Ebook The cutaneous lymphoid proliferations - A comprehensive textbook of lymphocytic infiltrates of the skin (2nd edition): Part 1

(BQ) Part 1 book The cutaneous lymphoid proliferations - A comprehensive textbook of lymphocytic infiltrates of the skin presents the following contents: Introduction to the classification of lymphoma; the therapy of cutaneous T cell lymphoma; molecular analysis in cutaneous lymphoid proliferation; benign lymphocytic infiltrates; reactive lymphomatoid tissue reactions mimicking cutaneous T and B cell lymphoma,...

The Cutaneous Lymphoid Proliferations The Cutaneous Lymphoid Proliferations A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin Second Edition Cynthia M Magro MD Professor of Pathology and Laboratory Medicine Department of Pathology, Cornell University Weill Cornell Medicine New York, NY, USA A Neil Crowson MD Clinical Professor of Dermatology, Pathology, and Surgery Director of Dermatopathology at the University of Oklahoma and Regional Medical Laboratory President of Pathology Laboratory Associates Tulsa, OK, USA Martin C Mihm MD Clinical Professor of Pathology and Dermatology, Harvard Medical School Director of Melanoma Program, Dermatology, Brigham and Women’s Hospital Co-Director of Melanoma Program, Dana-Farber and Brigham and Women’s Cancer Center Director, Mihm Cutaneous Pathology Consultative Service Brigham and Women’s Hospital Boston, MA, USA Copyright © 2016 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey 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this book is available from the Library of Congress ISBN: 9781118776261 Cover images: middle left and bottom right – courtesy of Dr Shivakumar Subramaniyam Printed in Singapore 10 Contents Acknowledgments, viii Introduction to the Classification of Lymphoma, Kiel Lukes–Collins, and Working Formulation classifications, WHO, REAL, EORTC, and the Combined WHO/EORTC classifications, Summary, References, Appendix: Definitions of key terms and techniques, The Therapy of Cutaneous T Cell Lymphoma, 14 Benjamin H Kaffenberger, Mark A Bechtel, and Pierluigi Porcu Introduction, 14 Diagnostic work-up and staging procedures, 14 CTCL therapies, 15 Goals of therapy in advanced-stage CTCL, 16 Extracorporeal photopheresis (ECP), 17 Interferons, 17 Retinoids, 17 Immunotoxins, 18 Monoclonal antibodies, 18 Histone deacetylase inhibitors (HDACi), 19 Antibody drug conjugates (ADC), 19 Cytotoxic chemotherapy, 19 Investigational therapies, 20 TLR agonists and cytokines, 20 Allogeneic hematopoietic stem cell transplantation (allo-HSCT), 20 References, 21 Molecular Analysis in Cutaneous Lymphoid Proliferation, 23 Shabnam Momtahen, Cynthia Magro, and Carl Morrison Introduction, 23 Immunoglobulin and T cell receptor structure, 23 PCR design for determination of clonality, 24 Detection of PCR products for clonality, 24 Evaluation of results, 25 The value and utility of molecular diagnostics in primary cutaneous lymphomas, 26 Limitations of clonality assessment by PCR, 27 Case vignettes, 29 References, 36 Benign Lymphocytic Infiltrates, 37 Introduction, 37 Spongiotic and eczematous dermatitis, 37 Other spongiotic/eczematous tissue reactions, 40 Other causes of subacute eczematous dermatitis, 40 Interface dermatitis: cell-poor vacuolar interface dermatitis, 42 Interface dermatitis: lichenoid pattern, 46 Diffuse and nodular lymphocytic dermal infiltrates without atypia, 51 Diffuse and nodular lymphocytic infiltrates associated with autoimmune disease, 53 References, 57 Reactive Lymphomatoid Tissue Reactions Mimicking Cutaneous T and B Cell Lymphoma, 59 Lymphomatoid drug eruptions, 59 Molecular profile of lymphomatoid drug eruptions, 61 Pathogenetic basis of lymphomatoid drug reactions, 62 Reactive lymphomatoid lesions encountered in lesions of collagen vascular disease, 63 Angiomatous Variants of Pseudolymphoma, 67 Case vignettes, 69 References, 86 Precursor Lesions of Cutaneous T Cell Lymphoma, 89 Cutaneous T cell lymphoid dyscrasia, 89 Large plaque parapsoriasis, 90 Hypopigmented interface T cell dyscrasia: a unique indolent T cell dyscrasia, 91 Pigmented purpuric dermatosis (PPD), 92 Pityriasis lichenoides, 94 Idiopathic erythroderma (pre-Sézary), 96 Syringolymphoid hyperplasia with alopecia, 96 Folliculotropic T cell lymphocytosis/pilotropic T cell dyscrasia, 97 Idiopathic follicular mucinosis/alopecia mucinosa, 98 Keratoderma-like T cell dyscrasia, 99 Atypical lymphocytic lobular panniculitis, 100 Case vignettes, 102 References, 132 Marginal Zone Lymphoma and Other Related Post Germinal Center B Cell Lymphoproliferative Disorders of The Skin, 134 Marginal zone lymphoma, 134 Blastic marginal zone lymphoma, 140 Epidermotropic marginal zone lymphoma, 140 Castleman disease, 141 Primary cutaneous plasmacytoma, 142 Case vignettes, 145 References, 166 v vi Contents Primary Cutaneous Follicle Center Cell Lymphoma, 169 Clinical features, 169 Pathology, 169 Phenotypic profile, 171 Molecular studies, 172 Pathogenesis, 172 Cytogenetics, 172 Case vignettes, 174 Additional molecular and cytogenetic study, 185 References, 186 Primary Cutaneous Diffuse Large B-Cell Lymphoma Including the Leg Type and Precursor B Cell Lymphoblastic Lymphoma, 187 Primary cutaneous diffuse large B cell lymphoma, 187 Systemic diffuse large B cell lymphomas with a propensity to involve the skin, 197 Case vignettes, 200 Additional light microscopic, phenotypic, molecular, cytogenetic studies, 210 References, 215 10 Intravascular Lymphoma, 218 Clinical features, 218 Light microscopic findings, 219 Phenotypic profile, 219 Molecular and cytogenetic studies, 219 Pathogenesis, 219 Differential diagnosis, 219 Intravascular anaplastic large cell lymphoma, 219 Benign intravascular proliferations of histiocytes and reactive T cells, 220 Case vignettes, 221 References, 224 11 12 13 Cutaneous Mantle Cell Lymphoma, 225 Clinical features, 225 Light microscopic findings, 225 Phenotypic profile, 226 Molecular studies, 227 Cytogenetic profile, 227 Pathogenesis, 227 Case vignettes, 229 Additional molecular and cytogenetic studies, 233 References, 234 Mycosis Fungoides and Sézary Syndrome, 236 Definition, 236 Mycosis fungoides, 236 Sézary syndrome and erythrodermic mycosis fungoides, 243 Large cell transformation of mycosis fungoides, 251 Extracutaneous involvement in mycosis fungoides, 254 Case vignettes, 259 References, 271 CD30-Positive Lymphoproliferative Disorders Including Lymphomatoid Papulosis, Borderline CD30-Positive Lymphoproliferative Disease, Anaplastic Large Cell Lymphoma, and T-Cell-Rich CD30-Positive Large B Cell Lymphoma, 274 Introduction, 274 Lymphomatoid papulosis, 274 CD8+ lymphomatoid papulosis, including the type D variant, 278 Type E lymphomatoid papulosis (Case vignette 15), 278 Borderline CD30-positive lymphoproliferative disorders (type C LYP) (Case vignette 9), 279 Lymphomatoid papulosis with a rearrangement of chromosome 6p25.3, 279 Cutaneous anaplastic large cell lymphoma, 280 Small cell ALCL, 282 Additional unusual histologic variants of anaplastic large cell lymphoma, 282 Breast-implant-associated anaplastic large cell lymphoma, 282 Intravascular anaplastic large cell lymphoma, 282 Sarcomatoid anaplastic large cell lymphoma (Case vignette 14), 283 CD30-positive large B cell lymphoma, 285 Case vignettes, 286 References, 309 14 CD4+ Peripheral T Cell Lymphoma, Not Otherwise Specified, Including Primary Cutaneous Cd4+ Small/ Medium-Sized Pleomorphic T Cell Lymphoma, 312 Introduction, 312 Primary cutaneous CD4+ small/medium-sized pleomorphic T cell lymphoma, 312 CD30-negative large cell T cell lymphoma, 313 Cutaneous follicular helper T cell lymphoma, 314 Overview of overall prognosis of primary cutaneous peripheral T cell lymphoma, unspecified, 315 Evolution of the nomenclature of primary cutaneous CD4+ small/medium-sized pleomorphic T cell lymphoma, 319 Case vignettes, 320 References, 333 15 Subcutaneous Panniculitis-Like T Cell Lymphoma, 334 Clinical features, 334 Morphology, 336 Phenotype, 337 Molecular studies, 337 Differential diagnosis, 337 Case vignettes, 340 References, 349 16 CD8 T Cell Lymphoproliferative Disease of the Skin, 351 Overview, 351 Introduction, 351 Classification of primary CD8+ cutaneous T cell lymphomas, 352 Histomorphology of primary cutaneous CD8+ T cell lymphoma: primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma, and CD8+ variants of peripheral T cell lymphoma, NOS, including primary Contents cutaneous CD8+ granulomatous T cell lymphoma, 353 CD8 variant of lymphomatoid papulosis and other related CD30-positive T cell lymphoproliferative disorders of CD8 subtype, 354 Light microscopic findings, 354 Indolent CD8 positive lymphoid proliferation of the face and other body sites including acral surfaces, 355 CD8 prolymphocytic leukemia, 355 CD8 pseudolymphoma related to underlying HIV disease, 356 Drug-associated CD8+ pseudolymphoma, 356 Actinic reticuloid as a unique form of CD8+ pseudolymphoma, 356 Case vignettes, 357 References, 375 17 Nasal and Related Extranodal Natural Killer Cell/T Cell Lymphomas and Blastic Plasmacytoid Dendritic Cell Neoplasm, 377 Introduction, 377 Biology of NK and NK-like T cells, 377 NK/T-cell lymphoma, 379 Nasal NK/T cell lymphoma, 379 Nasal type NK/T cell lymphoma, 380 Aggressive NK cell lymphoma, 380 Role of Epstein–Barr virus in the evolution of NK/T cell lymphomas, 382 Blastic plasmacytoid dendritic cell neoplasm, 382 CD56-positive γ δ lymphoma involving the subcutaneous fat, 383 Chronic granular lymphocytosis/large granular cell leukemia, 384 Natural killer-like CD4+ T cell lymphoma, 384 EBV-associated NK/T cell lymphomas of the elderly, 385 Hydroa vaccineforme (HV)-like lymphoma, 385 Cutaneous intravascular NK T cell lymphoma, 386 Case vignettes, 387 References, 401 18 Primary Cutaneous γ δ T Cell Lymphoma, 404 Introduction, 404 Case vignettes, 409 Additional supplemental figures, 411 References, 414 19 Epstein–Barr Virus-Associated Lymphoproliferative Disease, 415 Introduction, 415 Hydroa vacciniforme-like EBV-associated T cell lymphoproliferative disease/mosquito bite hypersensitivity, 416 EBV+ cutaneous B cell lymphoproliferative disorder of the elderly, 420 EBV-associated mucocutaneous ulcer, 421 EBV + T cell lymphoproliferative disease of the elderly, 421 General principles regarding EBV-associated lymphomagenesis, 421 Pathogenetic link between EBV-associated B cell lymphoma and iatrogenic immune dysregulation related to either vii methotrexate or cyclosporine, 421 Case vignettes, 423 References, 432 20 Hodgkin Lymphoma of the Skin, 435 Clinical features, 435 Subtypes of Hodgkin lymphoma, 436 References, 447 21 Chronic Lymphocytic Leukemia of B Cell and T Cell Prolymphocytic Leukemia, 449 B cell chronic lymphocytic leukemia, 449 T cell prolymphocytic leukemia, 452 Case vignettes, 455 References, 471 22 Adult T Cell Leukemia/Lymphoma, 473 Clinical features, 473 Pathology, 474 Phenotypic studies, 475 Pathogenesis, 475 Infective dermatitis of childhood, 476 Case vignettes, 477 References, 484 23 Angioimmunoblastic Lymphadenopathy/ Angioimmunoblastic T Cell Lymphoma, 486 Clinical features, 486 Light microscopic findings, 487 Phenotypic studies, 488 Molecular studies, 488 Pathogenesis, 489 Case vignettes, 491 References, 497 24 Lymphomatoid Granulomatosis, 499 Introduction, 499 Clinical features, 499 Histopathology, 500 Histogenesis, 501 Clonality studies, 501 Differential diagnosis, 501 Treatment, 502 Case vignette, 503 References, 506 25 Cutaneous Infiltrates of Myeloid Derivation 507 Introduction, 507 Leukemia cutis, 507 Clonal histiocytopathy syndromes, 509 Histiocytopathy of factor XIIIA perivascular dermal dendritic cell origin, 514 Case vignettes, 517 References, 537 Index, 541 Acknowledgments The authors would like to express special thanks for editorial support to Arthi Kumar at New York-Presbyterian/Queens Hospital and Shabnam Momtahen of Weill Cornell Medicine Their assistance has been invaluable Cynthia M Magro A Neil Crowson Martin C Mihm viii 210 The Cutaneous Lymphoid Proliferations Additional light microscopic, phenotypic, molecular, cytogenetic studies Cutaneous B cell lymphoblastic lymphoma (Figures 9.35, 9.36, 9.37, 9.38, 9.39, and 9.40) Figure 9.35  Among those cytogenetic abnormalities associated with a bet- ter prognosis is a t(12:21)(p13;q22) results in the fusion of the TEL gene at 12p13 with the transcription factor encoding the AML1 gene at 21q22 (Source: Dr Nyla Heerema, Director of Cytogenetics, The Ohio State University Reproduced with permission.) 13 14 19 20 10 15 16 21 22 11 12 17 18 X Y Figure 9.36  A classic translocation associated with a poor prognosis is t(4:11) due to fusion of the MLL gene at 11q23 with AF4 at 4q21 (Source: Dr Nyla Heerema, Director of Cytogenetics, The Ohio State University Reproduced with permission.) Primary Cutaneous Diffuse Large B Cell Lymphoma Including the Leg Type and Precursor B Cell Lymphoblastic Lymphoma 211 13 19 14 10 15 11 16 20 21 12 17 18 22 X Y Figure 9.37  There is hyperdiploidy involving many of the chromosomes, a finding associated with a better prognosis (Source: Dr Nyla Heerema, Director of Cytogenetics, The Ohio State University Reproduced with permission.) 13 14 15 19 10 16 20 21 11 12 17 22 18 X Y Figure 9.38  Another cytogenetic abnormality associated with a poor prognosis is t(9:22), which results in fusion of BCR at 22q11.2 and the cytoplasmic tyrosinase kinase gene on chromosome (Source: Dr Nyla Heerema, Director of Cytogenetics, The Ohio State University Reproduced with permission.) Hypodiploid ALL Cell 13 14 15 19 20 21 10 11 12 16 17 18 22 X Y 25,X,+14,+21 Figure 9.39  Hypodiploidy denotes a worse prognosis (Source: Dr Nyla Heerema, Director of Cytogenetics, The Ohio State University Reproduced with permission.) 212 The Cutaneous Lymphoid Proliferations 13 19 14 20 15 21 10 16 22 11 17 X 12 18 Y 46,XX,der(19)t(1:19)(q23;p(13) Figure 9.40  This is an image of an acute lymphoblastic leukemia showing der(19)t(1;19) (Source: Dr Andrew Carroll, University of Alabama at Birming- ham Reproduced with permission.) Figure 9.41  In this photomicrograph, the so-called lymphoblastic morphology is captured The cells are intermediate in size with round nuclei, thin nuclear membranes, a finely dispersed chromatin and small amphophilic nucleoli Figure 9.42  The neoplasic cells express bcl-2 Primary Cutaneous Diffuse Large B Cell Lymphoma Including the Leg Type and Precursor B Cell Lymphoblastic Lymphoma 213 Figure 9.43  The lymphoid populace shows staining for CD10 Figure 9.44  Many of the neoplastic lymphocytes are positive for mum-1 (a) (b) (c) Figure 9.45  FISH analysis was performed on formalin-fixed paraffin-embedded (FFPE) tissue sections using the following probes: LSI bcl-6 dual color break apart probe, and IGH-bcl-2 dual color dual fusion probes, and IGH-MYC/CEP8 dual fusion probes (Abbott Molecular Inc., Des Plaines, IL), as per standard protocols Two hundred interphase nuclei were analyzed for representative fluorescence in situ hybridization (FISH) hybridization images showing: (a) Cells were hybridized with LSI bcl-6 dual color break apart probe Normal signal pattern for bcl-6 (b) Cells were hybridized with LSI IGH (Spectrum Green -SG)bcl-2 (Spectrum orange - SO) dual color dual fusion probes Additional copies of bcl-2 (white arrows) indicate gain of 18q (c) Cells were hybridized with LSI IGH (SG)-MYC (SO) dual fusion probes Fusion signals (white arrows) indicate rearrangement of IGH-MYC (Source: Dr Shivakumar Subramaniyam, Weill Cornell Medicine and currently Winthrop University Hospital Reproduced with permission.) 214 The Cutaneous Lymphoid Proliferations Figure  9.46  Interphase FISH hybridized with chromosome enumerator probe (CEP) labelled with Spectrum Green (SG) and LSI CDKN2A (P16) labelled with Spectrum Orange (SO) Arrows show allelic deletion of CDKN2A (Source: Dr Shivakumar Subramaniyam, Weill Cornell Medicine and currently Winthrop University Hospital Reproduced with permission.) Figure  9.47  Interphase FISH hybridized with chromosome enumerator probe (CEP) labelled with Spectrum Green (SG) and LSI CDKN2A (P16) labelled with Spectrum Orange (SO) Arrows show allelic deletion of CDKN2A (Source: Dr Shivakumar Subramaniyam, Weill Cornell Medicine and currently Winthrop University Hospital Reproduced with permission.) 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21(6):723–737 Yap LM, Blum R, Foley P, et al Clinical study of primary cutaneous B cell lymphoma using both the European Organization for Research and Treatment of Cancer and World Health Organization classifications Australas J Dermatol 2003; 44(2):110–115 Yoshino T, Okano M, Chen HL, Tsuchiyama J, Kondo E, Nishiuchi R, Teramoto N, Nishizaki K, Akagi T Cutaneous lymphocyte antigen is expressed on memory/ effector B cells in the peripheral blood and monocytoid B cells in the lymphoid tissue Cell Immunol 1999; 197:39–45 Zucca E, Conconi A, Pedrinis E, et al Nongastric marginal zone B cell lymphoma of mucosa-associated lymphoid tissue Blood 2003; 101:2489–2495 Chapter 10 Intravascular Lymphoma Clinical features Intravascular lymphoma is an aggressive and usually disseminated disease that mainly affects the elderly; B symptoms, anemia, and elevated serum lactate dehydrogenase levels are not uncommon (Willemze et al., 1987; Wick and Rocamora, 1988; Eros et al., 2002; Ferreri et al., 2004b) The older terminology for this condition was malignant angioendotheliomatosis; the neoplastic cells were held to be of endothelial cell derivation (Schnyder et al., 1971) The second reported case was that of Kauh and coworkers (1980), who described a 48-year-old man with fever and generalized asymptomatic erythematous telangiectatic plaques and patches It was not until 1985 that it was first proposed that malignant angioendotheliomatosis may represent an angiotropic lymphoma (Wrotnowski et al., 1985) In 1988, Wick and Rocamora distinguished malignant angioendotheliomatosis from reactive angioendotheliomatosis, the former a malignancy of lymphoid origin and the latter defining a form of reactive neovascularization (Wick and Rocamora, 1988) The term malignant angioendotheliomatosis has since been supplanted by the term intravascular lymphoma It is exclusively a disease of adults; the rare reports of reactive angioendotheliomatosis occurring in infancy reflect a lesion of proliferating endothelia (Brazzelli et al., 1999) This rare neoplasm is characterized by an intravascular proliferation of lymphoma cells, typically of B cell derivation (Bhawan, 1987; Brazzelli et al., 1999; Eros et al., 2002) There is a predilection to involve the skin and central nervous system (Eros et al., 2002; Ferreri et al., 2004b) Although fever may be a presenting symptom (Kuvliev et al., 1999), the clinical symptoms largely reflect the ischemic sequelae of vascular occlusion associated with the proliferating intravascular tumor cells While the brain and skin are the most common sites of disease, hepatosplenic (26%) and bone marrow infiltration (32%) are also found to be common Lymph node disease is seen in only 11% of cases (Ferreri et al., 2004b) When patients present with disease confined exclusively to the skin, the so-called cutaneous variant, they fare much better than those who present with skin disease in the setting of multiorgan involvement Those patients in whom the disease is localized to skin are often young women who typically have a normal platelet and leukocyte count (Demirer et al., 1994; Bogomolski-Yahalom et al., 1998; Ferreri et al., 2004b) Primary cutaneous intravascular lymphoma is extremely rare among Asians They tend to have an excellent prognosis and can be treated with local therapy, while those with more disseminated disease must receive multiagent chemotherapy Cutaneous intravascular B cell lymphoma is rare among Asians with intravascular lymphoma (Park et al., 2009) B cell intravascular lymphoma can be complicated by hemophagocytic syndrome, but the degree of cytopenia, coagulopathy, and liver dysfunction is less severe compared to that seen in patients with subcutaneous panniculitis-like T cell lymphoma in whom hemophagocytic syndrome develops This variant typically occurs in patients of Asiatic descent; the Asian variant of intravascular lymphoma manifests pancytopenia and hepatosplenomegaly, but usually lacks the neurological abnormality or skin lesions typical of classical intravascular lymphoma (Murase and Nakamura, 1999; Takahashi et al., 1999) (see Table 10.1) Table 10.1  Intravascular lymphoma Clinical Elderly Solitary or multiple indurated patches and plaques, often with superimposed petechiae and sometimes mimicking panniculitis Trunk and thighs are most often involved Central nervous system is commonly affected Hemophagocytic syndrome occurs in Asian variant Primary cutaneous form has a better prognosis Associated with Sjögren’s syndrome, lymphopenia and HIV disease Rare T cell variants show lung involvement without skin or CNS disease Histomorphology Intravascular aggregates of large atypical lymphoid cells Immunophenotype CD20, CD79a + (rare intravascular lymphomas are of T-cell +/-CD30 phenotype) CD5 +/− slg + (monoclonal) Rarely T cell variants Genetics Monoclonal rearrangement of the JH gene Therapy Systemic chemotherapy Intravascular lymphoma has been observed in the setting of states of immune dysregulation, including CD4 lymphopenia, acquired immunodeficiency syndrome, rheumatoid arthritis, and Sjögren syndrome (Chakravarty et al., 1993) Intravascular lymphoma has occurred following a diagnosis of extravascular B and T cell lymphomas of the lung (Tomasini et al., 2004) The cutaneous presentation is one of telangiectatic lesions, panniculitis, erythematous plaques, and tender nodules (Ozguroglu et al., 1997; Wolter et al., 2002; Dedic et al., 2003; Ferreri et al., 2004b) There are reports of hemangiomas and angiolipomas being involved by intravascular lymphoma (Chakravarty et al., 1993; Ozguroglu et al., 1997; Suh et al., 1997; Rubin et al., 1997; Smith et al., 2001; Wolter et al., 2002; Cerroni et al., 2004; Tomasini et al., 2004; Nixon et al., 2005) Fever may be the only presenting sign that has been described (Kuvliev et al., 1999) The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin, Second Edition Cynthia M Magro, A Neil Crowson and Martin C Mihm © 2016 John Wiley & Sons, Inc Published 2016 by John Wiley & Sons, Inc 218 Intravascular Lymphoma 219 Those cases of intravascular lymphoma of T cell phenotype are clearly rare, and their presentation clinically may deviate from classic intravascular lymphoma by virtue of lung involvement in the absence of skin and central nervous system disease (Au et al., 1997; Suh et al., 1997; Hsiao et al., 1999) Treatment is addressed in Chapter Briefly, systemic chemotherapy is warranted, including anthracycline and CHOP therapy in concert with granulocyte colony-stimulating factor and/or autologous bone marrow transplantation (Koizumi et al., 2001; Ferreri et al., 2004a, 2004b) Rituximab has also been used (Han et al., 2003) Despite advances in the treatment, this is still considered an aggressive lymphoma with a poor prognosis Light microscopic findings There is intravascular localization of tumor; the affected vessels are of small caliber and include capillaries, small arteries, and venules The vessels are ectatic and typically distended by intravascular nodular cellular aggregates; there is prominent localization to involve the superficial and mid-dermis The tumor cells are typically intermediate to large lymphocytes with blastic nuclear features and prominent nucleoli While there can be intravascular fibrin deposition, there are no concomitant vasculitic changes, nor is there extension of neoplastic lymphocytes into the surrounding tissue Admixed histiocytes or plasma cells are usually not seen Some cases manifest dominant localization within subcutaneous fat (Wick and Rocomora, 1988; Kanda et al., 1999; Eros et al., 2002; Dedic et al., 2003) Phenotypic profile The majority of these lymphomas are of B cell phenotype and therefore express pan-B-cell markers such as CD79a and CD20 (Figure 10.6) In some cases the critical cells express CD5, while others are CD10 positive In situ hybridization studies fail to detect EBV in those intravascular lymphomas of B cell derivation In contrast, EBV latent protein expression has been demonstrated in the nuclei of intravascular T cell lymphoma cases (Perniciaro et al., 1995; Suh et al., 1997; Khalidi et al., 1998; Hsiao et al., 1999; Kanda et al., 1999; Yegappan et al., 2001) CD47, also known as integrin-associated protein, may be expressed in intravascular lymphoma CD47 is a ubiquitous protein that prevents cell phagocytosis It also inhibits macrophage phagocytosis by signal regulatory protein alpha Its overexpression is associated with lymphoma dissemination and an activated phenotype (Starr et al., 2013) Osteopontin, expressed at high levels in a variety of aggressive tumors, is a common tissue protein that binds to various receptors, including integrin and CD44, involved in cell adhesion, migration, chemotaxis and survival In one anecdotal case of intravascular B cell lymphoma it was expressed at high levels (Starr et al 2013) within the neoplastic intravascular disposed B cells Other aspects of the phenotypic profile are associated with the mechanism of intravascular localization, as discussed below, including a lack of expression of CD54 and CD29 (Figures 10.7 and 10.8) Molecular and cytogenetic studies It is characteristic to observe hypermutated IgH genes, including cases exhibiting CD5 positivity militating against a pre-germinal center cell origin for those cases expressing CD5 (Kanda et al., 2001) Pathogenesis The purported basis for intravascular lymphomatosis has been held to reflect cytokine interaction between the neoplastic lymphoid cells, the endothelium, and the extravascular compartment Immunohistochemical studies on formalin-fixed tissue have shown localization of lymphocytes to the endothelium via specific markers, including CD29 (beta integrin subunit) and CD54, markers that are notably absent in these lymphomas CD29 and CD54 are critical to the egress of lymphocytes from their intravascular location into the extravascular tissue; their absence may account for the intravascular localization of the neoplasm In another study the intravascular lymphoma cells expressed CD49d (VLA-4), while endothelial cells expressed CD106 (CD49d ligand) Interaction between these adhesion molecules might contribute to the intravascular localization of these lymphomas (Kanda et al., 1999; Panzoni et al., 2000) (Figures 10.6, 10.7, and 10.8) With respect to the T cell variant, a memory T cell phenotype has been demonstrated Lymphocyte function-associated antigen-1s, CD11a and CD18, and intercellular adhesion molecule-1 have been demonstrated on the tumor cells and vascular walls in the lesions The data suggest that the intravascular localization of the tumor is really a function of tumor–endothelial cell interactions (Au et al., 1997; Suh et al., 1997) Differential diagnosis Patients with an antecedent history of other forms of lymphoma may exhibit a recurrent cutaneous process exhibiting intravascular localization, including cases of follicle center lymphoma, natural killer cell lymphoma (Gebauer et al., 2014), and anaplastic large cell lymphoma There are less than 10 reported cases of intravascular NK T cell lymphoma manifesting prominent CNS and bone marrow involvement, similar to the predisposed sites of involvement in conventional intravascular B cell lymphoma Intravascular anaplastic large cell lymphoma has emerged as a distinct clinical pathological entity as the condition can manifest exclusively in an intravascular location without concomitant extravascular disease In 1996 Carter and coworkers reported a case of intravascular B cell lymphoma developing in a patient with follicle center lymphoma of lymph node and bone marrow (Carter et al., 1996) The patient developed a skin disease showing intravascular localization of tumor The neoplastic cells showed a follicle center phenotype, characterized by positivity for bcl-2 and CD10 We reported a similar case of nodal follicular lymphoma relapsing years later in the skin as an intravascular lymphoma (Figures 10.9, 10.10, and 10.11) Intravascular anaplastic large cell lymphoma Intravascular anaplastic large cell lymphoma has emerged as a distinct entity with a total of nine reported cases involving the skin The median age of the reported patients is 56 (age range 33–86), with an equal sex distribution; three of the reported cases have concomitant extravascular disease in lymph nodes In our own case series (Nguyen et al., 2015), one patient had a conventional presentation of anaplastic large cell lymphoma, but developed recurrent disease a few years later that exhibited a primary intravascular localization All other cases present initially with pure intravascular 220 The Cutaneous Lymphoid Proliferations localization The prognosis of cases presenting with primary cutaneous disease is similar to other forms of primary cutaneous anaplastic large cell lymphoma In contrast, patients with a CD30 negative variant of intravascular T cell lymphoma have a poor prognosis (Krishnan et al., 2009; Wang et al., 2011; Iacobelli et al., 2012; Metcalf et al., 2013) Intravascular anaplastic large cell lymphoma tends to localize to lymphatics, as opposed to blood vessels Intrasinusoidal affinity of anaplastic large cell lymphoma is a welldescribed phenomenon in the lymph node and hence its localization to superficial dermal lymphatics may be reflective of an affinity of neoplastic cells to lymphatic endothelia (Samols et al., 2014) Benign intravascular proliferations of histiocytes and reactive T cells It is important to remember that reactive proliferations of lymphocytes and histiocytes can exhibit intravascular localization, hence defining a morphologic pattern that, at least architecturally, resembles intravascular lymphoma Reactive intravascular histiocytosis is seen in the setting of Rosenthal–Melkersson syndrome, localized granulomatous lymphangitis in patients with Crohn’s disease, and in the vicinity of knee and hip replacement surgery (Emanuel et al., 2015) Reactive CD30+ T cell infiltrates localized to lymphatics have been described in patients who have sustained trauma In this setting the CD30+ T cells not show loss of pan-T-cell markers nor is there expression of cytotoxic markers; CD56 and EBER studies are negative Most of the reported cases are in the context of direct trauma Kempf and coworkers described this reaction pattern in a patient with longstanding genital lichen sclerosus (Kempf et al., 2014) Intravascular Lymphoma 221 Case vignette Case vignette The patient presented with a generalized petechial skin rash with supervening livedo Diagnosis: Intravascular lymphoma (Figures 10.1, 10.2, 10.3, 10.4, and 10.5) Figure 10.1  The ectatic vessels contain intraluminal aggregates of lymphoid Figure 10.2  The lymphoid cells are monomorphous and large, with nuclei in the 20–25 μm size range Figure 10.3  The large monomorphous lymphoid cells manifest coarse chromatin and prominent, generally solitary nuclei Figure 10.4  A CD20 preparation decorates the intravascular tumor cells as cells; there is mural fibrin deposition B cells 222 The Cutaneous Lymphoid Proliferations Case vignette (Continued) Figure 10.5  A CD3 preparation decorates the reactive perivascular T lym- Figure 10.6  Intravascular B cell lymphoma will be highlighted by CD20 and CD79a Illustrated is CD20 Figure 10.7  A characteristic loss of CD29 contributes to the inability of the Figure 10.8  There is a significant diminution in the expression of CD54, also defining a distinctive feature of the abnormal phenotype of this lymphoma and one contributing to the intravascular localization of this lymphoma phocytes, but not the angiotropic neoplastic B cells neoplastic cells to manifest proper egress into extravascular tissues Intravascular Lymphoma 223 Case vignette The patient is a 73-year-old woman diagnosed with nodal follicular lymphoma in 2002 She presented with recurrent disease manifesting as multiple cutaneous nodules in 2009 Diagnosis: The biopsy confirmed a diagnosis of recurrent follicular lymphoma manifesting intravascular localization (Figures 10.9, 10.10, and 10.11) Figure 10.9  There are large atypical immunoblastic appearing cells occluding the vascular lumens Figure  10.10  The germinal center phenotype is manifested by positive staining for bcl-6 Figure  10.11  Mirroring the overexpression of CD10 in the nodal lymphoma is the prominent expression for CD10 in the recurrent intravascular tumor 224 The Cutaneous Lymphoid Proliferations References Au WY, Shek WH, Nicholls J, et al T-cell intravascular lymphomatosis (angiotropic large cell lymphoma): association with Epstein–Barr viral infection Histopathology 1997; 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Am J Clin Pathol 1985;83(2):244–248 Yegappan S, Coupland R, Arber DA, et al Angiotropic lymphoma: an immunophenotypically and clinically heterogeneous lymphoma Mod Pathol 2001; 14(11):1147–1156 ... 280 Small cell ALCL, 282 Additional unusual histologic variants of anaplastic large cell lymphoma, 282 Breast-implant-associated anaplastic large cell lymphoma, 282 Intravascular anaplastic large...    T 2a: all disease encompassing in a 15 -cm-diameter circular area    T2b: all disease encompassing in a >15 ≤30-cm-diameter circular area    T2c: all disease encompassing in a >30-cm-diameter... leukaemia-variant Lymphoplasmacytic lymphoma Waldenström macroglobulinemia Heavy chain diseases Alpha heavy chain disease Gamma heavy chain disease Mu heavy chain disease Plasma cell myeloma Solitary