Value of Interphase FISH for the Diagnosis of t(11;14)(q13;q32)
The diagnosis of skin lesions of mantle cell lymphoma (MCL) may be difficult at the onset of the disease. We observed 2 patients with papules of the trunk and 1 with diffuse infiltration of the trunk and the face and 2 subcutaneous nodules. Skin samples showed diffuse infiltration of the dermis (n = 1) or perivascular infiltration (n = 2). The infiltrate corresponded to centrocytic cells (n = 2) or pleomorphic blastoid cells (n = 1) with a B-cell phenotype: CD3-, CD5+ (2/3), CD20+, CD23-, and CD43+. In only 1 case was cyclin D1 immunoreactivity detected, and the t(11;14)(q13;q32) breakpoint was amplified from both lymph node and skin DNA. Competitive reverse transcriptase-polymerase chain reaction was not contributive for skin specimens. In all 3 cases, interphase fluorescence in situ hybridization (FISH) demonstrated t(11;14) fusion signals either on paraffin sections or on fresh frozen touch preparations of skin biopsies. The recognition of skin lesions of MCL from other B-cell infiltrates can be established by interphase FISH.
Mantle cell lymphoma (MCL) is a peripheral B-cell lymphoma with usual lymph node, blood, and bone marrow involvement at diagnosis. Skin involvement has been reported rarely in large series of MCLs with a maximum rate of 2% and has been documented in only 7 patients to the best of our knowledge ( Table 1 ). As most small B-cell lymphomas of the skin presumably originate from either the follicle center or its marginal zone but not from the mantle zone, MCL has not been included in the European Organization for Research and Treatment of Cancer (EORTC) classification of primary cutaneous lymphomas. However, a mantle-zone pattern has been suggested for a subset of primary cutaneous B-cell lymphoma.
Skin lesions may be the only manifestation of MCL during an extended period, and the lack of specific clinical features may hamper diagnosis. Whatever their primary or secondary origin, small B-cell infiltrates of the skin frequently pose differential diagnostic problems between reactive and neoplastic lesions.
The search for monoclonal rearrangement of the immunoglobulin gene is considered to be an ancillary diagnostic tool. The use of other cytogenetic or molecular markers such as t(14;18) for follicular lymphoma may be of limited value in the skin because cutaneous follicular lymphomas usually do not carry the t(14;18), as opposed to their nodal counterpart. It also is unknown whether cutaneous marginal zone lymphomas carry the t(1;14) or t(11;18) identified in subsets of mucosa-associated lymphoid tissue lymphoma. MCL, the malignant counterpart of naive CD5+ B cells located in the mantle zone of secondary follicles, is characterized by a reciprocal t(11;14)(q13;q32) leading to overexpression of CCND1/PRAD1 gene transcripts and the corresponding cyclin D1 protein, which acts as a positive signal for the transition from the G1 to S phase of the cell cycle. So far, the presence of the t(11;14) in skin lesions of MCL has not been demonstrated, although it can be achieved by several techniques.
Owing to the lack of a conventional karyotype, the fluorescence in situ hybridization (FISH) technique has been applied commonly to identify the t(11;14) in interphase nuclei prepared from peripheral blood samples and from frozen or paraffin-embedded tissue. The t(11;14) breakpoint also can be amplified by genomic polymerase chain reaction (PCR), but its variability on chromosome 11q13 generates a high rate of negative PCR results in at least half of all patients. Therefore, the detection of overexpression of PRAD1/CCND1/cyclin D1 by competitive reverse transcriptase-polymerase chain reaction (RT-PCR) with cyclin D2 and D3 transcripts has proved to be a rapid tool for the study of lymphoid cells but has not been used to study epithelial tissues with constitutive expression of CCND1/cyclin D1. Therefore, the immunohistochemical detection of cyclin D1 protein seems more appropriate for the study of skin specimens than a global protein analysis such as the Western blot. However, the sensitivity of immunohistochemical analysis for cyclin D1 detection may depend on the quality of fixation or on the antigen retrieval procedure.
Because we recently observed 3 patients with cutaneous MCL, we studied clinical and histologic features of their cases, in comparison with previously documented cases, to identify features that might permit proper recognition of skin involvement by MCL. As t(11;14) is a cytogenetic hallmark of MCL, we also evaluated the different techniques for its detection in skin specimens.
The diagnosis of skin lesions of mantle cell lymphoma (MCL) may be difficult at the onset of the disease. We observed 2 patients with papules of the trunk and 1 with diffuse infiltration of the trunk and the face and 2 subcutaneous nodules. Skin samples showed diffuse infiltration of the dermis (n = 1) or perivascular infiltration (n = 2). The infiltrate corresponded to centrocytic cells (n = 2) or pleomorphic blastoid cells (n = 1) with a B-cell phenotype: CD3-, CD5+ (2/3), CD20+, CD23-, and CD43+. In only 1 case was cyclin D1 immunoreactivity detected, and the t(11;14)(q13;q32) breakpoint was amplified from both lymph node and skin DNA. Competitive reverse transcriptase-polymerase chain reaction was not contributive for skin specimens. In all 3 cases, interphase fluorescence in situ hybridization (FISH) demonstrated t(11;14) fusion signals either on paraffin sections or on fresh frozen touch preparations of skin biopsies. The recognition of skin lesions of MCL from other B-cell infiltrates can be established by interphase FISH.
Mantle cell lymphoma (MCL) is a peripheral B-cell lymphoma with usual lymph node, blood, and bone marrow involvement at diagnosis. Skin involvement has been reported rarely in large series of MCLs with a maximum rate of 2% and has been documented in only 7 patients to the best of our knowledge ( Table 1 ). As most small B-cell lymphomas of the skin presumably originate from either the follicle center or its marginal zone but not from the mantle zone, MCL has not been included in the European Organization for Research and Treatment of Cancer (EORTC) classification of primary cutaneous lymphomas. However, a mantle-zone pattern has been suggested for a subset of primary cutaneous B-cell lymphoma.
Skin lesions may be the only manifestation of MCL during an extended period, and the lack of specific clinical features may hamper diagnosis. Whatever their primary or secondary origin, small B-cell infiltrates of the skin frequently pose differential diagnostic problems between reactive and neoplastic lesions.
The search for monoclonal rearrangement of the immunoglobulin gene is considered to be an ancillary diagnostic tool. The use of other cytogenetic or molecular markers such as t(14;18) for follicular lymphoma may be of limited value in the skin because cutaneous follicular lymphomas usually do not carry the t(14;18), as opposed to their nodal counterpart. It also is unknown whether cutaneous marginal zone lymphomas carry the t(1;14) or t(11;18) identified in subsets of mucosa-associated lymphoid tissue lymphoma. MCL, the malignant counterpart of naive CD5+ B cells located in the mantle zone of secondary follicles, is characterized by a reciprocal t(11;14)(q13;q32) leading to overexpression of CCND1/PRAD1 gene transcripts and the corresponding cyclin D1 protein, which acts as a positive signal for the transition from the G1 to S phase of the cell cycle. So far, the presence of the t(11;14) in skin lesions of MCL has not been demonstrated, although it can be achieved by several techniques.
Owing to the lack of a conventional karyotype, the fluorescence in situ hybridization (FISH) technique has been applied commonly to identify the t(11;14) in interphase nuclei prepared from peripheral blood samples and from frozen or paraffin-embedded tissue. The t(11;14) breakpoint also can be amplified by genomic polymerase chain reaction (PCR), but its variability on chromosome 11q13 generates a high rate of negative PCR results in at least half of all patients. Therefore, the detection of overexpression of PRAD1/CCND1/cyclin D1 by competitive reverse transcriptase-polymerase chain reaction (RT-PCR) with cyclin D2 and D3 transcripts has proved to be a rapid tool for the study of lymphoid cells but has not been used to study epithelial tissues with constitutive expression of CCND1/cyclin D1. Therefore, the immunohistochemical detection of cyclin D1 protein seems more appropriate for the study of skin specimens than a global protein analysis such as the Western blot. However, the sensitivity of immunohistochemical analysis for cyclin D1 detection may depend on the quality of fixation or on the antigen retrieval procedure.
Because we recently observed 3 patients with cutaneous MCL, we studied clinical and histologic features of their cases, in comparison with previously documented cases, to identify features that might permit proper recognition of skin involvement by MCL. As t(11;14) is a cytogenetic hallmark of MCL, we also evaluated the different techniques for its detection in skin specimens.
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