13 Orbital Lymphoma Bita Esmaeli and Misha Faustina

alignant lymphomas are neoplastic transfor- anterior but less commonly deep in the orbital mations of cells that reside predominantly apex (Figure 13.2). Mwithin lymphoid tissues. Lymphoid tumors The distinction between “primary” and “sec- are the most common primary orbital malignancy in ondary” orbital lymphoma is somewhat arbitrary. adults,1,2 yet they constitute only about 2% of all lym- Primary lymphomas are thought to be isolated to the phomas.3 Many studies have described the clinical and orbit, with the orbit as the only extranodal site of histopathologic features of primary orbital lym- involvement of lymphoma. Thus, by definition, phomas.1–4 However, the advent and popularity of “primary” orbital lymphomas are stage I. Secondary more sophisticated diagnostic tests such as positron orbital lymphomas are those in which the orbit is a emission tomography (PET) and gastrointestinal en- secondary extranodal site of involvement either doscopy will often lead to discovery of lymphoma else- where there was a previously diagnosed NHL or where in the body of a patient who has orbital or oc- where the orbital lymphoma is diagnosed simulta- ular adnexal lymphoma. This chapter discusses the neously with the discovery of systemic lymphoma. classification and staging workup for primary orbital Given the more recent sensitive tools such as PET lymphomas as well as the characteristics and course for detecting small foci of lymphoma and the rou- of systemic non-Hodgkin’s lymphoma (NHL), which tine use of bone marrow biopsies as part of the stag- may secondarily spread to the orbit or present with ing workup, we suspect that the incidence of truly involvement of the orbit at the time of initial diag- “primary” orbital lymphoma is lower than suggested nosis of systemic lymphoma.5,6 The section entitled in most textbooks. Table 13.1 compares some fea- Management reviews the treatment options currently tures of what have been termed primary versus sec- available for orbital lymphoma. The majority of pub- ondary orbital lymphomas, although these distinc- lished reports focus on the use of external-beam radi- tions are somewhat arbitrary and not applicable to ation therapy or systemic for treatment every patient with orbital lymphoma.6 of orbital lymphoma.7–11 In addition to these modali- ties, more recent treatment options are discussed, such as immunotherapy (monoclonal antibody ther- MORPHOLOGIC FEATURES apy), which may be effective in the treatment of low- grade non-Hodgkin’s lymphoma of the orbit.12 Accurate histopathologic evaluation is the most crit- ical diagnostic step in the management of orbital lym- phomas. Open incisional biopsy or fine-needle aspira- CLINICAL FEATURES tion of an orbital mass that is suspected to be a lymphoma is often necessary to establish the diagno- Lymphoid tumors are the most common primary or- sis and guide management. Tissue should arrive at the bital malignancy,1,2 constituting approximately 10% pathology department fresh (without preservatives) of all orbital tumors and 40 to 60% of lymphoprolif- and sterile. Care should be taken to avoid excessive erative disease in the orbit.5 The majority of orbital crushing or manipulation to preserve the tissue ar- lymphomas are non-Hodgkin’s type and are seen pri- chitecture. Under the hood in the pathology labora- marily in adults in the 50- to 70-year age group. tory, touch preps and permanent and frozen sections Orbital lymphomas are usually unilateral but may can be prepared. Additional fresh tissue is reserved for involve both orbits and demonstrate a predilection for special lymphoma studies.13,14 the lacrimal gland. Patients with orbital lymphoma Malignant lymphoma is diagnosed when diffusely usually present with a painless proptosis of insidious arranged population of immature and mitotically ac- onset, downward displacement of the , tive lymphocytes are found in the orbit.15,16 Histologic edema, a palpable nontender orbital mass, and hallmarks of this disease are monoclonal populations (Figure 13.1). Imaging studies usually confirm the pres- of B cells confirmed by immunohistochemical stud- ence of a mass, most commonly in the superior and ies, with prominent nucleoli, chromatin margination

133 134 PART THREE: PRIMARY TUMORS OF THE ORBIT past, the most commonly used system of classifica- tion for lymphoma was the National Cancer Insti- tute’s Working Formulation, which divided lym- phomas into low, intermediate, and high grades based on their histologic characteristics and morphologic features (Box 13.1). The availability of monoclonal an- tibodies, which identify surface antigens on lymphoid cells, has helped the classification of lymphomas based on their immunophenotype. The chromosomal and molecular characteristics of lymphomas are now studied routinely and correlated with their clinical be- FIGURE 13.1. Patient with a left lacrimal gland mass causing me- chanical ptosis of the left upper eyelid. havior. The Revised European–American Classifica- tion of Lymphoid Neoplasms (REAL) is the most re- cently and widely used pathology classification system based on morphology, immunophenotype, at the nuclear membrane, nuclear membrane irregu- genotype, and clinical features of the lymphoma (Box larities, and cellular atypia. 13.2).17 In this classification, lymphomas are catego- In addition to sections prepared with standard rized as indolent, aggressive, or highly aggressive. In hematoxylin eosin stain, lymphoma studies currently addition to the histologic subtypes included in the ear- utilized include the following: lier classification schemes, several new entities, such as the peripheral T-cell lymphomas, are included in • Immunohistochemistry: a sensitive technique to REAL.18 identify antigenic expression of lymphoma cells, which can aid in the histologic classification of lymphomas. The numerous target antigens char- INVESTIGATION acterized thus far include CD20 for mature B lym- phocytes, CD10 for precursor B lymphocytes, and As with lymphomas in other sites, detailed investiga- many others that help classify the lymphoma. tion is necessary to determine the stage of the disease • Flow cytometry: measures cellular parameters before a definitive treatment plan is established.19 A while a suspension of sampled cells flows through thorough staging workup is necessary to identify pa- a laser beam. Clonality of lymphocytes can be rap- tients with orbital lymphoma who may harbor addi- idly determined with flow cytometry. tional foci of lymphoma throughout the body, thus re- • Cytogenetics studies: evaluate chromosomal dele- quiring systemic or combined-modality treatment. tions, additions, and translocations by gene karyo- A complete history and physical examination may typing and are useful in evaluating tumors with provide evidence of systemic, although clinically characteristic chromosomal abnormalities. silent, disease or presence of constitutional signs. In • Molecular studies of the biopsied tissue: can pro- addition to a usually painless and nontender orbital vide additional information that may help charac- terize the type of lymphoma. The polymerase chain reaction can amplify the DNA or RNA, al- lowing for detection of minute genetic aberrations. Approximately 85 to 90% of orbital lymphomas are low-grade, diffuse proliferations of small, monoclonal B-cell lymphocytes (Figure 13.3). The remaining 10 to 15% have follicular or nodular characteristics. Lesions displaying high mitotic activity are most likely asso- ciated with extraorbital disease. Follicular lesions with germinal centers are more likely indicative of lo- calized disease.

CLASSIFICATION

Histologic classification of lymphoma has evolved and improved as newer techniques are utilized to eluci- FIGURE 13.2. Axial noncontrast, T1-weighted magnetic resonance date the antigenic expression, cytogenetic features, image of an intraconal lymphoma in the posterior left orbit and molecular characteristics of lymphomas. In the (asterisk). CHAPTER 13: ORBITAL LYMPHOMA 135

TABLE 13.1. Primary vs Secondary Orbital Lymphomas.

Primary lymphomas Secondary lymphomas Characteristics Isolated, extranodal, orbit is often the first site of Disseminated, systemic involvement, may appear lymphoma involvement late as part of generalized relapse Location Usually unilateral Usually unilateral Age Most common in 50- to 70-year-old age group Most common in 50- to 70-year old age group, but younger patients more likely to have high-grade lymphomas Sex M ϭ FMϭ F Histology Low-grade, indolent, small lymphocytic, follicular, More often intermediate- or high-grade (diffuse mixed or MALT or large cell type) but low-grade secondary orbital lymphomas also common

mass, which may be palpable or visible during the ex- well-defined orbital mass with molding to the globe, amination, there may be visual loss due to compres- , and orbital bones strongly suggests the di- sive , a condition revealed by a thor- agnosis of orbital lymphoma (Figure 13.4). On com- ough ophthalmic examination. puted tomography, lymphomas appear homogenous in Box 13.3 summarizes the recommended staging texture and isodense to muscle, showing mild en- workup for orbital lymphomas. An imaging study of hancement with contrast. the orbit is critical in delineating the extent of orbital Fine-needle cytology or open biopsy of orbital and involvement. A characteristic diffuse to moderately adnexal masses is often necessary to confirm the di- agnosis and help with the histologic classification of orbital lymphomas. Imaging studies of the abdomen, thorax, and pelvis are performed to rule out disseminated disease. A bone marrow aspiration is performed to rule out marrow in- volvement. Upper GI tract endoscopy and barium stud- ies are done to detect gastrointestinal involvement and are particularly important for certain subtypes of orbital lymphoma, such as with a predilection for gastrointestinal involvement. PET is replacing bone and gallium scans for de- tecting small foci of lymphoma throughout the body.

A BOX 13.1. U.S. National Cancer Institute Working Formulation of Non-Hodgkin’s Lymphomas

Low-Grade Lymphomas Small lymphocytic Follicular, predominantly small cleaved cell Follicular, mixed, small cleaved cell and large cell Intermediate-Grade Lymphomas Follicular, predominantly large cell Diffuse, mixed, small and large cell Diffuse, large cell (cleaved and noncleaved) B High-Grade Lymphomas FIGURE 13.3. Histologic findings for the lacrimal gland mass shown in Figure 13.1. (A) Histologic section (with H&E stain) demonstrates Diffuse large cell, immunoblastic a mostly with areas of diffuse infiltration by a Lymphoblastic (convoluted and non-convoluted) mixture of small cleaved and large noncleaved lymphoid cells. (B) Small noncleaved cell (Burkitt’s and Immunohistochemical staining of paraffin-embedded tissue sec- tions demonstrates that the lymphoma cells are positive for CD20, non-Burkitt’s) confirming B-cell lineage. 136 PART THREE: PRIMARY TUMORS OF THE ORBIT temic involvement is likely, systemic chemotherapy BOX 13.2. Revised European- or systemic immunotherapy may be more appropri- American Classification of Lymphoid ate. In some patients, combining systemic chemother- Neoplasms (REAL) apy with local radiation treatment is warranted.11,23 The therapeutic approach chosen for each patient varies Indolent Lymphomas according to the stage and histologic classification of Follicular lymphoma lymphoma in addition to other comorbid risk factors. B-chronic lymphocytic leukemia/small lymphocytic lymphoma Radiotherapy Lymphoplasmacytic lymphoma Marginal zone lymphoma (nodal, extranodal, Lymphomas are markedly radiosensitive. Primary ra- splenic) diotherapy for stage I indolent orbital lymphoma can T-cell/natural killer large cell granular achieve local control in more than 90% of patients, but the rate of distant relapse may be as high as 40% with lymphocyte leukemia 21,22 T-chronic lymphocytic leukemia/ external beam radiotherapy alone. The median to- prolymphocytic leukemia tal dose of radiation used in external beam radiother- apy for non-Hodgkin’s lymphoma of the orbit is 40 Gy Aggressive Lymphomas (range 20–50 Gy).22 Low-grade lesions are usually Mantle cell lymphoma treated with a 30 Gy dose; intermediate-grade lym- Diffuse large B-cell lymphoma phomas may be more appropriately treated with higher Peripheral T-cell lymphoma (unspecified) doses (Յ40 Gy). Distant relapse rates have been ob- Peripheral T-cell lymphoma (angioimmuno- served in 20 to 25% of patients with low-grade lym- blastic, angiocentric) phoma and 40 to 60% for higher grade lymphomas.21,24 T-cell/natural killer cell, hepatosplenic, Field arrangement varies according to tumor loca- intestinal T-cell lymphoma tion. Most studies of radiotherapy for primary orbital Anaplastic large cell lymphoma lymphoma have reported minimal acute ocular tox- icity, but long-term follow-up can demonstrate com- Highly Aggressive Lymphomas mon ocular side effects of , ocular Precursor T or B lymphoblastic leukemia/ surface irritation, and, occasionally, .24–28 To- lymphoma tal dose and length of time between fractions markedly Burkitt’s and Burkitt’s-like lymphoma influence the degree of ocular toxicity. A regimen of Adult T-cell leukemia/lymphoma daily radiation fractions less than 2.25 Gy reduces ra- diation-induced morbidity. A cumulative dose of 16.5 27 Source: Data from Harris NL, Jaffe ES, Stein H, et al. A revised European– Gy or higher is likely to lead to opacities. Ade- American classification of lymphoid neoplasms: a proposal from the Inter- quate shielding can decrease the risk of for- national Lymphoma Study Group. Blood 1994;84:1361–1392. mation and the amount of radiation delivery to the

It appears to be sensitive for detecting extranodal sites of involvement, including bone marrow.20 BOX 13.3. Recommended Staging The Ann Arbor Staging System is most commonly Workup for Orbital Lymphoma used to designate a stage for lymphomas and is sum- marized in Table 13.2. Thorough history and physical examination Dilated eye examination Complete blood count and biochemistry profile MANAGEMENT Liver function tests Chest radiography Most published reports advocate the use of external Computed tomography or magnetic resonance beam radiotherapy or systemic chemotherapy for imaging of orbit the treatment of primary orbital lymphomas.7,8,21,22 Computed tomography of abdomen, thorax, and While external beam radiotherapy may be successful pelvis in controlling local orbital disease in the majority of Bone marrow aspiration patients with low-grade indolent orbital lymphoma, Open or fine-needle biopsy of orbital mass the risk of distant relapse is not insignificant with ra- Upper endoscopy and barium studies diotherapy alone. For more aggressive histologic sub- Total body positron emission tomography types of orbital lymphoma for which widespread sys- CHAPTER 13: ORBITAL LYMPHOMA 137 therapy is carried out with alkylating agents such as cy- clophosphamide. For intermediate- to high-grade lym- phomas, initial combination chemotherapy is usually with a doxorubicin-containing regimen such as cy- clophosphamide, doxorubicin, vincristine, and pred- nisone (CHOP) or cyclophosphamide, vincristine, dox- orubicin, and dexamethasone (CVAD). The most common life-threatening toxic effect from chemo- therapy is myelosuppression, resulting in anemia, in- fection, and abnormal bleeding. Congestive heart fail- ure secondary to decreased left ventricular function is another significant toxicity of these regimens. Combined chemotherapy and A may be an appropriate option for intermediate- to high-grade lymphomas.23 The rationale for combined modality therapy originates from observations that systemic extranodal sites of relapse are common fol- lowing radiation therapy alone. Single-institution and cooperative group series, in which chemotherapy was combined with radiotherapy, have reported 5-year rates of relapse-free survival of 94 to 100% for stage I lym- phomas and 72 to 78% for stage II disease.23,30,31 Fur- thermore, overall life-threatening toxicity and cardiac toxicity are significantly lower in patients receiving combined chemotherapy and radiation because fewer cycles of chemotherapy may be required.23 Aggressive chemotherapy induction regimens fol- B lowed by stem cell transplantation have been investi- FIGURE 13.4. Magnetic resonance images in a patient with large- gated at the M. D. Anderson Cancer Center.32 Hyper- cell lymphoma demonstrate multiple intraorbital masses infiltrating CVAD, with escalated doses of cyclophosphamide, the lacrimal gland and the . (A) Axial noncon- trast T1-weighted image. (B) Coronal fat-suppressed, contrast-en- high-dose methotrexate, and cytarabine followed by hanced T1-weighted image. autologous or allogenic stem cell transplantation, can result in improved rates of remission for the more ag- gressive lymphomas. corneal surface. Despite shielding, tear film insuffi- Immunotherapy and Radioimmunotherapy for ciency and subsequent dry eye syndrome frequently Low-Grade Indolent NHL of the Orbit occur after radiation therapy for orbital lymphoma. Significant radiation vasculopathy of the and Although external beam radiotherapy is effective at optic nerve does not usually occur with the usual to- controlling orbital lymphomas, it is associated with tal dose used for orbital lymphoma (Ͻ 50 Gy).28 the risk of distant relapse and ocular toxicity. Sys- Newer approaches in radiation delivery could im- temic chemotherapy is an effective treatment for prove the treatment of orbital tumors in the future. Intensity-modulated conformal therapy, which prom- ises isodose delivery to tumors while sparing the un- TABLE 13.2. Ann Arbor Staging System for Lymphoma. involved neighboring structures, may minimize the ocular toxicity due to radiotherapy.29 Stage Description I* Involvement of a single lymph node region or lymphoid structure (e.g. spleen or Waldeyer ring) Systemic Chemotherapy or II* Involvement of two or more lymph node regions on same side of the diaphragm or localized involvement Combined Modality Therapy of an extranodal lymphoid structure and of one or more lymph node region on same side of Chemotherapy is usually indicated for the more ag- diaphragm gressive histologic subtypes of orbital lymphoma with III Involvement of lymph nodes on both sides of potential for future systemic involvement or with ex- diaphragm Ϯ extranodal sites IV Involvement of two or more extranodal sites or liver isting disseminated disease. or bone marrow Indolent lymphomas are very sensitive to both sin- aInvolvement of an extranodal organ or site is designated with the suffix E gle-agent and combination chemotherapy. Single-agent (stage IE or stage IIE). 138 PART THREE: PRIMARY TUMORS OF THE ORBIT higher grade or more advanced stages of lymphoma, Rituximab is well-tolerated and does not deplete but in the elderly patient the presence of comorbid marrow reserves. Most side effects are mild and infu- disease may mitigate against intensive chemotherapy sion related, usually occurring with the first infusion. approaches. Thus, new and alternative treatment op- The common reported side effects include transient tions for orbital lymphoma may be desirable. chills, fever, nausea, fatigue, headache, and pruritis; Recent reports have suggested that monoclonal an- less frequently there can be bronchospasm, hypoten- tibody therapy may be effective in the treatment of sion, rash, or anaphylaxis. low-grade NHLs.33–35 Investigators have characterized Radioimmunotherapy refers to administration of a the patterns of expression of surface antigens on B cells monoclonal antibody in combination with a radioac- and have developed targeted therapy with monoclonal tive ligand. Beta particles emitted by commonly used antibodies directed against several of these antigens. radioisotopes are tumoricidal over a distance of many One of these surface antigens is CD20, which is a hy- cell diameters, allowing eradication of antigen-nega- drophobic phosphoprotein that is expressed on mature tive tumor cells by radioactive cross fire from neigh- B cells and most B-cell malignancies but not on stem boring antigen-positive antibody-coated cells. This ad- cells, pre-B cells, or plasma cells. Rituximab (Rituxan) ditional mechanism for tumor lysis leads to a more is a genetically engineered chimeric mouse/human an- dramatic treatment effect than the nonradioactive tibody discovered in 1990 by IDEC Pharmaceuticals; antibody. it binds with high affinity to cells expressing the CD20 IDEC-Y2B8 (Zevalin) is a murine IgG1 ␬ mono- antigen and causes tumor lysis via both complement- clonal antibody directed against the CD20 antigen dependent and antibody-dependent cellular cytotoxic- that is conjugated to MX-DTPA and bound to the beta- ity.36 It also can sensitize chemoresistant human lym- emitting radioisotope yttrium-90.37 Zevalin is usually phoma cell lines and induce apoptosis in vitro. given as a single dose following an infusion of ritux- Rituximab was approved by the U.S. Food and Drug imab. Radioimmunothearpy with Zevalin in combi- Administration in 1997 for the indication of relapsed nation with rituximab has shown greater efficacy for or refractory CD20-positive B-cell low-grade or follic- treatment of low-grade lymphoma than rituximab ular NHL. It is the first monoclonal antibody approved alone. Dosimetry has shown that at doses of up to 0.4 for the treatment of cancer and the first single agent mCi/kg, no normal organ, including red marrow, re- approved specifically for therapy of lymphoma. It is ceived a radiation dose greater than 14 Gy.38 administered as an intravenous infusion at a dose of The experience at M. D. Anderson for treating low- 375 mg/m2 once weekly for 4 consecutive weeks. Out- grade lymphomas of the orbit with rituximab therapy patient therapy is feasible and is completed within 22 alone or in combination with Zevalin, its radioactive- days (treatment on days 1, 8, 15, and 22). The overall liganded counterpart, has been positive.12 Three pa- response rate to rituximab is 48% for relapsed low- tients with low-grade lymphoma of the orbit were grade lymphomas. The response rate is somewhat treated with four weekly doses of rituximab; two ad- higher for follicular lymphomas (58%).33–36 ditional patients were treated with one dose of ritux-

A B FIGURE 13.5. Computed tomography scans of the orbit in a pa- the inferior left orbit (arrows). (B) Two months after administration tient with low-grade follicular lymphoma of the left lacrimal gland. of rituximab and yttrium-90-labeled ibritumomab tiuxetan, the or- (A) Before monoclonal antibody treatment, a mass was visible in bital mass had shrunk considerably. CHAPTER 13: ORBITAL LYMPHOMA 139 imab followed by Zevalin. All five patients achieved tics of orbital lymphoid hyperplasia. Symp Orbital Dis complete resolution of their orbital lymphoma in re- 1979;86:948–966. 16. Freedman AS, Nadler LM. Non-Hodgkin’s lymphomas. In: Bast sponse to monocloncal antibody therapy (Figure RC, Kufe DW, Pollock RE, et al, eds. Cancer Medicine. 5th ed. 13.5). The potential benefits of radioimmunotherapy New York: BC Decker; 2000: Sec 36, Ch 130. include fewer side effects than accompany external 17. Harris NL, Jaffe ES, Stein H, et al. A revised European–Amer- beam radiation therapy and systemic chemotherapy, ican classification of lymphoid neoplasms: a proposal from the repeatability in case of recurrence, and a shorter du- International Lymphoma Study Group. Blood 1994;84:1361– 1392. ration of therapy than is possible with both the other 18. Armitage JO, Weisenburger DD. New approach to classifying two modalities. If in larger studies monoclonal non-Hodgkin’s lymphomas: clinical features of the major his- antibody treatment proves to be as effective as ex- tologic subtypes. J Clin Oncol 1998;16:2780–2795. ternal beam radiotherapy or chemotherapy for the 19. Bennett CL, Putterman A, Bitran JD, et al. Staging and ther- treatment of indolent lymphomas of the orbit, it apy of orbital lymphomas. Cancer 1986;57:1204–1208. 20. Carr R, Barrington S, Madan B, et al. Detection of lymphoma may indeed be an exciting alternative therapy for or- in bone marrow by whole-body positron emission tomography. bital lymphomas. Blood 1998;91:3340–3346. 21. Smitt MC, Donaldson SS. Radiotherapy is successful treatment References for orbital lymphoma. Int J Radiat Oncol Biol Phys 1993;26: 59–66. 1. Jakobiec FA, Font RL. Orbit: lymphoid tumors. In: Spencer 22. Esik O, Ikeda H, Mukai K, Kaneko A. A retrospective analy- WH, Font RL, Green WR, et al, eds. Ophthalmic Pathology: sis of different modalities for treatment of primary orbital non- An Atlas and Textbook. Vol. 3. 3rd ed. Philadelphia: WB Saun- Hodgkin’s lymphomas. Radiother Oncol 1996;38:13–18. ders; 1986:2663–2711. 23. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone 2. Ellis JH, Banks PM, Campbell RJ, Liesegang TJ. Lymphoid tu- compared with chemotherapy plus radiotherapy for localized mors of the ocular adnexa: clinical correlation with the work- intermediate- and high-grade non-Hodgkin’s lymphoma. ing formulation classification and immunoperoxidase staining N Engl J Med 1998;339:21–26. of paraffin sections. Ophthalmology 1985;92:1311–1324. 24. Bessell EM, Henk JM, Wright JE, et al. Orbital and conjuncti- 3. Hornblass A, Jakobiec FA, Reifler DM, et al. Orbital lymphoid val lymphoma treatment and prognosis. Radiother Oncol tumors located predominantly within extraocular muscles. 1988;13:237–244. Ophthalmology 1987;94:688–697. 25. Minehan KJ, Martenson JA, Garrity JA, et al. Local control and 4. Nikaido H, Mishima HK, Kiuchi Y, et al. Primary orbital ma- complications after radiation therapy for primary orbital lym- lignant lymphoma: a clinicopathology study of 17 cases. Graefes phoma: a case for low-dose treatment. Int J Radiat Oncol Biol Arch Clin Exp Ophthalmol 1991;229:206–209. Phys 1991;20:791–796. 5. Bairey O, Kremer I, Rokowsky E, et al. Orbital and adnexal in- 26. Bolek TW, Moyses HM, Marcus RB, et al. Radiotherapy in the volvement in systemic non-Hodgkin’s lymphoma. Cancer management of orbital lymphoma. Int J Radiat Oncol Biol 1994;73:2395–2399. Phys 1999;44:31–36. 6. Esmaeli B, Ahmadi MA, Manning J, et al. Clinical presenta- 27. Henk JM, Whitelocke RAF, Warrington AP, et al. Radiation tion and treatment of secondary orbital lymphoma. Oph- dose to the lens and cataract formation. Int J Radiat Oncol thalmic Plast Reconstr Surg 2002;18:247–253. Biol Phys 1993;25:815–820. 7. Mirabell R, Cella L, Weber D, et al. Optimizing radiotherapy 28. Stafford SL, Kozelsky TF, Garrity JA, et al. Orbital lymphoma: of orbital and paraorbital tumors: intensity-modulated x-ray radiotherapy outcome and complications. Radiother Oncol beams vs. intensity-modulated proton beams. Int J Radiat On- 2001;59:139–144. col Biol Phys 2000;47:1111–1119. 29. Dearnaly DF, Khoo VS, Norman AR, et al. Comparison of ra- 8. Letschert JG, Gonzalez DG, Koorneef L, et al. Results of ra- diation side-effects of conformal and conventional radiother- diotherapy in patients with stage I orbital non-Hodgkin’s lym- apy in prostate cancer: a randomized trial. Lancet 1999;353: phoma. Radiother Oncol 1991;22:36–44. 267–272. 9. Gordon LI, Harrington D, Anderson J, et al. Comparison of a 30. Cabanillas F, Rodriguez-Diaz PJ, Hagemeister FB, et al. Alter- second-generation combination chemotherapeutic regimen nating triple therapy for the treatment of intermediate grade with a standard regimen (CHOP) for advanced diffuse non- and immunoblastic lymphoma. Ann Oncol 1998;9:511–518. Hodgkin’s lymphoma. N Engl J Med 1992;327:1342. 31. Longo DL, Glatstein E, Duffey PL, et al. Treatment of local- 10. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a stan- ized aggressive lymphomas with combination chemotherapy dard regimen (CHOP) with three intensive chemotherapy reg- followed by involved-field radiation therapy. J Clin Oncol imens for advanced non-Hodgkin’s lymphoma. N Engl J Med 1989;7:1295–1302. 1993;328:1002. 32. Khouri I, Romaguera J, Kantarjian H, et al. Hyper-CVAD and 11. Hagemeister FB, McLaughlin P, Swan F, et al. Prognostic fac- high-dose methotrexate/cytarabine followed by stem-cell trans- tors and long-term results with CHOP-bleo and radiotherapy. plantation: an active regimen for aggressive mantle-cell lym- Blood 1991;77:942. phoma. J Clin Oncol 1998;16:3803–3809. 12. Esmaeli B, Murray JL, Ahmadi MA, et al. Immunotherapy for 33. McLaughlin P, Grillo-Lopez AJ, Liink BK, et al. Rituximab chi- low-grade non-Hodgkin’s secondary lymphoma of the orbit. meric anti-CD20 monoclonal antibody therapy for relapsed in- Arch Ophthalmol 2002;120:1225–1227. dolent lymphoma: half of patients respond to a four-dose treat- 13. Syed NA, Albert DM. Surgical pathology of ophthalmic plas- ment program. J Clin Oncol 1998;16:2825–2833. tic surgery. In: Albert DM, ed. Ophthalmic Surgery: Principles 34. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 and Techniques. Edinburgh: Blackwell Science; 1999:1648– (rituximab) anti-CD20 monoclonal antibody therapy in pa- 1658. tients with relapsed low-grade non-Hodgkin’s lymphoma. 14. Rosai J. In: Rosai J, ed. Ackerman’s Surgical Pathology. 8th ed. Blood 1997;90:2188–2195. St Louis: CV Mosby; 1996:1–12, 29–62. 35. Maloney D, Smith B, Appelbaum F. The anti-tumor effect of 15. Jakobiec FA, McLean I, Font R. Clinicopathologic characteris- monoclonal anti-CD20 antibody (Mab) therapy includes direct 140 PART THREE: PRIMARY TUMORS OF THE ORBIT

antiproliferative activity and induction of apoptosis in CD20 CD20 monoclonal antibody therapy of recurrent B-cell lym- positive non-Hodgkin’s lymphoma cell lines. Blood 1996; phoma. Clin Cancer Res 1996;2:457–470. 88(suppl):637. 38. Wiseman GA, White CA, Stabin M, et al. Phase I/II 90Y-Zev- 36. Leget GA, Czuczman MS. Use of rituximab, the new FDA-ap- valin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) ra- proved antibody. Curr Opin Oncol 1998;10:548–551. dioimmunotherapy dosimetry results in relapsed or refractory 37. Knox SJ, Goris ML, Trisler K, et al. Yttrium-90-labeled anti- non-Hodgkin’s lymphoma. Eur J Nucl Med 2000;27:766–777.