Stathmin, a Microtubule Destabilizing Protein, Is Overexpressed in Most High, but Not Low Grade, Cervical Squamous Intraepithelial Lesions
Brooke E Howitt, Marisa R Nucci, Ronny Drapkin, Chris P Crum, Michelle S Hirsch. Brigham & Women's Hospital, Boston, MA
Background: A fundamental controversy in using biomarkers to diagnose cervical precursors (ie, cervical intraepithelial neoplasia, CIN) is their specificity for CIN2/3. Stathmin (STMN), a microtubule destabilizingprotein important in mitosis, is overexpressed in a variety of malignancies, and may be associated with poor outcome. STMN expression in cervical neoplasia has never been explored.
Design: Cervical samples (N=191) of non-neoplastic (N=25), non-invasive neoplasia (N=82 CIN, N=19 AIS), invasive squamous cell carcinoma (SCC) (N=31), and invasive adenocarcinoma (ACA) (N=34) were evaluated for STMN, p16, and Ki67 expression by immunohistochemistry (IHC). H&E stained cervical biopsies were independently scored by 3 expert gynecologic pathologists. Squamous lesions were classified as benign, CIN1, CIN2, or CIN3 based on a majority diagnosis (≥2/3 agreeing); cases without agreement were reviewed together and majority opinion was obtained. Each diagnosis was correlated with STMN, p16, and Ki67 expression. IHC interpretation was blindly performed by 2 pathologists.
Results: A majority diagnosis was obtained in 187/191 cases on initial review. Squamous epithelia were classified as benign, CIN1, CIN2, and CIN3 in 25, 56, 11 and 15 cases, respectively. STMN was normally expressed in ectocervical basal cells and was absent in benign endocervix. Positive STMN staining was defined as immunoreactivity in at least 2/3 of the epithelial thickness. STMN was positive in 5/56 (9%) CIN1, 5/11 (45%) CIN2, and 14/15 (93%) CIN3 (p <0.001), and all cases of AIS, SCC, and ACA. In contrast, 25/56 (45%) CIN1, 11/11 (100%) CIN2, and 14/15 (93%) CIN3 lesions were p16 positive. p16 was also expressed in 5 (20%) benign biopsies. All 30 p16 positive benign and CIN1 biopsies were STMN negative. Ki67 was increased in all neoplastic and some non-neoplastic epithelia.
Conclusions: STMN is overexpressed in virtually all cervical carcinomas and CIN3 lesions. In contrast to p16, which can stain CIN1 and reactive epithelia, STMN has greater specificity for CIN3, and will distinguish these lesions from the majority of low grade precursors and negative cervical biopsies. STMN overexpression appears independent of proliferation, maturation, and HPV cytopathic effect, and may be useful in identifying higher grade CIN at greater risk for progression (CIN3). STMN can also be used to confirm AIS or invasive carcinoma. Further studies correlating STMN staining with lesion persistence or morphologic progression, in the context of CIN grade, are warranted.
Category: Gynecologic & Obstetrics
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 119, Tuesday Afternoon