Oncoproteins and tumor progression in papillary thyroid carcinoma: presence of epidermal growth factor receptor, c-erbB-2 protein, estrogen receptor related protein, p21-ras protein, and proliferation indicators in relation to tumor recurrences and patient survival.
BACKGROUND
The prognostic relevance of activated oncogenes and oncoproteins has not been well studied in papillary thyroid cancer, which is slow-growing, with only regional spread in most cases. Therefore, the influence of some protein markers and tumor cell proliferation on disease progress in a series of patients with surgically treated papillary thyroid carcinoma was studied.


METHODS
One hundred twenty-seven patients with papillary thyroid carcinoma larger than 10 mm in greatest dimension were studied retrospectively, and the majority were treated with total or near-total thyroidectomy. Immunohistochemical and flow cytometric analyses of paraffin embedded tumor material were performed and the results were related to time to recurrence and thyroid cancer deaths using the univariate product-limit survival analysis and the multivariate Cox' regression method.


RESULTS
Immunohistochemical expression of c-erbB-2 protein, estrogen receptor-related protein (p29), which may be regarded as an indicator of hormone-dependent growth, S-phase, G2M-phase, sex, age, histologic grade, and primary tumor extent were all of significant prognostic importance in univariate analyses of patient survival. In the final Cox' model, however, only male sex (P = 0.017), older age, (P < 0.00005) and high grade histologic features (P = 0.006) were associated independently with decreased survival. Among females, decreased expression of c-erbB-2 protein was independently related to decreased patient survival (P = 0.019). In multivariate analysis of time to recurrence, lymph node status (P = 0.0001), epidermal growth factor (EGF) receptor expression (P = 0.013) and estrogen receptor-related protein (P = 0.007) were independent risk indicators, and S-phase fraction (P = 0.074) showed a borderline significance.


CONCLUSIONS
In this study, sex, age, and histologic grade were independent indicators of deaths from thyroid cancer. Lymph node metastases, EGF-receptor expression, and decreased estrogen receptor-related protein staining persisted as prognostic variables in the final multivariate analysis of recurrence free survival. Alterations in these oncogenes thus seem to play some role in disease progression in papillary thyroid carcinoma, although conventional variables are still important as prognostic indicators.
Akslen
L A
LA
Department of Pathology, Gade Institute, Haukeland Hospital, Bergen, Norway.
Varhaug
J E
JE
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000032:analysis; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism*; D011003:Ploidies; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012044:Regression Analysis; D012189:Retrospective Studies; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D006360:Heat-Shock Proteins; D015513:Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C501009:HRAS protein, human