A Comparative Study on the Accuracy and Efficacy Between Dalton and CINtec® PLUS p16/Ki-67 Dual Stain in Triaging HPV-Positive Women

Abstract

Background: CINtec^® PLUS p16/Ki-67 dual-stained cytology (DS) is an alternative test to cytology in triaging human papillomavirus (HPV)-positive women. Dalton p16/Ki-67 Dual Stain kit employs the similar immunocytochemical detection and operating procedures with CINtec^® PLUS, but its accuracy and efficacy in triaging HPV-positive women need to be evaluated.

Methods: A total of 717 HPV-positive specimens of cervical exfoliated cells were included. Cytology, Dalton, and CINtec^® PLUS were subsequently performed, and two DS tests were separately completed in each of the same specimens. The results of two DS tests were head-to-head compared, and their efficacies to identify high-grade cervical intraepithelial neoplasia (CIN) were evaluated, using histopathology of biopsy as the golden standard.

Results: The overall positive rate of two DS tests were 28.31% for Dalton and 33.89% for CINtec^® PLUS (p < 0.05); both rose with the increased severity of histopathological and cytological abnormalities. Compared to CINtec^® PLUS, the positive rate of Dalton was significantly lower in the normal histopathology group (p < 0.05) and lower, but not significantly, in mild abnormal histopathology and cytology NILM and LSIL groups. Two DS tests showed a good consistency (Kappa value, 0.63; 95% CI, 0.557-0.688), with 100% of consistency in the cytology HSIL group. Inconsistency occurred mainly in the cytology NILM and LSIL groups, with more Dalton negative but CINtec^® PLUS positive. Compared to CINtec^® PLUS, Dalton showed similar sensitivity (94.59% vs. 91.89%), but significantly higher specificity (75.29% vs. 69.26%, p = 0.013) and accuracy (76.29% vs. 70.43%, p = 0.012), with a larger area under the curve (AUC) of 0.849 (95% CI, 0.800-0.899) for identifying CIN3+. The similar results were observed when identifying CIN2+.

Conclusions: Dalton presents the lower false positive rate and better efficacy in identifying high-grade CIN than CINtec^® PLUS, suggesting that Dalton may be superior to CINtec^® PLUS and an alternative technique for triaging primary HPV-positive women in cervical cancer screening.

Keywords: cervical cancer; cervical cancer screening; cervical intraepithelial neoplasia; human papillomavirus; p16/Ki-67 dual stain.

Figure 1

Flowchart of subject recruitment. HPV, human papillomavirus; NILM, negative for intraepithelial lesion or malignancy; ASC-US, atypical squamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesion; ASC-H, atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesions. ^aIncluded 3 of SCC (squamous cell carcinoma), 1 of AC (adenocarcinoma) and 1 of AGC-NOS (atypical glandular cell of undetermined significance).

Figure 2

Representative photos of p16/Ki-67 dual stain cytology. Cervical exfoliated cells negative (A) and positive (B) for for Dalton, negative (C), and positive (D) for CINtec^® PLUS, respectively. The brown cytoplasm/nuclear signal showed p16 staining alone, and the red nuclear signal showed Ki-67 staining alone. The positive p16/Ki-67 dual stain cell had both brown and red signal, which reflected the colocalization of p16 and Ki-67 in the same cell.

Figure 3

ROC curve analysis of Dalton and CINtec^® PLUS in detecting CIN3+ (A) and CIN2+ (B). (A) The AUC were 0.849 (95% CI, 0.800-0.899) for Dalton and 0.806 (95% CI, 0.747-0.865) for CINtec^® PLUS. (B) The AUC were 0.833 (95% CI, 0.787-0.879) for Dalton and 0.802 (95% CI, 0.754-0.849) for CINtec^® PLUS. ROC, receiver operating characteristic; CIN3+, cervical intraepithelial neoplasia grade 3 or worse; CIN2+, cervical intraepithelial neoplasia grade 2 or worse; AUC, area under the curve.