Splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, an indolent B-cell non-Hodgkin lymphoma, is the leukaemic manifestation of SMZL (Catovsky & Matutes, 1999). Despite its chronic clinical course and response to splenectomy (Mulligan et al, 1991; Parry-Jones et al, 2003), similar to other lymphoproliferative disorders, it may undergo transformation to high-grade lymphoma with the development of bulky lymphadenopathy or blastic cells in the blood and bone marrow. Due to the rarity of SMZL, there is a paucity of studies describing the clinical features at diagnosis and responses to therapy of SMZL patients who transform to high grade B-cell lymphoma. Camacho et al (2001) reported a series of 12 SMZL patients with histological progression to large B-cell lymphoma and Heintel et al (2003) published a case report of SMZL transforming to Burkitt lymphoma. The clinical features and outcome of the patients were not documented by Camacho et al (2001). In a series of 48 SMZL patients referred to our institution between 1988 and 2006, progression occurred in 31 patients (65%). We describe the clinical and laboratory features of nine of these 31 cases (29%) who had biopsy proven transformation to large B-cell lymphoma. In addition we document the cytogenetic features of these cases at the time of transformation, together with their response to therapy, progression-free and overall survival.
At presentation, the diagnosis of SMZL with circulating villous lymphocytes was based on peripheral blood and bone marrow morphology, immunophenotype, and a pattern of nodular/intra-sinusoidal bone marrow infiltration. The diagnosis was confirmed by spleen histology in seven cases. Chronic lymphocytic leukaemia (CLL), mantle cell and follicular lymphoma were excluded. Flow cytometry was performed on bone marrow and peripheral blood. An immunophenotypic score for CLL was generated using the system described by Matutes et al (1994); all cases had CLL scores <3. High-grade transformation was confirmed by peripheral blood morphology and histological examination of the bone marrow, lymph node, spleen or extra nodal tissue (Fig 1). Immunological markers confirmed the clonal B-cell nature of the cells with a phenotype identical to the SMZL cells at diagnosis with the same immunoglobulin light chain expression. The indications for repeat biopsy were either a poor response to therapy, clinical suspicion due to increased lymphadenopathy, B symptoms or a rising white cell count, or due to involvement of an unusual clinical site, such as the nasal septum. Therapy was at the physician’s discretion and there was no process of randomization or selection. All patients were given systemic chemotherapy at time of transformation, except patient 9, who was treated with involved field radiotherapy as the transformation was localized to the nasal septum.
A comparison of the clinical features at diagnosis with SMZL patients who did not undergo high-grade transformation is summarized in Table I. The χ2 test was used to compare these two groups and P-values <0·05 were considered significant. The median age at diagnosis of the cases that underwent transformation was 63 (range 40–76) years with a male to female ratio of 0·8. All cases had splenomegaly and bone marrow infiltration at diagnosis. The presenting haemoglobin ranged between 76 and 133 g/l (median, 114 g/l). The median white cell count was 21 × 109/l and median lymphocyte count at diagnosis was 17·9 × 109/l. Patients with SMZL who underwent high-grade transformation had a significantly greater incidence of peripheral lymph node involvement (44% vs. 15%, P = 0·03). In addition a higher proportion of cases had a monoclonal serum protein (44% vs. 22%, P = 0·06). In each case the paraprotein was IgM, and the serum concentration was <10 g/l. The serum lactate dehydrogenase was increased at diagnosis in only one case, and 8/9 patients responded to first line therapy with splenectomy, chemotherapy or radiotherapy.
|SMZL (subsequent transformation)||SMZL*||P-value|
|Median age (years)||63||69||0·71|
|Sex (male:female)||4:5 (0·8)||61:68 (0·9)||0·87|
|Splenomegaly||9/9 (100)||100/129 (77)||0·11|
|Bone marrow infiltration||9/9 (100)||84/92 (87)||0·46|
|Lymphadenopathy||4/9 (44)||19/124 (15)||<0·03|
|IgM paraprotein||4/9 (44)||24/129 (22)||0·06|
|Raised LDH||1/6 (17)||9/28 (32)||0·45|
|Response to initial therapy||8/9 (89)||19/20 (95)||0·55|
In our series of 48 SMZL patients, the rate of transformation to large B-cell lymphoma was 19% (9/48). The rate of transformation reported by Camacho et al (2001) was 13%. Although the numbers of patients in this study were small, due to the rarity of this disease, it appeared that the rate of transformation of SMZL was between that observed in CLL (1–10%) (Robertson et al, 1993) and follicular lymphoma (25–60%)(Acker et al, 1983; Horning & Rosenberg, 1984). Transformation to large B-cell lymphoma occurred at 6–192 months (median 45 months) after diagnosis with the exception of one patient, patient 6, in whom large B-cell lymphoma was detected at diagnosis on removal of the spleen. There were four cases of high-grade transformation in the bone marrow and five cases of transformation in a peripheral lymph node, extranodal tissue (nasal septum) or in the spleen. Patient 4 initially transformed in a peripheral lymph node, achieved a complete remission with combination chemotherapy, and then had a second transformation 6 years later in the bone marrow. Three of the five patients with high-grade transformation in the bone marrow had been previously treated with fludarabine and in one of these patients Epstein–Barr Virus encoded RNA (EBER) was detected immunohistochemically by in situ hybridization (Fig 1). Thornton et al (2005) suggested that fludarabine therapy predisposed CLL patients to EBV reactivation and subsequent transformation, and it is possible that EBV plays a similar role in SMZL patients although the numbers in this series were too small to make any firm conclusions. Cytogenetic abnormalities were detected in five patients at time of transformation. Two patients had a normal karyotype, while cytogenetic analysis was not available for patients 7 and 8. Two patients had deletions of chromosome 7q, which have been documented in approximately 40% of patients with SMZL and are associated with a more aggressive clinical course (Mateo et al, 1999; Sole et al, 2000). Abnormalities of the tumour suppressor gene, TP53, were detected in three patients, all of whom had transformed in the bone marrow. Patients 1 and 4b had TP53 deletions detected by fluorescence in situ hybridization, while patient 3 had a TP53 mutation detected by sequencing. In contrast to the study of Camacho et al (2001), in which the incidence of TP53 deletions was low (1/8 patients), our findings in transformed SMZL were consistent with the incidence of TP53 deletions in other transformed low-grade lymphomas, such as CLL and follicular lymphoma (Sander et al, 1993).
Responses to therapy are summarized in Table II. Although responses were seen in all but two cases, our study strongly suggests that the site of transformation influences the quality of response to treatment and overall survival. All five patients with transformation in a lymph node, spleen or extranodal tissue achieved a complete remission (CR), with a median progression-free survival of 44 months and median overall survival of 54 months. By contrast only one patient with evidence of transformation in the bone marrow achieved a CR, and median overall survival in this group was just 9 months. Six of the nine patients died, five of progressive disease.
|Patient||Previous chemotherapy||Indication for repeat biopsy||Salvage therapy||Response||Progression-free survival (months)||Overall survival (months)||Site of transformation|
|1||Chlorambucil||Poor clinical response to treatment||CHOEP Fludarabine||PR||15||25||Bone marrow|
|2||Nil||Rise in white cell count||PMitceBoM||No response||–||3||Bone marrow|
|3||Chlorambucil Fludarabine CHOP||Increased lymphadenopathy||DexaBEAM||PR||1||1||Bone marrow|
|4a||No||Increased lymphadenopathy||PMitceBoM||CR||48||72||Lymph node|
|4b||PMitceboM FCM||B symptoms||R-PMitceBoM||No response||–||3||Bone marrow|
|5||FC||B symptoms||RCHOP||CR||15||15||Bone marrow|
|6||No||Initial diagnostic biopsy||RCHOP||CR||40||40||Spleen|
|7||Chlorambucil||B symptoms||CHOP||CR||42||60||Lymph node|
|8||Chlorambucil||Increased lymphadenopathy||CHOP||CR||14||48||Lymph node|
|9||No||Unusual site of disease (nasal septum)||Radiotherapy||CR||6||6||Extra nodal (nasal septum)|
In comparison, transformation of follicular lymphoma to diffuse large B-cell lymphoma is associated with a median survival from transformation of 1·2 years. Advanced stage disease and high-risk follicular lymphoma international prognostic index (FLIPI) and international prognostic index (IPI) scores at diagnosis correlate with an increased risk of high-grade transformation (Montoto et al, 2007). Richter’s transformation of small lymphocytic lymphoma/CLL has a dismal prognosis, with poor response rates and median overall survival of less than 6 months (Robertson et al, 1993). Chemoimmunotherapy is effective in Richter’s transformation, with improved overall response rates but median overall survival remains limited (Tsimberidou et al, 2006).
In summary, the present study demonstrated that there is a significant subset of SMZL patients who will transform to high-grade lymphoma, and these patients have a significantly greater incidence of peripheral lymph node involvement at diagnosis compared to SMZL patients who do not transform. While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation appears to respond well to chemotherapy with durable progression-free and overall survival.