Usefulness of p16ink4a, ProEX C, and Ki-67 for the Diagnosis of Glandular Dysplasia and Adenocarcinoma of the Cervix Uteri

Abstract

Although the diagnostic criteria of in-situ and invasive adenocarcinomas of the cervix uteri are well established, the differentiation from benign mimics may be difficult and the morphologic features of the precursors of endocervical adenocarcinoma are still debated. In this study, we evaluated the usefulness of p16ink4a (p16), ProEX C, and Ki-67 for the diagnosis of endocervical adenocarcinoma and its precursors. Immunohistochemistry with p16, ProEX C, and Ki-67 was performed in 82 glandular lesions including 15 invasive adenocarcinomas, 29 adenocarcinomas in situ (AIS), 22 non-neoplastic samples, and 16 cases of glandular dysplasia (GD), which showed significant nuclear abnormalities but did not meet the diagnostic criteria for AIS. The immunohistochemical expression pattern was scored according to the percentage of the stained cells (0, 1+, 2+, and 3+ when 0% to 5%, 6% to 25%, 26% to 50%, and more than 50% of the cells were stained, respectively) and was evaluated for each antibody. p16 was at least focally expressed (1+ or more) in 14 of 15 invasive adenocarcinomas, in all AIS and in 7 negative samples. ProEX C and Ki-67 both scored 1+ or more in all adenocarcinomas and AIS and in 8 and 6 negative samples, respectively. Of the GD 15, 14, and 15 expressed p16, ProEX C, and Ki-67, respectively. The score differences between neoplastic and non-neoplastic samples were highly significant for each marker (P<0.001); however, the score distribution by marker differed significantly only in GD (P=0.006) in which, compared with the other markers, p16 showed more often a 3+ pattern. Our study shows that p16, Ki-67, and ProEX C may be helpful for the diagnosis of glandular lesions of the cervix uteri and may also improve the diagnostic accuracy of endocervical GD. In particularly problematic cases, the combination of p16 and a proliferation marker can provide additional help for the interpretation of these lesions.

Utility of ProExC and IMP3 immunocytochemical staining in atypical glandular cells of undetermined significance in liquid‐based cervical cytology

“…Prior studies performed on paraffin‐embedded tissue have demonstrated ProExC positivity in 100% of cases of invasive and in situ endocervical AC, and in 87.5% of cases of glandular dysplasia . Likewise, IMP3 positivity was found in 93% of cases of AIS when performed on paraffin‐embedded tissue …”

Role of Protein Biomarkers in the Detection of High-Grade Disease in Cervical Cancer Screening Programs

“…The performance of Ki-67 [16, 42, 67], p16 INK4a (reviewed in [24]), and BD ProEx C [62–64, 66, 68–72] in histological applications has been evaluated in many studies. The comparison of biomarker performance in the detection of high-grade cervical disease is difficult due to the variability in specimens, study design, antibodies, and scoring algorithms utilized.…”

“…Negri et al [68] evaluated the utility of p16 INK4a , ProEx C, and Ki-67 for the diagnosis of endocervical adenocarcinoma and its precursors. p16 INK4a was at least focally expressed in 93% (14/15) of invasive adenocarcinomas, 100% of AIS (29/29), and 32% (7/22) negative samples.…”

Ancillary Techniques in the Histopathologic Diagnosis of Squamous and Glandular Intraepithelial Lesions of the Uterine Cervix

“…Already discussed in the paragraphs concerning squamous intraepithelial lesions, p16 has also emerged as a potentially useful marker in the evaluation of glandular cervical alterations [20,[109][110][111]. Most AIS lesions show diffuse nuclear and/or cytoplasmic immunopositivity ( Figure 6).…”