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Pathology and clinical course of MALT lymphoma with plasmacytic differentiation
original article
Annals of Oncology 18: 2020–2024, 2007 doi:10.1093/annonc/mdm375 Published online 4 September 2007
Pathology and clinical course of MALT lymphoma with plasmacytic differentiation S. Wo¨hrer1, M. Troch1, B. Streubel2, M. Hoffmann3, L. Mu¨llauer2, A. Chott2 & M. Raderer1* Departments of 1Internal Medicine I; 2Pathology; 3Nuclear Medicine, Medical University of Vienna, Austria
Received 28 March 2007; revised 18 June 2007; accepted 27 June 2007
original article
mucosa-associated lymphoid tissue (MALT) lymphoma. To date, the influence of PCD on the clinical course of MALT lymphoma has not been assessed. Patients and methods: Therefore, we have retrospectively analysed the clinical characteristics and the course of the disease in 34 (25%) patients with PCD as compared with 101 (75%) MALT lymphoma patients without this histological feature. Results: Patients with PCD had significantly more extragastric lymphomas [28 of 34 (82%) versus 54 of 101 (53%), P = 0.003] and a significantly lower rate of t(11;18) [2 of 26 (8%) versus 22 of 72 (31%), P = 0.02]. There was no significant difference of age at diagnosis (62 versus 64 years, P = 0.64), relapse rate (48% versus 37%, P = 0.27), estimated median time to progression (43 versus 65 months, P = 0.14), monoclonal gammopathy (50% versus 44%, P = 0.63), t(14;18) involving IGH/MALT1 (11% versus 8%, P = 0.68), trisomy 3 (31% versus 27%, P = 0.69), trisomy 18 (8% versus 10%, P = 0.74) and the presence of autoimmune diseases between both groups (53% versus 37%, P = 0.09). Conclusion: In conclusion, we found that PCD is predominantly found in extragastric MALT lymphoma but has no significant impact on clinical course and prognosis. Key words: clinical course, MALT lymphoma, pathology, plasmacytic differentiation
introduction Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively common lymphoma and comprises 7% of all newly diagnosed non-Hodgkin’s lymphomas [1]. The clinical course is relatively indolent, and most patients die of causes unrelated to lymphoma [2]. Chronic inflammation, i.e. infectious agents or autoimmune diseases, seem to be a distinctive prerequisite for the development of MALT lymphoma [3]. The ongoing inflammatory stimulus leads to accumulation of aberrant extranodal lymphoid tissue, to the development of monoclonal B cells and finally to the emergence of clinically apparent MALT lymphoma. The presumed cell of origin of MALT lymphoma is the postgerminal marginal zone B cell that is thought to precede the plasma cell in the course of B-cell development [1]. However, the marginal zone contains a very heterogeneous B-cell population that can also differentiate in loco into plasma cells that secrete low-affinity antibodies. Therefore, the postgerminal centre origin for marginal zone B cells is far from being proved.
In fact, MALT lymphoma may include an abundant number of monoclonal plasma cells, a phenomenon termed plasmacytic differentiation (PCD). According to the literature, PCD is present in up to 30% of patients diagnosed with MALT lymphoma [1]. An analysis on the frequency of monoclonal immunoglobulin production carried out at our institution has indicated an association between PCD and monoclonal gammopathy [4]. In this series, however, the number of patients with PCD was relatively small as only 13 of 52 patients (25%) showed evidence of PCD. Interestingly, it was also found that MALT lymphoma with PCD can be visualised with positron emission tomography scan as opposed to the classical variant [5]. This result implied a different tumour biology of MALT with PCD and begged the question whether it differs also in the clinical course. Currently, the potential impact of PCD on the clinical course of MALT lymphoma is not clear. In view of this, we have analysed the clinical characteristics and the course of the disease in patients with PCD as compared with MALT lymphoma patients without this histological feature.
patients and methods *Correspondence to: M. Raderer, MD, Department of Internal Medicine I, Division of Oncology, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel/Fax: +43-1-40400-2296; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
A total of 135 patients (57 females/78 males) with a diagnosis of MALT lymphoma diagnosed and treated between 1997 and 2006 at our institution
Downloaded from http://annonc.oxfordjournals.org/ at University of Massachusetts Medical School on April 6, 2015
Background: The feature of plasmacytic differentiation (PCD) is present in up to 30% of patients diagnosed with
original article
Annals of Oncology
results A total of 135 patients were available for analysis; 53 (39%) had gastric, while 82 (61%) had extragastric MALT lymphoma (for detailed characteristics, see Table 1). Out of these 135 patients, 34 (25%) were found to have PCD. With regard to PCD, consensus was reached in all patients by blinded independent pathological assessment. There was no significant difference between the two groups (i.e. with or without PCD) with regard
Volume 18 | No. 12 | December 2007
to gender (22 males, 12 females, P = 0.34), median age {62 [interquartile range (IQR): 50–73] versus 64 [IQR: 50–74], P = 0.64} and median follow-up time [32.5 (IQR: 15–58) versus 39 (IQR: 21–60), P = 0.788] (Table 1). In addition, both groups had a comparable rate of multifocal disease [17 of 34 (50%) versus 42 of 101 (42%), P = 0.39]. Patients with PCD had a significantly higher rate of extragastric MALT lymphoma [28 of 34 (82%) versus 54 of 101 (53%), P = 0.003] (Table 2) and a significantly lower rate of t(11;18) (q21;q21) [2 of 26 (8%) versus 22 of 72 (31%), P = 0.02] compared with the group of patients without PCD. There was no difference in the presence of trisomy 3, trisomy 18 and t(14;18) [8 of 26 (31%)
Table 1. Patient characteristics
Male/female ratio Age (years) Extragastric disease Gastric disease Multifocal disease Trisomy 3 Trisomy 18 t(11;18) (q21;q21) t(14;18)-IGH/MALT1 Autoimmune disease Monoclonal gammopathy Median follow-up time Relapse Estimated median time to progression (months)
PCD
No PCD
P value
1.8 62 (IQR: 50–73) 82% (28/34) 17% (6/34) 50% (17/34) 31% (8/26)a 8% (2/26)a 8% (2/26)a 11% (3/27)a 53% (18/34) 50% (13/26)a
1.2 64 (IQR: 50–74) 53% (54/101) 47% (47/101) 42% (42/101) 27% (19/71)a 10% (7/71)a 31% (22/72)a 8% (6/71)a 37% (37/101) 44% (28/63)a
0.344 0.64 0.003 0.003 0.392 0.696 0.745 0.02 0.684 0.094 0.633
32.5 (IQR: 15–58)
39 (IQR: 21–60) 0.788
48% (15/31) 37% (37/99) 0.275 43 (IQR: 27–59) 65 (IQR: 34–96) 0.14
PCD, plasmacytic differentiation; IQR, interquartile range, t(11;18), translocation (11;18) (q21;q21); t(14;18), translocation (14;18) (q32;q21); figures in parentheses, affected patients/evaluated patients. a Data not available in every patient.
Table 2. Plasmacytic differentiation (PCD) with regard to location Location
PCD
Non-PCD
Stomach: 53 (39%) Salivary glands: 36 (27%) Thyroid: 7 (5%) Orbital adnexa: 11 (8%) Lymph nodes: 3 (2%) Lung: 9 (7%) Intestine: 8 (6%) Breast: 3 (2%) Liver: 2 (1.5%) Kidney: 2 (1.5%) Skin: 1 (1%) Total: 135 (100%)
6 11 5 3 0 3 5 1 0 0 0 34
47 25 2 8 3 6 3 2 2 2 1 101
(11%) (31%) (71%) (27%) (0%) (33%) (62%) (33%) (0%) (0%) (0%) (25%)
(89%) (69%) (29%) (73%) (100%) (67%) (38%) (67%) (100%) (100%) (100%) (75%)
doi:10.1093/annonc/mdm375 | 2021
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were available for analysis. Assessment of histology and PCD was carried out by two reference hematopathologists (AC, LM). Biopsy samples were evaluated according to the criteria established by Isaacson [6] and adopted in the recent World Health Organisation (WHO) classification for MALT lymphoma [7]. In all patients, immunologic phenotyping on paraffin sections was done for demonstration of light chain restriction and for the phenotype CD20+CD5-CD10-cyclinD1- which, in context with the microscopic appearance, is consistent with extranodal marginal zone B-cell lymphoma of MALT. PCD was defined as light-chain-restricted plasma cells growing in sheets, and was reassessed in all samples suggestive for lymphoma involvement in our patients (Figure 4). Presence of PCD was assessed according to the WHO classification [7] in an independent fashion by the two hematopathologists involved in the study. All patients underwent extensive staging before initiation of therapy, consisting of ophthalmologic and otorhinolaryngologic examination, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen and bone marrow biopsy as previously indicated [8]. Staging was carried out according to the Ann Arbor staging system as modified by Musshoff and Radaszkiewicz [9, 10]. Clinical information evaluated included age of the patient, time of initial diagnosis, site and extent of the lymphoma, occurrence of and time to progression (TtP), presence of monoclonal immunoglobulins as assessed by serum electrophoresis, quantitative measurements of IgG, IgM and IgA and immunofixation, treatment and survival. In addition, routine assessment of patients for an underlying autoimmune disease was carried out. Paraffin-embedded biopsy samples were tested for MALT lymphomaspecific genetic aberrations including t(11;18) (q21;q21), t(14;18) (q32;q21) involving IGH and MALT1, and trisomies 3 and 18. t(11;18) (q21;q21) involving API2 and MALT1 was assessed by RT-PCR, t(14;18) (q32;q21) involving IGH and MALT1, and trisomies 3 and 18 were investigated by FISH [11]. These genetic studies were carried out on representative biopsies where a diagnosis of MALT lymphoma had been established by histopathology if enough material was available. Treatment consisted of watchful waiting, exclusive Helicobacter pylori eradication therapy, local therapy (surgery or radiotherapy), systemic therapy (chemo- or immuno-chemotherapy) or a combination of local and systemic therapy. Various systemic approaches have been used as reported previously [12–17]. There was no significant difference with regard to treatment between both groups (P = 0.23). In total, 4% (n = 5) had no therapy, 16% (n = 22) exclusive Helicobacter pylori eradication therapy, 23% (n = 31) local therapy, 41% (n = 55) systemic therapy and 16% (n = 22) a combination of local and systemic therapy. The statistical analyses were done with the SPSS 14.0.1 (SPSS Inc.) program. Binary outcome variables were tested for significant differences with the chi-square test and the Fisher’s exact test, respectively. A P value <0.05 was considered statistically significant. The survival analyses were done with the Kaplan–Meier method and the log-rank test. Non-parametric continuous variables were tested for significance with the Mann–Whitney U test.
original article
discussion Out of our cohort of 135 patients, 34 (25%) were found to have PCD. This percentage is in keeping with previous reports [1] and again underscores that PCD is a common phenomenon in MALT lymphoma. There was no significant difference with regard to patient age (P = 0.64) and gender (P = 0.34). However, patients with PCD had a significantly higher rate of extragastric disease (P = 0.003). In view of this, it is interesting to note that the rate of multifocal disease was not statistically
Figure 1. Progression-free survival. Black line: no plasmacytic differentiation (PCD), broken line: PCD.
2022 | Wo¨hrer et al.
different, as extragastric MALT lymphomas have a significantly higher rate of dissemination as compared with their gastric counterpart [18]. In addition, also the rate of underlying autoimmune diseases was not significantly different (P = 0.094), although autoimmune diseases are thought to play an important part in the development of non-gastric MALT lymphomas especially of the salivary and thyroid gland. In view of this, one might hypothesize that PCD is a feature of extragastric MALT lymphoma per se. In our series, lymphomas with PCD had a very low rate of t(11;18) (q21;q21) as only two out of 26 evaluated patients had this translocation, whereas 22 out of 72 patients without PCD were positive (P = 0.02). This finding, however, has to be interpreted in view of the fact that t(11;18) (q21;q21) is predominantly found in gastric MALT lymphoma which—as mentioned before—rarely displays PCD. As opposed to previous reports [4, 20], there was no significant association between PCD and the presence of monoclonal gammopathy [4, 20] in our present analysis. This is slightly surprising, as one would expect that MALT lymphomas with PCD are closely related to plasma cell-derived tumours and would thus be able to produce and secrete mAbs. This hypothesis was also supported by the fact from a previous study that the immunoglobulin light chains on the surface of MALT lymphoma cells are often identical with those found in the patient’s serum. This indicates that the antibodies are indeed produced by the lymphoma cells [4] rather than being a perchance association of MALT lymphoma with monoclonal gammopathy of unknown significance, which might be expected only in a minority of (elderly) patients. The data from this largest analysis so far however did not show such an association and indicate that also MALT lymphomas without PCD are capable of producing monoclonal immunoglobulins.
Figure 2. Time to progression with regard to disease dissemination. Black line: no plasmacytic differentiation (PCD) and systemic disease, black broken line: no PCD and local disease, grey line: PCD and local disease, grey broken line: PCD and systemic disease.
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versus 19 of 71 (27%), P = 0.69; 2 of 26 (8%) versus 7 of 71 (10%), P = 0.74 and 3 of 27 (11%) versus 6 of 71 (8%), P = 0.68]. Autoimmune diseases were present in 40% (n = 55) of all patients with no statistically significant difference between both groups [18 of 34 (53%) versus 37 of 101 (37%), P = 0.09]. Monoclonal immunoglobulin production was found in 46% (n = 41) of all patients, with no significant difference between both groups [13 of 26 (50%) versus 28 of 63 (44%), P = 0.63]. The overall relapse rate was 40% (n = 52) and comparable between both groups [15 of 31 (48%) versus 37 of 99 (37%), P = 0.27] and was irrespective of treatment approach (local versus systemic). The estimated median TtP was also not significantly different {43 [confidence interval (CI): 27–59] months versus 65 [CI: 34–96] months, P = 0.14} (Figure 1) even when analysed with regard to initial disease dissemination (P = 0.371) (Figure 2). No significant difference was found in death rate [8 of 34 (23%) versus 12 of 101 (12%), P = 0.1] and overall survival (OS) (P = 0.084, median survival time not reached) (Figure 3). Helicobacter pylori was detected in 50 of 94 (53%) patients and the rate of infection was similar between both groups [17 of 26 (65%) versus 33 of 68 (49%), P = 0.14].
Annals of Oncology
Annals of Oncology
In addition, we also found a trend that patients with autoimmune diseases had a higher rate of PCD, though the association did not reach statistical significance (P = 0.1). Treatment of both groups was comparable as 50% of the PCD and 37% of the non-PCD group received systemic therapy (P = 0.2). The relapse rate as well as the estimated median TtP were not significantly different between the two groups (Figure 1) after a median follow-up time of 39 months. Interestingly, treatment with rituximab-containing regimens was equally
effective in patients with PCD, which was somewhat surprising since plasmacytic cells are devoid of CD20. Most of these patients, however, received an immuno-chemotherapy and the lack of activity of rituximab might have been blurred through the chemotherapy effect in these patients. One patient with PCD was treated solely with rituximab and responded well (complete remission) to this treatment. On the other hand, one patient without PCD who was also treated with rituximab monotherapy suffered from a relapsing lymphoma with a pure plasma cell histology [21]. Thus, the possible plasmacytic selection and the consecutive loss of effectiveness should be kept in mind during rituximab monotherapy. The OS curves were also not significantly different between the two groups and were typically low with the median survival time not reached (Figure 3). We used the TtP as a surrogate clinical end point for aggressiveness, as the low lymphomarelated death rate in MALT lymphoma generally does not make OS a useful parameter. If analysed separately with regard to local versus multifocal disease, PCD did not significantly influence TtP (Figure 2). This, together with the finding of a low genetic aberration rate, implies that PCD is not a sign of increased aggressiveness or progression of MALT lymphoma. During our study, no switch from normal to plasmacytic MALT lymphoma or vice versa occurred, which also indicates that PCD is an inherent feature present at initial diagnosis rather than being acquired in the course of the disease. In conclusion, we found that PCD is predominantly found in extragastric MALT lymphoma but has no significant impact on clinical course and prognosis. Furthermore, we indicate that the production of monoclonal immunoglobulin is not necessarily dependent on PCD but can also be found in normal MALT lymphoma.
Figure 4. MALT lymphoma of the orbit showing plasmacytic differentiation. Giemsa-stained section depicts area of densely packed mature plasma cells and plasmacytoid cells. Immunohistochemically these cells are CD20-negative but express CD138 and show j-light chain restriction.
Volume 18 | No. 12 | December 2007
doi:10.1093/annonc/mdm375 | 2023
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Figure 3. Overall survival. Black line: no plasmacytic differentiation (PCD), broken line: PCD.
original article
original article references
2024 | Wo¨hrer et al.
12. Jager G, Neumeister P, Brezinschek R et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study. J Clin Oncol 2002; 20(18): 3872–3877. 13. Raderer M, Jager G, Brugger S et al. Rituximab for treatment of advanced extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue lymphoma. Oncology 2003; 65(4): 306–310. 14. Jager G, Neumeister P, Quehenberger F et al. Prolonged clinical remission in patients with extranodal marginal zone B-cell lymphoma of the mucosaassociated lymphoid tissue type treated with cladribine: 6 year follow-up of a phase II trial. Ann Oncol 2006; 17(11): 1722–1723. 15. Raderer M, Wohrer S, Bartsch R et al. Phase II study of oxaliplatin for treatment of patients with mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005; 23(33): 8442–8446. 16. Raderer M, Wohrer S, Streubel B et al. Activity of rituximab plus cyclophosphamide, doxorubicin/mitoxantrone, vincristine and prednisone in patients with relapsed MALT lymphoma. Oncology 2007; 70(6): 411–417. 17. Wohrer S, Drach J, Hejna M et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP). Ann Oncol 2003; 14(12): 1758–1761. 18. Raderer M, Wohrer S, Streubel B et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol 2006; 24(19): 3136–3141. 19. Okabe M, Inagaki H, Ohshima K et al. API2-MALT1 fusion defines a distinctive clinicopathologic subtype in pulmonary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Am J Pathol 2003; 162(4): 1113–1122. 20. Van Huyen JP, Molina T, Delmer A et al. Splenic marginal zone lymphoma with or without plasmacytic differentiation. Am J Surg Pathol 2000; 24(12): 1581–1592. 21. Woehrer S, Streubel B, Chott A et al. Transformation of MALT lymphoma to pure plasma cell histology following treatment with the anti-CD20 antibody rituximab. Leuk Lymphoma 2005; 46(11): 1645–1649.
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1. Isaacson P, Mu¨ller-Hermelink HK, Piris MA et al. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In Jaffe ES, Harris NL, SHaVJ (eds): Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press 2001; 157–160. 2. Raderer M, Streubel B, Woehrer S et al. High relapse rate in patients with MALT lymphoma warrants lifelong follow-up. Clin Cancer Res 2005; 11(9): 3349–3352. 3. Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005; 23(26): 6370–6378. 4. Wohrer S, Streubel B, Bartsch R et al. Monoclonal immunoglobulin production is a frequent event in patients with mucosa-associated lymphoid tissue lymphoma. Clin Cancer Res 2004; 10(21): 7179–7181. 5. Hoffmann M, Wohrer S, Becherer A et al. 18F-fluoro-deoxy-glucose positron emission tomography in lymphoma of mucosa-associated lymphoid tissue: histology makes the difference. Ann Oncol 2006; 17(12): 1761–1765. 6. Isaacson P, Wright DH. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983; 52(8): 1410–1416. 7. International Lymphoma Study Group. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The NonHodgkin’s Lymphoma Classification Project. Blood 1997; 89(11): 3909–3918. 8. Raderer M, Vorbeck F, Formanek M et al. Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 2000; 83(4): 454–457. 9. Musshoff K. Clinical staging classification of non-Hodgkin’s lymphomas [author’s translation]. Strahlentherapie 1977; 153(4): 218–221. 10. Radaszkiewicz T, Dragosics B, Bauer P. Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: factors relevant to prognosis. Gastroenterology 1992; 102(5): 1628–1638. 11. Streubel B, Seitz G, Stolte M et al. MALT lymphoma associated genetic aberrations occur at different frequencies in primary and secondary intestinal MALT lymphomas. Gut 2006; 55(11): 1581–1585.
Annals of Oncology
Annals of Oncology 18: 2020–2024, 2007 doi:10.1093/annonc/mdm375 Published online 4 September 2007
Pathology and clinical course of MALT lymphoma with plasmacytic differentiation S. Wo¨hrer1, M. Troch1, B. Streubel2, M. Hoffmann3, L. Mu¨llauer2, A. Chott2 & M. Raderer1* Departments of 1Internal Medicine I; 2Pathology; 3Nuclear Medicine, Medical University of Vienna, Austria
Received 28 March 2007; revised 18 June 2007; accepted 27 June 2007
original article
mucosa-associated lymphoid tissue (MALT) lymphoma. To date, the influence of PCD on the clinical course of MALT lymphoma has not been assessed. Patients and methods: Therefore, we have retrospectively analysed the clinical characteristics and the course of the disease in 34 (25%) patients with PCD as compared with 101 (75%) MALT lymphoma patients without this histological feature. Results: Patients with PCD had significantly more extragastric lymphomas [28 of 34 (82%) versus 54 of 101 (53%), P = 0.003] and a significantly lower rate of t(11;18) [2 of 26 (8%) versus 22 of 72 (31%), P = 0.02]. There was no significant difference of age at diagnosis (62 versus 64 years, P = 0.64), relapse rate (48% versus 37%, P = 0.27), estimated median time to progression (43 versus 65 months, P = 0.14), monoclonal gammopathy (50% versus 44%, P = 0.63), t(14;18) involving IGH/MALT1 (11% versus 8%, P = 0.68), trisomy 3 (31% versus 27%, P = 0.69), trisomy 18 (8% versus 10%, P = 0.74) and the presence of autoimmune diseases between both groups (53% versus 37%, P = 0.09). Conclusion: In conclusion, we found that PCD is predominantly found in extragastric MALT lymphoma but has no significant impact on clinical course and prognosis. Key words: clinical course, MALT lymphoma, pathology, plasmacytic differentiation
introduction Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively common lymphoma and comprises 7% of all newly diagnosed non-Hodgkin’s lymphomas [1]. The clinical course is relatively indolent, and most patients die of causes unrelated to lymphoma [2]. Chronic inflammation, i.e. infectious agents or autoimmune diseases, seem to be a distinctive prerequisite for the development of MALT lymphoma [3]. The ongoing inflammatory stimulus leads to accumulation of aberrant extranodal lymphoid tissue, to the development of monoclonal B cells and finally to the emergence of clinically apparent MALT lymphoma. The presumed cell of origin of MALT lymphoma is the postgerminal marginal zone B cell that is thought to precede the plasma cell in the course of B-cell development [1]. However, the marginal zone contains a very heterogeneous B-cell population that can also differentiate in loco into plasma cells that secrete low-affinity antibodies. Therefore, the postgerminal centre origin for marginal zone B cells is far from being proved.
In fact, MALT lymphoma may include an abundant number of monoclonal plasma cells, a phenomenon termed plasmacytic differentiation (PCD). According to the literature, PCD is present in up to 30% of patients diagnosed with MALT lymphoma [1]. An analysis on the frequency of monoclonal immunoglobulin production carried out at our institution has indicated an association between PCD and monoclonal gammopathy [4]. In this series, however, the number of patients with PCD was relatively small as only 13 of 52 patients (25%) showed evidence of PCD. Interestingly, it was also found that MALT lymphoma with PCD can be visualised with positron emission tomography scan as opposed to the classical variant [5]. This result implied a different tumour biology of MALT with PCD and begged the question whether it differs also in the clinical course. Currently, the potential impact of PCD on the clinical course of MALT lymphoma is not clear. In view of this, we have analysed the clinical characteristics and the course of the disease in patients with PCD as compared with MALT lymphoma patients without this histological feature.
patients and methods *Correspondence to: M. Raderer, MD, Department of Internal Medicine I, Division of Oncology, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel/Fax: +43-1-40400-2296; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
A total of 135 patients (57 females/78 males) with a diagnosis of MALT lymphoma diagnosed and treated between 1997 and 2006 at our institution
Downloaded from http://annonc.oxfordjournals.org/ at University of Massachusetts Medical School on April 6, 2015
Background: The feature of plasmacytic differentiation (PCD) is present in up to 30% of patients diagnosed with
original article
Annals of Oncology
results A total of 135 patients were available for analysis; 53 (39%) had gastric, while 82 (61%) had extragastric MALT lymphoma (for detailed characteristics, see Table 1). Out of these 135 patients, 34 (25%) were found to have PCD. With regard to PCD, consensus was reached in all patients by blinded independent pathological assessment. There was no significant difference between the two groups (i.e. with or without PCD) with regard
Volume 18 | No. 12 | December 2007
to gender (22 males, 12 females, P = 0.34), median age {62 [interquartile range (IQR): 50–73] versus 64 [IQR: 50–74], P = 0.64} and median follow-up time [32.5 (IQR: 15–58) versus 39 (IQR: 21–60), P = 0.788] (Table 1). In addition, both groups had a comparable rate of multifocal disease [17 of 34 (50%) versus 42 of 101 (42%), P = 0.39]. Patients with PCD had a significantly higher rate of extragastric MALT lymphoma [28 of 34 (82%) versus 54 of 101 (53%), P = 0.003] (Table 2) and a significantly lower rate of t(11;18) (q21;q21) [2 of 26 (8%) versus 22 of 72 (31%), P = 0.02] compared with the group of patients without PCD. There was no difference in the presence of trisomy 3, trisomy 18 and t(14;18) [8 of 26 (31%)
Table 1. Patient characteristics
Male/female ratio Age (years) Extragastric disease Gastric disease Multifocal disease Trisomy 3 Trisomy 18 t(11;18) (q21;q21) t(14;18)-IGH/MALT1 Autoimmune disease Monoclonal gammopathy Median follow-up time Relapse Estimated median time to progression (months)
PCD
No PCD
P value
1.8 62 (IQR: 50–73) 82% (28/34) 17% (6/34) 50% (17/34) 31% (8/26)a 8% (2/26)a 8% (2/26)a 11% (3/27)a 53% (18/34) 50% (13/26)a
1.2 64 (IQR: 50–74) 53% (54/101) 47% (47/101) 42% (42/101) 27% (19/71)a 10% (7/71)a 31% (22/72)a 8% (6/71)a 37% (37/101) 44% (28/63)a
0.344 0.64 0.003 0.003 0.392 0.696 0.745 0.02 0.684 0.094 0.633
32.5 (IQR: 15–58)
39 (IQR: 21–60) 0.788
48% (15/31) 37% (37/99) 0.275 43 (IQR: 27–59) 65 (IQR: 34–96) 0.14
PCD, plasmacytic differentiation; IQR, interquartile range, t(11;18), translocation (11;18) (q21;q21); t(14;18), translocation (14;18) (q32;q21); figures in parentheses, affected patients/evaluated patients. a Data not available in every patient.
Table 2. Plasmacytic differentiation (PCD) with regard to location Location
PCD
Non-PCD
Stomach: 53 (39%) Salivary glands: 36 (27%) Thyroid: 7 (5%) Orbital adnexa: 11 (8%) Lymph nodes: 3 (2%) Lung: 9 (7%) Intestine: 8 (6%) Breast: 3 (2%) Liver: 2 (1.5%) Kidney: 2 (1.5%) Skin: 1 (1%) Total: 135 (100%)
6 11 5 3 0 3 5 1 0 0 0 34
47 25 2 8 3 6 3 2 2 2 1 101
(11%) (31%) (71%) (27%) (0%) (33%) (62%) (33%) (0%) (0%) (0%) (25%)
(89%) (69%) (29%) (73%) (100%) (67%) (38%) (67%) (100%) (100%) (100%) (75%)
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were available for analysis. Assessment of histology and PCD was carried out by two reference hematopathologists (AC, LM). Biopsy samples were evaluated according to the criteria established by Isaacson [6] and adopted in the recent World Health Organisation (WHO) classification for MALT lymphoma [7]. In all patients, immunologic phenotyping on paraffin sections was done for demonstration of light chain restriction and for the phenotype CD20+CD5-CD10-cyclinD1- which, in context with the microscopic appearance, is consistent with extranodal marginal zone B-cell lymphoma of MALT. PCD was defined as light-chain-restricted plasma cells growing in sheets, and was reassessed in all samples suggestive for lymphoma involvement in our patients (Figure 4). Presence of PCD was assessed according to the WHO classification [7] in an independent fashion by the two hematopathologists involved in the study. All patients underwent extensive staging before initiation of therapy, consisting of ophthalmologic and otorhinolaryngologic examination, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen and bone marrow biopsy as previously indicated [8]. Staging was carried out according to the Ann Arbor staging system as modified by Musshoff and Radaszkiewicz [9, 10]. Clinical information evaluated included age of the patient, time of initial diagnosis, site and extent of the lymphoma, occurrence of and time to progression (TtP), presence of monoclonal immunoglobulins as assessed by serum electrophoresis, quantitative measurements of IgG, IgM and IgA and immunofixation, treatment and survival. In addition, routine assessment of patients for an underlying autoimmune disease was carried out. Paraffin-embedded biopsy samples were tested for MALT lymphomaspecific genetic aberrations including t(11;18) (q21;q21), t(14;18) (q32;q21) involving IGH and MALT1, and trisomies 3 and 18. t(11;18) (q21;q21) involving API2 and MALT1 was assessed by RT-PCR, t(14;18) (q32;q21) involving IGH and MALT1, and trisomies 3 and 18 were investigated by FISH [11]. These genetic studies were carried out on representative biopsies where a diagnosis of MALT lymphoma had been established by histopathology if enough material was available. Treatment consisted of watchful waiting, exclusive Helicobacter pylori eradication therapy, local therapy (surgery or radiotherapy), systemic therapy (chemo- or immuno-chemotherapy) or a combination of local and systemic therapy. Various systemic approaches have been used as reported previously [12–17]. There was no significant difference with regard to treatment between both groups (P = 0.23). In total, 4% (n = 5) had no therapy, 16% (n = 22) exclusive Helicobacter pylori eradication therapy, 23% (n = 31) local therapy, 41% (n = 55) systemic therapy and 16% (n = 22) a combination of local and systemic therapy. The statistical analyses were done with the SPSS 14.0.1 (SPSS Inc.) program. Binary outcome variables were tested for significant differences with the chi-square test and the Fisher’s exact test, respectively. A P value <0.05 was considered statistically significant. The survival analyses were done with the Kaplan–Meier method and the log-rank test. Non-parametric continuous variables were tested for significance with the Mann–Whitney U test.
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discussion Out of our cohort of 135 patients, 34 (25%) were found to have PCD. This percentage is in keeping with previous reports [1] and again underscores that PCD is a common phenomenon in MALT lymphoma. There was no significant difference with regard to patient age (P = 0.64) and gender (P = 0.34). However, patients with PCD had a significantly higher rate of extragastric disease (P = 0.003). In view of this, it is interesting to note that the rate of multifocal disease was not statistically
Figure 1. Progression-free survival. Black line: no plasmacytic differentiation (PCD), broken line: PCD.
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different, as extragastric MALT lymphomas have a significantly higher rate of dissemination as compared with their gastric counterpart [18]. In addition, also the rate of underlying autoimmune diseases was not significantly different (P = 0.094), although autoimmune diseases are thought to play an important part in the development of non-gastric MALT lymphomas especially of the salivary and thyroid gland. In view of this, one might hypothesize that PCD is a feature of extragastric MALT lymphoma per se. In our series, lymphomas with PCD had a very low rate of t(11;18) (q21;q21) as only two out of 26 evaluated patients had this translocation, whereas 22 out of 72 patients without PCD were positive (P = 0.02). This finding, however, has to be interpreted in view of the fact that t(11;18) (q21;q21) is predominantly found in gastric MALT lymphoma which—as mentioned before—rarely displays PCD. As opposed to previous reports [4, 20], there was no significant association between PCD and the presence of monoclonal gammopathy [4, 20] in our present analysis. This is slightly surprising, as one would expect that MALT lymphomas with PCD are closely related to plasma cell-derived tumours and would thus be able to produce and secrete mAbs. This hypothesis was also supported by the fact from a previous study that the immunoglobulin light chains on the surface of MALT lymphoma cells are often identical with those found in the patient’s serum. This indicates that the antibodies are indeed produced by the lymphoma cells [4] rather than being a perchance association of MALT lymphoma with monoclonal gammopathy of unknown significance, which might be expected only in a minority of (elderly) patients. The data from this largest analysis so far however did not show such an association and indicate that also MALT lymphomas without PCD are capable of producing monoclonal immunoglobulins.
Figure 2. Time to progression with regard to disease dissemination. Black line: no plasmacytic differentiation (PCD) and systemic disease, black broken line: no PCD and local disease, grey line: PCD and local disease, grey broken line: PCD and systemic disease.
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versus 19 of 71 (27%), P = 0.69; 2 of 26 (8%) versus 7 of 71 (10%), P = 0.74 and 3 of 27 (11%) versus 6 of 71 (8%), P = 0.68]. Autoimmune diseases were present in 40% (n = 55) of all patients with no statistically significant difference between both groups [18 of 34 (53%) versus 37 of 101 (37%), P = 0.09]. Monoclonal immunoglobulin production was found in 46% (n = 41) of all patients, with no significant difference between both groups [13 of 26 (50%) versus 28 of 63 (44%), P = 0.63]. The overall relapse rate was 40% (n = 52) and comparable between both groups [15 of 31 (48%) versus 37 of 99 (37%), P = 0.27] and was irrespective of treatment approach (local versus systemic). The estimated median TtP was also not significantly different {43 [confidence interval (CI): 27–59] months versus 65 [CI: 34–96] months, P = 0.14} (Figure 1) even when analysed with regard to initial disease dissemination (P = 0.371) (Figure 2). No significant difference was found in death rate [8 of 34 (23%) versus 12 of 101 (12%), P = 0.1] and overall survival (OS) (P = 0.084, median survival time not reached) (Figure 3). Helicobacter pylori was detected in 50 of 94 (53%) patients and the rate of infection was similar between both groups [17 of 26 (65%) versus 33 of 68 (49%), P = 0.14].
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In addition, we also found a trend that patients with autoimmune diseases had a higher rate of PCD, though the association did not reach statistical significance (P = 0.1). Treatment of both groups was comparable as 50% of the PCD and 37% of the non-PCD group received systemic therapy (P = 0.2). The relapse rate as well as the estimated median TtP were not significantly different between the two groups (Figure 1) after a median follow-up time of 39 months. Interestingly, treatment with rituximab-containing regimens was equally
effective in patients with PCD, which was somewhat surprising since plasmacytic cells are devoid of CD20. Most of these patients, however, received an immuno-chemotherapy and the lack of activity of rituximab might have been blurred through the chemotherapy effect in these patients. One patient with PCD was treated solely with rituximab and responded well (complete remission) to this treatment. On the other hand, one patient without PCD who was also treated with rituximab monotherapy suffered from a relapsing lymphoma with a pure plasma cell histology [21]. Thus, the possible plasmacytic selection and the consecutive loss of effectiveness should be kept in mind during rituximab monotherapy. The OS curves were also not significantly different between the two groups and were typically low with the median survival time not reached (Figure 3). We used the TtP as a surrogate clinical end point for aggressiveness, as the low lymphomarelated death rate in MALT lymphoma generally does not make OS a useful parameter. If analysed separately with regard to local versus multifocal disease, PCD did not significantly influence TtP (Figure 2). This, together with the finding of a low genetic aberration rate, implies that PCD is not a sign of increased aggressiveness or progression of MALT lymphoma. During our study, no switch from normal to plasmacytic MALT lymphoma or vice versa occurred, which also indicates that PCD is an inherent feature present at initial diagnosis rather than being acquired in the course of the disease. In conclusion, we found that PCD is predominantly found in extragastric MALT lymphoma but has no significant impact on clinical course and prognosis. Furthermore, we indicate that the production of monoclonal immunoglobulin is not necessarily dependent on PCD but can also be found in normal MALT lymphoma.
Figure 4. MALT lymphoma of the orbit showing plasmacytic differentiation. Giemsa-stained section depicts area of densely packed mature plasma cells and plasmacytoid cells. Immunohistochemically these cells are CD20-negative but express CD138 and show j-light chain restriction.
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Figure 3. Overall survival. Black line: no plasmacytic differentiation (PCD), broken line: PCD.
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original article references
2024 | Wo¨hrer et al.
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