宫颈癌发生中细胞凋亡与p53基因蛋白及HPV感染的相关性

目的探讨子宫颈癌发生中细胞凋亡与p53基因蛋白表达及高危型人乳头样病毒(HPV)感染的关系.方法检测对象为正常宫颈鳞状上皮(NE)41例、重度非典型增生(SD)41例、原位癌(CIS)37例、早期浸润癌(MIC)31例、大细胞非角化型浸润癌(IC)40例共计190例手术切除福尔马林固定、石蜡包埋的组织标本.凋亡细胞的检出使用TDT-mediateddUTP-biotinnickendlabeling(TUNEL)方法,p53基因蛋白表达采用单克隆抗体免疫组织化学ABC染色方法,HPV16、18型E6DNA感染使用PCR方法进行检测.结果TUNEL标记率从NE到CIS组呈现有意义地减少(P＜0.01);在SD、CIS组,p53基因蛋白超表达者TUNEL标记率呈现有意义的低值(P＜0.05);高危型HPV感染与宫颈癌的发生有关,与细胞凋亡、p53基因蛋白表达未呈现直接的相关性改变.结论细胞凋亡参与宫颈癌发生的早期过程,其与p53基因蛋白超表达有关.     

p53 gene mutation is rare in human cervical carcinomas with positive HPV sequences

Chromosome 17p allelic losses and concurrent p53 mutations have been demonstrated in various human cancers. We therefore investigated the presence of chromosome 17p allelic loss and possible concurrent p53 mutation in 29 Korean cases of cervical carcinoma by restriction fragment length polymorphism (RFLP) analysis and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) over the region from exon 4 to exon 9 of the p53 gene. We also examined the expression of p53 in paraffin tissues by immunohistochemical staining and determined the incidence of human papillomavirus (HPV) sequences in the same tissues by multitype PCR analysis to correlate them to the allelic loss on chromosome 17p13 and p53 mutation. In the analysis of 29 cases, loss of heterozygosity (LOH) was observed in eight (40%) cases out of 20 informative cases and p53 mutation was observed in only one case (3.4%) at exon 5. So in the majority of cases with LOH on 17p in this series, mutation of p53 gene appeared to be rare. But we obtained three cases (10.3%) of positive immunoreactivity from 29 cases. Those cases may carry mutations outside of the regions examined by PCR-SSCP. HPV DNA was detected in 27 of 29 cases (93.1%). HPV types 8, 11, 16, and 18 were detected in the samples we tested, while only two (7.4%) out of 27 HPV positive cases exhibited overexpression for p53 without any demonstrable p53 mutation upon PCR-SSCP. These results suggest that HPV infection may play a role in inactivating wild-type p53 protein in cervical carcinomas. In conclusion, mutation and overexpression of p53 gene appear to be rare, particularly in cases of cervical carcinoma associated with positive HPV sequence.     

HPV16 E6小干扰RNA与宫颈癌细胞中E6 p53 p21关系的研究

目的 探讨HPV16E6小干扰RNA（siRNA）与宫颈癌CaSki细胞中E6、p53、p21之间的关系。方法 2004年9月至2005年3月于四川大学华西第二医院,应用化学合成针对HPV16E6的siRNA借脂质体转染CaSki细胞,实时荧光定量逆转录-聚合酶链反应（RT-PCR）和流式细胞术检测E6siRNA转染前后细胞中HPV16E6、p53、p21mRNA及其蛋白表达的变化。结果 转染24h,E6mRNA的表达显著低于空白组（P〈0.05）。各时间点p53、p21mRNA的表达差异无显著性意义（P〉0.05）。转染48h,E6蛋白表达明显下调,p53、p21蛋白表达相应升高。结论 HPV16E6siRNA能特异、高效地沉默宫颈癌细胞E6mRNA的表达,减少对野生型p53的降解,恢复p53蛋白的功能活性。RNA干扰（RNAi）技术可为HPV感染相关性疾病提供一种新的特异性基因治疗方法。     

Risk assessment and clinical impact of liquid-based cytology, oncogenic human papillomavirus (HPV) DNA and mRNA testing in primary cervical cancer screening (the FASE study)

Objective

New commercial HPV RNA assays require further validation studies in population-based cervical cancer screening settings.To assess the performance of (FDA-approved) APTIMA® HPV Assay (AHPV), Hybrid Capture 2 (HC2), in-house PCR genotyping, and ThinPrep LBC in population-based screening, stratified by three histological gold standards.

Study design

A multi-center trial in 5006 women undergoing routine screening in France was designed to compare the absolute and relative risks of diagnosing CIN3 + and CIN2 + lesions by different diagnostic tests.

Results

Reproducibility between the primary and second pathology reading was excellent for CIN3 + and CIN2 + endpoints (Cohen's kappa 0.948 and 0.854). Absolute risks (PPV) of different tests (AHPV, HC2, PCR genotyping, LBC) in diagnosing CIN2 + (15-20%) and CIN3 + (4-6%) were similar for the first, second, and consensus pathology readings. The relative risks of diagnosing these lesions by the four tests were also similar when the first, second or third pathology readings were employed. AHPV had the highest absolute risk of both histological endpoints, and detects 5% to 15% more CIN3 + and CIN2 + lesions, respectively, than LBC. Compared with HC2 assay, the relative risk of AHPV is 24% to 29% higher, with a significant difference in CIN2 + detection. With LBC as reference, AHPV had the best sensitivity/specificity balance measured by AUC (area under ROC curve) comparison test (significant for CIN2 +), and the colposcopy referral rate (9.2%) comparable to that of LBC (8.7%).

Conclusions

These data corroborate the suitability of AHPV for the primary cervical cancer screening.     

Clinical implications of the interaction between HPV and HIV infections

HIV-related immunodeficiency has complex effects on female genital HPV, which include increased risks of infection, multiple types, persistence, reactivation and the risk to develop pre-invasive and invasive disease.Reconstitution of immunity with anti-viral drugs improves cellular immunity, but the risk of HPV-related malignancy remains higher than background incidences and presents at younger ages. Early initiation of antiretroviral therapy (ART) allows improved retention of immune memory through existing antibodies and T-cell clones and improves long-term outcomes.Suggestions of a higher risk to contract HIV if there is existing genital HPV infection are supported and explained by pathophysiological cervical changes, including inflammation.HIV–HPV interactions should influence public health decisions towards prioritising large-scale prepubertal HPV-vaccine roll-out, secondary cervical cancer prevention and early detection programmes for HIV-infected women and early initiation of ART.This chapter will also focus on special considerations for the management of women with co-infection with these two viruses and genital HPV-related diseases.     

Diagnosis of cervical intraepithelial neoplasia and human papillomavirus infection: punch biopsy versus cervical smear

Summary In 102 patients referred to our colposcopy clinic because of one to three Papanicolaou smears indicating cervical intraepithelial neoplasia (CIN) and/or abnormal colposcopy, routine smears and colposcopically directed punch biopsies were taken simultaneously. For detection and typing of human papillomavirus (HPV)-DNA in situ hybridization was performed in all biopsies and in 46 of the cervical smears. In cases of dysplastic lesions the number of HPV 16/18 (40.5%) and 31/33 (42.9%) was markedly higher than HPV 6/11 (16.6%) infection rate. In cases where simultaneous in situ hybridization in biopsy specimen and cervical smears was performed 21.7% showed a HPV negative smear and a positive biopsy, in 6.5% the results were the other way round. In 34.9% of cases with CIN I and 9.5% of cases with CIN II verified by punch biopsy the cytological smear did not indicate dysplasia. Our data show that mild and moderate CIN lesions of the cervix as well as HPV infection are detected more frequently by a combination of cervical smear and colposcopically directed punch biopsy than by cervical smear alone.     

Predictive value of HPV DNA in lymph nodes in surgically treated cervical carcinoma patients--a prospective study

OBJECTIVE: High-risk types of HPV are etiological factors in cervical cancer. Lymph node involvement in cervical cancer patients reduces 5-year survival rates by 25-60%. However, the influence on survival of HPV DNA positivity in histopathologically negative lymph nodes remains unresolved. METHODS: The study included 116 of 148 patients who underwent Piver type III radical hysterectomy and pelvic lymphadenectomy and who showed HPV DNA positivity in the primary lesion. Lymph node tissues were tested for the presence of HPV DNA, using a PCR technique. RESULTS: We found the presence of HPV DNA sequences in lymph nodes dissected intraoperatively in 81 (69.83%) cases. In analysis, we compared patients from 3 groups: HPV- and metastatic-negative (LN HPV-M-); HPV-positive metastatic-negative (LN HPV+M-); and metastatic-positive (LN M+). We discovered that survival in groups LN M+ and LN HPV+M- did not differ statistically (p=0.37). However, the survival periods in these two groups differed when compared with LN HPV-M- patients (p<0.001). Using Cox's proportional hazards model, we found that the presence of lymph node HPV DNA, and FIGO stage, and primary lesion volume were independent parameters correlating with survival and mortality risk. CONCLUSION: We conclude that the presence of HPV DNA in lymph nodes is an early sign of metastasis and should be treated as such in prognostic outlook and planning the therapeutic strategy.     

Cadherins, catenins and cell cycle regulators: impact on survival in a Gynecologic Oncology Group phase II endometrial cancer trial

Objective

We evaluated the clinical relevance of catenins, cadherins and cell cycle regulators in stage IV or recurrent endometrial carcinoma in a multi-center phase II trial (GOG protocol #119).

Methods

Tissue microarrays of metastatic or recurrent (n = 42) tumor were developed and immunohistochemistry was performed. Average expression (percent staining x intensity) was assessed in tumor epithelium (^E) and stroma (^S) and categorized into tertiles (T1, T2, T3) for E-cadherin^E, N-cadherin^E, alpha-catenin^E, beta-catenin^E, gamma-catenin^E, p120-catenin^E and Ki-67^E; as negative, below median or above median for p16^E, p27^E and CD44^S; or as negative or positive for p53^E, Ki-67^S and APC^S (adenomatous polyposis coli). End points included response and survival.

Results

E-cadherin^E, p16^E, and p53^E varied by race (p = 0.003, p = 0.024, p = 0.002,) and N-cadherin^E, Ki-67^E, p16^E and p27^E by tumor type (p = 0.015, p = 0.011, p = 0.005, p = 0.021). Correlations were observed among E-cadherin^E with p120^E (r = 0.66), p53^E (r = − 0.32), alpha-catenin^E (r = 0.52), beta-catenin^E (r = 0.58), and gamma-catenin^E (r = 0.58). High E-cadherin^E (T2 or T3) versus low (T1) expression was associated with better survival in unadjusted (hazard ratio [HR] = 0.14, 95% confidence interval [CI] = 0.06–0.37 or HR = 0.17, 95% CI = 0.07–0.42) and adjusted models (HR = 0.18, 95% CI = 0.05–0.59 or HR = 0.22, 95% CI = 0.07–0.70). High p16^E versus negative expression was associated with worse survival in unadjusted (HR = 3.87, 95% CI = 1.74-8.61) and adjusted (HR = 4.18, 95% CI = 1.28–13.6) models. Positive versus negative expression of p53^E was associated with worse survival in unadjusted (HR = 2.31, 95% CI = 1.16–4.60) but not adjusted models.

Conclusions

E-cadherin^E and p16^E appear to be clinically relevant, independent prognostic factors in stage IV or recurrent endometrial cancers treated with Tamoxifen and Medroxyprogesterone acetate, and merit further study.     

The value of p16ink4a expression by fluorescence in situ hybridization in triage for high risk HPV positive in cervical cancer screening

Objectives

The aim of this study is to evaluate the effect of fluorescence in situ hybridization (FISH) detection for p16ink4a expression as an alternative triage for high risk HPV positive women in cervical cancer screening.

Methods

Totally 191 cervical cell specimens from women with HPV positive were collected. The p16ink4a expression by FISH and liquid-based thin-layer cytology was performed and followed by colposcopy with or without biopsied histologic examination for all participants. The relationship between p16ink4a expression and histologic diagnosis, as well as cytology was analyzed.

Results

The positive rate of p16ink4a was 5.35% in normal or inflammation cases, 56.67% in CIN 1, 83.78% in CIN 2-3, 100.00% in carcinoma, respectively, with a significance between < CIN2 and ≥ CIN 2 (P < 0.001). The p16ink4a expression presented a concordance trend as cytology grading, with a positive rate of 9.28% in NILM, 33.33% in ASCUS, 53.37% in LSIL, 81.25% in ASC-H, and 95% in HSIL, respectively. Compared with cytology, FISH detection for p16ink4a had a higher accuracy (84.8% vs. 74.34%), higher sensitivity (87.75% vs. 52.00%) and similar specificity (83.84% vs. 88.79%) for predicting ≥ CIN 2 lesions.

Conclusions

FISH detection specific to p16ink4a presents a high consistency with cytologic grading and has a higher accuracy for predicting high grade CIN than cytology in high risk HPV positive women. Our findings suggest that FISH detection for p16ink4a is a potential alternative triage for high-risk HPV positive women in cervical cancer screening.     

长期放置含铜IUD与ras、p53基因突变及HPV感染的关系

目的:探讨长期(5年以上)放置含铜宫内节育器(intrauterinedevice,IUD)与宫颈细胞ras、p53基因突变及人乳头瘤病毒(Humanpapillomaviruses,HPV)感染的关系。方法:采集宫颈脱落细胞学液基标本,采用伯塞斯达系统(thebethesdasystem,TBS)诊断标准行宫颈细胞病理学诊断;采用PCR-SSCP技术检测标本中H-ras、p53基因的表达;采用FQ-PCR技术检测肿瘤相关HPVDNA含量。结果:H-ras及p53基因表达在各组中均无改变;含铜IUD组中HPV6/11型阳性率为3.33%,DNA含量为8.80×107copy/ml,对照组中HPV6/11型阳性率为3.70%,DNA含量为6.75×107copy/ml,两组相比差异无统计学意义(P>0.05)。两组HPV16/18型均为阴性。结论:长期放置含铜IUD(带尾丝)对子宫颈无致突变作用,不增加肿瘤相关HPV感染,不增加子宫颈病变的发生率。     

Sequence variations of the late upstream region of HPV16 in cervical intraepithelial neoplasm and invasive carcinoma

Abstract. Pang T, Hu X, Ponten J. Sequence variations of the late upstream region of HPV16 in cervical intraepithelial neoplasm and invasive carcinoma.
HPV16 is the most common type of human papillomavirus (HPV) seen in cervical squamous cell carcinoma. A 78-bp promotor element at nt 4118–4196 called late upstream region (LUR), critical for the expression of late genes, has been identified recently. Late genes encode viral capsid proteins that coat viral DNA to form particles and serve as antigen. To elucidate whether there are any sequence variations within LUR of HPV16 and any difference of these sequence variations between cervical invasive squamous cell carcinoma (CIC) and cervical intraepithelial neoplasia (CIN), we sequenced HPV16 LUR from 50 cases of HPV16-positive CIC and CIN. We found that variation frequency in the late upstream region ranged from 0 to 4.2 except for two cases in which variation frequency was as high as 22.8%. Eight of 24 CINs and 17 of 26 CICs contained two or more variations (33% vs. 65%, P < 0.025). The results suggested that the sequence variations occurred more often in LUR of HPV16 than in other regions of HPV16 and the variations in HPV16 LUR might play a role in the process of carcinogenesis of cervical carcinoma.     

Clinical validation of high risk HPV DNA testing versus ThinPrep cytology for primary cervical cancer screening

Objective(s)To compare the validity of the high risk HPV DNA testing using the hybrid capture II technique (HC-II) to ThinPrep cytology for primary cervical cancer screening.DesignCross sectional pilot study.SettingDepartment of Obstetrics and Gynecology, Taiba Hospital, Sabah Al Salem, Kuwait.MethodsConsecutive 1923 cervical smear samples were taken for ThinPrep cytological screening and hr-HPV DNA testing using HC-II assay. Histological diagnoses were obtained from a total of 426 women who had positive results on screening and a group of women with negative screening and suspicious cervix underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment.Main outcome measuresSensitivity, specificity, positive predictive value and negative predictive value of screening methods.ResultsHPV was found positive in 15.5% of cases. 19/22 cases (86.4.1%) with a biopsy diagnosis of CIN2+ had a HC-II positive test. For CIN3, HC-II was positive in all cases (100%). Assuming a similar specificity level, the relative sensitivity of the HC-II test was higher when histologically confirmed high grade lesions (CIN2+ or CIN3+) were observed. HC-II test had the best sensitivity when defining cases as CIN2+ or CIN3+ (98.7% and 100%, respectively). When using the ASCUS+ cytological cutoff, the differences in CIN2+ and CIN3+ sensitivity between HC-II test and ThinPrep cytology were statistically not significant. Specificity of the ThinPrep cytology for any low and high grade histological lesions was clearly >95% when cytological diagnosis LSIL+ cutoff was used and nearly 100% when HSIL+ cutoff was used. All these specificity estimates were high compared with HC-II test. The specificity of the ThinPrep cytology decreased with about 10% when ASCUS+ was the cutoff. At cutoff ASCUS+, specificity of HC-II was comparable or only slightly lower than with ThinPrep ASCUS+ cytology with no statistically significant differences.ConclusionsThinPrep smears and hr-HPV DNA detection by HC-II performed very well with regard to identifying high grade lesions. HPV DNA testing is a promising new technology for cervical cancer prevention and can be used for primary screening in conjunction with cervical cytology for women aged 30 years and older.     

HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities

OBJECTIVE: To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities. METHODS: Autologous monocyte-derived DC were pulsed with recombinant HPV16 E7 or HPV18 E7 oncoproteins and administered to 4 cervical cancer patients. Vaccinations were followed by subcutaneous administration twice daily of low doses of human recombinant interleukin-2 (1 x 10(6) IU/m2) from day 3 to day 7. Safety, toxicity, delayed type hypersensitivity reactions (DTH), clinical responses, and induction of serological and cellular immunity against HPV16/18 E7 were monitored. RESULTS: The vaccine was well-tolerated in all patients and no local or systemic side effects or toxicity were recorded. Three out of four patients were found to be significantly immunocompromised before starting the vaccination treatment, as assessed by DTH with a panel of recall antigens. Specific humoral and cellular CD4+ T cell responses to the E7 vaccine were detected in 2 patients, as detected by ELISA and by IFN-gamma ELISpot assays, respectively. Increased numbers of E7-specific IFN-gamma secreting CD8+ T cells were detected in all patients after vaccination. Swelling and induration (i.e., a positive DTH response) to the intradermal injection of HPV E7 oncoprotein and/or irradiated autologous tumor cells were detected in two patients after six vaccinations. No objective clinical responses were observed. However, both patients who developed a positive DTH to the vaccine experienced a slow tumor progression (i.e., 13 months survival) while DTH unresponsive patients died within 5 months from the beginning of therapy. CONCLUSIONS: Autologous DC pulsed with HPV16/18 E7 proteins can induce systemic B and T cell responses in patients unresponsive to standard treatment modalities. However, treatment-induced immunosuppression may impose severe limitations on the efficacy of active vaccination strategies in late stage cervical cancer patients. DC-based vaccination trials are warranted in immunocompetent cervical cancer patients with early stage disease and/or limited tumor burden, and at significant risk for tumor recurrence or disease progression.     

人宫颈鳞癌和宫颈上皮内瘤变组织内HPV16 DNA及p53基因变异的研究

目的 本文采用常规PCR技术对40例宫颈鳞癌组织学标本和200例宫颈上皮内瘤变（CIN）Ⅰ～Ⅱ级的宫颈分泌物标本的HPV16 DNA及P53基因5～6，7～8外显子变异进行了研究，方法 采用常规PCR技术检测HPV16 DNA和p53基因及免疫组织化学方法检测P53基因。结果 在40例宫颈鳞癌标本中HPV16 DNA阳性检出率有20例（50％）；200例CIN标本中有76例（38％）。P53基因在40例宫颈鳞癌标本中有20例出现变异（50％），其中外显子5缺失10例（50％），外显子6缺失1例（5％），外显子7缺失3例（15％），外显子8缺失6例（30％）。200例CIN标本均未检出p53外显子5～6，7～8的变异，宫颈鳞癌HPVl6DNA阳性与p53基因变异的符合率为80％。结论HPVl6I）NA与宫颈鳞癌的发生有密切的相关性，p53基因在宫颈鳞癌组织中确实存在着变异。本研究认为常规PCR技术作为辅助诊断方法是一种快速、简单、适用于临床的方法。     

子宫颈上皮癌变过程中Ki67表达和HPV感染的研究

目的 研究Ki67表达和HPV感染在宫颈癌发生发展过程中的意义。方法 分别从正常宫颈(10例)、各级CIN(CIN Ⅰ19例,CIN Ⅱ9例,CIN Ⅲ16例)和宫颈鳞癌(8例)的石蜡标本提取基因组DNA,选取HPV L1区通用引物进行PCR扩增,测序,与已知HPV序列进行同源性分析。Ki67免疫组化染色。结果 正常宫颈组HPV DNA均为阴性。CIN Ⅰ组5/19例为高危型HPV(16/18型),8/19例为中危型(35型等),其余为低危型。CINⅡ和Ⅲ组高危和中危型HPV各占一半。宫颈癌组均为高危型,绝大部分为HPV16。Ki67指数随CIN级别的升高(CINⅠ:21.4±1.1,CINⅡ:31.8±3.5 CINⅢ:61.3±2.8)而明显增加(P<0.01)。结论Ki67指数反映出在宫颈上皮细胞癌变过程中细胞增殖活性的改变。HPV型别与CIN级别及转归密切相关。Ki67与HPV检查联合应用对评价CIN细胞增殖活性及其转归有重要的作用,对伴有HPV16/18 感染的CIN应密切追踪和积极处理。     

阴道微生态变化与宫颈人乳头瘤病毒感染及相关病变的关系

阴道微生态的变化或失调会导致阴道炎症的发生,阴道p H值是评价阴道微生态方便、快捷的指标。阴道p H升高时,宫颈HPV感染显著增加,多型别HPV感染率也增加,并且宫颈及阴道HPV感染引起的宫颈低度鳞状上皮内病变(LSIL)发生率升高。BV是最常见的阴道感染,其明显增加了宫颈HPV的感染风险;性传播性疾病病原体引起的感染(STI)的女性宫颈HPV感染的发生率较高;有研究提示,阴道假丝酵母菌感染、阴道滴虫感染与HPV感染无明显相关性。常见的阴道感染对宫颈病变的影响无肯定结论。     

Immune response to p53 and HPV-16 E6 proteins in patients with cervical cancer

Park JS, Kim CJ, Um SJ, Hwang ES, Kim HS, Park SN, Namkoong SE, Kim SJ. Immune response to p53 and HPV-16 E6 proteins in patients with cervical cancer. Int J Gynecol Cancer 1998; 8 : 328–335.
To investigate whether p53 autoantibodies could be found in the sera of patients with cervical cancers, we have therefore studied by radioimmunoprecipitation assay, using in vitro translated p53 protein, sera from such patients. The sero-positive patients for p53 were also evaluated in relation to immunoreactivity to p53 antigens by immunohistochemistry, for genomic alterations of p53 by PCR-SSCP, and for the presence of HPV-16/18 DNAs in the cervical cancer cells. In immunohistochemistry, expression of p53 protein was seen in 47% (14/30) of HPV-16 or -18 positive cervical cancers and 13 % (2/15) of HPV-16/18 negative cervical cancers ( P < 0.01). Eight out of 12 control ovarian cancers (67%) showed positive p53 staining in most tumor cells. Cases of cervical cancer and ovarian cancer, which were positively expressed p53 protein in the tissue or the sera, were studied for genomic alterations in exons 5–8 of the p53 by PCR-SSCP. Serum antibodies to in vitro translated p53 protein were found in two cases from 63 cervical cancers; one patient was stage IIA, having HPV-16 DNA in a tumor of squamous cell type, and another patient was stage IIIB, having HPV-16 and -18 DNAs in an adenocarcinoma. The cervical cancer tissues from the two sero-positive patients were also positive for p53 immunostaining. None of the cervical cancer samples showed aberrant bands, but three of eight cases of ovarian cancer which were positive for p53 protein by immunostaining were shown to have aberrant bands by PCR-SSCP. In contrast to ovarian cancers, alteration of p53 tumor suppressor gene and positive antibody response to p53 protein seem to be rare events in patients with cervical cancer.     

Verification of HPV16 as a good prognostic factor for cervical adeno-adenosquamous carcinoma via an international collaborative study

ObjectiveThis study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent good prognostic factor and investigate the impact of treatment modalities to cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC).Materials and methodsPatients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were retrospectively (1993–2014) and prospectively (since 2014) enrolled. DNA extraction from paraffin-embedded tissue (FFPE) specimens was used for HPV genotyping. Those with suspected endometrial origin were excluded for analysis.ResultsA total of 354 patients with valid HPV results were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types were HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). The HPV16-negativity rates varied widely across hospitals. 322 patients were eligible for prognostic analyses. By multivariate analysis, advanced stage (HR5.8, 95% confidence interval [CI] 2.1–15.8; HR5.8, 95% CI 1.6–20.5), lymph node metastasis (HR4.6, 95% CI 2.7–7.9; HR7.3, 95% CI 3.8–14.0), and HPV16-positivity (HR0.3, 95% CI 0.1–0.6; HR0.3, 95% CI 0.1–0.9) were independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Stage I patients with primary surgery had better 5-year PFS (82.8% vs 50.0% p = 0.020) and OS (89.3% vs 57.1%, p = 0.017) than those with non-primary surgery, while the propensity scores distribution were similar among the treatment groups.ConclusionThis study confirmed that HPV16-positivity was a good prognostic factor for PFS and OS in AD/ASC, and patients seemed to have better outcome with primary surgery than non-primary surgery.     

HPV L1壳蛋白联合HR-HPV分型、TCT检测对宫颈癌前病变及宫颈癌的诊断价值分析

目的探究人乳头瘤病毒L1(HPV L1)壳蛋白联合高危型HPV(HR-HPV)分型、液基薄层细胞学(TCT)检测对宫颈癌前病变及宫颈癌的诊断价值。方法选取2018年5月至2020年2月在西安交通大学第一附属医院接受宫颈癌筛查的妇女1094例为对象,以组织病理学检查结果进行分组,比较各组HPV L1壳蛋白表达水平、HR-HPV和TCT检测阳性率。结果TCT检测阳性率与HR-HPV阳性率存在明显差异(P<0.05)。组织病理学检查,共检出正常或炎症179例(对照组)、CIN 1组26例、CIN 2组44例、CIN 3组40例和宫颈癌组21例,宫颈癌组的TCT检测阳性率和HR-HPV阳性率最高,HPV L1壳蛋白表达水平最低(P<0.05)。HPV L1壳蛋白联合HPV分型、TCT检测诊断宫颈癌前病变及宫颈癌的AUC值分别为0.897和0.804(P<0.05)。结论HPV L1壳蛋白、HPV分型和TCT检测在宫颈癌前病变及宫颈癌的诊断中具有一定的临床价值。