title: Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study.
abstract: Despite clearly defined histologic criteria, the prediction of tumor behavior for patients with gastrointestinal stromal tumors (GIST) still poses a challenge to pathologists. Therefore, searching for alternative markers that allow for better prognostic evaluation is an important task. To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months). P16 protein expression was ascertained on tissue microarrays as well as on standard sections. Survival analyses were carried out in 157 patients. P16 loss was found in 50% of GISTs, there being no correlation with age, sex, histologic subtype, signs of necrosis, or metastases. Patients having p16-negative tumors had a worse prognosis than those with p16-positive tumors (P = 0.012) with a 2.3-fold relative increased risk of dying of disease. P16 loss identified a subgroup of gastric tumors with a worse prognosis (P = 0.03). The multivariate configural frequency analysis identified two "antitypes," whose observed frequency was found to be significantly lower than the expected frequency [i.e., marker combinations: p16 positive, no metastases, and death of disease and p16 loss, metastases, and still alive]. The "type" whose observed frequency was significantly higher than the expected frequency consisted of the following marker pattern: p16 loss, necrosis, and death of disease (P < 0.001). In the multivariate Cox regression analysis, p16 loss, necrosis, and metastases each had independent prognostic value. P16 loss is a common molecular abnormality in GISTs and might be used in routine diagnosis to identify patients with high-risk tumors.
authors.affiliation: Department of Pathology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Regine.Schneider-Stock@medizin.uni-magdeburg.de
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Carsten
authors.initials: C
authors.lastname: Boltze
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.forename: Brigitte
authors.initials: B
authors.lastname: Peters
authors.forename: Chris L
authors.initials: CL
authors.lastname: Corless
authors.forename: Petra
authors.initials: P
authors.lastname: Ruemmele
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Matthias
authors.initials: M
authors.lastname: Pross
authors.forename: Luigi
authors.initials: L
authors.lastname: Insabato
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.forename: Igor
authors.initials: I
authors.lastname: Iesalnieks
authors.forename: Stefan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Michel
authors.initials: M
authors.lastname: Heinrich
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.forename: Luigi
authors.initials: L
authors.lastname: Tornillo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D015622:Epithelioid Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16