Ocular Adnexal Lymphoma: Assessment of a Tumor-Node-Metastasis Staging System Mary E. Aronow, MD,1 Craig A. Portell, MD,2 Lisa A. Rybicki, MS,3 John W. Sweetenham, MD,2 Arun D. Singh, MD1 Purpose: To assess distribution, correlations, and prognostic effect of tumor (T), node (N), and metastasis (M) staging on relapse and survival. Design: Retrospective clinical review. Participants: Sixty-three patients diagnosed with primary ocular adnexal lymphoma (OAL) between January 1986 and November 2011. Methods: Complete ocular examination and systemic evaluation were performed. Patients were staged according to the American Joint Committee on Cancer (AJCC) seventh edition tumor-node-metastasis (TNM) clinical staging system for OAL and followed every 6 to 12 months (median follow-up, 27.9 months). Main Outcome Measures: Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral ocular adnexal structures, or other systemic site and overall survival. Results: There were 40 men (63.5%). The median age was 65 years (range, 24e85 years). The affected site was the conjunctiva in 27 patients (42.9%), orbit in 38 patients (60.3%), and eyelid in 3 patients (4.8%). The histologic subtype was extranodal marginal zone lymphoma (EMZL) in 51 patients (81.0%). A total of 14 patients (23.3%) had T1, 42 patients (70.0%) had T2, 1 patient (1.7%) had T3, and 3 patients (5.0%) had T4 disease. A total of 48 patients (82.8%) had N0 disease, and 10 patients (17.2%) had N1-4 disease. M stage was M0 in 47 patients (81.0%) and M1 in 11 patients (19.0%). With advanced T stage, there was an increase in both N1-4 (P ¼ 0.045) and M1 disease (P ¼ 0.041). M1 disease was greater among patients with N1-4 disease compared with N0 stage (50.0% vs. 12.5%, P ¼ 0.003). Overall, 18 patients (28.6%) relapsed and 6 patients (9.5%) died. In Cox analysis, relapse was not associated with T stage (hazard ratio [HR], 1.14 per 1 level increase, P ¼ 0.71), N stage (HR, 1.47; P ¼ 0.51 N1-4 vs. N0), or M stage (HR, 1.22; P ¼ 0.76 M1 vs. M0). T stage was not associated with survival (HR, 0.86; P ¼ 0.81), whereas N1-4 had marginally worse survival than N0 (HR, 5.35; P ¼ 0.07), and M1 had worse survival than M0 (HR, 9.27; P ¼ 0.008). Conclusions: The TNM staging system for primary OAL is useful for precise characterization of extent of local disease. Although T stage does not predict relapse or survival, N1-4 and M1 stages indicated less favorable survival. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:1915-1919 ª 2013 by the American Academy of Ophthalmology.
Ocular adnexal lymphoma (OAL) encompasses a heterogeneous group of lymphomas, the majority of which are lowgrade, B-cell, noneHodgkin lymphomas. The majority, approximately 80%, are of the extranodal marginal zone lymphoma (EMZL) histologic subtype.1 Ocular adnexal lymphoma can present as a single, localized tumor or it can be multifocal. It may affect unilateral or bilateral ocular adnexal structures. Disseminated disease involving regional, central, and peripheral lymph nodes, as well as other distant extranodal sites, also is observed. The 10-year, diseasespecific mortality is approximately 5% to 10%.2 The Ann Arbor staging system currently is widely used for malignant lymphoma; however, this system has several deficiencies for characterizing OAL because it results in a disproportionate staging distribution. Two-thirds of primary OAL cases present as a localized mass, which under the Ann Arbor system are classified as stage 1E.3e9 This precludes the ability to differentiate the majority of OAL cases from one another on the basis of disease extent within 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
the ocular adnexal structures, which may have important prognostic implications.10,11 More recently, a tumor-node-metastasis (TNM)ebased staging system for primary OAL has been developed under the guidance of the American Joint Committee on Cancer.12,13 This staging system addresses many of the shortcomings of the Ann Arbor system and more precisely defines disease extent. The ultimate goal of the proposed TNM-based system is to facilitate future studies aimed at identifying clinical and histomorphologic features of OAL of prognostic significance, and to assess treatment outcomes. To date, the feasibility of this system has been analyzed in only a limited capacity, comparing patients with EMZL affecting the conjunctiva alone with patients with disease extending to the orbit, eyelid, or adjacent structures.14 Moreover, OAL can be a multifocal disease, and involvement of lymph nodes and distant systemic disease need not reflect metastatic spread from the primary site. Therefore, it is possible that correlations between ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.02.003
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Ophthalmology Volume 120, Number 9, September 2013 advanced T stage with N and M stage may merely reflect the natural evolution of multifocal disease. The purpose of the present study was to describe the distribution of T, N, and M staging within a clinical cohort of individuals with primary OAL. In addition, correlation among T, N, and M stage was assessed to determine whether advancing T stage had an impact on N and M designation and similarly whether higher N stage affected M designation. The prognostic effect of T, N, and M stage on relapse and survival was also evaluated.
Methods Patients A total of 82 patients were diagnosed with OAL at the Cleveland Clinic between January 1986 and November 2011. Of these, 63 patients had no history of systemic lymphoma at the time of diagnosis and were therefore included in the present study of TNM-based clinical staging for primary OAL. This study was approved by the Cleveland Clinic and Case Comprehensive Cancer Center Institutional Review Boards. All research adhered to the tenets of the Declaration of Helsinki. In all cases, the diagnosis of OAL was confirmed by tissue biopsy performed at our institution or reviewed by a Cleveland Clinic staff pathologist when biopsy was performed elsewhere. The lymphoma histologic subtype also was identified on the basis of histomorphology, immunohistochemistry, or genotyping. Data were collected regarding patient age at diagnosis, gender, date of diagnosis, and extent of OAL involvement (affected ocular adnexal structures and laterality). This was accomplished by complete ophthalmic examination, including measurement of visual acuity, intraocular pressure, pupillary reflex testing, external inspection for regional lymph node involvement, exophthalmometry, ocular motility testing, slit-lamp examination, and dilated fundus examination. Bscan ultrasonography was performed in addition to neuroimaging (computed tomography [CT] or magnetic resonance imaging of the orbits) to identify occult orbital involvement. To screen for systemic lymphoma at the time of diagnosis, all patients were referred to an experienced medical oncologist at the Cleveland Clinic Taussig Cancer Institute for initial staging studies, which included a history, physical examination, and imaging with CT scan of the chest, abdomen, and pelvis. Blood work including a complete blood count and complete metabolic panel was performed in all cases. Additional hematologic studies and ancillary testing (e.g., bone marrow biopsy) were performed at the discretion of the treating oncologist.
TNM Staging of Ocular Adnexal Lymphoma TNM-based clinical staging was determined for each patient at the time of diagnosis according to the criteria outlined in the recently proposed American Joint Committee on Cancer seventh edition staging manual for OAL. This staging algorithm has been described in detail (Table 1; available at http://aaojournal.org).12,13 Briefly, the T stage defines the extent of lymphoma involvement of the ocular adnexal structures. Stage T1 disease characterizes conjunctival lymphoma, whereas T2 defines any OAL involving the orbit whether or not the conjunctiva is affected. Stage T3 implies involvement of the preseptal eyelid tissues (e.g., dermis, orbicularis, or eyelid skin) in addition to any conjunctival or orbital disease. Stage T4 describes lymphomatous invasion of the bony and soft-tissue structures external to the ocular adnexa, such as the periosteum, bone, nasopharynx, sinuses, and intracranial space. The N stage describes lymph node involvement in OAL. Regional lymph nodes of the
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ocular adnexa include the submandibular, preauricular, and cervical nodes. Distant lymph nodes include the central nodes located in the trunk and peripheral nodes at distant sites not draining the ocular adnexa. The N stage indicates whether the involved lymph node is regional (ipsilateral: N1, contralateral or bilateral: N2), peripheral (N3), or central (N4). Stage M describes the extent of extranodal sites and bone marrow infiltration. Patients were followed in an ophthalmic oncology clinic and by their medical oncologist every 6 to 12 months until the end of the study period in March 2012 (median follow-up 27.9 months). In addition to clinical examination, systemic surveillance with the previously mentioned imaging studies was performed to monitor for disease relapse and survival. Relapse was defined as lymphoma recurrence in the initial site of presentation, the contralateral ocular adnexal structures, or other systemic site. Survival was defined as overall survival. During the study period, 6 patients died. Of these deaths, 4 were lymphoma related.
Statistical Analysis The CochraneArmitage trend test was used to assess correlations among T, N, and M staging. This statistical test determined whether patients with more advanced T stage resulted in an increase in N or M stage, or if increasing N stage correlated with advanced M stage. Cox proportional hazards analysis was used to assess the prognostic effect of T, N, and M stage with relapse and survival. Results are presented as the hazard ratio (HR), 95% confidence interval (CI) for the HR, and the corresponding P value. Because of the small number of events for each outcome, T classification was analyzed as an ordinal variable rather than categorizing it into groups. KaplaneMeier analysis also was used to assess relapse and survival outcomes compared by T stage (T1 vs. T2 vs. T3-4), N stage (N0 vs. N1-4), and M stage (M0 vs. M1?). The log-rank test was used to determine the statistical significance of differences in relapse and survival outcomes.
Results A total of 63 patients with primary OAL were identified between January 1986 and November 2011. There were 40 men (63.5%) and 23 women (36.5%). The median age was 65 years (range, 24e85 years). Conjunctival involvement was present in 27 patients (42.9%), orbital disease was present in 38 patients (60.3%), eyelid disease was present in 3 patients (4.8%), and uveal infiltration was present in 10 patients (15.9%). The right ocular adnexal structures were involved in 20 patients (31.7%), the left ocular adnexal structures were involved in 25 patients (39.7%), and bilateral disease was observed in 18 patients (28.6%). The majority, 51 patients (81.0%), had extranodal marginal zone lymphoma (EMZL). Other histologic subtypes included follicular lymphoma in 3 patients (4.8%), diffuse large B-cell lymphoma in 3 patients (4.8%), mantle cell lymphoma in 1 patient (1.6%), or other not specified subtypes in 5 patients (7.9%) (Table 2; available at http:// aaojournal.org).
Distribution of T, N, and M Staging The T stage could be assessed in a total of 60 patients. In the remaining 3 cases, orbital imaging was not performed, and therefore the T stage could not be accurately defined. The majority, 42 patients (70.0%), had T2 disease. Advanced T stage was uncommon. In our cohort, there was 1 patient (1.7%) in the T3 stage and 3 patients (5.0%) with T4 disease. The N stage could be determined in 58 patients. Most patients (48 [82.8%]), had N0 disease. N1-4 stages were observed in 10 patients (17.2%). The
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Table 3. Distribution of T, N, and M Staging and Ann Arbor Staging TNM Ntotal T classification T1 T2 T3 T4 N classification N0 N1e4 M classification M0 M1
Ann Arbor* (N) N 14 42 1 3 48 10 47 11
(%) 60 23.3 70.0 1.7 5.0 58 82.8 17.2 58 81.0 19.0
I
II
III
IV
(% IE)
14 29 1 0
0 3 0 2
0 2 0 0
0 8 0 1
100.0 69.0 100.0 0.0
40 1
2 2
0 3
6 4
83.3 10.0
41 0
5 0
1 1
0 10
87.2 0.0
IE ¼ Stage I, extranodal lymphoma; TNM ¼ tumor-node-metastasis. *For Ann Arbor staging, all patients could be classified as stage I, II, III, or IV. Stage I denotes OAL in a localized region. Stage II indicates that the lymphoma is present in 2 separate regions, an affected lymph node or organ and a second affected area, and that both affected areas are confined to above or below the diaphragm. Stage III includes lymphomas that have spread to both sides of the diaphragm (including 1 organ or area near the lymph nodes or the spleen). Stage IV indicates disseminated involvement of extralymphatic organs and includes lymphoma with liver, bone marrow, or nodular pulmonary disease.
M stage could be identified in 58 patients and was M0 in 47 (81.0%) and M1 in 11 (19.0%) (Table 3). When the Ann Arbor staging system was applied to this cohort, the majority of patients were classified as stage 1E. In fact, of patients with T1-3 disease (n¼57), 77.2% were grouped as Ann Arbor stage IE. Of those with N0 disease (n¼48), 40 (83.3%) were stage IE, and of those with M0 disease (n¼47), 41 (87.2%) were stage IE.
Correlations among T, N, and M Staging With advancing T stage, there was an increasing percentage of both N1-4 (0.0% for T1, 21.1% for T2, and 25.5% for T3-T4, P ¼ 0.045) and M1 disease (0.0% for T1, 23.7% for T2, and 25.0% for T3-T4, P ¼ 0.041). In addition, the percentage of patients with M1 disease was greater among patients with N1-4 disease compared with N0 stage lymphoma (50.0% vs. 12.5%, P ¼ 0.003) (Table 4).
Prognostic Effect of T, N, and M Stage on Relapse and Survival Overall, 18 patients (28.6%) relapsed and 6 patients (9.5%) died after a median follow-up of 27.9 months. Of the 6 deaths, 4 were lymphoma related. Cox proportional hazards analysis indicated that relapse was not associated with T stage (HR, 1.14 per 1 level increase; P ¼ 0.71), N1-4 disease (HR, 1.47; P ¼ 0.51), or M1
T classification T1 T2 T3-T4 N classification N0 N1-4
P Value M1/Total
%
0/13 8/38 1/4
0.0 21.1 25.0
0.045
— —
—
— —
Discussion A TNM-based clinical staging system for OAL has the potential to allow for a more standardized and accurate assessment of disease extent in comparison with previously used staging systems. Although conceptually appealing, such a staging system has only been validated in limited capacity in a small cohort of patients with EMZL histology.14 In the present study, several practical considerations of applying a TNM-based staging system were identified. In our series, there was a disproportionate distribution of T2 disease. There were a total of 42 patients (70.0%) with T2 stage in comparison with T1 or T3-T4echaracterized OAL. In our cohort, T3 or T4 designation was rare and observed in only 4 patients (6.7%). The T-stage designation was not found to be statistically correlated with relapse or survival; however, the small number of cases of disease with advanced T stage may limit conclusions in this regard. In contrast, higher orders of both N and M staging were useful in predicting decreased survival. This finding underscores the importance of thorough systemic evaluation by an experienced medical oncologist at the time of initial diagnosis and continued surveillance with systemic imaging studies in patients with OAL with an emphasis on assessment of N and M staging. Uveal involvement was observed in 10 cases (15.9%) in the present series. Infiltration of the uvea in these individuals was present in addition to other overlapping ocular adnexal structures (conjunctiva, orbit, and eyelid). At present, coexisting uveal involvement in association with OAL is not a widely recognized pattern; however, the clinical findings can be subtle and therefore easily overlooked. There are important implications where staging (laterality), treatment, and prognosis are concerned. For example, a patient with unilateral conjunctival involvement and bilateral uveal infiltration would be classified as T1 under the currently proposed TNM staging system. Treatment of unilateral conjunctival disease will not address bilateral uveal involvement and may lead to higher rates of relapse in the contralateral eye. Although OAL by definition involves the ocular adnexal structures, the observation that Table 5. T, N, and M Stage versus Relapse and Survival: Cox Proportional Hazards Analysis Relapse Variable
Table 4. Correlations Among T, N, and M Staging N1-4/Total
disease (HR, 1.22; P ¼ 0.76) (Table 5; Fig 1). T stage was not prognostic for survival (HR, 0.86; P ¼ 0.81). N1-4 disease was marginally prognostic for worse survival (HR, 5.35; P ¼ 0.07). M1 disease was statistically significant for worse survival (HR, 9.27; P ¼ 0.008) (Table 5; Fig 2).
%
P Value
0/13 9/38 1/4
0.0 23.7 25.0
0.041
6/48 5/10
12.5 50.0
0.003
HR
95% CI
T classification Per 1-level 1.14 0.58e2.22 increase N classification N1-4/N0 1.47 0.47e4.57 M classification M1/M0 1.22 0.33e4.46
Survival P Value
HR
95% CI
P Value
0.71
0.86 0.26e2.89
0.81
0.51
5.35 0.86e33.32
0.07
0.76
9.27 1.79e47.93
0.008
CI ¼ confidence interval; HR ¼ hazard ratio.
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Figure 1. KaplaneMeier analysis of relapse by TNM stage: T (A), N (B), and M (C).
Figure 2. KaplaneMeier Analysis of survival by TNM stage: T (A), N (B), and M (C).
coexisting uveal infiltration is present in a significant proportion of cases is an important finding, and staging systems should be modified to address this.15 Orbital involvement occurs along a spectrum and may be readily apparent on clinical examination, for example, due to proptosis or reduced extraocular motility. However, occult orbital disease can be detected only with neuroimaging, by CT scan or magnetic resonance imaging.
B-scan ultrasonography is often more sensitive in identifying smaller extrascleral lesions than either of the aforementioned neuroimaging modalities. Relapse (local or distant) and survival are 2 important outcomes that concern both the patient and treating physician. With the use of the proposed TNM staging system, factors influencing relapse of OAL could not be identified. This may be due to several reasons: The current study may have been
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underpowered; patients with advanced T, N, or M staging may have been treated more aggressively; or TNM staging may not be truly predictive of relapse. Another important aspect of staging not addressed in the currently proposed TNM-based clinical staging system for OAL is the impact of histologic subtype on outcomes such as relapse and survival. The majority of OALs are of the lowgrade EMZL subtype. This was true in our series as well, with 51 patients (81.0%) demonstrating EMZL histologic subtype. It would be expected that low-grade, indolent lymphomas would portend a more favorable prognosis in comparison with their aggressive histologic counterparts irrespective of TNM stage. In the future, this aspect could be incorporated into the TNM-based clinical staging system and would then need to be validated in a larger series of patients. By definition, TNM-based cancer staging systems characterize the tumor extent, lymph node involvement, and metastatic spread of malignancies. On the basis of this information and known outcomes in large population studies, patients are then grouped into successively advanced stages based on T, N, and M designation. This staging is then useful for guiding management and predicting outcomes. Although treatment approach for OAL is not yet based on TNM-based staging, this should be a goal because the currently proposed system is validated using large clinical cohorts. A TNMbased staging system for OAL theoretically has a distinct advantage over the Ann Arbor system in that it allows for more precise characterization of local disease extent. This in turn provides greater staging distribution that may be useful for identifying prognostic factors, guiding treatment selection, and assessing newer therapies in the future. In conclusion, the present series identifies several practical aspects of a TNM-based clinical staging system for OAL. In particular, advancing N and M are correlated with poorer survival outcomes. Our series also identified limitations of the TNM system as it is currently proposed. Our findings of TNM-based clinical staging in OAL should be validated in a larger series.
References 1. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29:252–60.
2. Coupland SE, Hellmich M, Auw-Haedrich C, et al. Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases. Graefes Arch Clin Exp Ophthalmol 2004;242:130–45. 3. Coupland SE, Krause L, Delecluse HJ, et al. Lymphoproliferative lesions of the ocular adnexa: analysis of 112 cases. Ophthalmology 1998;105:1430–41. 4. Jenkins C, Rose GE, Bunce C, et al. Histological features of ocular adnexal lymphoma (REAL classification) and their association with patient morbidity and survival. Br J Ophthalmol 2000;84:907–13. 5. Decaudin D, de Cremoux P, Vincent-Salomon A, et al. Ocular adnexal lymphoma: a review of clinicopathologic features and treatment options. Blood 2006;108:1451–60. 6. Gardiner JA, White VA, Gascoyne RD, Rootman J. Histopathologic, immunophenotypic and genotypic analyses in ocular adnexal lymphoproliferative disorders. Aust N Z J Ophthalmol 1992;20:247–51. 7. Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol 2007;31:170–84. 8. Hatef E, Roberts D, McLaughlin P, et al. Prevalence and nature of systemic involvement and stage at initial examination in patients with orbital and ocular adnexal lymphoma. Arch Ophthalmol 2007;125:1663–67. 9. Plaisier MB, Sie-Go DM, Berendschot TT, et al. Ocular adnexal lymphoma classified using the WHO classification: not only histology and stage, but also gender is a predictor of outcome. Orbit 2007;26:83–8. 10. Knowles DM, Jakobiec FA, McNally L, Burke JS. 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 1990;21:959–73. 11. Johnson TE, Tse DT, Byrne GE Jr, et al. Ocular-adnexal lymphoid tumors: a clinicopathologic and molecular genetic study of 77 patients. Ophthal Plast Reconstr Surg 1999;15:171–9. 12. Coupland SE, White VA, Rootman J, et al. A TNM-based clinical staging system of ocular adnexal lymphomas. Arch Pathol Lab Med 2009;133:1262–7. 13. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. 14. Lee SE, Paik JS, Cho WK, et al. Feasibility of the TNM-based staging system of ocular adnexal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Am J Hematol 2011;86:262–6. 15. Fuller ML, Sweetenham J, Schoenfield L, Singh AD. Uveal lymphoma: a variant of ocular adnexal lymphoma [letter]. Leuk Lymphoma 2008;49:2393–7.
Footnotes and Financial Disclosures Originally received: October 24, 2012. Final revision: January 25, 2013. Accepted: February 5, 2013. Available online: May 9, 2013.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2012-1614.
1
Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio. 2
Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. 3
Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Supported in part through an unrestricted grant from Research to Prevent Blindness, Department of Ophthalmology, Cleveland Clinic, Lerner College of Medicine (ADS). Correspondence: Arun D. Singh, MD, Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail:
[email protected].
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