Human papillomavirus (HPV) genotyping and prognostic value of HPV E4 protein and transcription factors NANOG and SOX11 in atypical p16 patchy squamous epithelium of cervix

Radulovic, Maja Kebe; Ostrbenk, Anja; Poljak, Mario; Strojan-Flezar, Margareta

doi:10.2478/raon-2025-0038

Figures & Tables

Images of atypical squamous epithelium cases with patchy p16 reaction: (A–F). The same sample stained with HE and p16 at 200× magnification. Panels (A), (C), and (E) show HE staining, while panels (B), (D), and (F) show corresponding p16 staining.

Only case in the group with atypical squamous epithelium with patchy p16 expression and positive reaction for E4 human papillomavirus (HPV). The tissue was positive for HPV16 and 31 and the follow-up was negative. The same section at 100x magnification: (A) HE staining; (B) p16 staining, (C) Ki67 staining, (D) E4 HPV staining, (E) Nanog staining, F. SOX11 staining.

One of the three cases in the group with atypical squamous epithelium with patchy p16 with CIN3 on follow-up. The tissue was positive for human papillomavirus (HPV) 52, 53,56, 66, 73. The same section at 100x magnification: (A) HE. (B) p16 staining. (C) Ki67 staining. (D) E4 HPV staining. (E) Nanog staining. (F) SOX11 staining.

Immunohistochemical reactions in the only cervical intraepithelial neoplasia 3 (CIN3) case with a positive SOX11 reaction in study. The same section at 100x magnification: (A) HE. (B) p16 staining. (C) Ki67 staining. (D) E4 HPV staining. (E) Nanog staining. (F) SOX11 staining.

Biomarkers in the primary biopsy and follow-up in the groups with atypical squamous epithelium with a patchy and a null reaction to p16

Group	Case	Ki67	E4 HPV	Nanog	HPV genotypes	Follow-up sample	Follow-up diagnosis	Time from primary biopsy to follow-up sample
p16	1	1/3	-	1+	31, 52	biopsy	CIN1	2 years
null	2	3/3	-	-	53	biopsy	CIN2	2 years
	3	1/3	-	-	-	biopsy	CIN3	4 months
p16 patchy	4	0	-	-	39	cone	CIN1	8 months
	5	1/3	-	-	-	cone	CIN1	6 years
	6	3/3	-	1+	53	cone	CIN3	5 years
	7	3/3	-	-	52, 53, 56, 66, 73	Cervical amputation	CIN3	10 months
	8	1/3	-	-	44	cone	CIN3	10 months

Comparison of different biological markers between groups using Spearman correlation

Groups	p16	Ki67	HPV E4	Nanog	lrHPV tissue	hrHPV tissue	hrHPV: tissue+smear	lrHPV: tissue+smear
p16 null vs. p16 patchy	r = 1 p = 0.000	r = 0.000	r = 0.116	r = 0.089	r = 0.209	r = 0.384 p = 0.025	r = 0.274	r = 0.285
p16 patchy vs. condyloma	r = 0.000	r = 0.535 p = 0.001	r =0.280	r = 0.494 p = 0.004	r = 0.458 p = 0.007	r = 0.000	r=-0.186	r = 0.494 p = 0.004
p16 patchy vs. CIN1	r = 0343 p = 0.041	r = 0.35 p = 0.037	r = 0.81 p = 0.000	r = 0.532 p = 0.001	r = 0.354 p = 0.034	r = 0.161	r = -0.039	r = 0.359 p = 0.032
p16 patchy vs. CIN2	r = 1 p = 0.000	r = 0.66 p = 0.000	r = 0.728 p = 0.000	r = 0.632 p = 0.000	r = -0.193	r = 0.45 p = 0.007	r = 0.176	r = -0.089
p16 patchy vs. CIN3	r = 1 p = 0.000	r = 0.683 p = 0.000	r = 0.280	r = 0.575 p = 0.000	r = -0.375 p = 0.032	r = 0.594 p = 0.000	r = 0.433 p = 0.012	r = -0.433 p = 0.012
p16 null vs. condyloma	r = 1	r = 0.617 p = 0.004	r = 0.369	r = 0.664 p = 0.001	r = 0.704 p = 0.001	r = 0.464 p = 0.039	r = 0.066	r = 0.818 p = 0.000
p16 null vs. CIN1	r = 0.963 p = 0.000	r = 0.394	r = 0.84 p = 0.000	r = 0.691 p = 0.000	r = 0.568 p = 0.005	r = 0.569 p = 0.005	r = 0.233	r = 0.652 p = 0.001
p16 null vs. CIN2	r = 1	r = 0.735 p = 0.000	r = 0.756 p = 0.000	r = 0.728 p = 0.000	r = 0.000	r = 0.832 p = 0.000	r = 0.455 p = 0.034	r = 0.204
p16 null vs. CIN3	r = 1	r = 0.783 p = 0.000	r = 0.369	r = 0.665 p = 0.001	r = -0.302	r = 1	r = 0.739 p = 0.000	r = -0.302
Atypia (p16 patchy and null) vs. CIN2	r = 0.811 p = 0.000	r = 0.607 p = 0.000	r = 0.751 p = 0.000	r = 0.598 p = 0.000	r = -0.125	r = 0.521 p = 0.000	r = 0.231	r = -0.007

Immunohistochemical reactions to various biological markers and human papillomavirus (HPV) genotyping in tissue biopsy and previous cervical smear, where available, by study group

Group	p16	N	Ki67	N	E4 HPV	N	Nanog	N	HPV genotyping	N tissue	N smear
p16 null N = 11	Null	11	0	5	Neg.	11	Neg.	7	Neg	9	3
	Patchy	0	1/3	4	Pos.	0	1	4	lrHPV only	2	1
	En Block	0	2/3	0			2	0	hrHPV	0	3
			3/3	2			3	0
p16 patchy N = 24	Null	0	0	12	Neg.	23	Neg.	13	Neg	10	2
	Patchy	24	1/3	5	Pos.	1	1	11	lrHPV only	6	2
	En Block	0	2/3	3			2	0	hrHPV	8	12
			3/3	4			3	0
Condyloma N = 9	Null	0	0	0	Neg.	7	Neg.	0	Neg	0	1
	Patchy	9	1/3	2	Pos.	2	1	9	lrHPV only	6	2
	En Block	0	2/3	1			2	0	hrHPV	3	1
			3/3	6			3	0
CIN1 N = 12	Null	0	0	2	Neg.	2	Neg.	0	Neg	0	0
	Patchy	10	1/3	2	Pos.	10	1	12	lrHPV only	6	1
	En Block	2	2/3	4			2	0	hrHPV	6	3
			3/3	4			3	0
CIN2 N = 11	Null	0	0	0	Neg.	3	Neg.	0	Neg	1	0
	Patchy	0	1/3	0	Pos.	8	1	7	lrHPV only	2	0
	En Block	11	2/3	2			2	4	hrHPV	8	3
			3/3	9			3	0
CIN3 N = 9	Null	0	0	0	Neg.	7	Neg.	1	Neg	0	0
	Patchy	0	1/3	0	Pos.	2	1	3	lrHPV only	0	0
	En Block	9	2/3	0			2	3	hrHPV	9	4
			3/3	9			3	2

j_raon-2025-0038_Utab_001

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Follow-up histology, cytology, human papillomavirus (HPV) result by study groups (p16 null and p16 patchy)

Group	Follow up histo	N	Follow up cyto	N	Follow up HPV	N
p16 null (11 cases, 9 biopsies)	Neg	0	Neg	5	Neg	5
	CIN1	1	ASC-US	4	Pos	3
	CIN2	1	LSIL	0
	CIN3	1	HSIL	0
p16 patchy (24 cases, 17 biopsies)	Neg	0	Neg	5	Neg	4
	CIN1	2	ASC-US	6	Pos	5
	CIN2	0	LSIL	4
	CIN3	3	HSIL	2

Human papillomavirus (HPV) genotyping and prognostic value of HPV E4 protein and transcription factors NANOG and SOX11 in atypical p16 patchy squamous epithelium of cervix

Figures & Tables

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Biomarkers in the primary biopsy and follow-up in the groups with atypical squamous epithelium with a patchy and a null reaction to p16

Comparison of different biological markers between groups using Spearman correlation

Immunohistochemical reactions to various biological markers and human papillomavirus (HPV) genotyping in tissue biopsy and previous cervical smear, where available, by study group

j_raon-2025-0038_Utab_001

Follow-up histology, cytology, human papillomavirus (HPV) result by study groups (p16 null and p16 patchy)

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