Clinical behavior and treatment outcome of primary nasal diffuse large B-cell lymphoma

Authors

  • Ning-Ning Lu MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Ye-Xiong Li MD,

    Corresponding author
    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
    • Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P.R. China
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    • Fax: (011) 86-10-67706153

  • Wei-Hu Wang MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Jing Jin MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yong-Wen Song MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Li-Qiang Zhou MD,

    1. Department of Medical Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Shu-Lian Wang MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Yue-Ping Liu MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Xin-Fan Liu MD,

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Zi-Hao Yu MD

    1. Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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  • Y.-X.L. designed the research, analyzed the data, and wrote the article; N.-N.L. analyzed the data and wrote the article; W.-H.W., J.J., Y.-W.S., L.-Q.Z., S.-L.W., L.-Y.P., X.-F.L., and Z.-H.Y. selected the patients and analyzed the clinical data.

Abstract

BACKGROUND:

Nasal diffuse large B-cell lymphoma (DLBCL) is rare. The objective of this study was to evaluate the clinical features and treatment outcomes of patients with nasal DLBCL.

METHODS:

Twenty-five patients were included in the study. All patients received combination chemotherapy with or without radiotherapy.

RESULTS:

Patients with nasal DLBCL usually were older and were predominantly men with early stage disease, low frequency of B symptoms and elevated lactate dehydrogenase (LDH), good performance status, and a low-risk international prognostic index (IPI) score. The overall response rate after initial treatment was 76%, the 3-year overall survival (OS) rate for the whole group was 44%, and the median OS was 35 months. Performance status and IPI were significant prognostic factors for OS. For patients with IPI scores of 0 or 1, the 3-year OS rate was 54%, and the median OS was 52 months compared with 17% and 11 months, respectively, for patients with IPI scores of 2 or 3 (P = .033). The prognosis for patients who achieved a complete response (CR) was significantly better than that for patients who did not achieve a CR. Extranodal spread was the primary pattern of failure.

CONCLUSIONS:

The current results indicated that primary nasal DLBCL appears to have distinct clinical features; its poor outcome and propensity for extranodal failure illustrate the need for innovative therapies. Cancer 2011;. © 2011 American Cancer Society.

INTRODUCTION

Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous disease that depends mainly on the primary site of involvement.1-5 Patients with DLBCL that arises in different sites display a large variety of pathobiologic and clinical findings, which justify the identification of different variants and subtypes.4, 8-10 In contrast to lymphomas of the Waldeyer ring or paranasal sinuses, which are predominantly diffuse large B-cell lymphomas,11-13 nasal lymphomas are mainly of a natural killer (NK)/T-cell origin,14-18 and primary nasal DLBCL is extremely rare. Because of the rarity of this condition, few studies have addressed it as a separate entity: Most reports have included a mixture of NK/T-cell and B-cell lymphomas or have reported nasal DLBCL along with lymphomas of the paranasal sinuses or other upper aerodigestive tract locations.11-13, 19-23 Most previous reports have consisted of only small case series.20, 24 Therefore, to date, the clinical features and treatment outcomes of patients with primary nasal DLBCL have not been defined. Furthermore, the treatment options for primary nasal lymphomas have been based on extrapolation from the experience with lymph node DLBCL or nasal NK/T-cell lymphoma, so the optimal therapy for nasal DLBCL has yet to be determined.11-14 The objective of this study was to address the clinical features, pathways of tumor spread, and treatment outcomes in patients with nasal DLBCL.

MATERIALS AND METHODS

Patient Eligibility and Evaluation

The study group consisted of 25 patients with previously untreated nasal DLBCL who presented at the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China between 1999 and 2009. They accounted for 10% of all patients with nasal lymphoma who presented during this period. Primary nasal lymphoma was defined according to primary symptoms and the location of the majority of bulky tumor in the nasal cavity, as indicated previously.25, 26 For patients who had lymphoma involving both the nasal cavity and adjacent structures, primary location was based on an objective assessment of the tumor center as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). All diagnoses were confirmed by typical morphologic features and immunophenotypic evaluation. Immunohistochemical studies were positive for B-cell markers, such as cluster of differentiation 20 (CD20) (pan-B-cell antigen) and/or CD79α (immunoglobulin-α0), and were negative for T-cell or NK/T-cell markers, which included CD2 (cell surface antigen), CD3 (protein complex), CD45RO (cell surface antigen), and CD56 (neural cell adhesion molecule). Markers of germinal-center (GC) B-cell or activated B-cell-like subtypes, such as CD10 (neutral endopeptidase), B-cell lymphoma 6 protein (Bcl-6), and the multiple myeloma oncogene-1 (MUM-1), which have become available in recent years, were used to evaluate 12 patients in the latter part of this series. According to the algorithm published by Hans et al,27 5 patients had a GC subtype, and 7 patients had a non-GC subtype. Patients with nasal NK/T-cell lymphomas or B-cell lymphomas of the paranasal sinuses or extranasal upper aerodigestive tract were excluded from this study.

The Ann Arbor system was used for staging, which was based on the available records. Staging procedures included a clinical history; physical examination with fiber-optic nasopharyngoscopy; complete blood counts with serum biochemistry; lactate dehydrogenase (LDH); chest radiograph; CT scans and/or MRI of the head and neck; CT scans and/or MRI of the thorax, abdomen, and pelvis; and bone marrow aspiration or biopsy. The international prognostic index (IPI) score was calculated for each patient as described previously.28

Treatment

Chemotherapy was the primary treatment for nasal DLBCL. All patients received combination chemotherapy, which consisted of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP-like chemotherapy with or without rituximab, with or without involved-field radiotherapy. Overall, 17 patients received chemotherapy and radiotherapy, and 8 patients received chemotherapy alone. Rituximab combined with chemotherapy was received by the 10 most recent patients. Patients received a median of 5 cycles of chemotherapy.

Radiotherapy was received by patients who had early stage disease and those who had progressive or residual disease after chemotherapy. The median radiation dose to the primary tumor was 46 grays (Gy) (range, 40-56 Gy) at 2 Gy per fraction. The clinical target volume included the nasal cavity and ethmoid sinuses bilaterally and the ipsilateral maxillary sinuses and was extended to cover adjacent organs if involved.

Statistical Analysis

Treatment outcome was evaluated using the international workshop response criteria for lymphomas.29 Overall survival (OS) was measured from the start of initial treatment to the date of death from any cause or to the date of last follow-up. Progression-free survival (PFS) was measured from the date of initial treatment to the date of disease progression, recurrence, or death from lymphoma or other causes. Survival was calculated using the Kaplan-Meier method, and survival curves were compared by using the log-rank test.

RESULTS

Patient Characteristics

The clinical features of the 25 patients are presented in Table 1. The ratio of men to women was 2.6:1. The median age was 58 years, and approximately 50% of patients were aged ≥60 years. Only 1 patient had B symptoms. Elevated LDH levels were observed in 20% of patients. Most patients (88%) presented with localized disease. According to the Ann Arbor staging system, 18 patients had stage IE disease, 4 patients had stage IIE disease, and 3 patients had stage IIIE or IVE disease. The majority of patients presented with a good performance status (0-1) according to the Eastern Cooperative Oncology Group (ECOG) and low-risk IPI scores (0-1).

Table 1. Clinical Characteristics of Patients With Primary Nasal Diffuse Large B-Cell Lymphoma
CharacteristicNo. of Patients (%)
  1. Abbreviations: ECOG, European Cooperative Oncology Group; IPI, international prognostic index; LDH, lactate dehydrogenase.

Sex 
 Men18 (72)
 Women7 (28)
Age, y 
 Median48
 Range8-83
 >6012 (48)
Primary site 
 Left nasal cavity9 (36)
 Right nasal cavity8 (32)
 Bilateral nasal cavity8 (32)
Ann Arbor stage 
 I18 (72)
 II4 (16)
 III-IV3 (12)
Paranasal extension21 (84)
B symptoms1 (4)
Elevated LDH level5 (20)
ECOG score 
 0-120 (80)
 25 (20)
IPI 
 0-119 (76)
 2-36 (24)

Four patients with lymph node involvement presented initially with positive cervical lymph nodes. However, involvement of distant lymph nodes or extranodal sites without cervical lymph node metastasis was observed in 3 of 7 patients with stage IIE to IVE disease. Two patients had only mediastinal or para-aortic lymph node involvement, and the remaining patient with stage IVE disease had kidney metastasis without any lymph node involvement.

Response to Treatment and Outcome

An overall response to treatment was achieved by 19 patients (76%). The CR rate was 60%, the partial response rate was 16%, and 24% of patients had progressive disease. At the time of last follow-up, 11 patients had died (10 died of lymphoma, and 1 died of comorbid disease).

At a median follow-up of 37 months for surviving patients, the 3-year OS and PFS rates for all patients were 44% and 52.8%. The median OS was 35 months, and the median PFS was 52 months (Fig. 1).

Figure 1.

Overall survival is illustrated for all patients with primary nasal diffuse large B-cell lymphoma.

Prognostic Factors

Clinical features were evaluated to determine their prognostic significance on OS. Univariate analysis revealed that performance status and the IPI score were significant prognostic factors for OS (Table 2). The 3-year OS rate was 51%, and the median OS was 48 months for patients who had an ECOG performance status of 0 or 1 compared with a 3-year OS rate of 20% and a median OS of 18 months for patients who had an ECOG performance status of 2 (P = .025). The corresponding OS rate and median OS were 54% and 52 months, respectively, for patients who had an IPI score of 0 or 1 compared with 17% and 11 months, respectively, for patients who had an IPI score of 2 or 3 (P = .033) (Fig. 2).

Figure 2.

Overall survival is illustrated according to the international prognostic index (IPI).

Table 2. Univariate Analysis of Prognostic Factors in Patients With Primary Nasal Diffuse Large B-Cell Lymphoma
 Overall Survival 
CharacteristicAt 3 Years, %Median, moP
  1. Abbreviations: CR, complete response; ECOG, European Cooperative Oncology Group; IPI, international prognostic index; LDH, lactate dehydrogenase; NA, not available.

Sex   
 Men3727.163
 WomenNANA 
Age, y   
 ≤605035.407
 >604023 
Stage   
 I-II4436.650
 III-IV3313 
LDH   
 Normal5952.135
 Elevated2011 
ECOG score   
 0-15148.025
 2-32018 
IPI   
 0-15452.033
 2-31711 
CR after therapy   
 CR6752.008
 Non-CR1313 

The prognosis for patients who achieved a CR was significantly better than that for patients who achieved a partial response or progressive disease. The 3-year OS rate and median OS were 67% and 52 months, respectively, for patients who had a CR compared with 13% and 13 months, respectively, for those who did not achieve a CR (P = .008) (Fig. 3).

Figure 3.

Overall survival is illustrated for patients who achieved a complete response (CR) and patients who did not achieve a CR (non-CR).

For patients with stage IE and IIE disease, the 3-year OS rate and median OS were 44% and 36 months, respectively. Of 3 patients who had stage IIIE and IVE disease, 2 died of their disease at 11 months and 13 months, and 1 was alive at the last follow-up of 73 months. No significant difference in survival was observed between chemotherapy with or without rituximab, chemotherapy plus radiotherapy and chemotherapy alone, or GC B-cell and non-GC B-cell subtype, probably because of the small number of patients (data not shown).

Patterns of Failure

Ten patients (40%) had developed progressive disease or a relapse. The failure patterns were analyzed in 8 of these patients who had sufficient data available. Extranodal dissemination was the primary pattern of failure; 7 patients developed extranodal failures, and 3 of these patients also developed distant lymph node failure. Only 1 patient had a local relapse, and none of the patients had a lymphatic recurrence in the head and neck area. The sites of extranodal dissemination observed were the skin (n = 2), testis (n = 2), lung and spleen (n = 1), central nervous system (CNS) (n = 1), and stomach (n = 1).

DISCUSSION

Although extranodal, nasal-type NK/T-cell lymphoma of the nasal cavity has been recognized as a distinct clinicopathologic entity and has been widely evaluated,15, 17, 25, 30-34 there are scarce data describing the clinical behavior and treatment outcome of nasal DLBCL.20, 22, 23 The current report provides a comprehensive evaluation that focuses exclusively on clinical features and treatment outcomes. Patients who had nasal DLBCL shared some clinical similarities and had some disparities with patients who had lymph node DLBCL and nasal NK/T-cell lymphoma.3, 25, 26, 35 Most of the clinical features of primary nasal DLBCL, such as the male predominance, large proportion of early stage disease, good performance status, low-risk IPI scores, and frequent extranodal failure, are similar to the features of nasal NK/T-cell lymphoma.25, 26, 30-34 In addition, nasal DLBCL and lymph node DLBCL share some similar features, such as older age of presentation, low frequency of B symptoms, and sensitivity to doxorubicin-based chemotherapy3, 9; however, these features are in contrast to those of nasal NK/T-cell lymphoma.15, 25, 32 Another finding from this study was that patients with nasal DLBCL appeared to have an unfavorable prognosis.

In this series, nasal DLBCL was observed primarily in older adults (median age, 58 years) and predominantly in men. The majority of patients presented with stage IE or IIE disease, and only 12% of patients had stage IIIE or IVE disease. This finding differed from that reported in patients with lymph node DLBCL, in which there was a slight predominance of early stage disease,3, 9 but was similar to the stage distribution reported in other series of nasal NK/T-cell lymphoma and DLBCL of the Waldeyer ring, in which early stage disease was more frequent (>70% of patients).3, 6, 26, 35 Similar to these latter lymphoma subtypes, the majority of patients with nasal DLBCL presented with a good performance status and a low IPI score. In contrast, patients with lymph node DLBCL tended to have intermediate-risk or high-risk IPI scores.3, 9

The primary pattern of failure for patients with nasal DLBCL was extranodal dissemination. The skipping lymph node spread to areas outside the head and neck observed at presentation and the propensity for extranodal failure post-treatment were indicative of noncontiguous spread by nasal DLBCL, a pattern reminiscent of nasal NK/T-cell lymphoma.25, 26 We observed a low frequency of CNS relapse (4%) in patients with nasal DLBCL; thus, and the use of CNS chemoprophylaxis was not justified.

Although patients with nasal DLBCL tended to have a low tumor burden, as indicated by the large proportion of early stage disease and the low frequency of elevated LDH and B symptoms, they had an unfavorable prognosis, and <50% of patients were alive at 3 years (median OS, 35 months). After they received standard treatment with CHOP or CHOP-like chemotherapy with or without rituximab, patients with nasal DLBCL seemed to suffer an aggressive clinical course. The survival in this series of patients with nasal DLBCL was inferior to that of most series of patients with lymph node or Waldeyer ring DLBCL and was even inferior to the survival of patients with nasal NK/T-cell lymphoma.3, 6, 17, 25, 35 The 5-year OS rate for patients with DLBCL is approximately 80% for those with localized disease and at least 50% for those with advanced disease.36-40 Because of their differing chemosensitivities, the treatment options for patients DLBCL differ from those for patients with nasal NK/T-cell lymphoma.15, 25, 36-40 In our previous studies, we reported a 5-year OS rate of 71% to 77% for patients with early stage nasal or Waldeyer ring NK/T-cell lymphoma who received primary radiotherapy.25, 26, 33, 41-43 However, other studies have demonstrated that patients with B-cell or T-cell lymphomas of the sinonasal tract or nose and nasopharynx had a higher survival rate than those with NK/T-cell lymphoma.12, 20 It should be noted that the prognosis for patients with DLBCL varies according to the primary disease site.2-9 Several studies have demonstrated that patients with DLBCL of the Waldeyer ring or gastrointestinal tract had better survival than those with lymph node DLBCL or DLBCL of the CNS.2, 3, 6, 9

Because of the rarity of the disease, the prognostic factors in nasal DLBCL have not been previously addressed. The current series demonstrates that performance status and IPI score are important prognostic factors. Patients with good performance status and low-risk IPI had a favorable survival rate, whereas those with poor performance status and intermediate-risk IPI scores had a very poor prognosis. Similarly, previous studies have indicated that the IPI score is an effective predictor of treatment outcome in patients with DLBCL and nasal NK/T-cell lymphoma.14, 25, 28, 44

Data from this study have demonstrated that primary nasal DLBCL appears to have clinical behavior and features that are distinct from those of lymph node DLBCL or nasal NK/T-cell lymphoma. The poor prognosis and propensity for extranodal failure observed in these patients illustrates the need for more effective or experimental therapies. Future work should be directed at exploration of the genome and gene expression profiling to achieve a better understanding of the biologic and clinical features of primary nasal DLBCL.

FUNDING SOURCES

This work was supported by grants from the National Natural Science Foundation of China (30870736 and 81071829).

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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