BCL2 Rearrangement in Follicular Lymphoma
BCL2 Rearrangement in Follicular Lymphoma
Objectives To study the diagnostic value of BCL2 rearrangement in follicle center lymphoma (FCL) presenting as primary skin lesions, evaluate its prevalence and the prognostic value in primary cutaneous FCL (PCFCL), and assess prognostic factors in PCFCL.
Methods Fifty-three patients with a cutaneous presentation of FCL without a history of nodal lymphoma were selected retrospectively. Clinical and histologic data were collected together with staging and follow-up data. A fluorescence in situ hybridization (FISH) test for BCL2 split probes was performed on skin biopsy specimens.
Results Initial staging procedures identified 47 PCFCLs and six cases of secondary skin involvement of FCL (SSIFCL). FISH detected seven cases carrying a BCL2 rearrangement: four (8.5%) of 47 PCFCLs and three (50%) of six SSIFCLs. These seven cases coexpressed BCL2 and CD10. In PCFCL, cutaneous relapse rate was 42.6%. A small/medium centrocytic cell population was associated with a higher probability of skin relapse in univariate (P = .008) and multivariate (P = .028) analysis, and BCL2 rearrangement detection was associated with secondary extracutaneous spreading (P = .05).
Conclusions We observed that BCL2 rearrangement in PCFCL is rare, associated with initial positivity of staging (diagnostic value) or with secondary extracutaneous spreading (prognostic value). In selected cases with BCL2-CD10 coexpression, FISH testing could detect patients with poor outcome and require closer monitoring.
Primary cutaneous lymphomas (PCLs) of B-cell origin account for 25% of all PCLs. Three main types of primary cutaneous B-cell lymphomas are recognized: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type. PCFCL, representing approximately 55% of all primary cutaneous B-cell lymphomas, is the most common B-cell lymphoma to occur as a primary tumor of skin. PCFCL usually involves the head and neck or trunk, with solitary or grouped plaques and tumors, while multifocal skin lesions are possible. Morphologically, PCFCL exhibits a proliferation of neoplastic follicle center cells, usually a mixture of small/medium and large centrocytes (sometimes spindle-shaped type) and a variable proportion of centroblasts. Architectural pattern is variable along a continuum from follicular, nodular, sometimes focally periadnexal to diffuse growth patterns. PCFCL, even with a predominance of large cells (large centrocytes or centroblasts), has an indolent behavior characterized by a 5-year survival rate of 95% as opposed to the 41% rate of PCLBCL, leg type. Multifocal lesions do not have a poorer outcome than solitary lesions. PCFCL on the leg displays a poorer prognosis, with 5-year disease-specific survival reported at 41%. Skin relapse is observed in 30% to 45% of patients. Recurrence does not affect prognosis and is usually confined to the skin. Secondary extracutaneous dissemination may occur in 5% to 10% of cases. Furthermore, secondary skin involvement by nodal follicular lymphoma (SSIFCL) may share clinicopathologic similarities with PCFCL, especially if skin lesions are the initial manifestation of a systemic disease. Therefore, a negative staging is required to assert PCFCL and to rule out SSIFCL since both diseases require a different treatment.
The hallmark of nodal follicular lymphoma is the t(14;18)(q32;q21) translocation, which consists of a reciprocal translocation between the BCL2 proto-oncogene and the immunoglobulin heavy chain (IgH) gene, leading to the overexpression of BCL2 protein. Therefore, the t(14;18) should be detected either by polymerase chain reaction (PCR) for BCL2-IgH breakpoint amplification or by fluorescence in situ hybridization (FISH) for either BCL2-IgH fusion or BCL2 separation or split. In nodal follicular lymphoma, interphase FISH has detected a higher rate of positive cases for BCL2 rearrangement than the BIOMED-2 PCR protocol. While the BCL2 rearrangement is observed in 80% to 90% of cases of follicular lymphoma, this genetic alteration was not detected in several series of PCFCL, including the one from our group using both FISH and PCR with BIOMED-2 techniques. However, Streubel et al found a BCL2-IgH fusion by FISH in 41% of PCFCL cases, although they were not able to amplify the BCL2-IgH breakpoint by the BIOMED2 PCR protocol in FISH-positive cases. Alternatively, PCR amplification of the BCL2-IgH breakpoint provided positive results in some series of PCFCL cases, but we clearly demonstrated that molecular detection alone is able to pick up B cells carrying BCL2-JH rearrangement as described in healthy carriers Table 1. Besides the technical aspects, most of the above studies did not provide extensive staging and follow-up data that may account for such discordance in patients with different inclusion criteria.
This prompted us to analyze by FISH the prevalence of the BCL2 rearrangement in follicle center lymphoma (FCL) with skin presentation before staging procedures. The main goal of this study was to estimate the prevalence of BCL2 rearrangement in the largest series of PCFCL cases studied so far and to determine if the detection of a BCL2 rearrangement could represent a biomarker that would help patient management at diagnosis. Thanks to an extended follow-up, we also investigated prognostic factors that would predict relapse or extracutaneous spreading in PCFCL.
Abstract and Introduction
Abstract
Objectives To study the diagnostic value of BCL2 rearrangement in follicle center lymphoma (FCL) presenting as primary skin lesions, evaluate its prevalence and the prognostic value in primary cutaneous FCL (PCFCL), and assess prognostic factors in PCFCL.
Methods Fifty-three patients with a cutaneous presentation of FCL without a history of nodal lymphoma were selected retrospectively. Clinical and histologic data were collected together with staging and follow-up data. A fluorescence in situ hybridization (FISH) test for BCL2 split probes was performed on skin biopsy specimens.
Results Initial staging procedures identified 47 PCFCLs and six cases of secondary skin involvement of FCL (SSIFCL). FISH detected seven cases carrying a BCL2 rearrangement: four (8.5%) of 47 PCFCLs and three (50%) of six SSIFCLs. These seven cases coexpressed BCL2 and CD10. In PCFCL, cutaneous relapse rate was 42.6%. A small/medium centrocytic cell population was associated with a higher probability of skin relapse in univariate (P = .008) and multivariate (P = .028) analysis, and BCL2 rearrangement detection was associated with secondary extracutaneous spreading (P = .05).
Conclusions We observed that BCL2 rearrangement in PCFCL is rare, associated with initial positivity of staging (diagnostic value) or with secondary extracutaneous spreading (prognostic value). In selected cases with BCL2-CD10 coexpression, FISH testing could detect patients with poor outcome and require closer monitoring.
Introduction
Primary cutaneous lymphomas (PCLs) of B-cell origin account for 25% of all PCLs. Three main types of primary cutaneous B-cell lymphomas are recognized: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type. PCFCL, representing approximately 55% of all primary cutaneous B-cell lymphomas, is the most common B-cell lymphoma to occur as a primary tumor of skin. PCFCL usually involves the head and neck or trunk, with solitary or grouped plaques and tumors, while multifocal skin lesions are possible. Morphologically, PCFCL exhibits a proliferation of neoplastic follicle center cells, usually a mixture of small/medium and large centrocytes (sometimes spindle-shaped type) and a variable proportion of centroblasts. Architectural pattern is variable along a continuum from follicular, nodular, sometimes focally periadnexal to diffuse growth patterns. PCFCL, even with a predominance of large cells (large centrocytes or centroblasts), has an indolent behavior characterized by a 5-year survival rate of 95% as opposed to the 41% rate of PCLBCL, leg type. Multifocal lesions do not have a poorer outcome than solitary lesions. PCFCL on the leg displays a poorer prognosis, with 5-year disease-specific survival reported at 41%. Skin relapse is observed in 30% to 45% of patients. Recurrence does not affect prognosis and is usually confined to the skin. Secondary extracutaneous dissemination may occur in 5% to 10% of cases. Furthermore, secondary skin involvement by nodal follicular lymphoma (SSIFCL) may share clinicopathologic similarities with PCFCL, especially if skin lesions are the initial manifestation of a systemic disease. Therefore, a negative staging is required to assert PCFCL and to rule out SSIFCL since both diseases require a different treatment.
The hallmark of nodal follicular lymphoma is the t(14;18)(q32;q21) translocation, which consists of a reciprocal translocation between the BCL2 proto-oncogene and the immunoglobulin heavy chain (IgH) gene, leading to the overexpression of BCL2 protein. Therefore, the t(14;18) should be detected either by polymerase chain reaction (PCR) for BCL2-IgH breakpoint amplification or by fluorescence in situ hybridization (FISH) for either BCL2-IgH fusion or BCL2 separation or split. In nodal follicular lymphoma, interphase FISH has detected a higher rate of positive cases for BCL2 rearrangement than the BIOMED-2 PCR protocol. While the BCL2 rearrangement is observed in 80% to 90% of cases of follicular lymphoma, this genetic alteration was not detected in several series of PCFCL, including the one from our group using both FISH and PCR with BIOMED-2 techniques. However, Streubel et al found a BCL2-IgH fusion by FISH in 41% of PCFCL cases, although they were not able to amplify the BCL2-IgH breakpoint by the BIOMED2 PCR protocol in FISH-positive cases. Alternatively, PCR amplification of the BCL2-IgH breakpoint provided positive results in some series of PCFCL cases, but we clearly demonstrated that molecular detection alone is able to pick up B cells carrying BCL2-JH rearrangement as described in healthy carriers Table 1. Besides the technical aspects, most of the above studies did not provide extensive staging and follow-up data that may account for such discordance in patients with different inclusion criteria.
This prompted us to analyze by FISH the prevalence of the BCL2 rearrangement in follicle center lymphoma (FCL) with skin presentation before staging procedures. The main goal of this study was to estimate the prevalence of BCL2 rearrangement in the largest series of PCFCL cases studied so far and to determine if the detection of a BCL2 rearrangement could represent a biomarker that would help patient management at diagnosis. Thanks to an extended follow-up, we also investigated prognostic factors that would predict relapse or extracutaneous spreading in PCFCL.
