Splenic marginal zone lymphoma (SMZL) is an uncommon lowgrade B-cell lymphoma that has been recognized as a unique clinicopathologic entity in the WHO (World Health Organization) classification.1 Although the clinical, morphological and immunophenotypic features of SMZL are well established, the genetic features of SMZL are not well understood. Characteristic cytogenetic abnormalities that are thought to be primary pathogenetic events have been identified in several mature B-cell neoplasms. Many of these, such as t(11;14)/IGH-CCND1 in mantle cell lymphoma and t(14;18)/IGH-BCL2 in follicular lymphoma, are balanced translocations that juxtapose the immunoglobulin enhancer region with a cellular proto-oncogene, resulting in constitutive activation of the proto-oncogene. However, an analogous cytogenetic abnormality has not been identified in SMZL. On the basis of karyotyping, there have been sporadic reports of balanced translocations in SMZL involving 14q32, 2p11–12 and 22q11, presumably corresponding to IGH, IGK and IGL translocations, respectively. However, the prevalence of these translocations is unknown, and the specific genes involved have rarely been demonstrated. From comparative genomic hybridization, it was found that frequent copy number imbalances in SMZL include gains of the long arm of chromosomes 3 (17–23%) and 12 (14–19%) and loss of the long arm of chromosome 7 (14–21%).2–6 There has been particular interest in the latter abnormality, and fine mapping has demonstrated that the common deleted region spans 7q31.33–7q33,5 and may even span a narrower region from 7q32.1 to 7q32–3.7 However, its prevalence in SMZL has not been well established.
To determine the prevalence of IG translocations and del(7q) in SMZL, we performed interphase fluorescence in situ hybridization (FISH) on 210 paraffin-embedded SMZL specimens from 210 patients. We also performed karyotypic analysis on 28 cases from this cohort in which fresh or frozen samples were available. All patients had a primary diagnosis of SMZL based on morphology and immunophenotype, using the criteria of the WHO Classification of Haematopoietic and Lymphoid Tissues and consented to research use of their tissue.
For FISH analysis, tissue microarrays were constructed using paraffin-embedded tissue from all SMZL, and interphase FISH was performed on tissue microarray sections as previously described.8 All 210 cases were screened using two-color breakapart (BAP) FISH probes for IGH (Vysis Inc., Downers Grove, IL, USA), IGK and IGL (homebrew9), which were composed of SpectrumOrange- and SpectrumGreen-labeled DNA probes that hybridize regions flanking the IGH, IGK and IGL breakpoints, respectively. In cases in which an IGH, IGK or IGL translocation was identified, BAP and dual-fusion probes for loci such as BCL2, BCL3, BCL6, CCND1, CCND3, CDK6, MALT1 and PAX5 (Vysis Inc. and homebrew) were used as needed to identify translocation partners. All 210 cases were also screened with a homebrew two-color probe for del(7q), consisting of a SpectrumGreen-labeled control probe at 7p22.3 and a SpectrumOrange-labeled probe at 7q32.1. The bacterial artificial chromosomes (BACs) (BACs: RP11-786I1, RP11-66F23, CTD-2529B23 and RP11-198N5) were selected based on previous fine mapping studies for deletion of 7q in SMZL5 (Figure 1). Also, 114 cases were screened using a two-color BAP probe for BCL6 (Vysis Inc.), and 60 cases were screened using two-color BAP probes for BCL2, CCND1, CDK6, MALT1 and PAX-5 (Vysis Inc. and homebrew) and a two-color dual fusion FISH probe for API2-MALT1 (Vysis Inc.). SpectrumOrange-labeled signals are referred to as red (R), SpectrumGreen-labeled signals as green (G) and SpectrumOrange-SpectrumGreen fusion signals as fusion (F). Tissue microarray specimens were screened by FISH by one microscopist (ML). Spots that contained at least 50 cells were deemed acceptable for screening, exceeding the minimum value of 20 cells recommended for FISH evaluation of HER2 status in breast carcinoma. 10 For BAP and dual-fusion probes, a minimum of 20 abnormal cells were required for the sample to be considered abnormal.8 For the del(7q) probe, a cohesive group of at least 20 cells, of which at least 80% were abnormal, was required for the sample to be considered abnormal, exceeding the previously established cutoff value of 55% for a deletion-FISH probe.11 FISH failure rates varied between 6 and 13% of cases depending on the probe, averaging approximately 10%.
Figure 1.
Map of two-color fluorescence in situ hybridization (FISH) probe used to detect del(7)(q32). The SpectrumOrange-labeled probe at 7q32.1 utilizes bacterial artificial chromosomes that were selected based on previous fine mapping studies for deletion of 7q in splenic marginal zone lymphoma.5 The control probe at 7p22.3 is labeled with SpectrumGreen.
The FISH and karyotypic results are listed in Table 1. IG translocations were detected in 15 SMZL: 13/180 involved IGH (6%), 1/196 involved IGK (0.5%) and 1/192 involved IGL (0.5%). Heterozygous del(7)(q32) was detected in 27/167 cases (16%), six of which were corroborated by karyotype. One also had an IGH translocation although the partner was unknown. No cases with homozygous del(7)(q32) were identified. The translocation frequencies of other gene loci were as follows: BCL6—2%, CDK6—4%, PAX-5—4%, BCL2—0%, CCND1—0% and MALT1—0%. IG translocation partners were identified in six cases: IGH-PAX5 (n = 2, one case corroborated by karyotype; see below and Figure 2), IGH-BCL6 and IGHIRF4/ MUM1 (n = 1; both translocations were present in the same tumor cells, also corroborated by karyotype; see below and Figure 3), IGH-CCND3 (n = 1), IGK-CDK6 (n = 1) and IGHBCL3 (n = 1). The last case also had a BCL6 translocation involving an unknown partner gene. Translocation partners were not identified in the remaining nine cases, one of which involved both IGH alleles, despite an exhaustive search by FISH. One case had a CDK6 translocation that did not involve an IG gene. Ten percent of the cases had extra BCL6 signals, consistent with complete/partial trisomy 3, and 18% of the cases had extra MALT1, BCL2 and CEN18 signals, consistent with complete/partial trisomy 18. Six of these cases also had a translocation as shown by FISH.
Table 1.
Karyotypes and abnormal FISH results in SMZL
| Study case no. |
FISH results | FISH result interpretation |
FISH/karyotype concordant |
Karyotype |
|---|---|---|---|---|
| 1 | +CCND1 | +11 | ||
| 2 | del(7)(q32) | del(7)(q32) | NA | |
| 4 | Normal | Normal | Yes | 46,XX,del(11)(q13q23)[7]/46,XX[13] |
| 10 | del(7)(q32) | del(7)(q32) | Yes | 46,XX,del(7)(q22q34),der(14)t(3;14)(q12;q31)[2]/46,idem,dup(6)(p25p23)[9]/ 46,XX[9] |
| 11 | Normal | Normal | Yes | 46,XX[13] |
| 12 | +MALT1,+BCL2,+CEN18 | +18 | Yes | 47,XX,+18[6]/idem,del(13)(q12q14)/46,XX[10] |
| 14 | +BCL6,+CCND1,+API2,+CEN11, +MALT1,+BCL2,+CEN18,split CDK6 |
CDK6-?,+3, +11,+18 |
NA | |
| 17 | del(7)(q32),+del(7)(q32) | del(7)(q32), +del(7)(q32) |
NA | |
| 21 | del(7)(q32) | del(7)(q32) | Yes | 46,(XY)[9]/46,XY,der(7)t(6;7)(q25;q31.2),del(6)(q21q25)[7] |
| 22 | del(7)(q32) | del(7)(q32) | NA | |
| 25 | Normal | Normal | Yes | 46,XX[20] |
| 26 | IGH-CCND3 | IGH-CCND3 | NA | |
| 28 | IGH-BCL6 and IGH-MUM1 | IGH-BCL6 and IGH-MUM1 |
Yes | 46,XX,+X,t(3;14)(q27;q32),−6,t(6;14)(p25;q32), der(17)t(6;17)(p21;p13)[20] |
| 30 | del(7)(q32) | del(7)(q32) | NA | |
| 33 | +BCL6 | +3 | NA | |
| 38 | IGK-CDK6,+BCL2,+CEN18 | IGK-CDK6,+18 | NA | |
| 40 | Normal | Normal | Yes | 46,XY,t(5;6)(q11;q23)[13]/46,XY[4] |
| 42 | del(7)(q32) | del(7)(q32) | NA | |
| 43 | +MALT1,+BCL2,+CEN18 | +18 | NA | |
| 47 | del(7)(q32) | del(7)(q32) | NA | |
| 50 | Split IGH,+MALT1,+BCL2, +CEN18 |
IGH-?,+18 | NA | |
| 51 | +BCL2 | +18 | NA | |
| 52 | del(7)(q32) | del(7)(q32) | NA | |
| 53 | IGH-PAX5,+BCL6,+MALT1, +BCL2,+CEN18 |
IGH-PAX5,+3,+18 | Yes | 46,XY/48,XY,+3,t(9;14)(p13.2;q32),+18cp |
| 54 | Normal | Normal | Yes | 46,XX[20] |
| 56 | del(7)(q32) | del(7)(q32) | NA | |
| 58 | Normal | Normal | Yes | 46,XY |
| 60 | Split IGH,del(7)(q32) | IGH-?,del(7q) | Yes | 46,XX,t(1;15)(p11;q11),del(8)(q12),del(18q),del(14q),del(7)(q22q33) |
| 61 | Normal | Normal | Yesa | del(7)(q22q33) |
| 63 | del(7)(q32) | del(7)(q32) | Yes | 44,XY, −20, −21,t(1;3)(q21;q21),del(8)(q22qter), −7,+der7,t(7;17)(p12;p12),del(7)(q32) |
| 64 | Split IGH×2 | IGH-? X 2 | NA | |
| 65 | Normal | Normal | Yes | 85–90,XXY,1q−,t(1;2)(q21;q21)3p−,der(4),5p−,6q−, 9p−,dup(10q),der(14q),der(17q),der(20q) |
| 66 | Normal | Normal | Yes | dup(10q),der(14q),der(17q),der(20q) |
| 67 | Normal | Normal | Yes | 46XY |
| 72 | del(7)(q32) | del(7)(q32) | NA | |
| 79 | Split IGL | IGL-? | NA | |
| 83 | Normal | Normal | Yes | 46,XX |
| 84 | del(7)(q32) | del(7)(q32) | Yes | 47,XY,del(7q?),t(1;2)(q32;q32),add (17)(p13) |
| 89 | del(7)(q32) | del(7)(q32) | NA | |
| 90 | IGH-PAX5,+BCL2 | IGH-PAX5,+18 | NA | |
| 94 | Normal | Normal | Yes | 46,XX,t(2;17) |
| 96 | Normal | Normal | Yes | 46,XX,del(9)(p13p23) |
| 99 | Normal | Normal | Yes | 46,XY, t(2;6) cons/46XY,t(2;6) t(1;3)/46XY,t(2;6) t(13;21) |
| 100 | del(7)(q32) | del(7)(q32) | Yes | 46,XX,del(7)(q21q32) |
| 101 | Normal | Normal | Yes | 46,XX |
| 104 | IGH-BCL3 and split BCL6 | IGH-BCL3 and BCL6-? |
No | 46,XY |
| 105 | Normal | Normal | Yesb | 46,XX,+3, −Y |
| 109 | Normal | Normal | Yes | 49,XY,+3,+12,+19 |
| 110 | del(7)(q32) | del(7)(q32) | Yes | 46,XY,del(7)(q31;qter) |
| 120 | Split IGH | IGH-? | NA | |
| 122 | del(7)(q32) | del(7)(q32) | NA | |
| 124 | Split IGH | IGH-? | NA | |
| 131 | Split IGH | IGH-? | NA | |
| 135 | del(7)(q32) | del(7)(q32) | NA | |
| 138 | del(7)(q32) | del(7)(q32) | NA | |
| 145 | del(7)(q32) | del(7)(q32) | NA | |
| 146 | Split IGH | IGH-? | NA | |
| 147 | del(7)(q32) | del(7)(q32) | NA | |
| 155 | Multiple signals, all probes | Polyploidy | NA | |
| 161 | del(7)(q32) | del(7)(q32) | NA | |
| 172 | del(7)(q32) | del(7)(q32) | NA | |
| 184 | del(7)(q32) | del(7)(q32) | NA | |
| 191 | Split IGH | IGH-? | NA | |
| 198 | del(7)(q32) | del(7)(q32) | NA | |
| 210 | del(7)(q32) | del(7)(q32) | NA |
Abbreviations: BAP, breakapart; FISH, fluorescence in situ hybridization; SMZL, splenic marginal zone lymphoma.
Split IGH = separation of IGH BAP probe (1R1G1F pattern).
Split IGL = separation of IGL BAP probe (1R1G1F pattern).
Split BCL6 = separation of BCL6 BAP probe (1R1G1F pattern).
del(7q) FISH probe failed in this case.
BCL6 probe (at 3q27) not performed in this case.
Figure 2.
Metaphase and interphase fluorescence in situ hybridization (FISH) demonstrating IGH-PAX5 fusion in a splenic marginal zone lymphoma specimen with an abnormal karyotype (48,XY, + 3,t(9;14)(p13.2;q32), + 18cp). There are two yellow fusion signals (yellow arrows), indicating IGH-PAX5 fusion, in both the metaphase spread and the interphase nucleus.
Figure 3.
Metaphase fluorescence in situ hybridization (FISH) demonstrating both IGH-BCL6 fusion and IGH-IRF4/MUM1 fusion in the same cells in a splenic marginal zone lymphoma specimen with an abnormal karyotype (46,XX, + X,t(3;14)(q27;q32), −6,t(6;14)(p25;q32), der(17)t(6;17)(p21;p13)). (a) A two-color IGH-BCL6 dual fusion FISH probe shows two yellow fusion signals (yellow arrows) indicating IGH-BCL6 fusion as well as an extra green IGH signal (green arrows) consistent with the presence of IGH-IRF4/MUM1 fusion on the other allele. (b) A two-color IGH-IRF4/MUM1 D-FISH probe shows two yellow fusion signals (yellow arrows) indicating IGH-IRF4/MUM1 fusion as well as an extra green IGH signal (green arrows) consistent with the presence of IGH-BCL6 fusion on the other allele.
Karyotypes were obtained from 18 fresh and 10 frozen SMZL samples (Table 1). Fresh samples were cultured using standard techniques. Frozen cell suspensions were thawed, plated (1 × 106 cells ml−1) in culture media containing bovine serum albumin (1 g per 10 ml of phosphate-buffered saline), mercaptoethanol (0.37 µl ml−1 of phosphate-buffered saline), CpG (14 mg ml−1), interleukin-15 (10 µg ml−1), interleukin-2 (2.5 × 106 U ml−1) and RPMI Glut Max media, and incubated at 37°C for 5 days. Twenty metaphases were analyzed from all specimens, whenever possible, using standard cytogenetic techniques. Of the 20 cases with an abnormal karyotype, 7 contained a single cytogenetic abnormality, including 3 cases with del(7q) and one case each with del(11)(q13q23), t(5;6)(q11;q23), del(9)(p13p23) and t(2;17) (further breakpoint information not available), and the remaining 13 had a complex karyotype. Interphase FISH was performed on a paraffin section of the SMZL possessing del(9)(p13p23), but no abnormalities involving PAX5 were identified. Three cases with a complex karyotype (no. 90, no. 28 and no. 60) had 14q abnormalities including t(9;14)(p13.2;q32) (confirmed by FISH to have IGHPAX5 fusion; Figure 2), t(3;14)(q27;q32) and t(6;14)(p25;q32) (confirmed by FISH to have IGH-BCL6 fusion and IGH-MUM1/ IRF4 fusion in the same cells; Figure 3) and del(14q) (confirmed by FISH to have an IGH translocation involving an unknown partner gene, as well as del(7q)). Recurrent abnormalities included del(7q) (n = 6), trisomy 3 (n = 3), trisomy 18 (n = 2), del(6q) (n = 2) and del(8q) (n = 2).
Immunophenotypic data (flow cytometric and/or immunohistochemical) using antibodies directed against CD20, CD3, CD5, CD23, CD10 and κ- and λ-immunoglobulin light chains were available in 54 cases. Of the nine cases (17%) that showed coexpression of CD5, seven (78%) had a cytogenetic abnormality by FISH and/or karyotyping, including IGH-PAX5, IGHCCND3, a CDK6 translocation, del(7q), trisomy 18 (n = 2) and trisomy 11. Of the 44 cases that lacked CD5 coexpression, 12 (27%) had a cytogenetic abnormality, most commonly del(7q) (67%).
Much of the previous cytogenetic data on SMZL are based on peripheral blood karyotyping and are not necessarily from patients who had a diagnosis of SMZL based on spleen histology. This is the first large investigation of the genetics of SMZL in which all specimens were required to be classic SMZL by histology and immunophenotype. By performing interphase FISH studies on 210 SMZLs, we have demonstrated that the incidence of IG translocations is 7%, with 6% involving IGH and 0.5% involving IGK and IGL, respectively. A variety of IG translocation partners, resulting in translocations such as IGHPAX5, IGH-BCL6, IGH-IRF4/MUM1, IGH-BCL3, IGH-CCND3 and IGK-CDK6, were identified. Most of these translocations, including t(9;14)(p13;q32),12–15 t(3;14)(q27;q32),7,16,17 t(14;19)(q32;q13),4,14,18 t(2;7)(p11;q21–22)19–21 and t(6;14) (p21.1;q32.3),22 have been previously demonstrated karyotypically in small numbers of SMZL, and in at least one case each, there has been molecular characterization of the genes involved by FISH or other methods (that is, IGH-PAX5, IGH-BCL6, IGHBCL3, IGK-CDK6 and IGH-CCND3, respectively). To our knowledge, we have identified the first case of an IGH-IRF4/ MUM1-positive SMZL. In 54% of our cases, the IGH translocation partner could not be identified despite extensive FISH studies. Small numbers of SMZLs possessing a translocation involving 14q32 (presumably IGH) and a variety of breakpoints, including 1p34,23 1q32,7 3p13,24 3q13,14 4p13,17 6p12,25 9p13,12 10q2425 and 19p13,26 as well as those involving 2p11– 12 or 22q11 (presumably IGK or IGL, respectively) and other breakpoints such as 12q24,27 13p1128 and 11q2327 have been previously reported. However, the genes involved in these translocations have not been identified.
Most SMZLs in the literature with translocations involving 14q32, 2p11–2 or 22q11 have complex karyotypes, with the majority having 3–5 abnormalities. Furthermore, translocations involving 14q32, 2p11–2 or 22q11 have sometimes been found only in a subclone rather than the primary clone.14 In our cohort, the three cases with IGH translocations in which metaphases were available (no. 28, no. 60 and no. 90) all had complex karyotypes, although each consisted of a single clone without subclones. None of the cases in the present study and only four previously reported karyotypically abnormal SMZL have a balanced translocation involving 14q32, 2p11–2 or 22q11 as the sole cytogenetic abnormality.21,25,27 These findings suggest that in the majority of SMZL cases IG translocations may represent a secondary genetic event and do not help define the primary genetic event. This may explain why such a variety of translocations involving different pathways are present in a single disease process.
All SMZLs in this cohort lacked translocations involving BCL2, CCND1 or MALT1, suggesting that the pathogenesis of SMZL differs from that of follicular lymphoma, mantle cell lymphoma and mucosa-associated lymphoid tissue lymphoma. BCL6 gene rearrangements, which are most commonly associated with follicular lymphoma and diffuse large B-cell lymphoma but have also been described in other B-cell lymphomas such as mucosa-associated lymphoid tissue lymphoma and nodal marginal zone lymphoma, were present in two of our cases. Both had multiple genetic abnormalities by FISH and one also had a complex karyotype, suggesting that BCL6 translocations may occasionally occur in SMZL but are usually secondary genetic events. CD5 coexpression has been previously described in SMZL and was present in 17% of our cases. It was usually associated with cytogenetic abnormalities, especially translocations and aneuploidy, while most SMZL with del(7q) were CD5-negative.
There has been considerable interest in deletion of 7q in SMZL. On the basis of prior studies, the incidence of del(7q) in SMZL is 17% by conventional cytogenetics 2,3,25,27 and 19% by comparative genomic hybridization.2,3,5 This corresponds well to the incidence of 16% that we obtained by interphase FISH, using a probe that was designed based on previous fine mapping studies that showed that the common deleted region extended from 7q31.33 to 7q33. Del(7q) coupled with an IG translocation was present in only one case in our study (0.5%), which is approximately the incidence that would be expected if these two abnormalities were to occur together by random chance alone. Occasional cases of SMZL with coincident del(7q) and translocations involving 2p11–2 and/or 14q32 have been described.12,19,25,29 Del(7q) is more likely to be the sole cytogenetic abnormality than a balanced translocation involving 2p11–12, 14q32 or 22q11, suggesting that del(7q) is more likely than an IG translocation to be associated with a primary pathogenetic event in SMZL. However, as the vast majority of cytogenetically abnormal SMZL have a complex karyotype, it is likely that the primary pathogenetic event in SMZL cannot be identified by karyotypic analysis and may involve a different type of genetic abnormality such as a point mutation or a microRNA abnormality. Additional studies will be necessary to address these possibilities.
Acknowledgements
This work was supported in part by Grant CA97274 from the National Institutes of Health, Bethesda, MD, USA.
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