive (e.g., SRV, SIV) and opportunistic viruses (e.g., Lymphocryptovirus, c-herpesvirus, adenovirus), as well as, primary and opportunistic bacteria (e.g., yersinia psedotuberculosis, and Helicobacter spp.) may trigger benign reactive process, lymphoid hyperplasia, in NHPs in captivity. J Med Primatol 43 (2014) 498–502 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hablolvarid
Colonic nodular lymphoid hyperplasia
Conclusion DNLH is a rare but problematic disease, in humans, with respect to diagnosis and treatment. In this report, a case of NLH of the colon, comparable with DNLH, in a vervet monkey is described and discussed. The author has tried to introduce some immunosuppresive (e.g., SRV, SIV) and opportunistic viruses (e.g., lymphocryptovirus, c-herpesvirus, adenovirus), as well as, primary and opportunistic bacteria (e.g., yersinia
psedotuberculosis and Helicobacter spp.) that may trigger benign reactive process, lymphoid hyperplasia, in NHPs in captivity. Acknowledgment The author wishes to thank Mr. Mohammad Mahdi Gharaghozloyan for his technical assistance and thanks all staffs of the Department of Pathology of Razi Vaccine & Serum Research Institute, Karaj, Iran.
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