title: c-erbB-2 oncoprotein is overexpressed in poorly vascularised squamous cell carcinomas of the head and neck, but is not associated with response to cytotoxic therapy or survival.
abstract: The prognostic and predictive role of c-erbB-2 oncoprotein in human malignancies remains controversial. The pattern of expression and the biological behaviour of c-erbB-2 protein was investigated in a series of 89 locally advanced squamous carcinomas of the head and neck. Possible associations between c-erbB-2 and T,N-stage, histological grade, microvessel density and the expression of bcl-2 and p53 proteins were sought. Biopsy material had been collected prior to the initiation of treatment which consisted of platinum based induction chemotherapy or concurrent chemotherapy and radiotherapy. In all cases, follow-up of at least 2 years duration was available. Positive staining was seen in 27 out of 89 (30.4%) cases and was invariably cytoplasmic, exhibiting strong reactivity in more than 50% of tumour cells. Such c-erbB-2 overexpressing tumours were not associated with a response to radiotherapy and/or induction chemotherapy. Further, survival analysis did not disclose any difference in the overall or relapse free survival between c-erbB-2 positive and negative cases. Similarly, no relationship was found with T,N-stage, histological grade and bcl-2 or p53 expression. There was, however, a significant inverse association between c-erbB-2 expression and microvessel density (p = 0.0001). Interestingly, tumours with low vascular grade (VG; MS < 26) and positive c-erbB-2 expression were less frequently associated with local aggressiveness compared to c-erbB-2 negative tumours and low VG (5/27 vs. 12/18; p = 0.001), or to c-erbB-2 negative tumours and high VG (MS > 27) (5/27 vs. 19/44; p = 0.03). These differences were statistically significant but were not related to treatment response or prognosis. Nonetheless, when patients with highly angiogenic tumours were analysed for survival, irrespective of the c-erbB-2 status, they showed a poorer prognosis than those having a low microvessel density (p = 0.06 and 0.05 for overall and relapse free survival, respectively). Six out of 89 patients presented with distant metastases, five of which had tumours negative for c-erbB-2 expression. Our results seem to indicate that the pattern of c-erbB-2 expression in locally advanced inoperable head and neck cancer is exclusively cytoplasmic. c-erbB-2 reactivity is of little value in predicting survival or chemo-radiotherapeutic response. Expression of genes related to angiogenesis or other invasion and migration pathways are, apparently, more important.
authors.affiliation: Department of Pathology, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece.
authors.forename: A
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: M I
authors.initials: MI
authors.lastname: Koukourakis
authors.forename: E
authors.initials: E
authors.lastname: Sivridis
authors.forename: G
authors.initials: G
authors.lastname: Fountzilas
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D016019:Survival Analysis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D016190:Carboplatin; D002945:Cisplatin; D005472:Fluorouracil; D002955:Leucovorin; D008727:Methotrexate; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53