宫颈病变中HPV DNA检测与IHC检测P16蛋白的关联性研究

doi:10.19401/j.cnki.1007-3639.2025.03.006

摘要/Abstract

摘要：

背景与目的：人乳头状瘤病毒（human papilloma virus，HPV）感染状态在宫颈癌前病变诊断和宫颈癌分型中具有重要意义，而在宫颈病变中高危型（high-risk，HR）HPV感染通常与P16蛋白的过表达密切相关，因此在临床上对组织样本进行病理学诊断时将免疫组织化学（immunohistochemistry，IHC）检测的P16蛋白表达作为判断HPV感染情况的重要依据，但两者之间仍有部分不一致，其相关性有待深入研究，以更好地指导临床实践。方法：回顾性收集复旦大学附属肿瘤医院2020年1月—2023年12月进行宫颈活检或手术的618例患者的临床病理学资料（伦理批号：050432-4-2307E），采用聚合酶链反应（polymerase chain reaction，PCR）反向点杂交法检测HPV DNA多亚型，包括HR和低危型（low-risk，LR）；采用IHC检测P16蛋白水平，比较两者的一致率，评估P16表达在判断HPV感染时的灵敏度和特异度。618例宫颈病变患者中，宫颈鳞癌92例，宫颈腺癌257例，高级别鳞状上皮内病变（high-grade squamous intraepithelial lesions，HSIL）79例，低级别鳞状上皮内病变（low-grade squamous intraepithelial lesions，LSIL）105例，慢性宫颈炎85例。结果：在宫颈鳞癌中，HR-HPV和P16的阳性率分别为88.0%（81/92）和91.3%（84/92），一致率为90.2%（83/92），P16在判断HR-HPV感染中的灵敏度和特异度为96.3%和45.5%；在宫颈腺癌中，HR-HPV和P16的阳性率分别为54.5%（140/257）和58.8%（151/257），一致率为82.5%（212/257），P16在判断HR-HPV感染中的灵敏度和特异度为87.9%和76.1%；在HSIL中，HR-HPV和P16的阳性率分别为75.9%（60/79）和70.9%（56/79），一致率为82.2%（65/79），P16在判断HR-HPV感染中的灵敏度和特异度为85.0%和73.7%；在LSIL中，HR-HPV和P16的阳性率分别为73.3%（77/105）和8.5%（9/105），一致率为33.3%（35/105），P16在判断HR-HPV感染中的灵敏度和特异度为10.4%和96.4%；在慢性宫颈炎中，HR-HPV和P16的阳性率分别为20.0%（17/85）和0.0%（0/85），一致率为80.0%（68/85），P16在判断HR-HPV感染中的灵敏度和特异度为0.0%和100.0%。在宫颈鳞癌、宫颈腺癌及HSIL中P16阳性与HPV16/18呈显著正相关（P=0.000），而在LSIL及慢性宫颈炎中无显著相关性（P>0.05）。结论：在宫颈鳞癌及宫颈腺癌中，P16阳性表达与HPV DNA阳性（HPV感染）的一致率较高，尤其P16表达与HPV16/18亚型感染显著相关。HSIL中P16阳性表达可以初步反映HPV感染情况，但在LSIL及慢性宫颈炎中，P16表达难以准确地反映HPV感染情况。P16与HPV DNA检测不一致可能受感染亚型、病理学类型、样本质量等多种因素影响，实际工作中应仔细分析或用多种方法确定HPV的感染状态。

关键词: 宫颈病变, 人乳头状瘤病毒, P16免疫组织化学, 宫颈鳞癌, 宫颈腺癌, 高级别鳞状上皮内病变, 低级别鳞状上皮内病变, 慢性宫颈炎, 一致率

Abstract:

Background and purpose: Human papilloma virus (HPV) infection status is crucial for diagnosing cervical precancerous lesions and classifying cervical cancer. High-risk (HR) HPV is often linked to P16 protein overexpression, so P16 detection via immunohistochemistry (IHC) is commonly used to assess HPV infection. However, the differences between HPV status and P16 expression remains unclear. An in-depth study of the correlation between HPV and P16 is essential for clinical guidance. Methods: We retrospectively collected clinical and pathological data of cervical lesions from 618 patients diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center from January 2020 to December 2023 (Ethical number: 050432-4-2307E). Polymerase chain reaction (PCR) reverse dot hybridization was used to detect HPV including HR and low-risk (LR) subtypes, and immunohistochemistry was used to detect P16 for comparative analysis. Based on different clinical and pathological diagnoses, the sensitivity and specificity of P16 expression in evaluating HPV infection were evaluated. Among the 618 cases of cervical lesions, there were 92 cases of cervical squamous cell carcinoma, 257 cases of cervical adenocarcinoma, 79 cases of high-grade squamous intraepithelial lesions (HSIL), 105 cases of low-grade squamous intraepithelial lesions (LSIL), and 85 cases of chronic cervical inflammation. Results: According to clinical diagnosis, the HR-HPV positive rate in cervical squamous cell carcinoma was 88.0% (81/92), the P16 positive rate was 91.3% (84/92), and the overall consistency rate between P16 and HPV detection was 90.2% (88/92); for HR-HPV infection, the sensitivity and specificity of P16 were 96.3% and 45.5%. The positive rate of HR-HPV in adenocarcinoma was 54.5% (140/257), the positive rate of P16 was 58.8% (151/257), and the overall consistency rate between P16 and HPV detection was 82.5% (212/257); for HR-HPV infection, the sensitivity and specificity of P16 were 87.9% and 76.1%. In HSIL, the HR-HPV positive rate was 75.9% (60/79), the positive rate of P16 was 70.9% (56/79), and the overall consistency rate between P16 and HR-HPV detection was 82.2% (65/79); for HR-HPV infection, the sensitivity and specificity of P16 were 85.0% and 73.7%. In LSIL, the HR-HPV positive rate was 73.3% (77/105), the positive rate of P16 was 8.5% (9/105), and the overall consistency rate between P16 and HR-HPV detection was 33.3% (35/105); for HR-HPV infection, the sensitivity and specificity of P16 were 10.4% and 96.4%. In chronic cervical inflammation, the HR-HPV positive rate was 20% (17/85), the positive rate of P16 was 0.0% (0/85); for HR-HPV infection, the sensitivity and specificity of P16 were 0.0% and 100.0%. There was a significant positive correlation between P16 positivity and HPV16/18 in cervical squamous cell carcinoma, adenocarcinoma, and HSIL (P=0.000), while there was no significant correlation in LSIL and chronic cervical inflammation (P>0.05). Conclusion: In cervical squamous cell carcinoma and adenocarcinoma, the consistency of P16 expression and HPV DNA positivity are high, especially in HPV16/18 subtype. There is a good concordance between HR-HPV positivity and P16 protein overexpression. The positive expression of P16 in HSIL may initially reflect HPV infection status. However, in LSIL and chronic cervicitis, P16 expression may not accurately correlate with HPV infection. The inconsistency between P16 and HPV DNA testing could be influenced by multiple factors, including HPV subtypes, histopathological categories, specimen quality, and technical limitations. In clinical practice, it is recommended to conduct comprehensive analysis or employ multiple diagnostic methods to confirm HPV infection status for precise evaluation.

Key words: Cervical lesions, Human papilloma virus, P16 immunohistochemistry, Cervical squamous cell carcinoma, Cervical adenocarcinoma, High-grade squamous intraepithelial lesions, Low-grade squamous intraepithelial lesions, Chronic cervical inflammation, Consistency

中图分类号:

R711.74

王皓晨, 贾利晴, 杨瑜, 王乾, 郁成礼, 田田, 毕蕊, 涂小予, 柏乾明, 朱晓丽, 周晓燕, 任敏. 宫颈病变中HPV DNA检测与IHC检测P16蛋白的关联性研究[J]. 中国癌症杂志, 2025, 35(3): 298-308.

WANG Haochen, JIA Liqing, YANG Yu, WANG Qian, YU Chengli, TIAN Tian, BI Rui, TU Xiaoyu, BAI Qianming, ZHU Xiaoli, ZHOU Xiaoyan, REN Min. A study on the correlation between HPV DNA and IHC P16 expression in cervical lesions[J]. China Oncology, 2025, 35(3): 298-308.

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Variable	Case
Age at diagnosis/year
≤40	321 (51.9)
>40	297 (48.1)
Pathological type
Squamous cell carcinom	92 (14.9)
Cervical adenocarcinoma	257 (42.6)
Usual-type	146 (23.6)
Mucinous adenocarcinoma	19 (3.1)
Gastric-type	38 (6.1)
Other	54 (8.7)
HSIL	79 (12.8)
LSIL	105 (17.0)
Inflammation	85 (14.8)
Tumor size cm
≤4	171 (27.7)
>4	156 (25.2)
Unknow	22 (3.6)
NA	269 (43.5)
Lymph node metastasis
Yes	220 (35.6)
No	121 (19.6)
Unkonw	8 (1.3)
NA	269 (43.5)
FIGO installment
Ⅰ	42 (6.8)
Ⅱ	89 (14.4)
Ⅲ	103 (16.7)
Ⅳ	92 (14.9)
Unknown	23 (3.7)
NA	269 (43.5)
Treatment
Preoperative treatment	19 (3.1)
Operative treatment	118 (19.1)
Operative+chemoradiotherapy	205 (33.2)
Disease follow-up visits	248 (40.1)
Unknown	28 (4.5)

HPV subtypes	Cervical squamous cell carcinoma	Cervical adenocarcinoma	HSIL	LSIL	Inflammation
HR-HPV
16	55 (59.7)	68 (26.5)	18 (22.8)	17 (16.2)	7 (8.2)
18	10 (10.9)	62 (24.1)	7 (8.9)	8 (7.6)	4 (4.7)
31	8 (8.7)	2 (0.8)	8 (10.1)	2 (1.9)	1 (1.2)
33	2 (2.2)	2 (0.8)	8 (10.1)	7 (6.7)	0 (0.0)
35	0 (0.0)	0 (0.0)	1 (1.3)	1 (1.0)	0 (0.0)
39	0 (0.0)	1 (0.4)	1 (1.3)	1 (1.0)	0 (0.0)
45	1 (1.1)	6 (2.3)	3 (3.8)	0 (0.0)	0 (0.0)
51	0 (0.0)	0 (0.0)	2 (2.5)	12 (11.4)	0 (0.0)
52	3 (3.3)	1 (0.4)	6 (7.6)	17 (16.2)	3 (3.5)
53	2 (2.2)	0 (0.0)	1 (1.3)	5 (4.8)	3 (3.5)
56	1 (1.1)	0 (0.0)	0 (0.0)	4 (3.8)	0 (0.0)
58	2 (2.2)	0 (0.0)	6 (8.9)	10 (9.5)	0 (0.0)
59	3 (3.3)	0 (0.0)	2 (2.5)	3 (2.9)	0 (0.0)
66	1 (1.1)	1 (0.4)	0 (0.0)	5 (4.8)	2 (2.4)
68	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.9)	3 (3.5)
83	0 (0.0)	1 (0.4)	0 (0.0)	0 (0.0)	0 (0.0)
82	0 (0.0)	0 (0.0)	2 (2.5)	1 (1.0)	0 (0.0)
LR-HPV
6	0 (0.0)	0 (0.0)	3 (3.8)	2 (1.9)	1 (1.2)
11	0 (0.0)	1 (0.4)	1 (1.3)	5 (4.8)	0 (0.0)
42	0 (0.0)	0 (0.0)	0 (0.0)	4 (3.8)	0 (0.0)
43	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.9)	0 (0.0)
81	1 (1.1)	1 (0.4)	2 (2.5)	5 (4.8)	0 (0.0)

Item	HR-HPV⁺ n (%)	HR-HPV^- n (%)	Case n	P value	Kappa value
P16⁺	78 (96.3)	6 (54.4)	84	0.508	0.473
P16^-	3 (3.7)	5 (45.5)	8
Case n	81	11	92

Item	HPV16/18⁺	HPV non-16/18⁺	HPV^-
P16⁺	64 (98.5)	14 (82.3)	6 (60.0)
P16^-	1 (1.5)	3 (17.6)	4 (40.0)
Case n	65	17	10

Item	HR-HPV⁺ n (%)	HR-HPV^- n (%)	Case n	P value	Kappa value
P16⁺	123 (87.9)	28 (23.9)	151	0.135	0.644
P16^-	17 (12.1)	89 (76.1)	106
Case n	140	117	257