Erreger bei Tumoren der okulären Adnexe

Zusammenfassung

In den vergangenen Jahren wurden Erreger zunehmend als ein wichtiger pathogenetischer Faktor verschiedener maligner Tumoren der okulären Adnexe erkannt. Viele dieser Viren und Bakterien beeinflussen den Zellzyklus und die physiologische Apoptose. Lymphome der okulären Adnexe, insbesondere das extranodale Marginalzonenlymphom, werden in manchen Regionen durch Chlamydophila psittaci und Helicobacter pylori verursacht. Epstein-Barr-Viren scheinen bei dem Natural-Killer/T-Zell-Lymphom-Subtyp eine Rolle zu spielen, wie sie bei dem Burkitt-Lymphom bereits länger bekannt ist. Bakterien scheinen eine reaktive lymphoide Proliferation zu induzieren, während Viren direkt die lymphoiden Zellen befallen und den Zellzyklus beeinflussen und die Apoptose unterdrücken mit der nachfolgenden malignen Entartung. Im Allgemeinen sind Proteine, die zur Zellzyklusprogression führen, wie z. B. das Retinoblastomprotein, erhöht und Eiweiße, die den Zellzyklusfortgang unterdrücken (wie z. B. p16 und p21) abwesend oder funktionsuntüchtig. Die Inaktivierung von p53 durch Mutation seines Gens führt zu einer Erhöhung eines defekten p53 Proteins und zur Einschränkung der Apoptose, wodurch die onkogenen Zufallsmutationen wirksam werden können. Die konjunktivale intraepitheliale Neoplasie (CIN) ist im Vergleich zu dem Pendant der Zervix, der zervikalen intraepithelialen Neoplasie, weniger häufig mit einer HPV-Infektion verbunden. Aufgrund der CIN-Lokalisation scheinen besonders UVB-Strahlen eine Rolle bei ihrer Entstehung zu spielen, wodurch es zu einer p53-Inaktivierung und nachfolgender Hemmung der Apoptose kommt. HIV-Positivität scheint ebenfalls die Entwicklung von CIN und Bindehautkarzinomen zu begünstigen, in den letzten Jahren mit zunehmender Fallzahl. Das Kaposi-Sarkom tritt bei HIV-infizierten Personen selten an der okulären Adnexe auf und scheint mit dem kaposi-sarkomaassoziierten Herpes-Virus (KSHV) oder HHV8 zusammenzuhängen. Das KSHV-assoziierte Latency Associated Nuclear Antigen (LANA) Protein bindet an den negativen Regulator Glycogen-Synthase Kinase-3 (GSK-3), und bedingt im Kern eine zellzyklusabhängige Ansammlung von GSK-3, welches Beta-Catenin stabilisiert und seine Konzentration erhöht. Die neuen Erkenntnisse über diese verschiedenartigen Erreger und Zellzyklusbeeinträchtigungen mögen einen Einfluss auf die Entwicklung neuer therapeutischer Strategien haben.

Abstract

In recent years, infectious agents have been increasingly recognised as an important pathogenetic factor for various malignant tumours of the ocular adnexa. Many of these viruses and bacteria affect the cell cycle and physiological apoptosis. Ocular adnexal lymphoma (OAL), especially extranodal marginal cell lymphoma, is associated with Chlamydophila psittaci and Helicobacter pylori in certain geographic regions. Epstein-Barr virus seems to play a role in the natural killer/T-cell lymphoma subtype of the orbit, as has long been described for Burkitt lymphoma. Bacteria seem to induce reactive lymphoid proliferation, while viruses directly infect the lymphoid cells, affecting the cell cycle and suppressing apoptosis, with subsequent malignant transformation. In general, proteins leading to cell cycle progression, like retinoblastoma protein, are elevated, and proteins inhibiting cell cycle progression, like p16 and p21, are absent or unable to function normally. Inactivation of p53 by mutation of its DNA, which leads to elevation of defective p53 protein and inhibition of apoptosis, allows oncogenic by-chance mutations to become effective. Conjunctival intraepithelial neoplasia (CIN) is less strongly associated with HPV infection than is cervical intraepithelial neoplasia. Based on the localisation of CIN, ultraviolet B radiation seems to play a primary role, leading to p53 inactivation and subsequent inhibition of apoptosis. HIV positivity also seems to aid the development of CIN and conjunctival squamous cell carcinoma, with an increasing number of cases during recent years. Kaposi sarcoma rarely occurs at the ocular adnexa in HIV-positive individuals and seems to be associated with Kaposi sarcoma-associated Herpes virus (KSHV) or HHV8. The KSHV-encoded latency associated nuclear antigen (LANA) protein binds to the negative regulator glycogen-synthase kinase-3 (GSK-3), causing a cell cycle-dependent nuclear accumulation of GSK-3, which stabilises beta-catenin and increases its levels. The findings regarding these various infectious agents and cell cycle alterations might aid the development of new therapeutic strategies.

Schlüsselwörter

okuläre Tumoren - Pharmakologie - Infektiologie

Key words

pharmacology - ocular tumours - infectious diseases

Literatur

• 1 Abrams J T, Balin B J, Vonderheid E C. Association between Sezary T cell-activating factor, Chlamydia pneumoniae, and cutaneous T cell lymphoma.  Ann N Y Acad Sci. 2001;  941 69-85
• 2 Anttila T I, Lehtinen T, Leinonen M. et al . Serological evidence of an association between chlamydial infections and malignant lymphomas.  Br J Haematol. 1998;  103 150-156
• 3 Ateenyi-Agaba C. Conjunctival squamous-cell carcinoma associated with HIV infection in Kampala, Uganda.  Lancet. 1995;  345 695-696
• 4 Ateenyi-Agaba C, Weiderpass E, Tommasino M. et al . Papillomavirus infection in the conjunctiva of individuals with and without AIDS: an autopsy series from Uganda.  Cancer Lett. 2006;  239 98-102
• 5 Auw-Haedrich C, Coupland S E, Kapp A. et al . Long term outcome of ocular adnexal lymphoma subtyped according to the REAL classification.  Br J Ophthalmol. 2001;  85 63-69
• 6 Bayerdorffer E, Neubauer A, Rudolph B. et al . Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group.  Lancet. 1995;  345 1591-1594
• 7 Beral V, Bull D, Darby S. et al . Risk of Kaposi’s sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS.  Lancet. 1992;  339 632-635
• 8 Bosch F X, Lorincz A, Munoz N. et al . The causal relation between human papillomavirus and cervical cancer.  J Clin Pathol. 2002;  55 244-265
• 9 Cartron G, Dacheux L, Salles G. et al . Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene.  Blood. 2002;  99 754-758
• 10 Chan C C, Shen D, Mochizuki M. et al . Detection of Helicobacter Pylori and Chlamydia Pneumoniae Genes in Primary Orbital Lymphoma.  Trans Am Ophthalmol Soc. 2006;  104 62-70
• 11 Chang Y, Cesarman E, Pessin M S. et al . Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma.  Science. 1994;  266 1865-1869
• 12 Chanudet E, Zhou Y, Bacon C M. et al . Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions.  J Pathol. 2006;  209 344-351
• 13 Chisi S K, Kollmann M K, Karimurio J. Conjunctival squamous cell carcinoma in patients with human immunodeficiency virus infection seen at two hospitals in Kenya.  East Afr Med J. 2006;  83 267-270
• 14 Coiffier B. Rituximab in combination with CHOP improves survival in elderly patients with aggressive non-Hodgkin’s lymphoma.  Tumori. 2002;  88 S26-S28
• 15 Coupland S E, Foss H D, Anagnostopoulos I. et al . Immunoglobulin VH gene expression among extranodal marginal zone B-cell lymphomas of the ocular adnexa.  Invest Ophthalmol Vis Sci. 1999;  40 555-562
• 16 Coupland S E, Foss H D, Assaf C. et al . T-cell and T/natural killer-cell lymphomas involving ocular and ocular adnexal tissues: a clinicopathologic, immunohistochemical, and molecular study of seven cases.  Ophthalmology. 1999;  106 2109-2120
• 17 Daibata M, Nemoto Y, Togitani K. et al . Absence of Chlamydia psittaci in ocular adnexal lymphoma from Japanese patients.  Br J Haematol. 2006;  132 651-652
• 18 Cremoux de P, Subtil A, Ferreri A J. et al . Re: Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas.  J Natl Cancer Inst. 2006;  98 365-366
• 19 De Vita S, Sansonno D, Dolcetti R. et al . Hepatitis C virus within a malignant lymphoma lesion in the course of type II mixed cryoglobulinemia.  Blood. 1995;  86 1887-1892
• 20 Demidem A, Lam T, Alas S. et al . Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs.  Cancer Biother Radiopharm. 1997;  12 177-186
• 21 Dugel P U, Gill P S, Frangieh G T. et al . Treatment of ocular adnexal Kaposi’s sarcoma in acquired immune deficiency syndrome.  Ophthalmology. 1992;  99 1127-1132
• 22 Eng H L, Lin T M, Chen S Y. et al . Failure to detect human papillomavirus DNA in malignant epithelial neoplasms of conjunctiva by polymerase chain reaction.  Am J Clin Pathol. 2002;  117 429-436
• 23 Feltgen N, Auw-Hadrich C. [Exceptional conjunctival tumor in a young allergic woman].  Ophthalmologe. 2005;  102 1204-1206
• 24 Ferreri A J, Guidoboni M, Ponzoni M. et al . Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas.  J Natl Cancer Inst. 2004;  96 586-594
• 25 Ferreri A J, Ponzoni M, Guidoboni M. et al . Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy.  J Clin Oncol. 2005;  23 5067-5073
• 26 Ferreri A J, Ponzoni M, Guidoboni M. et al . Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial.  J Natl Cancer Inst. 2006;  98 1375-1382
• 27 Ferreri A J, Ponzoni M, Martinelli G. et al . Rituximab in patients with mucosal-associated lymphoid tissue-type lymphoma of the ocular adnexa.  Haematologica. 2005;  90 1578-1579
• 28 Fogla R, Biswas J, Kumar S K. et al . Squamous cell carcinoma of the conjunctiva as initial presenting sign in a patient with acquired immunodeficiency syndrome (AIDS) due to human immunodeficiency virus type-2.  Eye. 2000;  14 (Pt 2) 246-267
• 29 Foran J M, Rohatiner A Z, Cunningham D. et al . European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma.  J Clin Oncol. 2000;  18 317-324
• 30 Ford J N, Jennings P A, Spradbrow P B. et al . Evidence for papillomaviruses in ocular lesions in cattle.  Res Vet Sci. 1982;  32 257-259
• 31 Franzin F, Efremov D G, Pozzato G. et al . Clonal B-cell expansions in peripheral blood of HCV-infected patients.  Br J Haematol. 1995;  90 548-552
• 32 Frucht-Pery J, Sugar J, Baum J. et al . Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience.  Ophthalmology. 1997;  104 2085-2093
• 33 Gates A E, Kaplan L D. AIDS malignancies in the era of highly active antiretroviral therapy.  Oncology (Williston Park). 2002;  16 657-665, discussion 665, 668 – 670
• 34 Ghabrial R, Quivey J M, Dunn J P. et al . Radiation therapy of acquired immunodeficiency syndrome-related Kaposi’s sarcoma of the eyelids and conjunctiva.  Arch Ophthalmol. 1992;  110 1423-1426
• 35 Giaconi J A, Karp C L. Current treatment options for conjunctival and corneal intraepithelial neoplasia.  Ocul Surf. 2003;  1 66-73
• 36 Goebel Jr N, Serr A, Mittelviefhaus H. et al . Chlamydia psittaci, Helicobacter pylori and ocular adnexal lymphoma-is there an association? The German experience.  Leuk Res. 2007;  31 1450-1452
• 37 Goedert J J. The epidemiology of acquired immunodeficiency syndrome malignancies.  Semin Oncol. 2000;  27 390-401
• 38 Goedert J J, Cote T R. Conjunctival malignant disease with AIDS in USA.  Lancet. 1995;  346 257-258
• 39 Gracia E, Froesch P, Mazzucchelli L. et al . Low prevalence of Chlamydia psittaci in ocular adnexal lymphomas from Cuban patients.  Leuk Lymphoma. 2007;  48 104-108
• 40 Grünberger B, Hauff W, Lukas J. et al . ”Blind” antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa.  Ann Oncol. 2006;  17 484-487
• 41 Gunalp I, Gunduz K, Duruk K. Orbital exenteration: a review of 429 cases.  Int Ophthalmol. 1995;  19 177-184
• 42 Hasche H, Eck M, Lieb W. [Immunochemical demonstration of human herpes virus 8 in conjunctival Kaposi’s sarcoma].  Ophthalmologe. 2003;  100 142-144
• 43 Heinz C, Fanihagh F, Steuhl K P. Squamous cell carcinoma of the conjunctiva in patients with atopic eczema.  Cornea. 2003;  22 135-137
• 44 Hirst L W. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution.  Ophthalmology. 2007;  114 976-982
• 45 Hummer J, Gass J D, Huang A J. Conjunctival Kaposi’s sarcoma treated with interferon alpha-2a.  Am J Ophthalmol. 1993;  116 502-503
• 46 Jazirehi A R, Vega M I, Chatterjee D. et al . Inhibition of the Raf-MEK1 / 2-ERK1 / 2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin’s lymphoma B cells by Rituximab.  Cancer Res. 2004;  64 7117-7126
• 47 Jung S M, Lin H C, Chu P H. et al . Expression of cell cycle-regulatory proteins, MIB-1, p16, p53, and p63, in squamous cell carcinoma of conjunctiva: not associated with human papillomavirus infection.  Virchows Arch. 2006;  448 301-305
• 48 Kallen C, Reinhard T, Schilgen G. et al . [Atopic keratoconjunctivitis: probably a risk factor for the development of conjuntival carcinoma].  Ophthalmologe. 2003;  100 808-814
• 49 Kaposi M. Idiopatisches multiples Pigmentsarkom der Haut.  Arch Dermatol Syph. 1872;  4 265
• 50 Karcioglu Z A, Issa T M. Human papilloma virus in neoplastic and non-neoplastic conditions of the external eye.  Br J Ophthalmol. 1997;  81 595-598
• 51 Karp C L, Scott I U, Chang T S. et al . Conjunctival intraepithelial neoplasia. A possible marker for human immunodeficiency virus infection?.  Arch Ophthalmol. 1996;  114 257-261
• 52 Kedes D H, Operskalski E, Busch M. et al . The seroepidemiology of human herpesvirus 8 (Kaposi’s sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission.  Nat Med. 1996;  2 918-924
• 53 Kiire C A, Dhillon B. The aetiology and associations of conjunctival intraepithelial neoplasia.  Br J Ophthalmol. 2006;  90 109-113
• 54 Kirova Y M, Belembaogo E, Frikha H. et al . Radiotherapy in the management of epidemic Kaposi’s sarcoma: a retrospective study of 643 cases.  Radiother Oncol. 1998;  46 19-22
• 55 Klein G, Pearson G, Henle G. et al . Relation between Epstein-Barr viral and cell membrane immunofluorescence in Burkitt tumor cells. 3. Comparison of blocking of direct membrane immunofluorescence and anti-EBV reactivities of different sera.  J Exp Med. 1969;  129 697-705
• 56 Knowles D M, Athan E, Ubriaco A. et al . Extranodal noncutaneous lymphoid hyperplasias represent a continuous spectrum of B-cell neoplasia: demonstration by molecular genetic analysis.  Blood. 1989;  73 1635-1645
• 57 Kurumety U R, Lustbader J M. Kaposi’s sarcoma of the bulbar conjunctiva as an initial clinical manifestation of acquired immunodeficiency syndrome.  Arch Ophthalmol. 1995;  113 978
• 58 Lauer S A, Malter J S, Meier J R. Human papillomavirus type 18 in conjunctival intraepithelial neoplasia.  Am J Ophthalmol. 1990;  110 23-27
• 59 Laurila A L, Anttila T, Laara E. et al . Serological evidence of an association between Chlamydia pneumoniae infection and lung cancer.  Int J Cancer. 1997;  74 31-34
• 60 Lecuit M, Suarez F, Lortholary O. [Immunoproliferative small intestinal disease associated with Campylobacter jejuni].  Med Sci (Paris). 2004;  20 638-640
• 61 Lee G A, Hirst L W. Incidence of ocular surface epithelial dysplasia in metropolitan Brisbane. A 10-year survey.  Arch Ophthalmol. 1992;  110 525-527
• 62 Lee S B, Au Eong K G, Saw S M. et al . Eye cancer incidence in Singapore.  Br J Ophthalmol. 2000;  84 767-770
• 63 Levin I, Romano S, Steinberg M. et al . Lymphogranuloma Venereum: Rectal Stricture and Carcinoma.  Dis Colon Rectum. 1964;  7 129-134
• 64 Liu Y C, Ohyashiki J H, Ito Y. et al . Chlamydia psittaci in ocular adnexal lymphoma: Japanese experience.  Leuk Res. 2006;  30 1587-1589
• 65 Luppi M, Longo G, Ferrari M G. et al . Additional neoplasms and HCV infection in low-grade lymphoma of MALT type.  Br J Haematol. 1996;  94 373-375
• 66 Malik M O, El Sheikh E H. Tumors of the eye and adnexa in the Sudan.  Cancer. 1979;  44 293-303
• 67 Malope B I, Pfeiffer R M, Mbisa G. et al . Transmission of Kaposi sarcoma-associated herpesvirus between mothers and children in a South African population.  J Acquir Immune Defic Syndr. 2007;  44 351-355
• 68 Mathas S, Rickers A, Bommert K. et al . Anti-CD20- and B-cell receptor-mediated apoptosis: evidence for shared intracellular signaling pathways.  Cancer Res. 2000;  60 7170-7176
• 69 McDonnell J M, Mayr A J, Martin W J. DNA of human papillomavirus type 16 in dysplastic and malignant lesions of the conjunctiva and cornea.  N Engl J Med. 1989;  320 1442-1446
• 70 McDonnell J M, McDonnell P J, Sun Y Y. Human papillomavirus DNA in tissues and ocular surface swabs of patients with conjunctival epithelial neoplasia.  Invest Ophthalmol Vis Sci. 1992;  33 184-189
• 71 McLaughlin P, Grillo-Lopez A J, Link B K. et al . Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.  J Clin Oncol. 1998;  16 2825-2833
• 72 Moslehi R, Devesa S S, Schairer C. et al . Rapidly increasing incidence of ocular non-hodgkin lymphoma.  J Natl Cancer Inst. 2006;  98 936-939
• 73 Moubayed P, Mwakyoma H, Schneider D T. High frequency of human papillomavirus 6 / 11, 16, and 18 infections in precancerous lesions and squamous cell carcinoma of the conjunctiva in subtropical Tanzania.  Am J Clin Pathol. 2004;  122 938-943
• 74 Muccioli C, Belfort Jr R, Burnier M. et al . Squamous cell carcinoma of the conjunctiva in a patient with the acquired immunodeficiency syndrome.  Am J Ophthalmol. 1996;  121 94-96
• 75 Mulder M M, Heddema E R, Pannekoek Y. et al . No evidence for an association of ocular adnexal lymphoma with Chlamydia psittaci in a cohort of patients from the Netherlands.  Leuk Res. 2006;  30 1305-1307
• 76 Nakamura Y, Mashima Y, Kameyama K. et al . Detection of human papillomavirus infection in squamous tumours of the conjunctiva and lacrimal sac by immunohistochemistry, in situ hybridisation, and polymerase chain reaction.  Br J Ophthalmol. 1997;  81 308-313
• 77 Newton R, Ferlay J, Reeves G. et al . Effect of ambient solar ultraviolet radiation on incidence of squamous-cell carcinoma of the eye.  Lancet. 1996;  347 1450-1451
• 78 Newton R, Ziegler J, Ateenyi-Agaba C. et al . The epidemiology of conjunctival squamous cell carcinoma in Uganda.  Br J Cancer. 2002;  87 301-308
• 79 Nuckel H, Meller D, Steuhl K P. et al . Anti-CD20 monoclonal antibody therapy in relapsed MALT lymphoma of the conjunctiva.  Eur J Haematol. 2004;  73 258-262
• 80 Paavonen J, Vesterinen E, Meyer B. et al . Genital Chlamydia trachomatis infections in patients with cervical atypia.  Obstet Gynecol. 1979;  54 289-291
• 81 Panda A, Bajaj M S, Balasubramanya R. et al . Topical mitomycin C for conjunctival-corneal squamous cell carcinoma.  Am J Ophthalmol. 2003;  135 122-123, author reply 123 – 124
• 82 Poole T R. Conjunctival squamous cell carcinoma in Tanzania.  Br J Ophthalmol. 1999;  83 177-179
• 83 Reff M E, Carner K, Chambers K S. et al . Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD 20.  Blood. 1994;  83 435-445
• 84 Rigacci L, Nassi L, Puccioni M. et al . Rituximab and chlorambucil as first-line treatment for low-grade ocular adnexal lymphomas.  Ann Hematol. 2007;  86 565-568
• 85 Roggero E, Zucca E, Mainetti C. et al . Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin.  Hum Pathol. 2000;  31 263-268
• 86 Rosado M F, Byrne G E, Ding Jr F. et al . Ocular adnexal lymphoma: a clinicopathologic study of a large cohort of patients with no evidence for an association with Chlamydia psittaci.  Blood. 2006;  107 467-472
• 87 Rose P P, Bogyo M, Moses A V. et al . Insulin-like Growth Factor II Receptor-mediated intracellular Retention of Cathepsin B is essential for transformation of endothelial cells by Kaposi’s sarcoma associated herpesvirus.  J Virol. 2007;  81 (15) 8050-8062
• 88 Sacchi S, Pozzi S, Marcheselli R. et al . Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma.  Cancer. 2007;  110 121-128
• 89 Saegusa M, Takano Y, Hashimura M. et al . HPV type 16 in conjunctival and junctional papilloma, dysplasia, and squamous cell carcinoma.  J Clin Pathol. 1995;  48 1106-1110
• 90 Schechter B A, Nagler R S. Successful treatment with 5-Fu.  Ophthalmology. 2003;  110 1262-1263, author reply 1263
• 91 Schmack I, Kruse F E, Bauer A. et al . [Neurodermatitis. A risk factor for the development of squamous cell carcinoma].  Ophthalmologe. 2006;  103 141-143
• 92 Scott I U, Karp C L, Nuovo G J. Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia.  Ophthalmology. 2002;  109 542-547
• 93 Shan D, Ledbetter J A, Press O W. Apoptosis of malignant human B cells by ligation of CD 20 with monoclonal antibodies.  Blood. 1998;  91 1644-1652
• 94 Shields C L, Demirci H, Karatza E. et al . Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors.  Ophthalmology. 2004;  111 1747-1754
• 95 Shields J A, Shields C L, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture.  Arch Ophthalmol. 1997;  115 808-815
• 96 Shields J A, Shields C L, Suvarnamani C. et al . Orbital exenteration with eyelid sparing: indications, technique, and results.  Ophthalmic Surg. 1991;  22 292-297
• 97 Shimoyama Y, Oyama T, Asano N. et al . Senile Epstein-Barr virus-associated B-cell lymphoproliferative disorders: a mini review.  J Clin Exp Hematop. 2006;  46 1-4
• 98 Shipp M A. Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has ”high-risk” disease?.  Blood. 1994;  83 1165-1173
• 99 Sjo N C, Foegh P, Juhl B R. et al . Role of Helicobacter pylori in conjunctival mucosa-associated lymphoid tissue lymphoma.  Ophthalmology. 2007;  114 182-186
• 100 Smith J S, Munoz N, Herrero R. et al . Evidence for Chlamydia trachomatis as a human papillomavirus cofactor in the etiology of invasive cervical cancer in Brazil and the Philippines.  J Infect Dis. 2002;  185 324-331
• 101 Spencer W H. Chapter 2: Conjunctiva. Spencer, WH Ophthalmic Pathology: an atlas and textbook Philadelphia; WB Saunders 1996 2nd ed
• 102 Sun E C, Fears T R, Goedert J J. Epidemiology of squamous cell conjunctival cancer.  Cancer Epidemiol Biomarkers Prev. 1997;  6 73-77
• 103 Timm A, Stropahl G, Schittowski M. et al . [Association of malignant tumors of the conjunctiva and HIV infection in Kinshasa (D. R. Congo). First results].  Ophthalmologe. 2004;  101 1011-1016
• 104 Tulvatana W, Bhattarakosol P, Sansopha L. et al . Risk factors for conjunctival squamous cell neoplasia: a matched case-control study.  Br J Ophthalmol. 2003;  87 396-398
• 105 Tuppurainen K, Raninen A, Kosunen O. et al . Squamous cell carcinoma of the conjunctiva. Failure to demonstrate HPV DNA by in situ hybridization and polymerase chain reaction.  Acta Ophthalmol (Copenh). 1992;  70 248-254
• 106 Vargas R L, Fallone E, Felgar R E. et al . Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci? The University of Rochester experience.  Leuk Res. 2006;  30 547-551
• 107 Viejo-Borbolla A, Schulz T F. Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV8): key aspects of epidemiology and pathogenesis.  AIDS Rev. 2003;  5 222-229
• 108 Waddell K M, Downing R G, Lucas S B. et al . Corneo-conjunctival carcinoma in Uganda.  Eye. 2006;  20 893-899
• 109 Walboomers J M, Jacobs M V, Manos M M. et al . Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.  J Pathol. 1999;  189 12-19
• 110 Woog J J, Kim Y D, Yeatts R P. et al . Natural killer/T-cell lymphoma with ocular and adnexal involvement.  Ophthalmology. 2006;  113 140-147
• 111 Wotherspoon A C, Ortiz-Hidalgo C, Falzon M R. et al . Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma.  Lancet. 1991;  338 1175-1176
• 112 You C, Ryu M, Huh J. et al . Ocular adnexal lymphoma is highly associated with Chlamydia psittaci.  Eur J Cancer. 2005;  3 282-283
• 113 Zinzani P L, Alinari L, Stefoni V. et al . Rituximab in primary conjunctiva lymphoma.  Leuk Res. 2005;  29 107-108