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Keywords:

  • nodal marginal zone lymphoma;
  • low-grade non-Hodgkin lymphoma;
  • marginal zone;
  • prognosis;
  • hepatitis C virus

Summary

  1. Top of page
  2. Summary
  3. Material and methods
  4. Results
  5. Discussion
  6. References

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63 years) with primary nodal marginal zone B-cell lymphoma. Forty-five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low-risk, 34% as intermediate-risk, and 33% as high-risk. The 5-year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (P = 0·02), age > 60 years (P = 0·05) and raised lactate dehydrogenase (P = 0·05). In multivariate analysis, only FLIPI predicted a worse OS (P = 0·02).

The term monocytoid B-cell lymphoma has been used since 1986 (Sheibani et al, 1986) to define neoplasms containing monocytoid B-cells, irrespective of involvement of nodal and/or extranodal sites (Fisher et al, 1995). Nodal monocytoid B-cell lymphoma was listed in the Revised European-American Classification of lymphoid neoplasms (REAL classification) as a provisional entity under the term nodal marginal zone lymphoma (MZL) (Harris et al, 1994). Finally, the World Health Organisation (WHO) lymphoma classification (Jaffe et al, 2001) considered primary nodal marginal zone B-cell lymphoma +/− monocytoid cells as an established entity.

Primary nodal marginal zone B-cell lymphoma is a rare disease accounting for nearly 2% of lymphoid neoplasms. Diagnosis requires lymph node localisation in the absence of prior or concurrent involvement of mucosa-associated lymphoid tissue (MALT) or spleen. Biologically, the pattern of immunoglobulin heavy-chain variable region mutations (Conconi et al, 2001) suggests that it may arise from different subsets of marginal zone B-cells. In addition, nodal MZL is frequently associated with hepatitis C virus (HCV) infection with preferential use of particular VH segments (Marasca et al, 2001).

Because of the small number of patients reported to date (Armitage & Weisenburger, 1998; Nathwani et al, 1999; Berger et al, 2000; Camacho et al, 2003; Traverse-Glehen et al, 2006) this uncommon lymphoma remains a clinical problem.

We carried out a study to define the clinical presentation and prognosis of primary nodal marginal zone B-cell lymphoma. Here we report the results on a series of 47 newly diagnosed patients.

Material and methods

  1. Top of page
  2. Summary
  3. Material and methods
  4. Results
  5. Discussion
  6. References

We studied the clinical features of 47 patients with newly diagnosed primary nodal MZL between 1994 and 2004. Approval was obtained from the Institutional Review Board of Intergruppo Italiano Linfomi (I.I.L.) for this retrospective study, which was based on the use of archival data. Data management and analysis were performed in accordance to the Helsinki Declaration of 1964, as revised in 2000.

Paraffin sections of lesional tissue (lymph nodes, bone marrow trephines) and immunohistochemical stains from all the cases were available for review by expert haematopathologists. Marginal zone B-cell lymphoma diagnosis was made according to WHO classification criteria. In all cases, the lymphoma population showed morphological (small to medium sized centrocyte-like or monocyoid B cells) and immunophenotypic (CD20+, CD79a+, CD5, bcl-1, CD10 and bcl-6) features consistent with a marginal zone origin. No patient showed MALT or splenic location of lymphoma at diagnosis.

Results

  1. Top of page
  2. Summary
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Clinical features

The clinical and biological features of the 47 patients with primary nodal MZL are reported in Table I. Six patients had stage I, five stage II, 15 stage III and 21 stage IV. Twenty-three patients (49%) had abdominal adenopathy, 46 (98%) superficial, and 12 (26%) thoracic adenopathy; 43 patients (91%) had lymph nodes above the diaphragm, 32 (68%) below the diaphragm, and 28 (60%) in both sides. A monoclonal component was detected in seven patients (6 IgM, 1 IgG). Four patients had an autoimmune background (autoimmune haemolytic anaemia, systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome). HCV serology was positive in nine of 38 (24%) and HCV-RNA was detectable in four of eight patients studied. Cryoglobulins were present in two of 14 cases tested. Hepatitis B surface antigen was positive in one of 38 patients. A history of solid neoplasia was reported in eight patients (previous in six, concomitant in one, subsequent in one). The Follicular Lymphoma International Prognostic Index (FLIPI) was applicable to 46 patients: 33% ranked in the low, 34% in the intermediate and 33% in the high risk group.

Table I.   Clinical features of 47 patients with primary nodal marginal zone B-cell lymphoma and comparison with data from prior reports.
 Present studyBerger et al (2000)Camacho et al (2003)Traverse-Glehen et al (2006)Armitage and Weisenburger (1998)Nathwani et al (1999)
  1. ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; HCV, Hepatitis C virus; FLIPI, Follicular Lymphoma International Prognostic Index.

  2. *Karnofsky score ≤ 70.

  3. ‡Mass ≥ 5 cm.

  4. †5% GI tract involvement.

Number of patients473722212020
Male (%)364332674244
Median age (years)635462545859
Age > 60 years (%)6435
ECOG score ≥2 (%)612·5147*0*
B symptoms (%)1513·5103714
Stage III–IV (%)776841767471
Peripheral lymph nodes (%)989595100
Abdominal/thoracic lymph nodes (%)234985
Head and neck localisation (%)53117181
Bone marrow involvement (%)454329623228
Liver involvement (%)0513
Splenomegaly (%)000
Spleen involvement (%)0025
Pleural localisation (%)03
Number of extranodal sites >1 (%)025016†
Bulky tumour (%)111731‡
Haemoglobin <120 g/l (%)113124
Blood involvement (%)1111924
Serum albumin <35 g/l (%)710
LDH >normal values (%)154043484036
β2-microglobulin >3 mg/l (%)45334129
M component (%)15833
HCV serology positive (%)24200
IPI (%)
 Low risk3731486057
 Low-intermediate risk2228472736
 High-intermediate risk3524  
 High risk6175137
5-year OS (%)695579645756

Treatment

Thirty-two patients received chemotherapy: 18 CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin and prednisone), three CVP (cyclophosphamide, vincristine, prednisone), nine chlorambucil, two fludarabine. Five patients were treated with radiotherapy alone and three with rituximab alone. One patient received front-line autotransplant. Six patients were followed without therapy. Twenty-one patients (57%) achieved a complete response and nine (24%) a partial response, for an overall response rate of 81%.

Pattern of progression and survival

After a median follow up of 2·6 years, no patient had developed splenic or MALT involvement during the course of disease. Median overall survival (OS) was not reached and the 5-year OS was 69% (95% CI 52–86%) (Fig 1A). Death occurred in 10 patients (related to lymphoma in nine). The median event-free survival (EFS) was 2·5 years, and the 5-year EFS was 29% (95% CI 11–47%).

image

Figure 1.  (A) Overall survival (OS) and event-free survival (EFS) of 47 patients with primary nodal marginal zone lymphoma. (B) Overall survival of 47 patients with primary nodal marginal zone lymphoma according to the Follicular Lymphoma International Prognostic Index (FLIPI).

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Prognostic factors

In univariate analysis, the following factors were associated with a poorer OS: FLIPI (P = 0·02), age > 60 years (P = 0·05), lactate dehydrogenase (LDH) above normal (P = 0·05). HCV positivity was of borderline significance (P = 0·06). The following factors were associated with a shorter EFS: B symptoms (P = 0·001), FLIPI score (P = 0·009) (Fig 1B), use of chemotherapy (containing anthracycline in 56%) (P = 0·01) and no response to treatment (P = 0·0001). In the multivariate analysis, FLIPI retained statistical significance in predicting a worse OS [P = 0·02, hazard ratio (HR) 3·5]; positive HCV serology was of borderline significance (P = 0·06, HR 4·4). The following parameters were predictive of shorter EFS: haemoglobin <120 g/l (P = 0·02, HR 14·3), and use of chemotherapy (P = 0·04, HR 21).

Discussion

  1. Top of page
  2. Summary
  3. Material and methods
  4. Results
  5. Discussion
  6. References

Histological and molecular characteristics of primary nodal MZL have been amply reported. In contrast, data on clinical presentation, prognosis and outcome are limited. As a consequence, although usually considered an indolent disorder, this entity is the least clinically defined among low-grade B-cell lymphomas.

Because of the rarity of this lymphoma, it is difficult to collect large series of patients with purely nodal disease. While some prior studies on nodal MZL include patients with pleural effusion or gastrointestinal disease, the present study includes only patients with lymph node localisation in the absence of prior or concurrent involvement of MALT or spleen. In addition, during the course of disease no patient showed signs of MALT or splenic disease, or pleural effusion. These data demonstrate that MZL can have an exclusive nodal expression at onset and during the course of the disease. Moreover, in primary nodal MZL we confirmed a relatively high HCV-seroprevalence, as reported by our group for splenic MZL (Arcaini et al, 2006). Regarding the outcome, in our series the FLIPI score identified one third of patients with a significantly shorter survival.

In conclusion, primary nodal B-cell MZL shows a distinct indolent behaviour; given the relative rarity of this lymphoma, the demonstration of the validity of FLIPI seems to be of clinical utility.

References

  1. Top of page
  2. Summary
  3. Material and methods
  4. Results
  5. Discussion
  6. References
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