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Identification of oropharyngeal squamous cell carcinomas with active HPV16 involvement by immunohistochemical analysis of the retinoblastoma protein pathway
Author(s) -
Holzinger Dana,
Flechtenmacher Christa,
Henfling Nataly,
Kaden Ines,
Grabe Niels,
Lahrmann Bernd,
Schmitt Markus,
Hess Jochen,
Pawlita Michael,
Bosch Franz X.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28142
Subject(s) - immunohistochemistry , rna , tissue microarray , biology , retinoblastoma protein , cancer research , retinoblastoma , cyclin d1 , biopsy , oncogene , cell cycle , biomarker , pathology , cancer , medicine , gene , genetics
Viral oncogene RNA expression is regarded as reliable biomarker to identify oropharyngeal squamous cell carcinomas (OPSCC) with active HPV16 involvement. This study addressed whether the expression profile of the cellular proteins p16 INK4a , pRb, Cyclin D1 and p53 provide surrogate marker combinations that identify OPSCC with active HPV16 in situations where only formalin‐fixed biopsies are available. Protein expression was analyzed by immunohistochemistry on tissue microarrays created from 188 OPSCC of which the HPV16 DNA and RNA status had been established previously from snap‐frozen biopsies. Associations of single markers and of marker combinations with HPV16 DNA, viral RNA expression patterns and overall survival as primary end point were evaluated by statistical analysis. Most tumors with active HPV16 involvement (RNA + group; n = 40) showed a specific protein pattern, that is, high p16 INK4a (80%), low pRb (85%), low Cyclin D1 (95%) and normal p53 (73%). This pattern was significantly different from the pattern observed in HPV DNA‐negative tumors (HPV – group) and in HPV16 DNA‐positive tumors lacking viral RNA expression patterns (RNA – group). The combination of high p16 INK4a and low pRb levels was distinctly superior to p16 INK4a alone; it was strongly associated with RNA + tumors (OR 41.4, 95%CI 10.7–162.5), with improved survival (HR 0.37, 95%CI 0.2–0.8) and had best predictive values (78% sensitivity, 93% specificity, 78% PPV, 93% NPV). In conclusion, if only formalin‐fixed biopsy material is available, the marker combination high p16 INK4a /low pRb is well suited to identify OPSCC with biologically active HPV16 which represent a distinct OPSCC entity with improved prognosis.