Progress in immunocytochemical staining for cervical cancer screening

Figures & data

Figure 1 The cellular model of each marker positive staining.

Note: (A) Negative staining; (B) H&E staining; (C) Ki-67 nuclear positive staining; (D) p16 cytoplasmic positive staining; (E) p16 cytoplasmic and Ki-67 nuclear co-positive staining; (F) ProEx™ C nuclear positive staining; (G) HPV L1 capsid protein nuclear positive staining; (H) Claudin 1 membranous positive staining; (I) IMP3 cytoplasmic positive staining; (J) Feulgen-thionin staining for DNA; and (K) RKIP nuclear and cytoplasmic positive staining.

Abbreviations: HPV, human papillomavirus; IMP3, insulin-like growth factor-II mRNA-binding protein 3; RKIP, Raf kinase inhibitor protein.

Table 1 Diagnostic performance of the p16/Ki-67 dual staining in primary screening for detecting CIN 2+

Study	Population	Sensitivity (%)			Specificity (%)
		p16/Ki-67	Cytology	HR-HPV	p16/Ki-67	Cytology	HR-HPV
Ikenberg et al^Citation20	Age range: 18–65 years	86.7	68.5	–	95.2	95.4	–
	30–65 years	84.7	–	93.7	96.2	–	93
	18–29 years	89.4	71.9	–	92	92.6	–
Yu et al^Citation21	Total population	90.9	93.5	94.4	79.5	76.2	76.9
	Screening population	75.0	65.0	100	79.5	76.2	76.9

Abbreviations: CIN 2+, cervical intraepithelial neoplasia 2 and above; HPV, human papillomavirus; HR-HPV, high-risk HPV.

Table 2 Triage performance of the p16/Ki-67 dual staining in patients referred to colposcopy for detecting CIN 2+

	Population	Sensitivity (%)		Specificity (%)		PPV (%)		NPV (%)
		p16/Ki-67	HPV 16/18	p16/Ki-67	HPV 16/18	p16/Ki-67	HPV 16/18	p16/Ki-67	HPV 16/18
Petry et al^Citation24	HPV+ TCT–	91.9	–	82.1	–	34.5	–	99.1	–
Uijterwaal et al^Citation26	HPV+ TCT–	68.8	43.8	72.8	79.4	25.2	22.1	94.6	91.4
	HPV+ ≥ASCUS	91.0	–	30.6	–	50.5	–	81.5	–
Wentzensen et al^Citation25	HPV+ ASCUS/LSIL	86.4	47.6	59.5	80.8	–	–	–	–
Donà et al^Citation23	Colposcopy	79.7%	–	73.5%	–	–	–	–	–

Abbreviations: CIN 2+, cervical intraepithelial neoplasia 2 and above; HPV, human papillomavirus; LSIL, low-grade squamous intraepithelial lesion; NPV, negative predictive value; TCT, ThinPrep cytologic test.

Table 3 Triage performance of the p16/Ki-67 dual staining in patients with ASCUS/LSIL for detecting CIN 2+

	Population	Sensitivity (%)		Specificity (%)		PPV (%)		NPV (%)
		p16/Ki-67	HR- HPV	p16/Ki-67	HR- HPV	p16/Ki-67	HR- HPV	p16/Ki-67	HR- HPV
Schmidt et al^Citation27	ASCUS	92.2	90.9	80.6	36.3	–	–	–	–
	LSIL	94.2	96.4	68.0	19.1	–	–	–	–
Bergeron et al^Citation28	ASCUS	94.4	100	78.7	60.4	–	–	–	–
	LSIL	85.7	98.4	53.3	15.6	–	–	–	–
Yu et al^Citation21	ASCUS/LSIL	87.5	91.7	66.4	55.8	37.5	32.4	95.8	96.7

Abbreviations: ASCUS, atypical squamous cells of undetermined significance CIN 2+, cervical intraepithelial neoplasia 2 and above; HR-HPV, high-risk human papillomavirus; LSIL, low-grade squamous intraepithelial lesion; NPV, negative predictive value.

Table 4 Triage performance of the p16/Ki-67 dual staining in patients with HPV+ for detecting CIN 2+

	Population	Sensitivity (%)		Specificity (%)		PPV (%)		NPV (%)
		p16/Ki-67	Cytology	p16/Ki-67	Cytology	p16/Ki-67	Cytology	p16/Ki-67	Cytology
Uijterwaal et al^Citation26
Wright et al^Citation29	HPV+	70.3	51.8	75.6	76.1	26.2	21.1	95.4	92.7
Ovestad et al^Citation32		88.0	79.0	31.0	35.0	48.0	31.0	78.0	70.0
Yu et al^Citation21		92.7	94.5	52.7	53.5	63.5	64.4	89.0	91.6

Abbreviations: CIN 2+, cervical intraepithelial neoplasia 2 and above; HPV, human papillomavirus; NPV, negative predictive value; PPV, positive predictive value.

Table 5 Diagnostic performance of other staining marker for detecting CIN 2+

	Population	Cytologic marker	Sensitivity (%)	Specificity (%)
Kelly et al^Citation39	Abnormal cytology	ProEx™ C	85.3	71.7
		Cytology test	50.0	91.3
Tambouret et al^Citation40	Screening	ProEx C	81.0	82.0
		ProEx C Cytology test	92.0	84.0
Alaghehbandan et al^Citation41	ASCUS	ProEx C	71.6	74.6
	LSIL	ProEx C	67.6	60.0
Byun et al^Citation46	ASC-H/LSIL-H	L1	95.2	34.3
		L1+p16/Ki67+HR-HPV	100	53.1
Benczik et al^Citation48	Colposcopy	p16	52.0	85.1
		Claudin 1	53.3	77.0
		P16/claudin1	69.3	73.6
		Cytology test	–	–
Wei et al^Citation53	≥ LSIL	P16/IMP3	81.4–71.9	96.5–88.9
		Cytology test	59.5–63.9	90.1–73.6
	SCC	P16/IMP3	92.0	83.6
		Cytology test	88.0	95.9
Li et al^Citation58	≥ ASCUS	Feulgen-thionin	32.0	90.0
		Feulgen-thionin/Ki67	45.0	90.0
Al-Awadhi et al^Citation62	HPV+	RKIP	84.6	34.6

Abbreviations: CIN 2+, cervical intraepithelial neoplasia 2 and above; HPV, human papillomavirus; HR-HPV, high-risk HPV; IMP3, insulin-like growth factor-II mRNA-binding protein 3; LSIL, low-grade squamous intraepithelial lesion; RKIP, Raf kinase inhibitor protein; SCC, squamous cell carcinoma.

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