The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Barr virus positive (EBV+) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term "primary cutaneous CD4+ small/medium T-cell lymphoma" was modified to "primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder" because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

[1]  R. Willemze,et al.  High Incidence and Clinical Significance of MYC Rearrangements in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type , 2018, The American journal of surgical pathology.

[2]  L. Cerroni,et al.  Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type. , 2018, The Journal of investigative dermatology.

[3]  D. Elder,et al.  WHO classification of skin tumours , 2018 .

[4]  D. Fanoni,et al.  Primary cutaneous acral CD8 positive T‐cell lymphoma with extra‐cutaneous involvement: A long‐standing case with an unexpected progression , 2017, Journal of cutaneous pathology.

[5]  S. Swerdlow WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues , 2017 .

[6]  R. Willemze,et al.  Recommendations for treatment in folliculotropic mycosis fungoides: report of the Dutch Cutaneous Lymphoma Group , 2017, The British journal of dermatology.

[7]  M. Duvic,et al.  Clinical characteristics, risk factors and long-term outcome of 114 patients with folliculotropic mycosis fungoides , 2017, Archives of Dermatological Research.

[8]  M. Bagot,et al.  Usefulness of KIR3DL2 to Diagnose, Follow-Up, and Manage the Treatment of Patients with Sézary Syndrome , 2017, Clinical Cancer Research.

[9]  L. Pincus,et al.  Primary cutaneous B-cell lymphomas with large cell predominance-primary cutaneous follicle center lymphoma, diffuse large B-cell lymphoma, leg type and intravascular large B-cell lymphoma. , 2017, Seminars in diagnostic pathology.

[10]  K. Elenitoba-Johnson,et al.  A new molecular paradigm in mycosis fungoides and Sézary syndrome. , 2017, Seminars in diagnostic pathology.

[11]  S. Swerdlow Cutaneous marginal zone lymphomas. , 2017, Seminars in diagnostic pathology.

[12]  W. Kempf A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders. , 2017, Seminars in diagnostic pathology.

[13]  S. Ascani,et al.  Primary cutaneous B‐cell lymphoma other than marginal zone: clinicopathologic analysis of 161 cases: Comparison with current classification and definition of prognostic markers , 2016, Cancer medicine.

[14]  R. Willemze,et al.  Clinical Staging and Prognostic Factors in Folliculotropic Mycosis Fungoides. , 2016, JAMA dermatology.

[15]  D. Cappellen,et al.  MYD88 Somatic Mutation Is a Diagnostic Criterion in Primary Cutaneous Large B-Cell Lymphoma. , 2016, The Journal of investigative dermatology.

[16]  M. Feinmesser,et al.  New insights into folliculotropic mycosis fungoides (FMF): A single-center experience. , 2016, Journal of the American Academy of Dermatology.

[17]  R. Willemze,et al.  No TP63 rearrangements in a selected group of primary cutaneous CD30+ lymphoproliferative disorders with aggressive clinical course. , 2016, Blood.

[18]  M. Felcht,et al.  Evaluation of Immunophenotypic and Molecular Biomarkers for Sézary Syndrome Using Standard Operating Procedures: A Multicenter Study of 59 Patients. , 2016, The Journal of investigative dermatology.

[19]  J. Merlio,et al.  Sézary Syndrome: Translating Genetic Diversity into Personalized Medicine. , 2016, The Journal of investigative dermatology.

[20]  M. Felcht,et al.  Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases , 2015, The British journal of dermatology.

[21]  A. Rosenwald,et al.  CD68 expression is a discriminative feature of indolent cutaneous CD8‐positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8‐positive cutaneous lymphomas , 2015, The British journal of dermatology.

[22]  M. Piris,et al.  Primary cutaneous anaplastic large cell lymphomas with 6p25.3 rearrangement exhibit particular histological features , 2015, Histopathology.

[23]  R. Willemze,et al.  Diagnostic and prognostic significance of CDKN2A/CDKN2B deletions in patients with transformed mycosis fungoides and primary cutaneous CD30‐positive lymphoproliferative disease , 2015, The British journal of dermatology.

[24]  A. Feldman,et al.  Anaplastic Large Cell Lymphomas: ALK Positive, ALK Negative, and Primary Cutaneous , 2015, Advances in anatomic pathology.

[25]  K. Elenitoba-Johnson,et al.  A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders. , 2014, Blood.

[26]  T. Petrella,et al.  High frequency and clinical prognostic value of MYD88 L265P mutation in primary cutaneous diffuse large B-cell lymphoma, leg-type. , 2014, JAMA dermatology.

[27]  W. Wilson,et al.  ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. , 2014, Blood.

[28]  R. Willemze,et al.  Methotrexate-associated B-cell Lymphoproliferative Disorders Presenting in the Skin: A Clinicopathologic and Immunophenotypical Study of 10 Cases , 2014, The American journal of surgical pathology.

[29]  S. Horwitz,et al.  Multicenter Case Series of Indolent Small/Medium-Sized CD8+ Lymphoid Proliferations With Predilection for the Ear and Face , 2014, The American Journal of dermatopathology.

[30]  T. Petrella,et al.  Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma , 2014, Modern Pathology.

[31]  W. Klapper,et al.  Peripheral T‐cell and NK‐cell lymphomas and their mimics; taking a step forward – report on the lymphoma workshop of the XVIth meeting of the European Association for Haematopathology and the Society for Hematopathology , 2014, Histopathology.

[32]  C. Schmidt,et al.  Nuclear factor-κB pathway-activating gene aberrancies in primary cutaneous large B-cell lymphoma, leg type. , 2014, The Journal of investigative dermatology.

[33]  F. Climent,et al.  Primary cutaneous marginal zone B-cell lymphoma: Response to treatment and disease-free survival in a series of 137 patients , 2013 .

[34]  A. Feldman,et al.  Chromosomal Rearrangements of 6p25.3 Define a New Subtype of Lymphomatoid Papulosis , 2013, The American journal of surgical pathology.

[35]  J. Plaza,et al.  Hydroa vacciniforme-like cutaneous T-cell lymphoma: clinicopathologic and immunohistochemical study of 12 cases. , 2013, Journal of the American Academy of Dermatology.

[36]  S. Swerdlow,et al.  Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. , 2013, American journal of clinical pathology.

[37]  S. Swerdlow,et al.  Cutaneous B-cell lymphoproliferative disorders: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. , 2013, American journal of clinical pathology.

[38]  M. Piris,et al.  TCR-&ggr; Expression in Primary Cutaneous T-cell Lymphomas , 2013, The American journal of surgical pathology.

[39]  L. Michel,et al.  Use of PLS3, Twist, CD158k/KIR3DL2, and NKp46 gene expression combination for reliable Sézary syndrome diagnosis. , 2013, Blood.

[40]  T. Petrella,et al.  Indolent CD8+ lymphoid proliferation of acral sites: a clinicopathologic study of six patients with some atypical features , 2013, Journal of cutaneous pathology.

[41]  T. Mentzel,et al.  Angioinvasive Lymphomatoid Papulosis: A New Variant Simulating Aggressive Lymphomas , 2013, The American journal of surgical pathology.

[42]  W. Klapper,et al.  ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study , 2013, Haematologica.

[43]  R. Willemze,et al.  Differential expression of programmed death-1 (PD-1) in Sézary syndrome and mycosis fungoides. , 2012, Archives of dermatology.

[44]  David I. Smith,et al.  Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. , 2012, Blood.

[45]  T. Naoe,et al.  EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. , 2012, Blood.

[46]  R. Willemze,et al.  Expression of Programmed Death-1 in Primary Cutaneous CD4-Positive Small/Medium-Sized Pleomorphic T-Cell Lymphoma, Cutaneous Pseudo-T-Cell Lymphoma, and Other Types of Cutaneous T-Cell Lymphoma , 2012, The American journal of surgical pathology.

[47]  R. Dummer,et al.  EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. , 2011, Blood.

[48]  A. Feldman,et al.  Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies , 2011, Modern Pathology.

[49]  S. Swerdlow,et al.  Cutaneous Marginal Zone Lymphomas Have Distinctive Features and Include 2 Subsets , 2010, The American journal of surgical pathology.

[50]  M. Piris,et al.  EBV-associated Cutaneous NK/T-cell Lymphoma: Review of a Series of 14 Cases From Peru in Children and Young Adults , 2010, The American journal of surgical pathology.

[51]  J. Scarisbrick,et al.  Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  Z. Argényi,et al.  A Variant of Lymphomatoid Papulosis Simulating Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma. Description of 9 Cases , 2010, The American journal of surgical pathology.

[53]  R. Willemze,et al.  IgM Expression on Paraffin Sections Distinguishes Primary Cutaneous Large B-cell Lymphoma, Leg Type From Primary Cutaneous Follicle Center Lymphoma , 2010, The American journal of surgical pathology.

[54]  E. Jaffe,et al.  EBV Positive Mucocutaneous Ulcer—A Study of 26 Cases Associated With Various Sources of Immunosuppression , 2010, The American journal of surgical pathology.

[55]  H. Kerl,et al.  Primary Cutaneous CD4+ Small-/Medium-Sized Pleomorphic T-Cell Lymphoma: A Cutaneous Nodular Proliferation of Pleomorphic T Lymphocytes of Undetermined Significance? A Study of 136 Cases , 2009, The American Journal of dermatopathology.

[56]  T. Petrella,et al.  Fine-mapping chromosomal loss at 9p21: correlation with prognosis in primary cutaneous diffuse large B-cell lymphoma, leg type. , 2009, The Journal of investigative dermatology.

[57]  E. Campo,et al.  Primary Cutaneous CD4+ Small/Medium-sized Pleomorphic T-cell Lymphoma Expresses Follicular T-cell Markers , 2009, The American journal of surgical pathology.

[58]  R. Bende,et al.  The majority of cutaneous marginal zone B-cell lymphomas expresses class-switched immunoglobulins and develops in a T-helper type 2 inflammatory environment. , 2008, Blood.

[59]  C. Massone,et al.  The prognosis of early mycosis fungoides is not influenced by phenotype and T‐cell clonality , 2008, The British journal of dermatology.

[60]  G. Pinkus,et al.  Primary Cutaneous ALCL With Phosphorylated/Activated Cytoplasmic ALK and Novel Phenotype: EMA/MUC1+, Cutaneous Lymphocyte Antigen Negative , 2008, The American journal of surgical pathology.

[61]  A. López-Guillermo,et al.  Primary cutaneous small/medium CD4+ T-cell lymphomas: a heterogeneous group of tumors with different clinicopathologic features and outcome. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  T. Kuzel,et al.  Folliculotropic mycosis fungoides: an aggressive variant of cutaneous T-cell lymphoma. , 2008, Archives of dermatology.

[63]  A. Dogan,et al.  Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indolent behavior , 2008, Modern Pathology.

[64]  T. Petrella,et al.  Indolent CD8-positive Lymphoid Proliferation of the Ear: A Distinct Primary Cutaneous T-cell Lymphoma? , 2007, The American journal of surgical pathology.

[65]  D. Weisenburger,et al.  Epstein-Barr Virus Negative Clonal Plasma Cell Proliferations and Lymphomas in Peripheral T-cell Lymphomas: A Phenomenon With Distinctive Clinicopathologic Features , 2007, The American journal of surgical pathology.

[66]  T. Petrella,et al.  Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases. , 2007, Archives of dermatology.

[67]  C. Meijer,et al.  Reclassification of 300 primary cutaneous B-Cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  Y. Tomita,et al.  Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. , 2007, The Journal of rheumatology.

[69]  E. Jordanova,et al.  Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  P. Leboit Pathology and genetics of skin tumours , 2006 .

[71]  C. Massone,et al.  Primary cutaneous large B-cell lymphomas: clinicopathologic features, classification, and prognostic factors in a large series of patients. , 2005, Blood.

[72]  Nicola Pimpinelli,et al.  WHO-EORTC classification for cutaneous lymphomas. , 2005, Blood.

[73]  G. Wood,et al.  Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential. , 2003, Human pathology.

[74]  M. Piris,et al.  Hydroa-Like Cutaneous T-Cell Lymphoma: A Clinicopathologic and Molecular Genetic Study of 16 Pediatric Cases from Peru , 2002, Applied immunohistochemistry & molecular morphology : AIMM.

[75]  R. Willemze,et al.  Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. , 2002, Archives of dermatology.

[76]  T. Okamura,et al.  Mosquito allergy and Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disease. , 2001, Blood.

[77]  K. Ohshima,et al.  Hypersensitivity to mosquito bites as the primary clinical manifestation of a juvenile type of Epstein-Barr virus-associated natural killer cell leukemia/lymphoma. , 2001, Journal of the American Academy of Dermatology.

[78]  C. Meijer,et al.  Primary and secondary cutaneous CD30+lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment , 2000 .

[79]  Akiba,et al.  The association of latent Epstein–Barr virus infection with hydroa vacciniforme , 1999, The British journal of dermatology.

[80]  C. Meijer,et al.  Demonstration of clonal immunoglobulin gene rearrangements in cutaneous B-cell lymphomas and pseudo-B-cell lymphomas: differential diagnostic and pathogenetic aspects. , 1992, The Journal of investigative dermatology.