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Secondary Cutaneous Vasculitislike MALT Lymphoma With an IGL-MYC Fusion

Secondary Cutaneous Vasculitislike MALT Lymphoma With an IGL-MYC Fusion Report of a Case A 62-year-old man presented with mucosa-associated lymphoid tissue (MALT) lymphoma manifesting primarily in the oropharyngeal mucosa, bone marrow, and peripheral blood and consequently manifesting a distinct type of secondary skin involvement. At diagnosis, the malignant bone marrow cells showed no chromosomal translocations (including MYC break points) as evidenced by fluorescence in situ hybridization analysis (FISH). Three months later, and 1 week after receiving therapy with rituximab, the patient developed a purpuric exanthema resembling allergic vasculitis (Figure 1A and B). Moreover, his upper arms displayed bluish livedolike lesions (Figure 1C and D). Biopsy specimens from both types of lesions revealed infiltrates of monomorphic lymphoplasmacytoid tumor cells (CD20+, CD79a+, Bcl-2+, λ+, CD5−, CD23−, TdT−, CD34−, CD10−, CD30−, CD138−, and Ki67 proliferation index <3%) (Figure 1E-H). Using a procedure described previously,1,2 we performed interphase FISH on lesional skin biopsy specimens targeting the IGH, IGL, IGK, MYC, BCL6, and MALT1 loci and surprisingly discovered an IGL-MYC fusion, which indicates the presence of the translocation (8;22)(q24;q11) (Figure 2C and Table). Three cycles of chemotherapy with rituximab and cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone followed by rituximab and fludarabine, cyclophosphamide, and mitoxantrone resulted in transient remission only. Figure 1. View LargeDownload Clinical and histopathologic case photographs. The patient displayed purpuric papules on his hips resembling allergic vasculitis (A and B) and bluish reticular indurations on his upper arms resembling livedo reticularis (C and D). E, Perivascular and periadnexal nodular infiltrates of densely packed monomorphic lymphocytes with many erythrocytes admixed are seen in a skin section from the arm; the infiltrate extends to the subcutaneous fat tissue (hematoxylin-eosin, original magnification ×20 for primary photograph and ×400 for the insert). Giemsa stain reveals prominent nuclei and a pale cytoplasm of the tumor cells (F) (original magnification ×600), which express CD20 (G) and CXC receptor 4 (H) (original magnification ×200 for both G and H); besides cytoplasmic staining, the nuclei of many tumor cells are positive for CXC receptor 4. Figure 2. View LargeDownload Fluorescence in situ hybridization (FISH). We performed FISH on paraffin-embedded lesional tissue sections and evaluated at least 200 nuclei. A, Interphase nuclei hybridized with the Locus Specific Identifier MYC break-apart probe (Abbott Molecular, Des Plaines, Illinois). The 2 nuclei show 1 intact MYC allele with a colocalization of the red (MYC proximal) and green (MYC distal) signals, and a dissociation of the green and red signals (arrows) indicating that MYC is involved in a translocation. B, Interphase nuclei hybridized with an IGL break-apart probe (as described in Martíin-Subero et al2). The 2 nuclei display a significant dissociation of the red (IGL proximal) and green (IGL distal) signals (arrows) indicating the presence of a translocation affecting the IGL. C, Interphase nuclei hybridized with an IGL/MYC dual-color, dual-fusion probe: red signal, 8q24 (MYC locus); green signal, 22q11 (IGL locus). The presence of fused red and green signals (arrows) indicate that an IGL/MYC fusion due to a translocation t(8;22)(q24;q11) has taken place. The isolated red and green signals point to the unrearranged MYC and IGL alleles, respectively. Table. View LargeDownload Chromosomal Aberrations on Lesional Skin Tissue as Detected by Interphase FISHa Comment In addition to having a gastric origin, MALT lymphomas may also originate in different internal organs, including the Waldeyer pharyngeal ring. They may spread to various extramucosal sites such as lymph nodes and bone marrow (as in the case of our patient), and they very rarely involve the skin. In contrast to primary cutaneous marginal zone B-cell lymphomas, which rarely show any chromosomal abnormalities,3 MALT lymphomas frequently present various recurrent chromosomal translocations, depending on their primary tissue manifestation.4 Primary cutaneous marginal zone B-cell lymphomas have no MYC translocations,3 and secondary cutaneous lesions of MALT lymphomas have not been investigated. Translocations involving the MYC gene acquired as secondary chromosomal aberration steps have been associated with disease progression in MALT lymphoma.5 Juxtaposing the MYC oncogene (8q24) to 1 of the IG loci can lead to MYC deregulation, which causes dysregulation of proliferation and apoptosis. Also, in our patient the MYC translocation (8;22)(q24;q11) seems to have occurred as a secondary event. The fact that the tumor cells in the bone marrow biopsy specimen detected at the time of diagnosis did not carry the MYC break points is in agreement with this hypothesis. To our knowledge, secondary cutaneous MALT lymphoma mimicking vasculitis has not been described before. True leukocytoclastic cutaneous vasculitis has been reported after therapy with rituximab, but never lymphoma skin infiltrations (with or without vasculitislike aspects).6 Recently, gastric and extragastric MALT lymphomas have been characterized for their expression of distinct chemokine receptor patterns, probably contributing to their differential homing.7 Stromal derived factor 1, which is widely expressed by the cutaneous microvasculature, has been shown to attract chemokine CXC receptor 4 (CXCR4)-expressing B-cell lymphoma cells. In our case, skin lymphoma cells displayed a strong cytoplasmic expression of CXCR4, possibly explaining their migration into the skin and the vasculitislike aspect (Figure 1H). In addition, a strong nuclear expression of CXCR4 was present, which might be related to tumor progression. It remains to be investigated whether translocations involving the MYC gene may facilitate a secondary spread of MALT lymphoma to the skin and/or correlate with vasculitislike skin infiltration. Back to top Article Information Correspondence: Dr Kaune, Department of Dermatology and Venereology, Georg August University Göttingen, Von Siebold Straße 3, 37075 Göttingen, Germany (kkaune@gwdg.de). Financial Disclosure: None reported. Funding/Support: Dr Kaune was supported in part by the Research Program, Faculty of Medicine, Georg August University Göttingen. Additional Contributions: Elena Schmitke provided expert technical assistance, and Hans K. Müller-Hermelink, MD, confirmed the histologic diagnosis. Lorenz Trümper, MD, was the treating physician in charge of the patient's medical care. References 1. Mitelman F ISCN 1995: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: S Karger; 1995 2. Martíin-Subero JIHarder LGesk S et al. Interphase FISH assays for the detection of translocations with breakpoints in immunoglobulin light chain loci. Int J Cancer 2002;98 (3) 470- 474PubMedGoogle ScholarCrossref 3. Hallermann CKaune KMGesk S et al. Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol 2004;123 (1) 213- 219PubMedGoogle ScholarCrossref 4. Streubel BSimonitsch-Klupp IMüllauer L et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004;18 (10) 1722- 1726PubMedGoogle ScholarCrossref 5. van Krieken JHRaffeld MRaghoebier SJaffe ESvan Ommen GJKluin PM Molecular genetics of gastrointestinal non-Hodgkin's lymphomas: unusual prevalence and pattern of c-myc rearrangements in aggressive lymphomas. Blood 1990;76 (4) 797- 800PubMedGoogle Scholar 6. Kandula PKouides PA Rituximab-induced leukocytoclastic vasculitis: a case report. Arch Dermatol 2006;142 (2) 246- 247PubMedGoogle ScholarCrossref 7. Deutsch AJAigelsreiter ASteinbauer E et al. Distinct signatures of B-cell homeostatic and activation-dependent chemokine receptors in the development and progression of extragastric MALT lymphomas. J Pathol 2008;215 (4) 431- 444PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

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Publisher
American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archdermatol.2009.166
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Abstract

Report of a Case A 62-year-old man presented with mucosa-associated lymphoid tissue (MALT) lymphoma manifesting primarily in the oropharyngeal mucosa, bone marrow, and peripheral blood and consequently manifesting a distinct type of secondary skin involvement. At diagnosis, the malignant bone marrow cells showed no chromosomal translocations (including MYC break points) as evidenced by fluorescence in situ hybridization analysis (FISH). Three months later, and 1 week after receiving therapy with rituximab, the patient developed a purpuric exanthema resembling allergic vasculitis (Figure 1A and B). Moreover, his upper arms displayed bluish livedolike lesions (Figure 1C and D). Biopsy specimens from both types of lesions revealed infiltrates of monomorphic lymphoplasmacytoid tumor cells (CD20+, CD79a+, Bcl-2+, λ+, CD5−, CD23−, TdT−, CD34−, CD10−, CD30−, CD138−, and Ki67 proliferation index <3%) (Figure 1E-H). Using a procedure described previously,1,2 we performed interphase FISH on lesional skin biopsy specimens targeting the IGH, IGL, IGK, MYC, BCL6, and MALT1 loci and surprisingly discovered an IGL-MYC fusion, which indicates the presence of the translocation (8;22)(q24;q11) (Figure 2C and Table). Three cycles of chemotherapy with rituximab and cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone followed by rituximab and fludarabine, cyclophosphamide, and mitoxantrone resulted in transient remission only. Figure 1. View LargeDownload Clinical and histopathologic case photographs. The patient displayed purpuric papules on his hips resembling allergic vasculitis (A and B) and bluish reticular indurations on his upper arms resembling livedo reticularis (C and D). E, Perivascular and periadnexal nodular infiltrates of densely packed monomorphic lymphocytes with many erythrocytes admixed are seen in a skin section from the arm; the infiltrate extends to the subcutaneous fat tissue (hematoxylin-eosin, original magnification ×20 for primary photograph and ×400 for the insert). Giemsa stain reveals prominent nuclei and a pale cytoplasm of the tumor cells (F) (original magnification ×600), which express CD20 (G) and CXC receptor 4 (H) (original magnification ×200 for both G and H); besides cytoplasmic staining, the nuclei of many tumor cells are positive for CXC receptor 4. Figure 2. View LargeDownload Fluorescence in situ hybridization (FISH). We performed FISH on paraffin-embedded lesional tissue sections and evaluated at least 200 nuclei. A, Interphase nuclei hybridized with the Locus Specific Identifier MYC break-apart probe (Abbott Molecular, Des Plaines, Illinois). The 2 nuclei show 1 intact MYC allele with a colocalization of the red (MYC proximal) and green (MYC distal) signals, and a dissociation of the green and red signals (arrows) indicating that MYC is involved in a translocation. B, Interphase nuclei hybridized with an IGL break-apart probe (as described in Martíin-Subero et al2). The 2 nuclei display a significant dissociation of the red (IGL proximal) and green (IGL distal) signals (arrows) indicating the presence of a translocation affecting the IGL. C, Interphase nuclei hybridized with an IGL/MYC dual-color, dual-fusion probe: red signal, 8q24 (MYC locus); green signal, 22q11 (IGL locus). The presence of fused red and green signals (arrows) indicate that an IGL/MYC fusion due to a translocation t(8;22)(q24;q11) has taken place. The isolated red and green signals point to the unrearranged MYC and IGL alleles, respectively. Table. View LargeDownload Chromosomal Aberrations on Lesional Skin Tissue as Detected by Interphase FISHa Comment In addition to having a gastric origin, MALT lymphomas may also originate in different internal organs, including the Waldeyer pharyngeal ring. They may spread to various extramucosal sites such as lymph nodes and bone marrow (as in the case of our patient), and they very rarely involve the skin. In contrast to primary cutaneous marginal zone B-cell lymphomas, which rarely show any chromosomal abnormalities,3 MALT lymphomas frequently present various recurrent chromosomal translocations, depending on their primary tissue manifestation.4 Primary cutaneous marginal zone B-cell lymphomas have no MYC translocations,3 and secondary cutaneous lesions of MALT lymphomas have not been investigated. Translocations involving the MYC gene acquired as secondary chromosomal aberration steps have been associated with disease progression in MALT lymphoma.5 Juxtaposing the MYC oncogene (8q24) to 1 of the IG loci can lead to MYC deregulation, which causes dysregulation of proliferation and apoptosis. Also, in our patient the MYC translocation (8;22)(q24;q11) seems to have occurred as a secondary event. The fact that the tumor cells in the bone marrow biopsy specimen detected at the time of diagnosis did not carry the MYC break points is in agreement with this hypothesis. To our knowledge, secondary cutaneous MALT lymphoma mimicking vasculitis has not been described before. True leukocytoclastic cutaneous vasculitis has been reported after therapy with rituximab, but never lymphoma skin infiltrations (with or without vasculitislike aspects).6 Recently, gastric and extragastric MALT lymphomas have been characterized for their expression of distinct chemokine receptor patterns, probably contributing to their differential homing.7 Stromal derived factor 1, which is widely expressed by the cutaneous microvasculature, has been shown to attract chemokine CXC receptor 4 (CXCR4)-expressing B-cell lymphoma cells. In our case, skin lymphoma cells displayed a strong cytoplasmic expression of CXCR4, possibly explaining their migration into the skin and the vasculitislike aspect (Figure 1H). In addition, a strong nuclear expression of CXCR4 was present, which might be related to tumor progression. It remains to be investigated whether translocations involving the MYC gene may facilitate a secondary spread of MALT lymphoma to the skin and/or correlate with vasculitislike skin infiltration. Back to top Article Information Correspondence: Dr Kaune, Department of Dermatology and Venereology, Georg August University Göttingen, Von Siebold Straße 3, 37075 Göttingen, Germany (kkaune@gwdg.de). Financial Disclosure: None reported. Funding/Support: Dr Kaune was supported in part by the Research Program, Faculty of Medicine, Georg August University Göttingen. Additional Contributions: Elena Schmitke provided expert technical assistance, and Hans K. Müller-Hermelink, MD, confirmed the histologic diagnosis. Lorenz Trümper, MD, was the treating physician in charge of the patient's medical care. References 1. Mitelman F ISCN 1995: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: S Karger; 1995 2. Martíin-Subero JIHarder LGesk S et al. Interphase FISH assays for the detection of translocations with breakpoints in immunoglobulin light chain loci. Int J Cancer 2002;98 (3) 470- 474PubMedGoogle ScholarCrossref 3. Hallermann CKaune KMGesk S et al. Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas. J Invest Dermatol 2004;123 (1) 213- 219PubMedGoogle ScholarCrossref 4. Streubel BSimonitsch-Klupp IMüllauer L et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004;18 (10) 1722- 1726PubMedGoogle ScholarCrossref 5. van Krieken JHRaffeld MRaghoebier SJaffe ESvan Ommen GJKluin PM Molecular genetics of gastrointestinal non-Hodgkin's lymphomas: unusual prevalence and pattern of c-myc rearrangements in aggressive lymphomas. Blood 1990;76 (4) 797- 800PubMedGoogle Scholar 6. Kandula PKouides PA Rituximab-induced leukocytoclastic vasculitis: a case report. Arch Dermatol 2006;142 (2) 246- 247PubMedGoogle ScholarCrossref 7. Deutsch AJAigelsreiter ASteinbauer E et al. Distinct signatures of B-cell homeostatic and activation-dependent chemokine receptors in the development and progression of extragastric MALT lymphomas. J Pathol 2008;215 (4) 431- 444PubMedGoogle ScholarCrossref

Journal

Archives of DermatologyAmerican Medical Association

Published: Aug 1, 2009

Keywords: lymphoma, mucosa-associated lymphoid tissue

References