Fig. 1.20 PET scan showing systemic involvement with MALT lymphoma

eliminate the chronic antigen stimulus and eradicate any local infective cause. This has been shown to be of benefit in gastric MALT lymphoma with elimination of Helicobacter pylori resulting in regression or remission in 50–80% of patients [157]. Because the association with Chlamydia and other infective agents is not as clear in ocular adnexal MALT lymphoma, blind anti-Chlamydia therapy is not recommended but could be considered if a chlamydial infection has been proved in geographical areas where associated chlamydial infection has been demonstrated [1, 41, 59, 66].

1.11Follicular Lymphoma

Because FL can transform into DLBCL with accumulated genetic mutations, staging is critical to identify whether this has occurred. 18F-FDG PET has a special role when the most intense focus on PET should be biopsied to look for any such transformation. If the process has not transformed, staging is important. Localized

1.13Radiotherapy 11

disease should be treated with involved field radiotherapy (IFRT), and the addition of chemotherapy does not change survival. If disease is widespread, palliation is the aim, and initial management may be conservative. Treatment is initiated when there is bulky disease (>7 cm), more than three nodal groups are involved, or the patient has B symptoms or symptomatic splenomegaly [140]. Usually, this will be with combined rituximab and chemotherapy. Locoregional IFRT may be considered and is appropriate for ocular adnexal involvement. Radioimmunotherapy with 90Y-ibritumomab tiuxetan or 131I-tositumomab is also possible and is currently being evaluated. Advanced multiply relapsed disease may be treated with autologous stem cell transplant.

Newly diagnosed DLBCL patients are treated with curative intent. While cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) is the preferred chemotheraputic regime, R-CHOP has been shown to improve survival in a number of randomized controlled trials [25, 47, 60, 124, 125].

1.12Mantle Cell Lymphoma

The majority of ocular adnexal cases are secondary. R-CHOP for systemic MCL is associated with a 50% response rate, with duration of effect of less than 2 years. This lesion usually requires aggressive treatment with alternating or sequential non-cross-reacting chemotherapy regimes, giving a remission rate of 90%. Despite consolidation treatment with chemotherapy and autologous stem cell transplantation, overall 5-year disease-free survival is around 50% [40, 84, 90, 100, 102, 149]. One promising recent report of 21 cases of orbital or adnexal MCL found 80% 5-year survival in patients treated with rituximab and chemotherapy compared with an 8% 5-year survival in patients not treated with rituximab [127].

T-cell lymphomas are a diverse group of poorly understood entities that may rarely behave moderately aggressively and be curable, but more commonly they are aggressive and associated with a poor outcome. The ocular adnexa may be involved secondarily or less frequently as a primary process [27, 84, 149, 156].

1.13Radiotherapy

Having said all this, radiotherapy is currently the most common first-line treatment for primary OALD (Figs. 1.21 and 1.22). Superficial conjunctival and anterior orbital lesions are usually treated with electron beams,

Fig. 1.21 Clinical image left orbital MALT lymphoma at presentation

Fig. 1.22 Clinical image of same patient following 30-Gy external beam radiotherapy

whereas deeper orbital tissues are usually treated with photon beams. This achieves a local control of 85–100%, which may be dose related. Patients receiving less than 30 Gy had an 81% 5-year local control rate compared with 100% if the dose was more than 30 Gy [53]. There is a risk of distant spread of up to 25% over 10 years [53, 144]. One study showed a statistically significant reduction in distant spread (using Cox multivariate analysis) with a radiotherapy dose above 20 Gy [149]. This was highly significant for indolent lymphomas and approached significance for aggressive lymphomas.

Complications of radiotherapy include immediate soft tissue effects on the affected skin, conjunctiva, and ocular surface. Later complications, which are dose related, include xerophthalmia, cataract, retinopathy, and optic neuropathy.

Immunotherapy includes interferon and a range of monoclonal antibodies. There are limited reports of the use of interferon for OALD, with good response in the short follow-up time [13, 103] (Figs. 1.23 and 1.24).

The use of monoclonal antibodies, most commonly the anti-CD20 antibody rituximab, has underpinned the paradigm shift in lymphoma management in the last decade. Anti-CD20 antigens are expressed by all B cells and 90% of B-cell lymphomas throughout most stages of B-cell development, except at the very early pre-B-cell stage and with plasma cell differentiation. Rituximab contains human IgG1 and κ-constant regions with murine variable regions. The antibody kills CD20-positive cells using human complement and immune effector cells, augmenting complement-mediated lysis and antibodydependent cell-mediated cytotoxicity (ADCC), activating apoptosis and having a direct antiproliferative effect. Rituximab as a single agent has been used to treat indolent FL, was initially approved for use in relapsed or

Fig. 1.23 Clinical image left orbital follicular lymphoma at presentation

Fig. 1.24 Clinical image of same patient following single course of rituximab monotherapy with complete response and no recurrence in long-term follow-up

refractory FL [64, 105, 111], but has also shown benefit for marginal zone lymphoma, and lymphoplasmacytic and small cell lymphoma [20, 49, 118, 150]. Rituximab in combination with chemotherapy has been demonstrated to improve response rates, event-free survival, progres- sion-free survival, and overall survival in both FL and DLBCL [29, 30].

Initial reports of the use of rituximab for OALD confirmed the good overall response seen for most B-cell lymphomas elsewhere, with a generally low side-effect profile, mainly consisting of flulike symptoms [12, 38, 42, 119, 148]. Monoclonal antibody treatment of OALD needs further study to elucidate its role as a single agent; in combination with chemotherapy regimes; for initial treatment, relapsed, or refractory disease; or as maintenance therapy for OALD.

1.16Radioimmunotherapy

Conjugating a monoclonal antibody with a radioisotope allows the delivery of radiotherapy to tumor cells that bind the antibody as well as neighboring tumor cells that may not express the antigen, yet minimizing radiation to normal tissues. While a number of agents are currently under study or development, two radioimmunoconjugates, yttrium-90 ibritumomab tiuxetan (Zevalin, BiogenIDEC Pharmaceuticals, San Diego, CA, USA) and iodine-131 tositumomab (Bexxar, GlaxoSmithKline, Philadelphia, PA, USA) have U.S. Food and Drug

Administration approval for FL and transformed NHL that failed or relapsed from prior therapies, including rituximab and standard chemotherapy [19]. They have shown benefit as initial therapy, in sequential therapy with chemotherapy, and as consolidation therapy [31]. Further advances with pretargeted regimens and with fractionated therapy are currently being studied [121, 132].

Their application to OALD probably parallels that of other sites. Following favorable use of the modality in one patient [38], Esmaeli et al. reported the exciting early findings of a pilot study of the use of 90Y ibritumomab tiuxetan (Zevalin) as front-line treatment in 12 patients with early-stage extranodal indolent lymphoma of the ocular adnexa (nine MALT, three FL) [39]. Ten had a complete response, and two had a partial response, with a radiotherapy dose one tenth that of standard external beam radiotherapy. All patients experienced transient pancytopenia, but none had myelosuppression.

1.17Outcome

The majority of OALs are indolent, with patients enjoying a good quality of life in remission after treatment. Ophthalmologists need to be aware, however, that there is significant morbidity and mortality the longer the followup. The overall mortality with long-term follow-up for OAL is roughly 20–25% from pooled data [8, 26, 28, 53, 84, 85, 149]. The mortality varies, depending on the histological type of lymphoma, being lower for the more indolent lymphomas (EMZL 10%, follicular 20–25%), and higher for the more aggressive lesions (DLBCL 40–45%, MCL and T- and NK cell lymphoma 75–100%) [27, 84, 85, 102, 127, 149, 156].

1.18 The Future

Management of these disorders is entering an exciting epoch based on an improved understanding of the molecular basis and pathophysiology of the different lymphomas. Moving in tandem with improved diagnosis are improvements in imaging for more accurate initial staging and monitoring. Simple specific treatments designed to reduce chronic antigen stimulus may become available as we understand the basic disease mechanisms better. More complex therapies based on immunotherapy and radioimmunotherapy will emerge and it is hoped improve both patient quality of life and survival while reducing treatment-related complications.

References

1.Abramson DH, Rollins I, Coleman M (2005) Periocular

mucosa-associated lymphoid/low grade lymphomas: treat- 1 ment with antibiotics. Am J Ophthalmol 140:729–730

2.Adami J, Frisch M, Yuen J, et al (1995) Evidence of an association between non-Hodgkin’s lymphoma and skin cancer. BMJ 310:1491–1495

3.Agostinelli C, Piccaluga P, Went P (2008) Peripheral T cell lymphoma, not otherwise specified: the stuff of genes, dreams and therapies. J Clin Pathol 61:1160–1167

4.Aifantis I, Raetz E, Buonamici S (2008) Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol 8:380–390

5.Allen-Auerbach M, Quon A, Weber WA, et al (2004) Comparison between 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography and positron emission tomography/computed tomography hardware fusion for staging of patients with lymphoma. Mol Imaging Biol 6:411–416

6.Allen-Auerbach M, de Vos S, Czernin J (2008) The impact of fluorodeoxyglucose-positron emission tomography in primary staging and patient management in lymphoma patients. Radiol Clin N Am 46:199–121

7.Australian Cancer Network Diagnosis and Management of Lymphoma Guidelines Working Party. Guidelines for the diagnosis and management of lymphoma. The Cancer Council Australia and Australian Cancer Network, Sydney 2005

8.Auw-Haedrich C, Coupland SE, Kapp A, et al (2001) Long term outcome of ocular adnexal lymphoma subtyped according to the REAL classification. Br J Ophthalmol 85:63–69

9.Bahler D, Szankasi P, Kulkarni S (2009) Use of similar immunoglobulin VH gene segments by MALT lymphomas of the ocular adnexa. Mod Pathol. doi:10.1038/modpathol. 2009.42

10.Ben Simon GJ, Cheung N, McKelvie P, et al (2006) Oral chlorambucil for extranodal, marginal zone, B-cell lymphoma of mucosa associated lymphoid tissue of the orbit. Ophthalmology 113:1209–1213

11.Bende R, Smit L, van Noesel C (2007) Molecular pathways in follicular lymphoma. Leukemia 2:18–29

12.Benetatos L, Alymara V, Asproudis I, et al (2006) Rituximab as first line treatment for MALT lymphoma of extraocular muscles. Ann Hematol 85:625–626

13.Blasi MA, Gherlinzoni F, Calvisi G, et al (2001) Local chemotherapy with interferon-alpha for conjunctival mucosaassociated lymphoid tissue lymphoma: a preliminary report. Ophthalmology 108:559–562

14.Byrne GI, Ojcius DM (2004) Chlamydia and apoptosis: life and death decisions of an intracellular pathogen. Nat Rev Microbiol 2:802–808

15.Cahill M, Barnes C, Moriarty P, et al (1999) Ocular adnexal lymphoma–a comparison of MALT lymphoma with other histological types. Br J Ophthalmol 83:742–747

16.Campbell L (2005) Cytogenetics of lymphomas. Pathology 37:493–507

17.Carbonne PP, Kaplan HS, Mushoff HS, et al (1971) Report of the nomenclature committee on Hodgkin’s disease staging. Cancer Res 311:860–861

18.Chan-Kai B, Yen M (2005) Combined PET/CT imaging of orbital lymphoma. Am J Ophthalmol 140:531–533

19.Cheson BD (2003) Radioimmunotherapy of non-Hodgkin’s lymphomas. Blood 101:391–398

20.Cheson BD, Leonard JP (2008) Monoclonal antibody therapy for B-cell non-Hodgkin’s lymphoma. N Engl J Med 359: 613–626

21.Ci W, Polo J, Melnick A (2008) B-cell lymphoma 6 and the molecular pathogenesis of diffuse large B-cell lymphoma. Curr Opin Hematol 15:381–390

22.Clarke CA, Glaser SL (2002) Changing incidence of nonHodgkin lymphomas in the United States. Cancer 94: 2015–2023

23.Cleary ML, Sklar J (1984) Lymphoproliferative disorders in cardiac transplant recipients are multiclonal lymphomas. Lancet ii 8401:489–493

24.Coffee R, Lazarchick J, Chévez-Barios P, et al (2005) Rapid diagnosis of orbital mantle cell lymphoma utilizing fluorescent in situ hybridization technology. Am J Ophthalmol 140:554–555

25.Coiffier B, Lepage E, Briere J, et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

26.Coupland SE, Krause L, Delecluse HJ, et al (1998) Lymphoproliferative lesions of the ocular adnexa. Analysis of 112 cases. Ophthalmology 105:1430–1441

27.Coupland SE, Foss H-D, Assaf C, et al (1999) T-cell and T/ natural killer-cell lymphomas involving ocular and ocular adnexal tissues. Ophthalmology 106:2109–2120

28.Coupland SE, Hellmich M, Auw-Haedrich C, et al (2004) Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases Graefe’s. Arch Clin Exp Ophthalmol 242:130–145

29.Czuczman MS, Weaver R, Alkuzweny B, et al (2004) Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 22:4711–6 [Erratum (2005) J Clin Oncol 23 248]

30.Czuczman MS, Koryzna A, Mohr A, et al (2005) Rituximab in combination with fludarabine chemotherapy in lowgrade or follicular lymphoma. J Clin Oncol 23:694–704

31.Davies AJ (2007) Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I131 tositumomab. Oncogene 26:3614–3628

32.De Paepe P, de Wolf-Peeters C (2007) Diffuse large B-cell lymphoma: a heterogeneous group of non-Hodgkin lymphomas comprising several distinct clinicopathological entities. Leukemia 21:37–43

33.Decaudin D, Dendale R, Lumbroso-Le R (2008) Treatment of mucosa-associated lymphoid tissue-type ocular adnexal lymphoma. Anticancer Drugs 19:673–680

34.Decaudin D, Dolcetti R, deCremoux P, et al (2008) Variable association between Chlamydia psittaci infection and ocular adnexal lymphomas: methodological biases or true geographical variation? Anticancer Drugs 19:761–765

35.Demirci H, Shields CL, Karatza EC, et al (2008) Orbital lymphoproliferative tumors analysis of clinical features and systemic involvement in 160 cases. Ophthalmology 115:1626–1631

36.Devesa SS, Fears T (1992) Non-Hodgkin’s lymphoma time trends: United States and international data. Cancer Res 52(19 Suppl):5432s–54340s

37.Ellis JH, Banks PM, Campbell RJ, et al (1985) Lymphoid tumors of the ocular adnexa. Clinical correlation with the working formulation classification and immunoperoxidase staining of paraffin sections. Ophthalmol 92:1311–1324

38.Esmaeli B, Murray JL, Ahmadi MA, et al (2002) Immunotherapy for low-grade non-Hodgkin secondary lymphoma of the orbit. Arch Ophthalmol 120:1225–1227

39.Esmaeli B, McLaughlin P, Pro B, et al (2009) Prospective trial of targeted radioimmunotherapy with Y-90 ibritumomab tiuxetan (Zevalin) for front-line treatment of early-stage extranodal indolent ocular adnexal lymphoma. Ann Oncol 20:709–714

40.Evens AM, Winter JN, Hou N, et al (2008) A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma. Br J Haematol 140: 385–393

41.Ferreri AJ, Guidoboni M, De Conciliis C, et al (2004) Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 96:586–594

42.Ferreri AJ, Ponzoni M, Martinelli G, et al (2005) Rituximab in patients with mucosal-associated lymphoid tissue-type lymphoma of the ocular adnexa. Haematologica 90: 1578–1579

43.Ferreri AJ, Viale E, Guidoboni M, et al (2006) Clinical implications of hepatitis C virus infection in MALT-type lymphoma of the ocular adnexa. Ann Oncol 17:769–772

44.Ferreri AJ, Dolcetti R, Du M-Q, et al (2008) Ocular adnexal MALT lymphoma: an intriguing model for antigen-driven lymphomagenesis and microbial-targeted therapy. Ann Oncol 19:835–846

45.Ferry JA, Fung CY, Zukerberg L, et al (2007) Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol 31:170–184

46.Filipovich AH, Mathur A, Karmat D, et al (1992) Primary immunodeficiencies: genetic risk factors for lymphoma. Cancer Res 52(19 Suppl):5465s–5467s

47.Fisher RI, Gaynor ER, Dahlberg S, et al (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002–1006

48.Fisher S, Fisher R (2004) The epidemiology of nonHodgkin’s lymphoma. Oncogene 23:6524–6534

49.Foran JM, Rohatiner AZ, Cunningham D, et al (2000) 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 18:317–324 [Erratum (2000) J Clin Oncol 18:2006]

50.Freeman C, Berg JW, Cutler SJ (1972) Occurrence and prognosis of extranodal lymphomas. Cancer 29:252–260

51.Freidberg J, Fisher R (2008) Diffuse large B-cell lymphoma. Hematol Oncol Clin N Am 22:941–952.

52.Fueger B, Yeom K, Czernin J, et al (2009) Comparison of CT, PET, and PET/CT for staging of patients with indolent non-Hodgkin’s lymphoma. Mol Imaging Biol. (Epub 20 Mar 2009)

53.Fung CY, Tarbell NJ, Lacarelli MJ, et al (2003) Ocular adnexal lymphoma: clinical behaviour of distinct World Health Organization classification subtypes. Int J Radiat Oncol Biol Phys 57:1382–1391

54.Garner A, Rai AH, Wright JE (1983) Lymphoproliferative disorders of the orbit: an immunological approach to diagnosis and pathogenesis. Br J Ophthalmol 67:561–569

55.Gausas RE, Gonnering RS, Lemke B, et al (1999) Identification of human orbital lymphatics. Ophthal Plast Reconstr Surg 15:252–259

56.Gausas RE, Daly T, Fogt F (2007) D2-40 expression demonstrates lymphatic vessel characteristics in the dural portion of the optic nerve sheath. Ophthal Plast Reconstr Surg 23:32–36

57.Gayed I, Eskandari F, McLaughlin P, et al (2007) Value of positron emission tomography in staging ocular adnexal lymphomas and evaluating their response to therapy ophthalmic. Surg Lasers Imaging 38:319–325

58.Goedert JJ (2000). The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol 27: 390–401

59.Grünberger B, Hauff W, Lukas J, et al (2006) “Blind” antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa. Ann Oncol 17:484–487

60.Habermann TM, Weller EA, Morrison VA, et al (2006) Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:3121–3127

In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) Pathology and genetics of tumours of haematopoietic and lymphoid tissue. IARC Press, Lyon, pp 121–126

162. Harris NL, Isaacson PG (1999) What are the criteria for distinguishing MALT from non-MALT lymphoma at extranodal sites? Am J Clin Pathol 111(Suppl 1): S126–S1332

63.Henderson JW (1994) Hemotopoietic tumors. In: Henderson JW (ed) Orbital tumors, 3rd ed. Raven, New York, pp 279–307

64.Hiddemann W, Kneba M, Dreyling M, et al (2005) Frontline therapy with rituximab added to the combination of cylophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725–3732

65.Hu S, Federman D, Ma F, et al (2005) Skin cancer and nonHodgkin’s lymphoma: examining the link. Dermatol Surg 31:76–82

66.Husain A, Roberts D, Pro B, et al (2007) Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics. Cancer 110:809–815

67.Hutchings M, Specht L (2008) PET/CT in the management of haematological malignancies. J Haematol 80:369–380

68.Isaacson PG (1999) Mucosa-associated lymphoid tissue lymphoma. Semin Hematol 36:139–147

69.Isaacson PG (2000) The current status of lymphoma classification. Br J Haematol 109:258–266

70.Isaacson PG, Wright DH (1983) Malignant lymphoma of mucosa-associated lymphoid tissue. Cancer 52:1410–1416

71.Isaacson PG, Wright DH (1984) Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 53:2515–2524

72.Isaacson PG, Muler-Hermelink HK, Piris MA, et al (2001) Extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue (MALT lymphoma). In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) Pathology and genetics of tumors of haematopoietic and lymphoid tissue. IARC Press, Lyon, pp 157–160

73.Jaffe ES, Harris NL, Diebold J, et al (1999) World health organisation classification of neoplastic disease of the hematopoietic and lymphoid tissues. Am J Clin Pathol 111(Suppl):S8–S12

74.Jakobiec FA (1982) Orbital inflammations and lymphoid tumours. Trans New Orleans Acad Ophthalmol 30:52–85

75.Jakobiec FA (1983) Ocular inflammatory disease: the lymphocyte redivivus. Am J Ophthalmol 96:384–391

76.Jakobiec FA, Knowles DM (1989) An overview of ocular adnexal lymphoid tumors. Trans Am Ophthalmol Soc 87: 420–442

characteristics of orbital lymphoid hyperplasia. Ophthalmology 86:948–966

78.Jakobiec FA, Iwamoto T, Knowles DM (1982) Ocular adnexal lymphoid tumors. Correlative ultrastructural and immunologic marker studies. Arch Ophthalmol 100:84–98

79.Jakobiec FA, Iwamoto T, Patell M, et al (1986) Ocular adnexal monoclonal lymphoid tumors with a favourable prognosis. Ophthalmology 93:1547–1557

80.Jakobiec FA, Neri A, Knowles DM (1987) Genotypic monoclonality in immunophenotypically polyclonal orbital lymphoid tumors. A model of tumor progression in the lymphoid system. Ophthalmology 94:980–994

81.Jardin F, Ruminy P, Bastard C, et al (2007) The BCL6 protooncogene: a leading role during germinal center development and lymphomagenesis. Pathol Biologie 55:73–83

82.Jares P, Colomer D, Campo E (2007) Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 7:750–762

83.Jemal A, Siegel R, Ward E, et al (2008) Cancer statistics. CA Cancer J Clin 58:71–96. (Epub 20 Feb 2008)

84.Jenkins C, Rose GE, Bunce C, et al (2000) Histological features of ocular adnexal lymphoma (REAL classification) and their association with patient morbidity and survival. Br J Ophthalmol 84:907–913

85.Jenkins C, Rose GE, Bunce C, et al (2003) Clinical features associated with survival of patients with lymphoma of the ocular adnexa. Eye 17:809–820

86.Jensen A, Olesen A, Dethlefsen C, et al (2008) Chronic diseases requiring hospitalization and risk of non-melanoma skin cancers—a population based study from Denmark. J Invest Dermatol 128:926–931

87.Jost PJ, Ruland J (2007) Aberrant NFkappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood 109: 2700–2707

88.Juweid M, Cheson B (2006) Positron-emission tomography and assessment of cancer therapy. N Engl J Med 354: 496–507

89.Kadin M (2003) Genetic and molecular genetic studies in the diagnosis of T-cell malignancies. Hum Pathol 34: 322–329

90.Khouri IF, Romaguera J, Kantarjian H, et al (1998) HyperCVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16:3803–3809

91.Kinlen L (1992) Immunosuppressive therapy and acquired immunological disorders. Cancer Res 52(19 Suppl): 5474s–5476s

92.Knop E, Knop N (2001) Lacrimal drainage—associated lymphoid tissue (LDALT): a part of the human mucosal immune system. Invest Ophthalmol Vis Sci 42:566–574

93.Knop E, Knop N 2005 The role of eye-associated lymphoid tissue in corneal immune protection. J Anat 206: 271–285

94.Knowles DM, Jakobiec FA (1980) Orbital lymphoid neoplasms: a clinicopathologic study of 60 patients. Cancer 46: 576–589

95.Knowles DM, Jakobiec FA (1982) Ocular adnexal lymphoid neoplasms: clinical, histopathologic, electron microscopic, and immunologic characteristics. Hum Pathol 13:148–162

96.Knowles DM, Jakobiec FA, Halper JP (1979) Immunologic characterization of ocular adnexal lymphoid neoplasms. Am J Ophthalmol 87:603–619

97.Knowles DM, Halper JP, Jakobiec FA (1982) The immunologic characterization of 40 extranodal lymphoid infiltrates:indistinguishingbetweenbenignpseudolymphoma and malignant lymphoma. Cancer 49:2321–2335

98.Knowles DM, Jakobiec FA, McNally L (1990) Lymphoid hyperplasia and malignant lymphoma occurring in the ocular adnexa (orbit, conjunctiva, and eyelids): a prospective multiparametric analysis of 108 cases during 1977 to 1987. Hum Pathol 21:959–973

99.Küppers R, Klein U, Hansmann M-L, et al (1999) Cellular origin of human B-cell lymphomas. N Engl J Med 341(20):1520–1529

100.Lenz G, Dreyling M, Hoster E, et al (2005) Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23:1984–1992

101.Li BZ, Lu HF, Zhou XY, et al (2008) Frequency of genetic aberrations of mucosa-associated lymphoid tissue lymphoma of different sites. Zhonghua Bing Li Xue Za Zhi 37:604–608

102.Looi A, Gascoyne RD, Chaanabhai M, et al (2005) Mantle cell lymphoma in the ocular adnexal region. Ophthalmology 112:114–119

103.Lucas RS, Mortimore R, Sullivan TJ, et al (2003) Interferon treatment of childhood conjunctival lymphoma. Br J Ophthalmol 87:1191

104.Mannami T, Yoshino T, Oshima K, et al (2001) Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: characterization of MALT lymphoma and reactive lymphoid hyperplasia. Mod Pathol 14:641–649

105.Marcus R, Imrie K, Solal-Celigny P, et al (2008) A phase III study of rituximab plus CVP versus CVP alone in patients with previously untreated advanced follicular lymphoma: updated results with 53 months’ median follow-up and analysis of outcomes according to baseline prognostic factors. J Clin Oncol 26(28):4579–86.

106.Margo CE, Mulla ZD (1998) Malignant tumors of the orbit. Analysis of the Florida Cancer Registry. Ophthalmology 105:185–190

107.Matthews JM, Moreno LI, Dennis J, et al (2008) Ocular adnexal lymphoma: no evidence for bacterial DNA associated with lymphoma pathogenesis. Br J Haematol. (Epub ahead of print 19 May 2008)

108.Medeiros LJ, Harris NL (1989) Lymphoid infiltrates of the orbit and conjunctiva. A morphologic and immunophenotypic study of 99 cases. Am J Surg Pathol 13:459–471

109.Medeiros LJ, Harris NL (1990) Immunohistologic analysis of small lymphocytic infiltrates of the orbit and conjunctiva. Hum Pathol 21:1126–1131

110.Medeiros LJ, Harmon DC, Linggood RM, et al (1989) Immunohistologic features predict clinical behaviour of orbital and conjunctival lymphoid infiltrates. Blood 74: 2121–2129

111.McLaughlin P, Grillo-López AJ, Link BK, et al (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy of relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833

112.Miyairi I, Byrne GI (2006) Chlamydia and programmed cell death. Curr Opin Microbiol 9:102–108

113.McKelvie PA, McNab AA, Francis IC, et al (2001) Ocular adnexal lymphoproliferative disease: a series of 73 cases. Clin Exp Ophthalmol 29:387–393

114.Morgan G (1975) Lymphocytic tumours of the orbit. Mod Probl Ophthalmol 14:355–360

115.Morgan G, Harry J (1978) Lymphocytic tumours of indeterminate nature: a 5-year follow-up of 98 conjunctival and orbital lesions. Br J Ophthalmol 62:381–383

116.Moslehi R, Devesa SS, Schairer C, et al (2006) Rapidly increasing incidence of ocular non-Hodgkin lymphoma. J Natl Cancer Inst 98:936–939

117.Nakata M, Matsuno Y, Katsumata N, et al (1999) Histology according to the revised European-American lymphoma classification significantly predicts the prognosis of ocular adnexal lymphoma. Leuk Lymphoma 32:533–543

118.Nguyen DT, Amess JA, Doughty H, et al (1999) IDECC2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol 62:76–82

119.Nuckel H, Meller D, Steuhl KP, et al (2004) Anti-CD20 monoclonal antibody therapy in relapsed MALT lymphoma of the conjunctiva. Eur J Haematol 73:258–262

120.Nutting CM, Shah-Desai S, Rose GE, et al (2006) Thyroid orbitopathy possibly predisposes to late-onset of periocular lymphoma. Eye 20:645–648

121.Otte A, van de Wiele C, Dierckx RA (2009) Radiolabeled immunotherapy in non-Hodgkin’s lymphoma treatment: the next step. Nucl Med Commun 30:5–15

122.Pals ST, De Gorter DJ Spaargaren M (2007) Lymphoma dissemination: the other face of lymphocyte homing. Blood 110:3102–3111

123.Perry C, Herishanu Y, Metzer U, et al (2007) Diagnostic accuracy of PET/CT in patients with extranodal marginal zone MALT lymphoma. Eur J Haematol 79:205–209

124.Pfreundschuh M, Trumper L, Osterborg A, et al (2006)

125.Pfreundschuh M, Schubert J, Ziepert M, et al (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20 B-cell lymphomas:arandomisedcontrolledtrial(RICOVER-60). Lancet Oncol 9:105–116

126.Polito E, Galieni P, Leccisotti A (1996) Clinical and radiological presentation of 95 orbital lymphoid tumors. Graefes Arch Clin Exp Ophthalmol 234:504–509

127.Rasmussen P, Sjo LD, Prause JU (2009) Mantle cell lymphoma in the orbital and adnexal region. Br J Ophthalmol. (Epub ahead of print 7 May 2009)

128.Roe R, Finger PT, Kurli M, et al (2006) Whole-body positron emission tomography/computed tomography imaging and staging of orbital lymphoma. Ophthalmology 113: 1854–1858

129.Romagosa Y, Hu S, Kirsner R (2008) Chronic diseases and non-Melanoma skin cancer: is there an association? J Invest Dermatol 128:768

130.Roos E (1991) Adhesion molecules in lymphoma metastasis. Cancer Metastasis Rev 10:33–48

131.Schotterfield D, Beebe-Dimmer J (2006) Chronic inflammation: a common and important factor in the pathogenesis of neoplasia. CA Cancer J Clin 56:69–83

132.Sharkey RM, Press OW, Goldenberg DM (2009) A reexamination of radioimmunotherapy in the treatment of non-Hodgkins lymphoma: prospects for dual-targeted antibody/radioantibody therapy. Blood 113:3891–3895

133.Shen D, Yuen HKL (2006) Detection of chlamydia pneumonia in a bilateral orbital mucosa-associated lymphoid tissue lymphoma. Am J Ophthalmol 141:1162–1163

134.Shields JA (1989) Lymphoid tumors and leukemias. In: Shileds JA, Saunders WB (eds). Diagnosis and management of orbital tumors. Lippincott, Philadelphia, pp 316–340

135.Shipp MA, Harrington DP, Anderson JR, et al (1993) International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329(14):987–994

136.Sjo LD (2009) Ophthalmic lymphoma: epidemiology and pathogenesis. Acta Ophthalmol 87 Thesis 1:1–20

137.Sjo LD, Ralfkiaer E, Prause JU, et al (2008) Increasing incidence of ophthalmic lymphoma in Denmark from 1980 to 2005. Invest Ophthalmol Vis Sci 49:3283–3288

138.Smith JS, Munoz N, Herrero R, et al (2002) Evidence for Chlamydia trachomatis as a human papillomavirus cofac-

tor in the etiology of invasive cervical cancer in Brazil and the Philippines. J Infect Dis 185:324–331

139.Smith M (2008) Mantle cell lymphoma: advances in biology and therapy. Curr Opin Hematol 15:415–421

140.Solal-Celigny P, Lepage E, Brousse N, et al (1993) Recombinant interferon alfa-2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. Groupe d’Etude des Lymphomes de l’Adulte. N Engl J Med 329:1608–1614

141.Solal-Seligny P, Roy P, Colombat P, et al (2004) Follicular lymphoma international prognostic index. Blood 104:1258–1265

142.Song EK, Kim SY, Kim TM et al (2008) Efficacy of chemotherapy as a first-line treatment in ocular adnexal extranodal marginal zone B-cell lymphoma. Ann Oncol 19: 242–246

143.Spagnolo DV, Ellis DW, Juneja S, et al (2004) The role of molecular studies in lymphoma diagnosis: a review. Pathology 36:19–44

144.Stefanovic A, Lossos I (2009) Extranodal marginal zone lymphoma of the ocular adnexa. Blood. (Prepublished online 16 April 2009)

145.Stein H (2001) Hodgkin lymphomas: introduction. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) Pathology and genetics of tumours of haematopoietic and lymphoid tissue. IARC Press, Lyon, p 239

146.Streubel B, Simonitsch-Klupp I, Mullauer L, et al (2004) Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 18:1722–1726

147.Sullivan TJ, Valenzuela AA (2006) Imaging features of ocular adnexal lymphoproliferative disease. Eye 20: 1189–1195

148.Sullivan TJ, Grimes D, Bunce I (2004) Monoclonal antibody treatment of orbital lymphoma. Ophthal Plast Reconstr Surg 20:103–106

149.Sullivan TJ, Whitehead K, Williamson R, et al (2005) Lymphoproliferative disease of the ocular adnexa: a clinical and pathologic study with statistical analysis of 69 patients. Ophthal Plast Reconstr Surg 21:177–188

150.Treon SP, Agus DB, Link B, et al (2001) CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother 24: 272–279

151.Valenzuela AA, Allen C, Grimes D, et al (2006) Positron emission tomography in the detection and staging of ocular adnexal lymphoproliferative disease. Ophthalmology 113:2331–2337

152.Westacott S, Garner A, Moseley IF, et al (1991) Orbital lymphoma vs reactive lymphoid hyperplasia: an analysis of the use of computed tomography in differential diagnosis. Br J Ophthalmol 75:722–725