c-erbB-2 Oncoprotein Overexpression in Uterine Cervix Carcinoma With Glandular Differentiation:A Frequent Event But Not an Independent Prognostic Marker Because It Occurs Late in the Disease

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Abstract
The c-erbB-2 proto-oncogene (HER-2/neu) codes for a transmembrane, tyrosine kinase, 185 kD oncoprotein (pl85erbB2), which is related to the epidermal growth factor receptor. pl85erbB2 overexpression occurs in carcinomas at many sites, including the uterine cervix, and predicts poor clinical outcome. The authors hypothesize that pl85erbB2 immunohistochemistry will provide additional information in the evaluation of uterine cervix carcinomas with glandular differentiation (CCGD), a difficult and more frequent clinical problem. Paraffin sections from 82 CCGDs including 41 pure adenocarcinomas and 41 adenosquamous carcinomas (7 glassy cell predominant and 34 exhibiting a gland forming component) are immunostained with anti-pl85erbB2 (CBI1 monoclonal, Novacastra Laboratories, Newcastle upon Tyne, UK). Seventy-seven percent of CCGDs exhibit pl85erbB2 immunoreactivity with distinct plasma membrane localization (M) in 50%, the remaining 27% show cytoplasmic staining only. Adjacent benign tissue is negative. The pl85erbB2 staining intensity and distribution is as follows: 54.9% strong diffuse (SD, ≥50% cells positive) with 40.2% M, 17.1% strong focal (SF, erbB2 (P <.01); all other histopathologic features show no association. Follow-up information is available in 77 patients: 37 exhibit recurrent disease (8 pelvic, 15 distant and 14 both) at 1 to 144 months (mean 34, median 16) and 40 were disease free at 12 to 216 months (mean 75, median 64). Strong pl85erbB2 immunoreactivity predicts recurrence at 24 months (P <.05) but not overall recurrence at longer follow-up periods. Recurrent disease is associated with nuclear grade (P <.00001); high clinical stage (P <.001); vascular space invasion (P <.001); large size on clinical exam or pathologic evaluation (P <.005); and pelvic lymph node involvement (P <.05). Considering only patients in good prognosis groups, pl85erbB2 immunoreactivity does not predict recurrence. Strong pl85erbB2 immunoreactivity is associated with stage 3,4 disease (P <.01). pl85erbB2 expression is associated with CCGD carcinogenesis but occurs late in the disease, in patients who present at late stage, hindering its prognostic predictive value. pl85erbB2 immunolocalization may have a diagnostic role in confirming CCGD in histologically challenging cases, predicting high stage at initial biopsy.and defining therapeutic strategies.

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