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Hematologic Malignancies
June 01, 2006

Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

Publication: Journal of Clinical Oncology

Abstract

Purpose

Gene expression profiling studies have reported upregulated mRNA expression of forkhead box protein P1 (FOXP1) in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 rearrangements and expression of its protein occur in mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we investigated FOXP1 expression in its relationship to morphology, genetic features, and prognosis in a series of 70 MALT lymphomas.

Patients and Methods

All samples were morphologically reviewed and stained for FOXP1. Presence of structural and/or numeric aberrations of the FOXP1, BCL10, and MALT1 genes was investigated. For all patients, a complete clinical data set was collected.

Results

We detected nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of nongerminal center phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18.

Conclusion

The data presented show that FOXP1 expression is an independent prognostic factor in MALT lymphomas. The data also support the hypothesis that a subgroup of nongerminal center DLBCLs (those marked by FOXP1 expression and trisomy 3 and 18) might represent a large-cell variant of MALT lymphomas.

Introduction

Among the genetic aberrations reported to occur in mucosa-associated lymphoid tissue (MALT) lymphomas, the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) are well known because they seem to be specific for or at least closely related to this type of B-cell non-Hodgkin's lymphoma; these translocations result in the API2-MALT1, IGH-BCL10, and IGH-MALT1 rearrangements, respectively.1-6 Two of these affected genes, BCL10 and MALT1, play a crucial role in the antigen receptor signaling pathway leading to activation of nuclear factor-kappa B.7-9 Recently, forkhead box protein P1 (FOXP1) was identified as a translocation partner of IGH in MALT lymphomas as well as in diffuse large B-cell lymphoma (DLBCL).10,11 The FOXP1 gene is located at 3p13 (www.ensembl.org) and codes for a member of the FOX family of transcription factors.12 This family includes numerous proteins that take part in a wide range of normal developmental events, including the control of cellular differentiation and proliferation, immune regulation, and signal transduction.13 Spontaneous mutations of these molecules have been identified in various congenital disorders.14,15 FOX transcription factors are also implicated in carcinogenesis through retroviral integration, transcriptional regulation, chromosomal translocation, and gene amplification.16-22
Although the physiologic role of FOXP1 in lymphoid tissue is still unclear, it has shown to be expressed in normal activated B cells using genomic-scale expression profiling and in mantle-zone and some germinal center (GC) B cells using immunohistochemistry.23,24 The significance of FOXP1 overexpression in lymphomas is still debated, but the strong nuclear expression of FOXP1 in a subset of DLBCLs argues for a possible role in the pathogenesis of this group of aggressive B-cell lymphomas. One study found FOXP1 to be predominantly expressed in non-GC DLBCLs (71%) compared with GC DLBCLs (48%), but it did not predict clinical outcome.25 Two other studies found FOXP1 expression to be associated with inferior survival; one of the studies correlated strong nuclear FOXP1 expression to poor prognosis in BCL2-positive, t(14;18)(IGH;BCL2)–negative, non-GC DLBCLs.26,27 Recent studies also revealed FOXP1 expression in follicular center lymphoma as well as marginal zone lymphoma.11,28
In view of the recently described FOXP1 rearrangement in MALT lymphoma and the possible association of strong nuclear FOXP1 expression with worse clinical outcome in non-GC DLBCL, this study investigated FOXP1 expression in a series of MALT lymphomas in its relationship to histology, genetic aberrations, and clinical outcome. It was found that not only is FOXP1 a significant predictor of unfavorable clinical outcome, but also that FOXP1-positive MALT lymphomas, marked by a polymorphic histology and by trisomy 3 and 18, are at risk of transforming into aggressive DLBCLs. For the latter reason, 10 de novo DLBCLs (marked by FOXP1 positivity and trisomy 3 and 18) were added to this study to investigate whether this subset of DLBCLs is linked to MALT lymphoma.

Patients and Methods

Patient Selection

We retrospectively studied 91 consecutive MALT lymphoma patients diagnosed between 1994 and 2004 at the University Hospital of Katholieke Universiteit Leuven. In 70 patients, formalin- and/or B5-fixed paraffin-embedded blocks, fresh tissue, and a complete clinical data set were available; only these patients were included in the study. Anatomic locations of these MALT lymphomas are listed in Table 1. Some of these patients were included in previous studies.1,2,11,29-33 All MALT lymphomas were reviewed according to the WHO criteria.34
Ten de novo DLBCL patients were added to this study. These patients were part of a large collection of DLBCL patients who were included in a previous study,35 and selection was based on a non-GC phenotype, FOXP1 positivity, and presence of trisomy 3 and 18.

Clinical Data

The patients' records were reviewed, and the following data were collected: clinical symptoms, medical history, laboratory data, diagnostic procedures, staging information, treatment, and follow-up. Staging included computed tomography of the abdomen and thorax in all patients, with additional positron emission tomography in 48 patients. A bone marrow biopsy was performed in all patients. The International Prognostic Index was calculated when possible. Because this index can only be applied to indolent forms of lymphoma with a smaller degree of accuracy compared with DLBCLs, it was not included in statistical analysis.

Morphology and Immunohistochemistry

Histologic examination was performed on paraffin-embedded tissue using hematoxylin and eosin stainings. Each sample was evaluated with regard to the morphologic spectrum of its neoplastic proliferation.
Paraffin sections were immunostained for FOXP1 with the mouse monoclonal antibody JC12 (kindly donated by A.H. Banham, University of Oxford, Oxford, United Kingdom) according to a previously published protocol.11 FOXP1 immunostainings were scored as negative (with occasional cells having weak nuclear FOXP1 expression), moderately positive (with part of the tumor cells featuring nuclear FOXP1 expression with variable intensity), or strongly positive (with nearly all tumor cells showing strong, uniform nuclear FOXP1 expression). Subdivision of DLBCLs into GC and non-GC subtypes was based on the algorithm of Hans et al25 using an immunohistochemical panel including the mouse monoclonal antibodies CD10 (Novocatra, Newcastle, United Kingdom), BCL2 (Dakocytomation, Glostrup, Denmark), BCL6 (Dakocytomation), and MUM1 (Dakocytomation).

Fluorescence in Situ Hybridization

All 70 MALT lymphoma patients were analyzed by interphase fluorescence in situ hybridization (FISH) for structural and numerical aberrations of the BCL10 (1p22), FOXP1 (3p13), API2 (11q21), IGH (14q32), and MALT1 (18q21) genes, as previously described.11,33 Centromere-specific alpha-satellite probes were used to verify aneuploidy of chromosomes 3 and 18.

Statistical Analysis

The baseline characteristics were compared using Fisher's exact test or χ2 test, when appropriate. Survival analysis was performed to assess the relationships between the various variables and disease-free survival (DFS) and overall survival (OS) by using the product-limit method of Kaplan-Meier. The P values for these analyses were based on the log-rank test. DFS and OS were measured from the time of initial therapy to relapse or to death, respectively. The Cox proportional hazards model was used to assess the joint effects of the variables found to be associated with OS or DFS in the Kaplan-Meier analyses. For all tests, significance was accepted when P < .05. Statistical analyses were performed using Statview 5.0.1 (SAS Institute, Cary, NC).

Results

Patient Characteristics

The mean patient age was 61 years, with a male-to-female ratio of 1.2:1. Ann Arbor stage I and II disease was present in 51 (72.8%) and four (5.7%) patients, respectively, whereas 15 patients (21.4%) presented with stage IV disease. Sixty-eight patients (97.1%) were treated with curative intent; only these patients were included in survival analysis. In one patient, a wait and see policy was adopted; the one remaining patient refused therapy. Localized therapy was applied in 34 patients; 18 were treated with surgical resection of the lymphoma site, 14 were treated with localized radiotherapy, and two were treated with a combination of both. Twelve patients received chemotherapy as single therapy, eight patients were treated with combined chemotherapy and radiotherapy, and eight patients were treated with adjuvant chemotherapy (and radiotherapy in three patients) after surgery. Of these 28 patients, 22 received anthracycline-containing combination chemotherapy, predominantly cyclophosphamide, doxorubicin, vincristine, and prednisone. Because of the correlation between gastric MALT lymphoma and Helicobacter pylori, antibiotic eradication therapy was the first-line choice in 12 patients; in six patients, eradication therapy did not result in lymphoma regression, and a gastrectomy was performed. A total of 65 patients (95.6%) achieved a complete response after initial therapy. More than 50% of the patients were observed for at least 5 years. The mean OS time was 66.8 months (range, 0 to 139 months), with a median DFS time of 61.4 months. Relapse occurred in 10 patients (14.7%), with a median DFS time in those patients of 29.3 months. Five patients (7.4%) were documented with evolution to or the simultaneous presence of a DLBCL (cytogenetically related to the primary MALT lymphoma). Fourteen patients (20.6%) died; three of these deaths resulted from lymphoma progression, and all deaths occurred within 5 years from diagnosis.

Morphology and Immunohistochemistry

Given the cellular composition of the tumor, this series of MALT lymphomas could be subdivided into the following two subsets: MALT lymphomas with a monomorphic histology (n = 53; 75.7%) and MALT lymphomas with a polymorphic histology (n = 17; 24.3%; Figs 1A and 1B). A monomorphic histology was defined as a proliferation predominantly composed of centrocyte-like cells (with no or minimal variation in shape and size) mixed up with a small number of lymphocyte-like cells and large activated B cells. A polymorphic histology defines MALT lymphomas comprising a mixture of cells, including small lymphocyte-like and centrocyte-like cells and a variable number of scattered large activated B cells (the latter cells were never growing in solid or sheet-like proliferations). Monomorphic and polymorphic MALT lymphomas represent both parts of the morphologic spectrum of MALT lymphomas as described by the WHO classification.34
In total, 20 MALT lymphomas (28.6%) displayed a nuclear positivity for the FOXP1 protein; 12 of these lymphomas were marked by moderate FOXP1 positivity (two of them featuring a polymorphic histology), and the remaining eight lymphomas showed strong FOXP1 positivity (all but one of them featuring a polymorphic histology; Fig 1C). In the FOXP1-positive polymorphic lymphomas, both smaller and larger B cells expressed FOXP1 with comparable intensity. Of the eight patients with MALT lymphomas with strong FOXP1 expression, four were documented with evolution to a DLBCL, whereas a DLBCL was present at diagnosis in a fifth patient (Table 2); all five DLBCLs featured strong nuclear FOXP1 positivity as well. In contrast, none of the 12 MALT lymphomas with moderate FOXP1 expression and none of the 50 FOXP1-negative MALT lymphomas evolved to a DLBCL, although relapse of the lymphoma was documented in four patients (33.3%) and two patients (4%), respectively. The five DLBCLs that originating from MALT lymphomas featured a similar histology, being a diffuse proliferation of large lymphoid cells with oval to round, vesicular nuclei with fine chromatin and two to four membrane-bound nucleoli (Fig 1D). In all of these DLBCLs, the neoplastic cells displayed a great variability in shape and size. The 10 de novo DLBCLs included in this study strongly resembled the five DLBCLs that developed from FOXP1-positive MALT lymphomas.

FISH

The translocations t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14) (p22;q32), and t(3;14)(3p13;q32) occurred mutually exclusive and were detected in seven cases (10%), two cases (2.9%), one case (1.5%), and one case (1.5%), respectively (Table 1). In 25 patients (35.7%), an increased number of fused MALT1 and/or FOXP1 signals was found as a result of trisomy/polysomy 18 (8.6%), trisomy 3 (10%), or trisomy/polysomy 3 and 18 (17.1%). In total, 35 MALT lymphomas (50%) did not display any BCL10-, MALT1-, or FOXP1-related FISH-detectable aberrations.
Numeric aberrations of chromosomes 3 and/or 18 corresponded well with a polymorphic histology (P = .0001); 12 (70.6%) of 17 polymorphic MALT lymphomas were documented with a trisomy/polysomy 3 and/or 18, whereas this was only the case for 13 (24.5%) of the 53 monomorphic MALT lymphomas. Aneuploidy of chromosomes 3 and/or 18 was observed more frequently in FOXP1-positive MALT lymphomas (10 of 20 lymphomas; 50%) than in FOXP1-negative MALT lymphomas (13 of 50 lymphomas; 26%). This percentage was even higher in the group with strong FOXP1 positivity (six of eight lymphomas; 75%) compared with the group with moderate FOXP1 positivity (four of 12 lymphomas; 33.3%). Finally, the five MALT lymphomas with strong FOXP1 expression that evolved to or presented with a DLBCL were all, except for one, characterized by trisomy 3 and 18; the remaining lymphoma featured the IGH/FOXP1 rearrangement (Table 2).

Statistical Analysis

The specific relationship between clinical features and prognosis and FOXP1 immunophenotype, morphology, and genetic features is summarized in Tables 3, 4, and 5. These data illustrate the significant impact of FOXP1 expression on relapse rate and 5-year DFS; a polymorphic histology, Ann Arbor stage IV disease, and bone marrow involvement were also shown to have a significant adverse impact on relapse rate and 5-year DFS (Fig 2). When all univariate significant variables were included in a multivariate analysis, only FOXP1 expression reached statistical significance (P = .0058; relative risk = 10.9; 95% CI, 2 to 58.8). None of the univariate variables was significantly associated with 5-year OS. However, all three MALT lymphomas resulting in death featured strong FOXP1 positivity, a polymorphic histology, and trisomy 3 and 18 (these numbers were too small to perform statistical analysis). From all variables included in this study, transformation to a DLBCL was only significantly associated with FOXP1 positivity (P = .0041) and a polymorphic histology (P = .0351); multivariate analysis was not possible given the low number of patients (n = 5). Remarkably, polymorphic MALT lymphomas affected mainly female patients with advanced-stage disease at diagnosis and were significantly associated with the presence of autoimmune diseases (P = .0061).

Discussion

Here, we show that FOXP1 expression has prognostic significance (with impact on relapse rate and DFS) in patients with de novo MALT lymphomas. So far, FOXP1 expression was only known to be associated with poor clinical outcome in DLBCL patients.26,27 However, although this series comprises 70 patients, the lymphomas arose at different anatomic sites, which do not all share the same clinical behavior. Therefore, our data may require further confirmation by analysis of FOXP1 expression in larger series based on single extranodal sites.
Interestingly, by adding morphologic and genetic characteristics to the FOXP1 phenotype, we were able to identify a subset of MALT lymphomas with high probability of evolution to a DLBCL. Of the eight patients with MALT lymphomas with strong FOXP1 positivity, four evolved to a DLBCL, whereas a DLBCL was present at diagnosis in a fifth patient. In all of these five patients, the primary MALT lymphoma featured a polymorphic histology, and the DLBCL could be linked to the MALT lymphoma because of (cyto)genetic similarities. Four of these five MALT lymphomas were marked by trisomy 3 and 18; CR was achieved in only one patient, whereas the other three patients died because of lymphoma progression. The remaining patient did not harbor a trisomy 3 and 18 but was documented instead with a t(3;14)(p13;q32), juxtaposing FOXP1 to IGH, which explains the strong nuclear FOXP1 expression. This patient presented with a gastric MALT lymphoma and a cervical lymph node affected by a DLBCL (both lymphomas featured the IGH/FOXP1 rearrangement), and CR was achieved; this lymphoma was methotrexate associated. Although extremely rare, three other incidents of methotrexate-associated MALT lymphomas have been reported36-38; however, it remains debated whether methotrexate treatment increases the risk of lymphoma development.39,40 Although relapse was documented in four (33.3%) of 12 MALT lymphomas with moderate FOXP1 expression and in two of the FOXP1-negative MALT lymphomas (4%), none of these lymphomas evolved to a DLBCL.
Among the 50 FOXP1-negative MALT lymphomas, a polymorphic histology and the presence of trisomy/polysomy 3 and/or 18 were much less frequently observed compared with the FOXP1-positive MALT lymphomas, and they were documented in only 16% and 30% of the FOXP1-negative MALT lymphomas, respectively. However, in this subgroup, just as in the FOXP1-positive subgroup, a polymorphic histology was significantly associated with aneuploidy of chromosomes 3 and/or 18 (P = .0086); trisomy/polysomy 3 and/or 18 was detected in 75% of the polymorphic FOXP1-negative lymphomas, whereas it was only observed in 21.4% of the monomorphic FOXP1-negative lymphomas. As shown in Table 3, a polymorphic morphology was also a significant predictor of an unfavorable clinical outcome; this finding is in line with observations that low-grade gastric MALT lymphomas with an increased number of large cells are associated with a more aggressive behavior.41 Therefore, on the basis of all these data, we propose that MALT lymphomas can be subdivided into the following two subgroups representing different clinicopathologic entities: monomorphic MALT lymphomas presenting with a low incidence of trisomy/polysomy 3 and/or 18 and a good prognosis (low relapse rate, favorable DFS) versus polymorphic MALT lymphomas characterized by a high incidence of trisomy/polysomy 3 and/or 18 and a poor clinical outcome (high relapse rate, unfavorable DFS). The monomorphic group predominantly affects men with early-stage disease at diagnosis, whereas the polymorphic subgroup comprises MALT lymphomas affecting mainly female patients with advanced-stage disease at diagnosis and a high coincidence of autoimmune diseases. Within the latter group, strong FOXP1 positivity defines lymphomas that are likely to transform into a DLBCL.
Further classification of the five DLBCLs originating from primary MALT lymphomas presented in this study using the algorithm of Hans et al25 showed that the t(3;14)(p13;q32)–positive DLBCL belonged to the GC group, whereas the four other lymphomas (all marked by trisomy 3 and 18) displayed a non-GC DLBCL phenotype. This finding supports our previous hypothesis that a subset of non-GC DLBCLs (at least marked by trisomy 3 and 18) represents a large-cell variant of marginal zone lymphoma.11 This concept is in line with observations from other groups showing that FOXP1 expression in DLBCLs is predominantly expressed within the non-GC subgroup25-27 and that this lymphoma subset is characterized by a high incidence of complete or partial trisomies 3 and 18.11,42 Moreover, one of these studies correlated strong nuclear FOXP1 expression with poor prognosis in BCL2-positive, t(14;18)(IGH;BCL2)–negative non-GC DLBCLs27; of interest, the non-GC DLBCLs originating from FOXP1-positive, polymorphic MALT lymphomas in our series were marked by strong BCL2 expression as well (data not shown). These findings prompted us to review the morphology of 10 de novo DLBCLs selected on the basis of a non-GC phenotype, FOXP1 positivity, and presence of trisomy 3 and 18. Surprisingly, all of these DLBCLs strongly resembled the DLBCLs developing from polymorphic MALT lymphomas, and seven of these 10 lymphomas arose at extranodal sites, further supporting the close relationship between polymorphic MALT lymphomas and DLBCLs that are both marked by FOXP1 positivity and trisomy 3 and 18.
In 11 of the 20 FOXP1-positive MALT lymphomas, there was no evidence of structural or numeric aberrations of the FOXP1 locus, suggesting that mechanisms other than underlying genetic alterations can upregulate FOXP1 expression. Moreover, little is known about the mechanisms by which the FOXP1 transcription factor could contribute to lymphomagenesis or to the transformation from a MALT lymphoma into a more aggressive DLBCL. Although our study does not provide insight into the oncogenic pathways involved with FOXP1, our findings nevertheless define a distinct subgroup of MALT lymphomas characterized by a polymorphic histology and presence of trisomy 3 and 18 that are at risk of transforming into a non-GC DLBCL if they show, in addition, strong nuclear FOXP1 positivity.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Xavier Sagaert, Pascale de Paepe, Iwona Wlodarska, Christiane De Wolf-Peeters
Provision of study materials or patients: Gregor Verhoef, Jose Thomas, Iwona Wlodarska, Christiane De Wolf-Peeters
Collection and assembly of data: Xavier Sagaert, Pascale de Paepe
Data analysis and interpretation: Xavier Sagaert, Louis Libbrecht, Vera Vanhentenrijk, Christiane De Wolf-Peeters
Manuscript writing: Xavier Sagaert, Louis Libbrecht, Iwona Wlodarska, Christiane De Wolf-Peeters
Final approval of manuscript: Xavier Sagaert, Gregor Verhoef, Jose Thomas, Iwona Wlodarska, Christiane De Wolf-Peeters
Fig 1. (A) A mucosa-associated lymphoid tissue (MALT) lymphoma with a monomorphic histology. (B) A MALT lymphoma with a polymorphic histology. (C) Strong nuclear forkhead box protein P1 (FOXP1) positivity in a MALT lymphoma. (D) Histology of a diffuse large B-cell lymphoma marked by FOXP1 positivity and trisomy 3 and 18.
Fig 2. Kaplan-Meier analysis of disease-free survival (DFS) in 68 patients diagnosed with mucosa-associated lymphoid tissue lymphoma and treated with curative intent. (A) DFS according to forkhead box protein P1 (FOXP1) expression. (B) DFS according to morphology. (C) DFS according to Ann Arbor staging. (D) DFS according to bone marrow involvement.
Table 1. Frequency of MALT1, BCL10, and FOXP1 Aberrations in Mucosa-Associated Lymphoid Tissue Lymphomas Relative to the Lymphoma Site and Their Relationship to Morphologic Features
Site and MorphologyPatients Analyzedt(11;18)t(1;14)t(14;18)t(3;14)Trisomy 3Trisomy/Polysomy 18Trisomy 3 and Trisomy/Polysomy 18Other
GI tract, No.2450011*1115
Lung, No.410001020
Nasopharynx, No.101000000
Tonsil, No.100000100
Salivary gland, No.1410002137
Thyroid gland, No.200000101
Ocular adnexa, No.18002§022§310
Skin, No.300000021
Breast, No.100000010
Tongue, No.200001001
Monomorphic histology, No.53702§132732
Polymorphic histology, No.1701004453
Total         
    No.707121761235
    %100101.52.92.9108.617.150
Abbreviations: MALT, mucosa-associated lymphoid tissue; FOXP1, forkhead box protein P1.
*
This patient also harbored a MALT1 amplification.
This patient had five signals using centromeric probe 18, confirming the presence of pentasomy 18; all other patients listed in this column featured atrisomy 18.
One of these patients had four signals using centromeric probe 18, confirming the presence of tetrasomy 18 besides trisomy 3; all other patients listed in this column featured a trisomy 3 and a trisomy 18.
§
One of these patients harbored both a t(14;18)(q32;q21) and atrisomy 3 and 18.
The polymorphic lymphomas were observed in the nasopharynx (one of one patient), tonsil (one of one patient), lung (two of four patients), tongue (one of two patients), skin (two of three patients), salivary glands (five of 14 patients), ocular adnexa (three of 18 patients), and the GI tract (two of 24 patients).
Table 2. Characteristics of MALT Lymphomas With Strong Nuclear FOXP1 Positivity
Patient No.Location of Primary LesionMorphologyFISH-Documented Genetic AberrationsSexAge (years)StageTreatmentClinical Follow-Up InformationFollow-Up (months)
1StomachPolymorphict(3;14)(p14.1;q32)Female77IVGastrectomy, interruption MTXThis patient presented with a gastric MALT lymphoma and a cervical lymph node affected by a DLBCL; CR was achieved after therapy54
2TonsilPolymorphicPentasomy 18Male36I ACHVmP-BV; radiation (30 Gy)CR64
3Salivary glandPolymorphicTrisomy 3; tetrasomy 18Male70I AECHVmP-BV; radiation (36 Gy)CR88
4OrbitaMonomorphict(14;18)(q31;q21)Female70I AERadiation (20 Gy)CR118
5OrbitaPolymorphicTrisomy 3 + 18Male63I AERadiation (30 Gy)Multiple relapses (orbita, lung, and gluteus) with evolution to a DLBCL (cervical lymph node); PD resulted in death despite secondary therapy57
6OrbitaPolymorphicTrisomy 3 + 18Female45IV*DHAP; radiation (30 Gy)Multiple relapses (breast, spleen, and orbita) with evolution to a DLBCL (inguinal lymph node); PD resulted in death despite secondary therapy42
7SkinPolymorphicTrisomy 3 + 18Female71IV*Chlorambucil and methylprednisoloneCutaneous relapse (DLBCL) with CR* after secondary chemotherapy57
8SkinPolymorphicTrisomy 3 + 18Male61I AECHOPCutaneous relapse (DLBCL) with PD* resulting in death, despite secondary therapy58
Abbreviations: MALT, mucosa-associated lymphoid tissue; FOXP1, forkhead box protein P1; FISH, fluorescence in situ hybridization; MTX, methotrexate; DLBCL, diffuse large B-cell lymphoma; CR, complete remission; CHVmP-BV, cyclophosphamide, doxorubicin, teniposide, and prednisone with bleomycin and vincristine at midinterval; PD, progressive disease; DHAP, dexamethasone, cytarabine, and cisplatin; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone.
*
In patients 6 and 7, Ann Arbor disease stage IV was diagnosed because of bone marrow invasion.
Table 3. Correlation Between Clinical Features and FOXP1 Immunophenotype, Morphology, and Genetic Features
FOXP1 Immunophenotype, Morphology, and Genetic FeaturesNo. of PatientsMedian Age (years)Male-to-Female RatioAutoimmune Disease Ann Arbor Stage IV Increased LDH High/Intermediate and High IPI Bone Marrow Involvement 
    No.%No.%No.%No.%No.%
FOXP1             
    Negative5060.21.1:1161991836.792048
    Positive2061.31:1216.6650210.5315.815
Histology             
    Monomorphic5360.81.4:159.491736.1816.347.5
    Polymorphic1761.50.7:1635.5635.3213.3426.615.9
Trisomy or polysomy 3 and/or 18             
    Absence4561.61.5:1613.3715.6246.5818,624.4
    Presence2559.80.8:1520832314.2419312
Total70611.2:11115.71521.45*7.812*18.757.1
Abbreviations: FOXP1, forkhead box protein P1; LDH, lactate dehydrogenase; IPI, International Prognostic Index.
*
LDH and IPI was only known in 64 of the 70 patients.
Table 4. Correlation Between Prognosis and FOXP1 Immunophenotype, Morphology, and Genetic Features
FOXP1 Immunophenotype, Morphology, and Genetic FeaturesNo. of Patients Treated With Curative IntentCR PR PD Lymphoma-Related Deaths OS (months)DFS (months)5-Year OS (%)5-Year DFS (%)
  No.%No.%No.%No.(%)    
FOXP1             
    Negative494693.936.124.10067.266.180.6100
    Positive191910000842.1315.865.549.269.250
Histology             
    Monomorphic514894.135.947.80069.263.983.986.7
    Polymorphic171710000635.7317.665.953.961.570
Trisomy or polysomy 3 and/or 18             
    Absence444193.236.836.80068.765.085.290
    Presence242410000729.2312.563.154.854.760
Total686595.634.41014.734.466.861.477.382.5
Abbreviations: FOXP1, forkhead box protein P1; CR, complete remission; PR, partial remission; PD, progressive disease; OS, overall survival; DFS, disease-free survival.
Table 5. Variables Associated With FOXP1 Expression, Morphology, Genetics, DFS, and OS by Univariate Analysis
VariableFOXP1 Expression (P)Polymorphic Histology (P)Presence of Trisomy or Polysomy 3 and/or 18 (P)PD (P)OS (P)DFS (P)5-Year OS (P)5-Year DFS (P)
Age > 60 years.3827.7987.9618.4853.5836.3315> .9999.4332
Sex> .9617.1989.2826> .9999.0721.7795.4901.6984
Ann Arbor stage IV.3669.0993.5693.0042*.8016.0008*.6603.186*
B symptoms.8213.5861.4706> .9999> .9999> .9999
Autoimmune disease.7165.0061*.3340> .9999.6532.5558> .9999
LDH.8624.4185.1864> .9999.1760.6434.1405.4207
Bone marrow involvement.1679> .6563.4665.0403*.5762.0127*.5773.2793
FOXP1 expression.0001*.0509.0004*.5963.0001*.2498.0004*
Polymorphic histology.0001*.0007*.0143*.2991.0032*.1167.0066*
Presence of trisomy or polysomy 3 and/or 18.0509.0007*.1512.5446.1151.2680.0508
Abbreviations: FOXP1, forkhead box protein P1; PD, progressive disease; OS, overall survival; DFS, disease-free survival; LDH, lactate dehydrogenase.
*
Significant P values.

Acknowledgments

We thank Ursula Pluys, Miet Van Herck, Adriana Jablecka, and Lore Bernar for excellent technical assistance.
Supported by Grant No. G.0362.01 from the Fund for Scientific Research (FWO) Flanders; X.S. and L.L. are research fellows of FWO Flanders; and V.V. is a research fellow of the Belgian Federation Against Cancer.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Published In

Journal of Clinical Oncology
Pages: 2490 - 2497
PubMed: 16636337

History

Published in print: June 01, 2006
Published online: September 21, 2016

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Xavier Sagaert
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Pascale de Paepe
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Louis Libbrecht
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Vera Vanhentenrijk
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Gregor Verhoef
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Jose Thomas
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Iwona Wlodarska
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium
Christiane De Wolf-Peeters
From the Departments of Morphology and Molecular Pathology, Hematology, and Oncology and the Centre for Human Genetics, Catholic University Leuven, Leuven; and Department of Pathology, Ghent University, Ghent, Belgium

Notes

Address reprint requests to Sagaert Xavier, MD, Department of Morphology and Molecular Pathology, Katholieke Universiteit Leuven, Minderbroederstraat 12, B-3000 Leuven, Belgium; e-mail: [email protected]

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Xavier Sagaert, Pascale de Paepe, Louis Libbrecht, Vera Vanhentenrijk, Gregor Verhoef, Jose Thomas, Iwona Wlodarska, Christiane De Wolf-Peeters
Journal of Clinical Oncology 2006 24:16, 2490-2497

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