title: Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis.
abstract: BACKGROUND
  Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined.
  
  
  OBJECTIVE
  We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM.
  
  
  METHODS
  Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied.
  
  
  RESULTS
  Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM.
  
  
  CONCLUSIONS
  WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain. Electronic address: ivana@sescam.jccm.es.
authors.forename: Iván
authors.initials: I
authors.lastname: Álvarez-Twose
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría-NUCLEUS, University of Salamanca, Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Jara-Acevedo
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain.
authors.forename: José Mário
authors.initials: JM
authors.lastname: Morgado
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría-NUCLEUS, University of Salamanca, Salamanca, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: García-Montero
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez-Muñoz
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría-NUCLEUS, University of Salamanca, Salamanca, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Teodósio
authors.affiliation: Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain; Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Matito
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría-NUCLEUS, University of Salamanca, Salamanca, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mayado
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría-NUCLEUS, University of Salamanca, Salamanca, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Pathology Department, Hospital Virgen de la Salud, Toledo, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain; Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría-NUCLEUS, University of Salamanca, Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Escribano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D034701:Mastocytosis, Cutaneous / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D034721:Mastocytosis, Systemic / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012867:Skin / Q000473:pathology; D055815:Young Adult
chemical_list: D019009:Proto-Oncogene Proteins c-kit
keywords: KIT; Mast cell; imatinib; mastocytosis; well differentiated