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Clinical science
Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines Matthew C Sniegowski,1 Dianna Roberts,2 Mathieu Bakhoum,1,3 Peter Mc Laughlin,4 Vivian T Yin,1 Francesco Turturro,4 Bita Esmaeli1 1
Orbital Oncology and Ophthalmic Plastic and Reconstructive Surgery, Department of Plastic Surgery, Houston, Texasx, USA 2 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 The University of Texas Medical Branch at Galveston, Galveston, Texas, USA 4 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to Dr Bita Esmaeli, Orbital Oncology and Ophthalmic Plastic and Reconstructive Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1488, Houston, Texas 77030, USA; [email protected] Received 28 January 2014 Revised 21 March 2014 Accepted 29 March 2014 Published Online First 23 April 2014
ABSTRACT Background/aims To validate the prognostic significance of the American Joint Committee on Cancer (AJCC) seventh edition staging criteria for ocular adnexal lymphoma (OAL) of all histologic subtypes. Methods Retrospective review of clinical records for all consecutive patients with OAL treated from November 1998 to December 2012. Results 130 patients were evaluated, 82 with primary and 34 with secondary OAL. Fourteen patients were excluded due to incomplete records. 71 women (61.2%) and 45 men (38.8%) had a median age of 61.5 years. Patients were followed for a median of 32.5 months. Treatment varied, in part, related to lymphoma histologic subtype. Overall, there were 17 recurrences (8 local and 9 distant) in patients with primary OAL. For primary OAL, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 55.9% and 85.8%, respectively. For primary OAL, while there was a trend towards decreased 5-year DFS for more aggressive subtypes, this was not statistically significant. More advanced Ann Arbor stage was associated with decreased 5-year DFS; however, this trend was not statistically significant. However, increased AJCC seventh edition T category was associated with decreased 5-year DFS (T1=67.8%, T2=59.2%, T3=28.6%, T4=33.3%; p=0.025). Conclusion AJCC seventh edition T category was predictive of DFS in patients with OAL.
INTRODUCTION
To cite: Sniegowski MC, Roberts D, Bakhoum M, et al. Br J Ophthalmol 2014;98:1255–1260.
Ocular adnexal lymphoma (OAL) refers to malignant lymphoproliferative disease that involves the conjunctiva, lacrimal gland, eyelid, or orbit. Most OALs are low-grade B-cell non-Hodgkin lymphoma.1–3 OAL is the most common primary orbital malignancy in adults and accounts for approximately 34% of orbital malignancies.2 However, OAL accounts for only 8% of all extranodal lymphomas, and only 1–2% of all non-Hodgkin lymphomas.3–8 Historically, all lymphomas, including OAL, were staged according to the Ann Arbor staging classification. The Ann Arbor staging system was originally designed for Hodgkin lymphoma but was subsequently applied to non-Hodgkin and Hodgkin lymphoma.9 The Ann Arbor system does not take into account tumour size, location, or extent. Rather, the Ann Arbor system stages disease on the basis of the location of the involved lymph nodes, whether disease is on one or both sides of the diaphragm, whether extranodal involvement is present, and whether systemic constitutional
symptoms are present.9 10 One potential drawback of the Ann Arbor staging system is that it does not take into account the exact site-specific anatomic location of lymphoma (eg, eyelid vs orbit vs conjunctiva). Various studies have identified adverse prognostic factors for OAL, including age greater than 60 years, non-conjunctival anatomic site, lymph node involvement, and elevated lactate dehydrogenase level.11–13 In the seventh edition of its cancerstaging manual, the American Joint Committee on Cancer (AJCC) added a TNM staging system for OAL to include some of these prognostic variables, address the lack of anatomic descriptive details in the Ann Arbor system, and allow for potentially more detailed clinical staging.11–13 Since publication of the AJCC seventh edition staging system for OAL, there have been several reports on the applicability of this system for OAL, with differing conclusions.3 14–16 The purpose of our study was to further validate the prognostic significance of the AJCC seventh edition staging system for OAL in a relatively large cohort of patients from a tertiary cancer centre with a variety of histologic subtypes of OAL.
METHODS After obtaining institutional review board approval, the medical records of all patients with a diagnosis of OAL treated by the senior author (BE) between 1 November 1998, and 1 December 2012, at a single tertiary cancer centre were reviewed. For each patient, the following data were collected from the patient’s medical record: age, sex, anatomic site of involvement (orbit, eyelid, conjunctiva, or a combination), histologic subtype of lymphoma, elements of the staging workup, Ann Arbor stage at time of diagnosis, initial treatment modality, response to therapy, local or distant recurrence, time from completion of treatment to recurrence, follow-up time after diagnosis of OAL, and patient status at last contact. Patients who presented with ocular adnexal disease were defined as having primary OAL. Patients who had a known history of previously treated systemic lymphoma and subsequently presented to the orbital oncology service with recurrence in the ocular adnexa were defined as having secondary OAL. All patients were staged at the time of initial diagnosis of lymphoma. The staging workup included a bone marrow biopsy, positron emission tomography (PET) scan, contrast-enhanced CT of
Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Clinical science the chest, abdomen and pelvis, and gastrointestinal endoscopy at the discretion of the primary oncologist. In keeping with the convention used for staging OAL in many previous studies, we considered patients who had bilateral ocular adnexal disease, but no disease in any other anatomic site to have Ann Arbor stage IE disease.17 The strictest interpretation of Ann Arbor staging may result in classification of a patient with bilateral OAL as having stage IV disease. We felt that defining bilateral OAL as stage IV might constitute overstaging; however, we also acknowledge that labelling such disease as stage IE may underestimate stage since it is well established in the literature that the risk of developing systemic lymphoma is significantly higher with bilateral OAL than with unilateral OAL.6 18–21 This controversy in staging of bilateral OAL has led to the recommendation in the AJCC 7th edition to add the suffix ‘b’ to the staging designation for patients with bilateral disease. All patients were also staged in accordance with the recently published AJCC seventh edition criteria (table 1).
Table 1 American Joint Committee on Cancer T, N and M Categories for Ocular Adnexal Lymphoma, Seventh Edition35 Stage Definition Primary Tx T0 T1 T1a T1b T1c T2 T2a T2b
tumour (T) Lymphoma extent not specified No evidence of lymphoma Lymphoma involving the conjunctiva alone without orbital involvement Bulbar conjunctiva only Palpebral conjunctiva±fornix±caruncle Extensive conjunctival involvement Lymphoma with orbital involvement±any conjunctival involvement Anterior orbital involvement (±conjunctival involvement) Anterior orbital involvement (±conjunctival involvement+lacrimal involvement) T2c Posterior orbital involvement (±conjunctival involvement±anterior involvement±any extraocular muscle involvement) T2d Nasolacrimal drainage system involvement (±conjunctival involvement but not including nasopharynx) T3 Lymphoma with preseptal eyelid involvement±orbital involvement ±conjunctival involvement T4 Orbital adnexal lymphoma extending beyond orbit to adjacent structures, such as bone and brain T4a Involvement of nasopharynx T4b Osseous involvement (including periosteum) T4c Involvement of maxillofacial, ethmoidal and/or frontal sinuses T4d Intracranial spread Lymph node involvement (N) Nx Regional lymph nodes cannot be assessed N0 No evidence of lymph node involvement N1 Involvement of ipsilateral regional lymph nodes N2 Involvement of contralateral or bilateral regional lymph nodes N3 Involvement of peripheral lymph nodes not draining ocular adnexal region N4 Involvement of central lymph nodes Distant metastasis (M) M0 No evidence of involvement of other extranodal sites M1a Non-contiguous involvement of tissues or organs external to the ocular adnexa M1b Lymphomatous involvement of the bone marrow M1c Both M1a and M1b involvement
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RESULTS One hundred thirty patients with a diagnosis of OAL were identified through a search of the Ophthalmology Database at The University of Texas MD Anderson Cancer Center. Fourteen patients were excluded because of incomplete records or diagnosis of primary cutaneous T-cell lymphoma. Detailed review of the medical records for the remaining 116 patients revealed that 82 patients had primary OAL and 34 patients had secondary OAL.
PATIENTS WITH PRIMARY OAL Of the 82 patients with primary OAL, 52 (63%) were women and 30 (37%) were men. The median age of the patients with primary OAL was 61 years (range, 22–89 years). The median follow-up time was 38.9 months (range, 0.4–174.7 months). Fifty-four patients (66%) had mucosa-associated lymphoid tissue (MALT) lymphoma, 12 patients (15%) had follicular lymphoma, 12 patients (15%) had diffuse large B-cell lymphoma (DLBCL), and 1 patient (1%) each had indeterminate histologic subtype, mantle cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma (table 2). Fifty patients (61%) had localised OAL at the time of diagnosis, and 32 patients (39%) had systemic disease at the time of diagnosis. Twelve patients (15%) had bilateral OAL at the time of diagnosis. All patients were staged according to the Ann Arbor and the AJCC seventh edition staging systems. According to Ann Arbor staging, 50 patients (61%) had stage IE disease, 5 patients (6%) had stage IIE disease, no patient had stage III disease, and 27 patients (33%) had stage IV disease. According to AJCC seventh edition staging, 25 patients (30%) had T1 disease, 46 patients (56%) had T2 disease, 8 patients (10%) had T3 disease, and 3 patients (4%) had T4 disease (table 3).
Results of staging work-up Of the 82 patients with primary OAL, 72 patients (88%) had CT of the chest, abdomen and pelvis; 63 patients (77%) had PET/CT; 76 patients (93%) underwent bilateral bone marrow biopsies; and 29 patients (35%) underwent upper (± lower) endoscopy. Twenty-two patients (27%) had nodal involvement at presentation, and 25 patients (30%) had extranodal disease at presentation in addition to their ocular adnexal involvement. Bilateral bone marrow biopsy was positive for disease in 11 of 76 patients (14%). Gastrointestinal endoscopy was positive for disease in 2 of 29 patients (7%), 1 patient with mantle cell lymphoma and 1 patient with DLBCL.
Table 2 Distribution of histologic subtypes of primary ocular adnexal lymphoma Histology
Patients (n)
Percentage
MALT Follicular DLBCL Mantle cell Indeterminent* Peripheral T-cell lymphoma Lymphoplasmocytic
54 12 12 1 1 1 1
65.9 14.6 14.6 1.2 1.2 1.2 1.2
*Pathology could not distinguish between Burkitt and DLBCL. DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue.
Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Clinical science Table 3 Distribution of American Joint Committee on Cancer (AJCC) 7th edition TNM stage among patients in the cohort AJCC summary table AJCC stage
Patients
T1N0M0 T1N2M0 T1N4M0 bT1N0M0 bT1N0M1 T2N0M0 T2N1M0 T2N2M0 T2N0M1 T2N3M1 T2N4M1 bT2N0M0 bT2N1M0 bT2N0M1 bT2N2M1 bT2N4M1 T3N0M0 T3N0M1 T3N4M1 bT3N0M0 bT3N4M1 T4N0M0 T4N4M0 T4N4M1
19 1 1 3 1 21 2 1 7 1 8 2 1 1 1 1 3 1 2 1 1 1 1 1
Local and distant recurrence and disease-free survival Of the 82 patients with primary OAL, 17 patients (21%) experienced a recurrence; the median time to recurrence was 25.6 months. Of the recurrences, 8 (47%) were local recurrences in the ocular adnexa, and 9 (53%) were distant recurrences. The 5-year disease-free survival (DFS) rate for patients with primary OAL was 55.9%. Histologic subtype was not predictive of DFS ( p=0.46): the 5-year DFS rate was 60.1% for MALT lymphoma, 51.9% for follicular lymphoma, and 49.7% for DLBCL (figure 1). Ann Arbor stage was not predictive of 5-year DFS ( p=0.51): the
Figure 1 Disease-free survival as a function of histology in patients with primary ocular adnexal lymphoma (OAL).
Figure 2 Disease-free survival as a function of Ann Arbor stage in patients with primary ocular adnexal lymphoma (OAL).
5-year DFS rate was 58.9% for stage IE disease; 58.9% for stage IIE disease, and 37.5% for stage IV disease (figure 2). However, AJCC seventh edition T category was predictive of 5-year DFS (χ2 p=0.03): the 5-year DFS rate was 67.8% for T1 disease, 59.2% for T2 disease, 28.6% for T3 disease, and 33.3% for T4 disease (figure 3). There was a trend towards worse 5-year DFS in patients who presented with bilateral than in those who presented with unilateral disease at presentation (41.6% vs 59.6%), but this did not reach statistical significance (p=0.06). An interesting finding was that the presence of nodal disease (N1-4) was associated with significantly worse 5-year DFS (p=0.03): the 5-year DFS rate was 66.2% for N0 disease and 29.1% for N1-4 disease (figure 4). However, presence of bone marrow involvement or other extranodal involvement (M1) was not associated with a decreased 5-year DFS rate (55.3% for M0 disease and 57.4% for M1 disease; p=0.85).The AJCC seventh edition stages for patients with local recurrence, distant recurrence, or lymphoma-related death are listed in table 4.
Overall survival Of the 82 patients with primary OAL, 10 patients (12%) died during the study period. The 5-year overall survival (OS) rate for patients with primary OAL was 85.8%. Three patients with
Figure 3 Disease-free survival as a function of T category in patients with primary ocular adnexal lymphoma (OAL).
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Clinical science Treatment
Figure 4 Disease-free survival as a function of N category in patients with primary ocular adnexal lymphoma (OAL). primary OAL died of their disease, which yields a diseasespecific mortality rate of 4%. The AJCC seventh edition T category also was not predictive of OS, with the exception that patients with T4 disease had worse OS than those with T1-3 disease: the 5-year OS rate was 95.5% for T1 disease, 81.4% for T2 disease, 100% for T3 disease, and 33.3% for T4 disease (χ2 p=0.0002). All 12 patients with bilateral OAL were alive at the end of the study. The presence of nodal involvement (N1-4) was associated with a trend towards worse OS, but this was not statistically significant: the 5-year OS rate was 89.6% for N0 disease and 74.9% for N1-4 disease ( p=0.07). However, on subset analysis, the presence of central lymph node involvement (N4) was associated with significantly worse OS: the 5-year OS rate was 83.7% for N0-3 disease and 63% for N4 disease ( p=0.004). Interestingly, although patients with N4 disease had significantly worse OS, the presence of systemic involvement (M1 disease) was not associated with worse 5-year OS. The 5-year OS rate was 86.9% for M0 disease and 82.6% for M1 disease ( p=0.60). Male gender portended a worse prognosis: the 5-year OS rate was 94.5% for women but only 71.8% for men ( p=0.02). One of our most critical findings was the significant difference in OS between patients with primary OAL and those with secondary OAL. The 5-year OS rate was 85.8% for primary OAL but only 39.3% for patients with secondary OAL.
Of the 82 patients with primary OAL, 28 patients (34.1%) were treated with external beam radiotherapy alone, 27 patients (32.9%) were treated with chemotherapy alone, 14 patients (17.1%) were treated with radioimmunotherapy combined with rituximab, 8 patients (9.8%) were treated with a combination of chemotherapy and external beam radiotherapy, 1 patient (1.2%) was treated by surgical excision, and 4 patients (4.9%) elected to be observed. We found that the initial therapy varied greatly depending on the histology of the lymphoma, for instance, 48.1% of patients with MALT lymphoma were treated with external beam radiotherapy alone while no patient with follicular, DLBCL or mantle cell lymphoma was treated with external beam radiotherapy alone. Regarding treatment with chemotherapy, while only 25.9% of patients with MALT lymphoma received chemotherapy either alone or in combination with external beam radiotherapy, 58.3% of patients with follicular lymphoma received chemotherapy as part of their treatment, and 100% of patients with DLBCL received chemotherapy as part of their treatment.
PATIENTS WITH SECONDARY OAL Of the 34 patients with secondary OAL, 19 were women and 15 were men. The median age of the patients with secondary OAL was 63.5 years (range, 22–84 years). The median follow-up time after the diagnosis of secondary OAL was 22.6 months (range, 0.2–126.1 months). Nine patients (26%) had follicular lymphoma, 8 patients (24%) had MALT lymphoma, 8 patients (24%) had mantle cell lymphoma, 7 patients (21%) had DLBCL, and 1 patient each had indeterminate lymphoma and peripheral T-cell lymphoma. The 3-year OS rate after diagnosis of ocular adnexal involvement was 50%, and the 5-year OS rate after diagnosis of ocular adnexal involvement was 39.3%. Among patients with secondary OAL, histologic subtype was significantly associated with OS: the 5-year OS rate was 85.7% for MALT lymphoma, 50% for follicular lymphoma, and 16.7% for DLBCL ( p=0.006) (figure 5).
DISCUSSION Several interesting findings emerged from this analysis. First, we found that the AJCC seventh edition T category was predictive of DFS, whereas Ann Arbor stage appeared not to be. Prior to publication of the AJCC seventh edition staging criteria for OAL, several studies had evaluated prognostic factors for
Table 4 American Joint Committee on Cancer seventh edition stage for patients who experienced local recurrence, distant relapse, or lymphoma-related death Local recurrence
Distant relapse
Lymphoma-related death
T1aN0M0 T1bN0M0 T1bN0M0 T1bN0M0 bT1cN0M0 bT2bN1M0 T2cN0M0 T2dN1M0 bT3N0M0
T1aN0M0 T2aN4M1b bT2aN4M1b bT2cN2M1b T3N0M0
T2cN4M1a T4cN4M0 T4cN4M1a
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Figure 5 Overall survival as a function of T category in patients with secondary ocular adnexal lymphoma (OAL). Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Clinical science patients with OAL, but none had used the specific T designations in AJCC as a correlate for outcomes.11–13 17–20 The AJCC seventh edition staging criteria for OAL were designed with more descriptive T categories. Our data support the AJCC seventh edition in that T category was predictive of DFS. We also found that while patients with bilateral disease had a trend towards decreased DFS, this trend did not reach statistical significance. The finding of decreased DFS in bilateral compared to unilateral disease is also consistent with a recent study which found a significantly decreased 10-year progression-free survival in patients with bilateral disease.16 These findings support the use of the ‘b’ suffix for bilateral involvement in the AJCC criteria as opposed to stage IV designation for bilateral ocular adnexal involvement in the Ann Arbor staging system. Another interesting and somewhat surprising finding of our study was that histologic subtype was not predictive of DFS. Higher-grade histologic subtype, that is, non-MALT lymphoma and non-follicular OAL, have been reported in previous studies to be associated with a more advanced stage at presentation, as well as a higher incidence of disease progression, and the subsequent development of systemic disease.6 18–22 One potential explanation for our finding of lack of significant correlation between histologic subtype and DFS is that lower-grade lymphomas (eg, MALT lymphoma) are treated less aggressively than higher-grade lymphomas (DLBCL or mantle cell lymphoma). More aggressive histologic subtypes were treated with more aggressive treatments, thus neutralising the impact of histology on DFS. This possible explanation is consistent with the findings of a recent study which found treatment to be closely related to disease-free survival, where nearly 75% of patients with a recurrence were not treated with radiotherapy.15 In our current study, for the entire group of 82 patients with primary OAL, the 5-year OS rate was 85.8%, and only 3 patients (4%) died of their disease; thus patients with all histologic subtypes did well. Recently, several studies have attempted to validate the AJCC seventh edition staging for OAL, with differing results.3 14–16 In a study by Lee et al, 54 patients with MALT lymphoma were reviewed, and the authors found that patients with T1 disease had longer progression-free survival than patients with greater than T1 disease or bilateral T1 disease.3 In another study by Aronow et al,14 60 patients with primary OAL were analysed, and it was concluded that T category was not associated with relapse or survival on the basis of HRs calculated by Cox regression analysis. A different study by Graue et al,15 found that histology and treatment were more closely related to disease-free survival than AJCC 7th edition stage. Lastly, Rath et al,16 found that AJCC 7th edition was a good predictor of progression-free survival, mainly due to its distinction between unilateral and bilateral disease. In our study of 82 patients, we found that the AJCC seventh edition T category correlated significantly with DFS, but that only patients with T4 OAL had diminished OS. The differing conclusions among the studies are likely multifactorial, with differences in histology and severity of disease, as well as differing staging and treatment strategies all contributing. While our study is limited by its retrospective nature, we feel that within our cohort the diversity of histology and disease severity, along with a relatively uniform staging work-up contributes to establishing the validity of the AJCC 7th edition for OAL. In our study, 39% of patients had evidence of systemic (nonocular) lymphoma at presentation, which is consistent with a previous study of a smaller cohort from our centre by Hatef et al.21 To best evaluate the incidence of systemic disease at presentation and the risk of subsequent systemic relapse, it is critical to
evaluate the elements of the staging work-up.23–25 In our current study, 96% of patients had CT of the chest, abdomen and pelvis and/or PET/CT as part of their initial work-up, and 93% of patients had bilateral bone marrow biopsies. The fact that our incidence of systemic disease at presentation is slightly higher than incidences previously reported in the literature likely reflects the thoroughness of the initial screening at our institution.25 One of the challenges in evaluating the prognostic factors in patients with primary OAL is that primary OAL tends to be a low-grade malignancy with the vast majority of patients doing well with current treatment modalities. The 10-year diseasespecific mortality rate for OAL has been reported to be approximately 5–10% depending on histologic subtype.6 12 We found a 5-year disease-specific mortality rate of 3.7% for patients with primary OAL, which is consistent with prior reports.17 Similar to previous studies, we found that the 5-year OS rate for patients with secondary OAL was much worse than patients with primary OAL (39.3% vs 85.8%).26 This distinction was recognised by the AJCC seventh edition staging system for OAL, which specifies that the staging system is to be used exclusively for primary OAL.27 We draw three major conclusions from our study. First, the new AJCC seventh edition T category criteria for primary OAL are predictive of DFS. Second, a significant proportion of patients with OAL, upwards of one-third of patients, will have systemic disease at the time of presentation, and thus a thorough systemic work-up is essential for all patients with a new diagnosis of primary OAL. Third, a detailed history to determine whether the patient has a previous diagnosis of systemic lymphoma is critical, as patients with secondary OAL have significantly worse outcomes than patients with primary OAL. Contributors I confirm that all listed authors have contributed to this work and fit the description of a contributing author. Funding This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, CA016672. Competing interests None. Ethics approval MD Anderson Cancer Center IRB. Provenance and peer review Not commissioned; externally peer reviewed.
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Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines Matthew C Sniegowski, Dianna Roberts, Mathieu Bakhoum, Peter Mc Laughlin, Vivian T Yin, Francesco Turturro and Bita Esmaeli Br J Ophthalmol 2014 98: 1255-1260 originally published online April 23, 2014
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Clinical science
Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines Matthew C Sniegowski,1 Dianna Roberts,2 Mathieu Bakhoum,1,3 Peter Mc Laughlin,4 Vivian T Yin,1 Francesco Turturro,4 Bita Esmaeli1 1
Orbital Oncology and Ophthalmic Plastic and Reconstructive Surgery, Department of Plastic Surgery, Houston, Texasx, USA 2 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 The University of Texas Medical Branch at Galveston, Galveston, Texas, USA 4 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to Dr Bita Esmaeli, Orbital Oncology and Ophthalmic Plastic and Reconstructive Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1488, Houston, Texas 77030, USA; [email protected] Received 28 January 2014 Revised 21 March 2014 Accepted 29 March 2014 Published Online First 23 April 2014
ABSTRACT Background/aims To validate the prognostic significance of the American Joint Committee on Cancer (AJCC) seventh edition staging criteria for ocular adnexal lymphoma (OAL) of all histologic subtypes. Methods Retrospective review of clinical records for all consecutive patients with OAL treated from November 1998 to December 2012. Results 130 patients were evaluated, 82 with primary and 34 with secondary OAL. Fourteen patients were excluded due to incomplete records. 71 women (61.2%) and 45 men (38.8%) had a median age of 61.5 years. Patients were followed for a median of 32.5 months. Treatment varied, in part, related to lymphoma histologic subtype. Overall, there were 17 recurrences (8 local and 9 distant) in patients with primary OAL. For primary OAL, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 55.9% and 85.8%, respectively. For primary OAL, while there was a trend towards decreased 5-year DFS for more aggressive subtypes, this was not statistically significant. More advanced Ann Arbor stage was associated with decreased 5-year DFS; however, this trend was not statistically significant. However, increased AJCC seventh edition T category was associated with decreased 5-year DFS (T1=67.8%, T2=59.2%, T3=28.6%, T4=33.3%; p=0.025). Conclusion AJCC seventh edition T category was predictive of DFS in patients with OAL.
INTRODUCTION
To cite: Sniegowski MC, Roberts D, Bakhoum M, et al. Br J Ophthalmol 2014;98:1255–1260.
Ocular adnexal lymphoma (OAL) refers to malignant lymphoproliferative disease that involves the conjunctiva, lacrimal gland, eyelid, or orbit. Most OALs are low-grade B-cell non-Hodgkin lymphoma.1–3 OAL is the most common primary orbital malignancy in adults and accounts for approximately 34% of orbital malignancies.2 However, OAL accounts for only 8% of all extranodal lymphomas, and only 1–2% of all non-Hodgkin lymphomas.3–8 Historically, all lymphomas, including OAL, were staged according to the Ann Arbor staging classification. The Ann Arbor staging system was originally designed for Hodgkin lymphoma but was subsequently applied to non-Hodgkin and Hodgkin lymphoma.9 The Ann Arbor system does not take into account tumour size, location, or extent. Rather, the Ann Arbor system stages disease on the basis of the location of the involved lymph nodes, whether disease is on one or both sides of the diaphragm, whether extranodal involvement is present, and whether systemic constitutional
symptoms are present.9 10 One potential drawback of the Ann Arbor staging system is that it does not take into account the exact site-specific anatomic location of lymphoma (eg, eyelid vs orbit vs conjunctiva). Various studies have identified adverse prognostic factors for OAL, including age greater than 60 years, non-conjunctival anatomic site, lymph node involvement, and elevated lactate dehydrogenase level.11–13 In the seventh edition of its cancerstaging manual, the American Joint Committee on Cancer (AJCC) added a TNM staging system for OAL to include some of these prognostic variables, address the lack of anatomic descriptive details in the Ann Arbor system, and allow for potentially more detailed clinical staging.11–13 Since publication of the AJCC seventh edition staging system for OAL, there have been several reports on the applicability of this system for OAL, with differing conclusions.3 14–16 The purpose of our study was to further validate the prognostic significance of the AJCC seventh edition staging system for OAL in a relatively large cohort of patients from a tertiary cancer centre with a variety of histologic subtypes of OAL.
METHODS After obtaining institutional review board approval, the medical records of all patients with a diagnosis of OAL treated by the senior author (BE) between 1 November 1998, and 1 December 2012, at a single tertiary cancer centre were reviewed. For each patient, the following data were collected from the patient’s medical record: age, sex, anatomic site of involvement (orbit, eyelid, conjunctiva, or a combination), histologic subtype of lymphoma, elements of the staging workup, Ann Arbor stage at time of diagnosis, initial treatment modality, response to therapy, local or distant recurrence, time from completion of treatment to recurrence, follow-up time after diagnosis of OAL, and patient status at last contact. Patients who presented with ocular adnexal disease were defined as having primary OAL. Patients who had a known history of previously treated systemic lymphoma and subsequently presented to the orbital oncology service with recurrence in the ocular adnexa were defined as having secondary OAL. All patients were staged at the time of initial diagnosis of lymphoma. The staging workup included a bone marrow biopsy, positron emission tomography (PET) scan, contrast-enhanced CT of
Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Clinical science the chest, abdomen and pelvis, and gastrointestinal endoscopy at the discretion of the primary oncologist. In keeping with the convention used for staging OAL in many previous studies, we considered patients who had bilateral ocular adnexal disease, but no disease in any other anatomic site to have Ann Arbor stage IE disease.17 The strictest interpretation of Ann Arbor staging may result in classification of a patient with bilateral OAL as having stage IV disease. We felt that defining bilateral OAL as stage IV might constitute overstaging; however, we also acknowledge that labelling such disease as stage IE may underestimate stage since it is well established in the literature that the risk of developing systemic lymphoma is significantly higher with bilateral OAL than with unilateral OAL.6 18–21 This controversy in staging of bilateral OAL has led to the recommendation in the AJCC 7th edition to add the suffix ‘b’ to the staging designation for patients with bilateral disease. All patients were also staged in accordance with the recently published AJCC seventh edition criteria (table 1).
Table 1 American Joint Committee on Cancer T, N and M Categories for Ocular Adnexal Lymphoma, Seventh Edition35 Stage Definition Primary Tx T0 T1 T1a T1b T1c T2 T2a T2b
tumour (T) Lymphoma extent not specified No evidence of lymphoma Lymphoma involving the conjunctiva alone without orbital involvement Bulbar conjunctiva only Palpebral conjunctiva±fornix±caruncle Extensive conjunctival involvement Lymphoma with orbital involvement±any conjunctival involvement Anterior orbital involvement (±conjunctival involvement) Anterior orbital involvement (±conjunctival involvement+lacrimal involvement) T2c Posterior orbital involvement (±conjunctival involvement±anterior involvement±any extraocular muscle involvement) T2d Nasolacrimal drainage system involvement (±conjunctival involvement but not including nasopharynx) T3 Lymphoma with preseptal eyelid involvement±orbital involvement ±conjunctival involvement T4 Orbital adnexal lymphoma extending beyond orbit to adjacent structures, such as bone and brain T4a Involvement of nasopharynx T4b Osseous involvement (including periosteum) T4c Involvement of maxillofacial, ethmoidal and/or frontal sinuses T4d Intracranial spread Lymph node involvement (N) Nx Regional lymph nodes cannot be assessed N0 No evidence of lymph node involvement N1 Involvement of ipsilateral regional lymph nodes N2 Involvement of contralateral or bilateral regional lymph nodes N3 Involvement of peripheral lymph nodes not draining ocular adnexal region N4 Involvement of central lymph nodes Distant metastasis (M) M0 No evidence of involvement of other extranodal sites M1a Non-contiguous involvement of tissues or organs external to the ocular adnexa M1b Lymphomatous involvement of the bone marrow M1c Both M1a and M1b involvement
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RESULTS One hundred thirty patients with a diagnosis of OAL were identified through a search of the Ophthalmology Database at The University of Texas MD Anderson Cancer Center. Fourteen patients were excluded because of incomplete records or diagnosis of primary cutaneous T-cell lymphoma. Detailed review of the medical records for the remaining 116 patients revealed that 82 patients had primary OAL and 34 patients had secondary OAL.
PATIENTS WITH PRIMARY OAL Of the 82 patients with primary OAL, 52 (63%) were women and 30 (37%) were men. The median age of the patients with primary OAL was 61 years (range, 22–89 years). The median follow-up time was 38.9 months (range, 0.4–174.7 months). Fifty-four patients (66%) had mucosa-associated lymphoid tissue (MALT) lymphoma, 12 patients (15%) had follicular lymphoma, 12 patients (15%) had diffuse large B-cell lymphoma (DLBCL), and 1 patient (1%) each had indeterminate histologic subtype, mantle cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma (table 2). Fifty patients (61%) had localised OAL at the time of diagnosis, and 32 patients (39%) had systemic disease at the time of diagnosis. Twelve patients (15%) had bilateral OAL at the time of diagnosis. All patients were staged according to the Ann Arbor and the AJCC seventh edition staging systems. According to Ann Arbor staging, 50 patients (61%) had stage IE disease, 5 patients (6%) had stage IIE disease, no patient had stage III disease, and 27 patients (33%) had stage IV disease. According to AJCC seventh edition staging, 25 patients (30%) had T1 disease, 46 patients (56%) had T2 disease, 8 patients (10%) had T3 disease, and 3 patients (4%) had T4 disease (table 3).
Results of staging work-up Of the 82 patients with primary OAL, 72 patients (88%) had CT of the chest, abdomen and pelvis; 63 patients (77%) had PET/CT; 76 patients (93%) underwent bilateral bone marrow biopsies; and 29 patients (35%) underwent upper (± lower) endoscopy. Twenty-two patients (27%) had nodal involvement at presentation, and 25 patients (30%) had extranodal disease at presentation in addition to their ocular adnexal involvement. Bilateral bone marrow biopsy was positive for disease in 11 of 76 patients (14%). Gastrointestinal endoscopy was positive for disease in 2 of 29 patients (7%), 1 patient with mantle cell lymphoma and 1 patient with DLBCL.
Table 2 Distribution of histologic subtypes of primary ocular adnexal lymphoma Histology
Patients (n)
Percentage
MALT Follicular DLBCL Mantle cell Indeterminent* Peripheral T-cell lymphoma Lymphoplasmocytic
54 12 12 1 1 1 1
65.9 14.6 14.6 1.2 1.2 1.2 1.2
*Pathology could not distinguish between Burkitt and DLBCL. DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue.
Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Clinical science Table 3 Distribution of American Joint Committee on Cancer (AJCC) 7th edition TNM stage among patients in the cohort AJCC summary table AJCC stage
Patients
T1N0M0 T1N2M0 T1N4M0 bT1N0M0 bT1N0M1 T2N0M0 T2N1M0 T2N2M0 T2N0M1 T2N3M1 T2N4M1 bT2N0M0 bT2N1M0 bT2N0M1 bT2N2M1 bT2N4M1 T3N0M0 T3N0M1 T3N4M1 bT3N0M0 bT3N4M1 T4N0M0 T4N4M0 T4N4M1
19 1 1 3 1 21 2 1 7 1 8 2 1 1 1 1 3 1 2 1 1 1 1 1
Local and distant recurrence and disease-free survival Of the 82 patients with primary OAL, 17 patients (21%) experienced a recurrence; the median time to recurrence was 25.6 months. Of the recurrences, 8 (47%) were local recurrences in the ocular adnexa, and 9 (53%) were distant recurrences. The 5-year disease-free survival (DFS) rate for patients with primary OAL was 55.9%. Histologic subtype was not predictive of DFS ( p=0.46): the 5-year DFS rate was 60.1% for MALT lymphoma, 51.9% for follicular lymphoma, and 49.7% for DLBCL (figure 1). Ann Arbor stage was not predictive of 5-year DFS ( p=0.51): the
Figure 1 Disease-free survival as a function of histology in patients with primary ocular adnexal lymphoma (OAL).
Figure 2 Disease-free survival as a function of Ann Arbor stage in patients with primary ocular adnexal lymphoma (OAL).
5-year DFS rate was 58.9% for stage IE disease; 58.9% for stage IIE disease, and 37.5% for stage IV disease (figure 2). However, AJCC seventh edition T category was predictive of 5-year DFS (χ2 p=0.03): the 5-year DFS rate was 67.8% for T1 disease, 59.2% for T2 disease, 28.6% for T3 disease, and 33.3% for T4 disease (figure 3). There was a trend towards worse 5-year DFS in patients who presented with bilateral than in those who presented with unilateral disease at presentation (41.6% vs 59.6%), but this did not reach statistical significance (p=0.06). An interesting finding was that the presence of nodal disease (N1-4) was associated with significantly worse 5-year DFS (p=0.03): the 5-year DFS rate was 66.2% for N0 disease and 29.1% for N1-4 disease (figure 4). However, presence of bone marrow involvement or other extranodal involvement (M1) was not associated with a decreased 5-year DFS rate (55.3% for M0 disease and 57.4% for M1 disease; p=0.85).The AJCC seventh edition stages for patients with local recurrence, distant recurrence, or lymphoma-related death are listed in table 4.
Overall survival Of the 82 patients with primary OAL, 10 patients (12%) died during the study period. The 5-year overall survival (OS) rate for patients with primary OAL was 85.8%. Three patients with
Figure 3 Disease-free survival as a function of T category in patients with primary ocular adnexal lymphoma (OAL).
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Clinical science Treatment
Figure 4 Disease-free survival as a function of N category in patients with primary ocular adnexal lymphoma (OAL). primary OAL died of their disease, which yields a diseasespecific mortality rate of 4%. The AJCC seventh edition T category also was not predictive of OS, with the exception that patients with T4 disease had worse OS than those with T1-3 disease: the 5-year OS rate was 95.5% for T1 disease, 81.4% for T2 disease, 100% for T3 disease, and 33.3% for T4 disease (χ2 p=0.0002). All 12 patients with bilateral OAL were alive at the end of the study. The presence of nodal involvement (N1-4) was associated with a trend towards worse OS, but this was not statistically significant: the 5-year OS rate was 89.6% for N0 disease and 74.9% for N1-4 disease ( p=0.07). However, on subset analysis, the presence of central lymph node involvement (N4) was associated with significantly worse OS: the 5-year OS rate was 83.7% for N0-3 disease and 63% for N4 disease ( p=0.004). Interestingly, although patients with N4 disease had significantly worse OS, the presence of systemic involvement (M1 disease) was not associated with worse 5-year OS. The 5-year OS rate was 86.9% for M0 disease and 82.6% for M1 disease ( p=0.60). Male gender portended a worse prognosis: the 5-year OS rate was 94.5% for women but only 71.8% for men ( p=0.02). One of our most critical findings was the significant difference in OS between patients with primary OAL and those with secondary OAL. The 5-year OS rate was 85.8% for primary OAL but only 39.3% for patients with secondary OAL.
Of the 82 patients with primary OAL, 28 patients (34.1%) were treated with external beam radiotherapy alone, 27 patients (32.9%) were treated with chemotherapy alone, 14 patients (17.1%) were treated with radioimmunotherapy combined with rituximab, 8 patients (9.8%) were treated with a combination of chemotherapy and external beam radiotherapy, 1 patient (1.2%) was treated by surgical excision, and 4 patients (4.9%) elected to be observed. We found that the initial therapy varied greatly depending on the histology of the lymphoma, for instance, 48.1% of patients with MALT lymphoma were treated with external beam radiotherapy alone while no patient with follicular, DLBCL or mantle cell lymphoma was treated with external beam radiotherapy alone. Regarding treatment with chemotherapy, while only 25.9% of patients with MALT lymphoma received chemotherapy either alone or in combination with external beam radiotherapy, 58.3% of patients with follicular lymphoma received chemotherapy as part of their treatment, and 100% of patients with DLBCL received chemotherapy as part of their treatment.
PATIENTS WITH SECONDARY OAL Of the 34 patients with secondary OAL, 19 were women and 15 were men. The median age of the patients with secondary OAL was 63.5 years (range, 22–84 years). The median follow-up time after the diagnosis of secondary OAL was 22.6 months (range, 0.2–126.1 months). Nine patients (26%) had follicular lymphoma, 8 patients (24%) had MALT lymphoma, 8 patients (24%) had mantle cell lymphoma, 7 patients (21%) had DLBCL, and 1 patient each had indeterminate lymphoma and peripheral T-cell lymphoma. The 3-year OS rate after diagnosis of ocular adnexal involvement was 50%, and the 5-year OS rate after diagnosis of ocular adnexal involvement was 39.3%. Among patients with secondary OAL, histologic subtype was significantly associated with OS: the 5-year OS rate was 85.7% for MALT lymphoma, 50% for follicular lymphoma, and 16.7% for DLBCL ( p=0.006) (figure 5).
DISCUSSION Several interesting findings emerged from this analysis. First, we found that the AJCC seventh edition T category was predictive of DFS, whereas Ann Arbor stage appeared not to be. Prior to publication of the AJCC seventh edition staging criteria for OAL, several studies had evaluated prognostic factors for
Table 4 American Joint Committee on Cancer seventh edition stage for patients who experienced local recurrence, distant relapse, or lymphoma-related death Local recurrence
Distant relapse
Lymphoma-related death
T1aN0M0 T1bN0M0 T1bN0M0 T1bN0M0 bT1cN0M0 bT2bN1M0 T2cN0M0 T2dN1M0 bT3N0M0
T1aN0M0 T2aN4M1b bT2aN4M1b bT2cN2M1b T3N0M0
T2cN4M1a T4cN4M0 T4cN4M1a
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Figure 5 Overall survival as a function of T category in patients with secondary ocular adnexal lymphoma (OAL). Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Clinical science patients with OAL, but none had used the specific T designations in AJCC as a correlate for outcomes.11–13 17–20 The AJCC seventh edition staging criteria for OAL were designed with more descriptive T categories. Our data support the AJCC seventh edition in that T category was predictive of DFS. We also found that while patients with bilateral disease had a trend towards decreased DFS, this trend did not reach statistical significance. The finding of decreased DFS in bilateral compared to unilateral disease is also consistent with a recent study which found a significantly decreased 10-year progression-free survival in patients with bilateral disease.16 These findings support the use of the ‘b’ suffix for bilateral involvement in the AJCC criteria as opposed to stage IV designation for bilateral ocular adnexal involvement in the Ann Arbor staging system. Another interesting and somewhat surprising finding of our study was that histologic subtype was not predictive of DFS. Higher-grade histologic subtype, that is, non-MALT lymphoma and non-follicular OAL, have been reported in previous studies to be associated with a more advanced stage at presentation, as well as a higher incidence of disease progression, and the subsequent development of systemic disease.6 18–22 One potential explanation for our finding of lack of significant correlation between histologic subtype and DFS is that lower-grade lymphomas (eg, MALT lymphoma) are treated less aggressively than higher-grade lymphomas (DLBCL or mantle cell lymphoma). More aggressive histologic subtypes were treated with more aggressive treatments, thus neutralising the impact of histology on DFS. This possible explanation is consistent with the findings of a recent study which found treatment to be closely related to disease-free survival, where nearly 75% of patients with a recurrence were not treated with radiotherapy.15 In our current study, for the entire group of 82 patients with primary OAL, the 5-year OS rate was 85.8%, and only 3 patients (4%) died of their disease; thus patients with all histologic subtypes did well. Recently, several studies have attempted to validate the AJCC seventh edition staging for OAL, with differing results.3 14–16 In a study by Lee et al, 54 patients with MALT lymphoma were reviewed, and the authors found that patients with T1 disease had longer progression-free survival than patients with greater than T1 disease or bilateral T1 disease.3 In another study by Aronow et al,14 60 patients with primary OAL were analysed, and it was concluded that T category was not associated with relapse or survival on the basis of HRs calculated by Cox regression analysis. A different study by Graue et al,15 found that histology and treatment were more closely related to disease-free survival than AJCC 7th edition stage. Lastly, Rath et al,16 found that AJCC 7th edition was a good predictor of progression-free survival, mainly due to its distinction between unilateral and bilateral disease. In our study of 82 patients, we found that the AJCC seventh edition T category correlated significantly with DFS, but that only patients with T4 OAL had diminished OS. The differing conclusions among the studies are likely multifactorial, with differences in histology and severity of disease, as well as differing staging and treatment strategies all contributing. While our study is limited by its retrospective nature, we feel that within our cohort the diversity of histology and disease severity, along with a relatively uniform staging work-up contributes to establishing the validity of the AJCC 7th edition for OAL. In our study, 39% of patients had evidence of systemic (nonocular) lymphoma at presentation, which is consistent with a previous study of a smaller cohort from our centre by Hatef et al.21 To best evaluate the incidence of systemic disease at presentation and the risk of subsequent systemic relapse, it is critical to
evaluate the elements of the staging work-up.23–25 In our current study, 96% of patients had CT of the chest, abdomen and pelvis and/or PET/CT as part of their initial work-up, and 93% of patients had bilateral bone marrow biopsies. The fact that our incidence of systemic disease at presentation is slightly higher than incidences previously reported in the literature likely reflects the thoroughness of the initial screening at our institution.25 One of the challenges in evaluating the prognostic factors in patients with primary OAL is that primary OAL tends to be a low-grade malignancy with the vast majority of patients doing well with current treatment modalities. The 10-year diseasespecific mortality rate for OAL has been reported to be approximately 5–10% depending on histologic subtype.6 12 We found a 5-year disease-specific mortality rate of 3.7% for patients with primary OAL, which is consistent with prior reports.17 Similar to previous studies, we found that the 5-year OS rate for patients with secondary OAL was much worse than patients with primary OAL (39.3% vs 85.8%).26 This distinction was recognised by the AJCC seventh edition staging system for OAL, which specifies that the staging system is to be used exclusively for primary OAL.27 We draw three major conclusions from our study. First, the new AJCC seventh edition T category criteria for primary OAL are predictive of DFS. Second, a significant proportion of patients with OAL, upwards of one-third of patients, will have systemic disease at the time of presentation, and thus a thorough systemic work-up is essential for all patients with a new diagnosis of primary OAL. Third, a detailed history to determine whether the patient has a previous diagnosis of systemic lymphoma is critical, as patients with secondary OAL have significantly worse outcomes than patients with primary OAL. Contributors I confirm that all listed authors have contributed to this work and fit the description of a contributing author. Funding This research was supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, CA016672. Competing interests None. Ethics approval MD Anderson Cancer Center IRB. Provenance and peer review Not commissioned; externally peer reviewed.
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Sniegowski MC, et al. Br J Ophthalmol 2014;98:1255–1260. doi:10.1136/bjophthalmol-2013-304847
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Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines Matthew C Sniegowski, Dianna Roberts, Mathieu Bakhoum, Peter Mc Laughlin, Vivian T Yin, Francesco Turturro and Bita Esmaeli Br J Ophthalmol 2014 98: 1255-1260 originally published online April 23, 2014
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