title: Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome.
abstract: OBJECTIVE
  There is evidence that Hodgkin Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) could display some molecular and morphologic markers of cellular senescence (CS). We hypothesized that CS mechanisms may have potential prognostic relevance in cHL and investigated whether the expression of the well-established CS biomarkers p21(CIP1/WAF1) and p16(INK4a) by HRS cells might be predictive of the probability of event-free survival (EFS).
  
  
  METHODS
  The study analyzed a retrospective cohort of 147 patients and the results were validated on a cohort of 91 patients independently diagnosed and treated in a different institution. p16(INK4a) and p21(CIP1/WAF1) were categorized as dichotomous variables (< or ≥ 30% of HRS cells at diagnosis) and evaluated in univariate and multivariate analysis.
  
  
  RESULTS
  Both molecules were independent prognostic factors. A positive staining of one of the two molecules in more than 30% HRS cells predicted a better EFS (P < 0.01). p16(INK4a)/p21(CIP1/WAF1) together as a unique categorical variable (both <30%, either <30%, both ≥ 30%) sorted out three prognostic groups with better, intermediate, or worse outcome either overall or within I-II, bulky and advanced stages. The presence or the lack of the robust expression of p21(CIP1/WAF1) and/or p16(INK4a) defined the prognosis in our series.
  
  
  CONCLUSIONS
  These findings point to (i) the relevance of CS-related mechanisms in cHL, and to (ii) the prognostic value of a simple, reproducible, and low-cost immunohistochemical evaluation of p16(INK4a) and p21(CIP1/WAF1) expression.
authors.affiliation: Department of Pathology and Diagnostic, Anatomic Pathology Section, University of Verona, Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caliò
authors.affiliation: Department of Pathology and Diagnostic, Anatomic Pathology Section, University of Verona, Verona, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zamò
authors.affiliation: Vita-Salute San Raffaele University, Pathology and Lymphoid Malignancies Units, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Public Health and Community Medicine, Unit of Epidemiology and Medical Statistics, University of Verona, Verona, Italy.
authors.forename: Maria Elisabetta
authors.initials: ME
authors.lastname: Zanolin
authors.affiliation: Unit of Lymphoid Malignancies, Division of Onco-Hematological Medicine, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.affiliation: Department of Pathology and Diagnostic, Anatomic Pathology Section, University of Verona, Verona, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pedron
authors.affiliation: Department of Pathology and Diagnostic, Anatomic Pathology Section, University of Verona, Verona, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Montagna
authors.affiliation: Department of Pathology and Diagnostic, Anatomic Pathology Section, University of Verona, Verona, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Parolini
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Vadim E
authors.initials: VE
authors.lastname: Fraifeld
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Wolfson
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Hagai
authors.initials: H
authors.lastname: Yanai
authors.affiliation: Department of Medicine, Hematology Section, University of Verona, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pizzolo
authors.affiliation: Vita-Salute San Raffaele University, Pathology and Lymphoid Malignancies Units, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: Department of Medicine, Hematology Section, University of Verona, Verona, Italy. fabrizio.vinante@univr.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vinante
authors.affiliation: Department of Pathology and Diagnostic, Anatomic Pathology Section, University of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chilosi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21