Role of quantitative p16INK4A mRNA assay and digital reading of p16INK4A immunostained sections in diagnosis of cervical intraepithelial neoplasia

Visual interpretation of cervical biopsies is subjective and variable, generally showing fair to moderate inter‐reader agreement in distinguishing high from low grade cervical intraepithelial neoplasia (CIN). We investigated the performance of two objective p16 quantitative tests in comparison with visual assessment: (i) p16‐mRNA assay and (ii) digital analysis of sections stained for p16 protein. The primary analysis considered 232 high‐risk human papilloma virus positive (HPV+) samples from diagnostic cervical specimens. A p16 RT‐qPCR (p16‐mRNA assay) was run on mRNA extracted from formalin‐fixed paraffin‐embedded sections. Two p16 immunohistochemistry (IHC) readings, a visual read by a histopathologist (Visual IHC) and a digital read of a high‐resolution scan (Digital IHC), were done on adjacent sections. The worst reviewed CIN grade (agreed by at least two histopathologists) from up to two biopsies and a loop excision was taken, with CIN2/3 as the primary endpoint. Visual IHC attained a specificity of 70% (95%CI 61–77) for 85% (95%CI 77–91%) sensitivity. The four‐point Visual IHC staining area under the curve (AUC) was 0.77 (95%CI 0.71–0.82), compared with 0.71 (95%CI 0.64–0.77) for p16‐mRNA and 0.67 (95%CI 0.60–0.74) for Digital IHC. Spearman rank‐order correlations were: visual to p16‐mRNA 0.41, visual to digital 0.49 and p16‐mRNA to digital: 0.22. The addition of p16‐mRNA assay to visual reading of p16 IHC improved the AUC from 0.77 to 0.84 (p = 0.0049). p16‐mRNA testing may be complementary to visual IHC p16 staining for a more accurate diagnosis of CIN, or perhaps a substitute in locations with a lack of skilled pathologists.     

p16INK4A表达与宫颈癌患者临床病理特征及预后的关系

目的 探讨p16INK4A(p16)蛋白在宫颈癌和宫颈上皮内瘤变(CIN)中的表达及其与临床病理特征和预后的相关性.方法 选取宫颈活检和手术切除的宫颈癌患者的宫颈标本100例,CIN组织80例以及正常宫颈组织50例,采用免疫组织化学法对p16蛋白的表达进行检测,并对所得结果进行统计分析.结果 p16在宫颈癌组织、CIN组织与正常宫颈组织中的阳性表达率比较,差异有统计学意义(P<0.05);p16蛋白的表达强度和阳性表达率与宫颈病变程度呈正相关(r=0.545,P<0.05);p16蛋白阳性表达与宫颈癌的分化程度及淋巴结转移情况有关(P<0.05);p16阳性表达患者的3年生存率低于p16阴性表达患者(P<0.05).结论 p16蛋白表达与宫颈癌的发生、发展及不良预后有关,可以作为判断宫颈癌生物学行为和预后评价的指标.     

宫颈上皮内瘤变p16~(INK4a)和p53及Ki-67表达及其诊断价值探讨

目的:探讨用p16和p53及Ki-67等免疫组化标记作为宫颈上皮内瘤变(CIN)诊断的辅助指标。方法:选取我院档案CIN患者133例,年龄20～86岁,中位年龄46岁。经3位高年资病理医师复查确认,其中CIN 1级31例、CIN 2级37例和CIN 3级65例。另选同期我院宫颈慢性炎患者19例,浸润性鳞状细胞癌患者20例作为对照。采用SP法进行p16、p53和Ki-67免疫组化染色,结果独立评分。各级别CIN与免疫组化表达的关系采用单变量χ2检验和Spearman等级相关分析。结果:p16阳性表达位于细胞核或胞核伴胞质,p53和Ki-67定位于细胞核。p16、p53和Ki-67表达阳性率随着CIN的加重而升高,均与CIN级别呈正相关,r值分别为0.789、0.554和0.749,P<0.001。153例CIN 1+标本中p16、p53和Ki-67与组织学诊断符合率分别为96.7%(148/153)、71.9%(110/153)和88.2%(135/153)。在102例CIN 2+标本中,p16、p53和Ki-67免疫组化染色的敏感性分别为97.1%(99/102)、74.5%(76/102)和97.1%(99...     

Evaluation of cervical cone biopsies for coexpression of p16INK4a and Ki-67 in epithelial cells

Diffuse overexpression of p16(INK4a) in basal and parabasal cells of cervical epithelium is a hallmark of human papillomavirus-mediated transformation. Focal p16(INK4a) expression is occasionally observed in nondysplastic epithelium. In normal cells, expression of p16(INK4a) triggers cell cycle arrest. However, cells undergoing transformation in intraepithelial lesions actively proliferate. To prove that the different expression patterns of p16(INK4a) , i.e., focal versus diffuse, reflect biologically different entities, we hypothesized that p16(INK4a) -positive cells in epithelia displaying focal p16(INK4a) expression pattern do not coexpress proliferation-associated Ki-67 protein, while p16(INK4a) -positive cells in lesions with diffuse p16(INK4a) expression may do. A total of 138 cervical cone biopsies were stained for the expression of p16(INK4a) and Ki-67 using a primary antibody cocktail. All metaplastic lesions (n = 21) displayed focal staining for p16(INK4a) , and in all of these lesions p16(INK4a) -positive cells were found to be negative for Ki-67 expression. Diffuse expression of p16(INK4a) was observed in 12/21 (57.1%) cervical intraepithelial neoplasia (CIN) 1 lesions, all of them simultaneously showed Ki-67 immunoreactivity in a large proportion of p16(INK4a) -positive cells. Seventeen of 23 (73.9%) CIN2 lesions and all 27 (100%) CIN3/carcinoma in situ (CIS) as well as all 46 (100%) carcinoma cases displayed diffuse and combined expression of p16(INK4a) and Ki-67. Coexpression of Ki-67 and p16(INK4a) in the same cell is entirely restricted to cervical lesions displaying diffuse p16(INK4a) expression, whereas in lesions with focal p16(INK4a) expression, p16(INK4a) -expressing cells are negative for Ki-67. Thus, diffuse expression of p16(INK4a) reflects lesions with proliferation-competent cells, while p16(INK4a) -expressing cells associated with focal expression patterns are cell cycle arrested.     

p16INK4A immunohistochemical staining and predictive value for progression of cervical intraepithelial neoplasia grade 1: A prospective study in China

p16^INK4A is strongly expressed in tissues diagnosed as cervical intraepithelial neoplasia (CIN) and cancer in women infected with human papillomavirus (HPV), but few prospective studies have evaluated p16^INK4A as a marker for the risk of low‐grade CIN (CIN1) progression. We investigated the prevalence of p16^INK4A immunostaining by CIN grade and whether overexpression of p16^INK4A in CIN1 predicts future risk for high‐grade CIN in Chinese women. 6,557 Chinese women aged 30–49 years were screened from 2003 to 2005 using cytology and carcinogenic HPV test. Colposcopy was performed on women with any abnormal result. p16^INK4A Immunostaining was performed on biopsies from all women with CIN1, as well as randomly selected women with normal or CIN grade 2 and worse (CIN2+) biopsies. Women with CIN1 were followed up without treatment. Colposcopy was performed on all untreated women at a 2‐year interval. The prevalence of p16^INK4A staining was 2.7%, 42.7%, 75.5%, 79.6% and 100% among women with normal, CIN1, 2, 3 and cancer biopsies, respectively (p < 0.001). HPV positivity was strongly associated with p16^INK4A staining [odds ratios (OR) = 12.8; 95% confidence intervals (CI): 5.2–31.6]. p16^INK4A staining of CIN1 biopsies at baseline was associated with an increased risk of finding high‐grade CIN over 2 years of follow‐up (OR = 1.43; 95% CI: 0.52–3.91). The two‐year cumulative incidence of CIN2+ for p16^INK4A positive women was higher at 10.71% than for p16^INK4A negative women at 1.30% (crude RR = 8.25, 95% CI: 1.02–66.62). p16^INK4A overexpression is strongly associated with grade of CIN and risk of progression to high‐grade CIN in women with low‐grade lesions.     

Progression of Precancerous Cervical Lesion Predicted by p16 Protein Immunohistochemistry in Rajavithi Hospital

Objective: To assess the association of p16 immunohistochemical (IHC) staining in cervical squamous intraepitheliallesions (SIL) and progression of cervical intraepithelial neoplasia (CIN) 1 to CIN2+ or recurrence of CIN2+. Materialand Methods: A retrospective cohort study of women with newly diagnosed SIL from colposcopy-directed biopsy atRajavithi Hospital, 2013-2017. Pathologic specimens were reviewed and submitted to p16-IHC staining. Adjusted hazardratios (HR) of disease-free interval (DFI) and 95% confidence intervals (CI) were carried out using the Cox proportionalhazard regression model. Results: A total of 187 women was recruited, 91 cases of positive p16-IHC staining and 96cases of negative staining. With the median follow-up time of 22 months, women with positive p16-IHC had significantlylower 1-year DFI than those with negative p16-IHC (86.8% vs. 96.6%, p = 0.006). Women with CIN 1 had 22.6% ofpositive p16-IHC, while those with CIN2-3 had 86.7%. From multivariate analysis, the positive p16-IHC and age >35 years were the significant prognostic factors of progression/recurrent CIN2+ (adjusted HR 5.33, 95%CI 1.77-16.01,p = 0.003; and adjusted HR 5.80, 95%CI 1.34-25.08, p = 0.019, respectively). From subgroup analysis, the positivep16-IHC was the significant prognostic factor in women with initial CIN1 (HR 5.29, 95%CI 1.18-23.76, p = 0.030), butwas not associated with prognosis in women with initial CIN 2-3 (HR 2.13, 95%CI 0.28-16.38, p = 0.468). Conclusion:Overexpression of p16 protein has the prognostic significance of SIL. Using p16-IHC may help stratify patients aslow-risk and high-risk groups to progression/recurrence CIN2+.     

宫颈癌及其癌前病变组织中p16INK4a和PCNA的表达及临床意义

目的：探讨p16^INK4a、增殖细胞核抗原（proliferating cell nuclear antigen,PCNA）在宫颈癌及其癌前病变组织中的表达及临床意义。方法：采用免疫组化SP法检测p16^INK4a和PCNA在40例宫颈癌、33例宫颈上皮内瘤样变（cervical intraepithelial neoplasia,CIN）Ⅱ-Ⅲ、28例CINⅠ和10例正常宫颈组织标本中的表达。结果：1）p16^INK4a在正常宫颈组织中无表达。宫颈癌或CINⅡ-Ⅲ的p16^INK4a表达阳性率显著高于CINⅠ,P〈0.01。CINⅠ、CINⅡ-Ⅲ和宫颈癌PCNA表达阳性率显著高于正常宫颈,P〈0.01。p16^INK4a、PCNA表达强度随着宫颈病变程度的加重而增高,P〈0.001。2）宫颈癌不同组织学类型、病理组织分级和临床分期p16^INK4a表达阳性率及表达强度差异均无统计学意义,P〉0.05。在不同病理组织分级和临床分期中PCNA表达强度呈增强趋势,差异有统计学意义,P〈0.05。3）p16^INK4a、PCNA在CINⅠ和CINⅡ-Ⅲ组织中的表达均呈显著正相关,P〈0.01。结论：CINⅠp16^INK4a阳性表达是其发生质变的信号,PCNA可作为宫颈细胞异常增殖的灵敏标志。联合检测宫颈病变组织中p16^INK4a和PCNA的表达有助于对宫颈癌前病变进行早期诊断。     

高危型HPV负荷量和p16INK4A蛋白监测评估宫颈锥切术治疗CIN

[目的]评价高危型人乳头状瘤病毒HPV负荷量的检测和p16INK4A蛋白的表达在预测宫颈上皮内瘤变(CIN)宫颈锥切术后残存病变或复发中的意义.[方法]回顾性分析142例2008年10月至2010年12月因CIN行宫颈锥形切除术治疗患者的临床资料.所有患者均于宫颈锥形切除术前6个月以内和术后6～12个月进行HPV负荷量检测,并采用免疫组化方法检测HPV DNA阳性患者宫颈细胞中p16INK4A蛋白表达.[结果]宫颈锥切术前,随着CIN级别的上升,HPV负荷量以及p16INK4A蛋白表达均明显增强(P＜0.05).但在宫颈锥切术后,HPV负荷量和p16INK4A蛋白表达明显降低,宫颈锥切术前和术后两者之间差异有统计学意义(P＜0.05).[结论] HPV负荷量持续增高和p16INK4A蛋白持续呈强阳性是宫颈锥切术后发生残存病变或复发的高危因素,在监测HPV负荷量的同时检测p16INK4A蛋白的表达,对判断宫颈锥切术后发生残存病变或复发有重要意义.     

Expression of the p16INK4a and Ki-67 in relation to the grade of cervical intraepithelial neoplasia and high-risk human papillomavirus infection

Objective

The purposes of this study were to evaluate the expression of p16^INK4a (referred as to p16) and Ki-67 in cervical intraepithelial neoplasia (CIN), and the correlation between high-risk human papillomavirus (HPV) infection and the above biomarkers.

Methods

We analyzed 31 patients who were diagnosed with CIN at Kwandong University Myongji Hospital from October 2006 to September 2007. CIN specimens (CIN1, 12; CIN2, 6; CIN3, 13) were obtained by colposcopy-directed biopsy (CDB) or loop electrical excision procedure (LEEP). The expressions of p16 and Ki-67 were evaluated by immunohistochemical methods with antibodies to p16 and Ki67. The immunohistochemical staining results were classified into four grades: 0, 1, 2 and 3. HPV genotyping or Hybrid Capture-II test was used to detect high-risk HPV.

Results

The expression of p16 (p<0.001) and Ki-67 (p=0.003) were positively associated with CIN grade. p16 expressions increased significantly with high-risk HPV infection (p=0.014), especially HPV type 16 and 58. Ki-67 expression was not related with high-risk HPV. There was positive correlation between the expression of the p16 and Ki-67 (p=0.007).

Conclusion

CIN grade were positively related to the expression of p16 and Ki-67. p16 expressions of high-risk HPV specimens significantly increased more than Ki-67. Therefore, in the diagnosis of CIN and high-risk HPV infection, p16 can be a useful biomarker.     

Prognostic value of p16‐INK4A protein in women with negative or CIN1 histology result: A follow‐up study

P16‐INK4A overexpression has been proposed as a prognostic marker to manage the follow up of women with positive cytology and/or HPV test but without high‐grade cervical intraepithelial neoplasia (CIN2+). This study measures the relative risk (RR) of CIN2+ of p16 positive versus negative in these women. All the women referred to colposcopy from October 2008 to September 2010 with negative or CIN1 colposcopy‐guided biopsy were included in the study; women surgically treated or having a CIN2–3 were excluded. All baseline biopsies were dyed with hematoxylin and eosin and p16. Women were followed up according to screening protocols, with cytology or colposcopy at 6 or 12 months. CIN2/3 RRs and 95% confidence intervals (95%CI) were computed. Of 442 eligible women, 369 (83.5%) had at least one follow‐up episode. At baseline, 113 (30.6%) were CIN1, 248 (67.2%) negative, and 8 (2.2%) inadequate histology; 293 (79.4%) were p16‐negative, 64 (17.3%) p16 positive and 12 (3.2%) not valid. During follow up, we found ten CIN2 and three CIN3; of these, six were p16 positive (sensitivity 46%, 95% CI 19–75). The absolute risk among p16 positives was 9.4/100 compared to 1.7/100 of the p16 negatives (RR 5.5; 95% CI 1.7–17.4). The risk was also higher for CIN1 than for histologically negative women (RR 4.4; 95% CI 1.3–14.3). The RR for p16 in CIN1 did not change (RR 5.2; 95% CI 0.6–47.5). P16 overexpression is a good candidate for modulating follow‐up intensity after a negative colposcopy but is limited by its low prospective sensitivity.     

Evaluation of p16INK4a expression in ThinPrep cervical specimens with the CINtec p16INK4a assay

BACKGROUND.

The aim of this study was to examine p16^INK4a protein expression in ThinPrep (Cytyc Corporation, Marlborough, Mass) cervical specimens by using the CINtec p16^INK4a Cytology Kit (Dako, Glostrup, Denmark). The ability of this assay to accurately identify underlying high‐grade lesions was assessed by using follow‐up biopsies and comparing these results with Hybrid Capture 2 (Digene, Gaithersburg, Md) high‐risk HPV (hc₂) results.

METHODS.

Three hundred ninety‐eight residual ThinPrep samples were collected, and histological follow‐up data were retrieved for abnormal cytology specimens. After preparation of a Papanicolaou‐stained slide, a second slide was processed in preparation for p16^INK4a immunostaining. High‐risk human papillomavirus testing (hc₂) was also performed.

RESULTS.

Of the 163 cytologically abnormal samples, 6‐month biopsy follow‐up data were available for 45% of the specimens. At initial blinded evaluation, 21 of the 26 cases with cervical intraepithelial neoplasia (CIN) II/III follow‐up were positive for p16^INK4a, yielding an overall diagnostic sensitivity of 81%; 29 of the 47 cases diagnosed as CIN I or less were p16^INK4a negative, yielding a diagnostic specificity of 62%. In comparison, the hc₂ test results indicated a diagnostic sensitivity of 100% with a diagnostic specificity of 15%. After review of selected cases with CIN II/III follow‐up, 25 of 26 slides were deemed to be positive for p16^INK4a, increasing the diagnostic sensitivity to 96%.

CONCLUSIONS.

The CINtec p16^INK4a Cytology Kit, in combination with ThinPrep cervical samples, allowed clear evaluation of p16^INK4a protein overexpression. Diagnostic specificity of the CINtec p16^INK4a assay was significantly improved relative to hc₂. To increase p16^INK4a immunostaining in abnormal cells, a modified kit version with improved staining performance has been developed and is currently being evaluated. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.     

p16INK4a在宫颈液基细胞学辅助筛查中的标记意义

目的 评价p16INK4a在宫颈液基细胞学检查中的标记意义.方法 收集74例宫颈外口和颈管的脱落细胞标本,分别进行液基细胞学检测和p16INK4a免疫细胞化学染色,并应用杂交捕获二代法检测高危人乳头瘤病毒(HR-HPV)感染.结果 74例标本中,细胞学诊断未见癌细胞或癌前病变细胞(阴性)10例,意义不明的不典型鳞状细胞(ASC-US)15例,鳞状上皮内低度病变(LSIL)28例,不除外上皮内高度病变的不典型鳞状细胞(ASC-H)5例,鳞状上皮内高度病变(HSIL)11例,鳞状细胞癌(SCC)5例.各级别病变中,HR-HPV阳性者分别为1、4、3、9、7和5例,p16INK4a免疫细胞化学染色阳性者分别为2、5、3、8、9和5例.随着宫颈病变级别的上升,HR-HPV和p16INK4a免疫细胞化学染色阳性率均增高.结论 p16INK4a免疫细胞化学染色增强了对不典型细胞的区分能力,可以提高宫颈癌筛查的准确性.     

p16INK4a immunohistochemistry is a promising biomarker to predict the outcome of low grade cervical intraepithelial neoplasia: comparison study with HPV genotyping

Objective

In cervical intraepithelial neoplasia (CIN), p16^INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16^INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16^INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN.

Methods

p16^INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16^INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes.

Results

A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16^INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16^INK4a overexpression than for those not showing p16^INK4a overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16^INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively).

Conclusion

p16^INK4a overexpression was correlated with the outcome of CIN 1-2, and p16^INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping.     

p16INK4a免疫细胞化学检测在筛查宫颈癌中的作用

目的 探讨p16^INK4a免疫细胞化学检测在筛查宫颈癌及其癌前病变中的作用。方法 选择220例宫颈液基细胞学剩余标本,制作液基薄片进行p16^INK4a 免疫细胞化学检测,随访组织活检结果,并与高危人乳头瘤病毒（HR—HPV）DNA检测结果进行对照。结果 p16^INK4a在宫颈细胞学诊断的鳞状细胞癌（SCC）、鳞状上皮内高度病变（HSIL）、鳞状上皮内低度病变（LSIL）、非典型鳞状细胞-小除外上皮内高度病变（ASC—H）和非典型鳞状细胞-不能明确意义（ASC—US）病例的阳性表达率分别为100．0％（7／7）、92．2％（107／116）、24．3％（17／70）、100．0％（14／14）和36．4％（4／11）。150例p16^INK4a阳性者中,111例有组织活检诊断,其中宫颈上皮内瘤变（CIN）2级及以上病变者97例（87．4％）;70例p16^INK4a阴性者中,18例有组织活检诊断,无一例CIN2及以上病变。p16^INK4a在CIN2及以上病变与在CIN1之间的阳性表达率差异有统计学意义（P〈0.01）,而HR-HPV DNA的阳性率在两者之间差异无统计学意义。结论 p16^INK4a在宫颈HSIL及以上病变中高表达,有利于高危病例的筛选。     

高危型HPV分型和p16蛋白表达在宫颈病变诊断中的临床意义

目的:了解HPV高危型阳性的高级别鳞状上皮内瘤变(high-grade squamous intraepithelial lesion,HSIL)（CIN II-III）、慢性炎症及宫颈癌中HPV感染分型的不同分型和p16在不同组织中的表达情况,并分析其与HPV的相关性。方法:收集海南省人民医院就诊的海南籍宫颈疾病患者,其中包括HPV高危型阳性的HSIL患者100例、HPV高危型阳性慢性宫颈炎和宫颈癌患者各25例和HPV阴性慢性宫颈炎25例,收集宫颈病理组织,进行HPV分型和p16蛋白表达检测。结果:HPV高危型阳性宫颈病变中,检测出全部13种高危型亚型,主要为HPV16（16.67%）、HPV52（15.33%）、HPV58（12.67%）、HPV31（12.0%）,不同宫颈病变HPV分型结果具有高度统一性,差异不具有统计学意义（P=0.999）;HPV阴性慢性宫颈炎症组织、HPV高危型阳性慢性宫颈炎症组织、HSIL组织、宫颈癌组织中p16蛋白表达阳性率分别为12.0%、72.0%、84.0%、100.0%,不同宫颈病变p16蛋白表达差异具有统计学意义（P＜0.001）,随着宫颈病变的进展,p16蛋白表达逐渐增加,p16蛋白表达与宫颈病变的恶性程度具有正相关性。结论:海南籍宫颈病变患者其高危型HPV感染分型分布与目前研究一致,随着宫颈疾病进展加重, p16蛋白表达增加,HPV分型和p16蛋白联合检测对于诊断不同宫颈疾病具有重要价值。     

子宫颈癌及子宫颈上皮内瘤变组织中p16^INK4A的表达及其临床意义

目的探讨p16^INK4A蛋白在子宫颈癌及子宫颈上皮内瘤变组织中的表达及其临床意义。方法采用免疫组化法对62例子宫颈鳞癌、40例子宫颈上皮内瘤变（CIN）、30例慢性宫颈炎组织的p16州K4A表达及其临床意义进行比较分析。结果p16^INK4A在慢性子宫颈炎组织中的高表达率为100％（30／30），而在子宫颈癌组织中的高表达率为53．2％（33/62），子宫颈CIN组织中的高表达率为70．0％（28／40），p16^INK4A在后两组中的高表达率与慢性子宫颈炎组相比具有显著的统计学意义（P〈0．05，P〈0．005），而且P16^INK4A低表达与子宫颈癌的组织学级别高、淋巴结转移多和TNM分期晚显著相关。结论p16^NIK4A蛋白的表达与子宫颈癌的临床病理因素密切相关，可能是一个预测子宫颈癌预后的重要指标。     

p16^INK4a和p14^ARF蛋白在宫颈癌和肺癌中的差异表达

[目的]研究宫颈癌和肺癌中p16INK4a和p14ARF蛋白表达水平的差异及意义。[方法]应用免疫组化方法检测50例宫颈癌和127例肺癌组织中p16INK4a和p14ARF蛋白表达。[结果]50例宫颈癌中,p16INK4a和p14ARF蛋白全部阳性表达;127例肺癌中,p16INK4a和p14ARF蛋白阳性表达率分别为61.42%和30.79%;宫颈癌和肺癌中p16INK4a和p14ARF蛋白表达差异均有显著性（P〈0.01）。[结论]p16INK4a和p14ARF蛋白在宫颈癌中过表达,而在肺癌中缺失表达。提示p16INK4a和p14ARF蛋白在宫颈癌和肺癌的发生发展中所起的作用和作用机制可能不同。