Possible prognostic significance of human papillomavirus type in cervical cancer

While several different human papillomaviruses (HPV) have been associated with cancer of the cervix, it is yet to be determined if specific HPV types have clinical or prognostic significance. To address this question, 30 cases of invasive carcinoma (squamous carcinoma, adenosquamous carcinoma, and adenocarcinoma) with HPV DNA sequences detectable in the tissue were analyzed. HPV type was determined by Southern blot DNA hybridization. Clinical information was obtained by chart review, and all biopsy and surgical specimens were reviewed microscopically without knowledge of HPV type. HPV 16 was detected in 14 cases, HPV 18 in 6, and HPV 31 in 2. In eight samples there were distinctly different, but as yet uncharacterized, HPV DNAs. Of the factors evaluated, tumor grade was found to have a statistically significant relationship to HPV type. Eighty-three percent of HPV 18-associated tumors were grade 3 tumors (5 of 6) as compared to only 7% of HPV 16-associated tumors (1 of 14) (P = 0.002). Age at diagnosis and nodal status in relation to HPV type exhibited a trend but were not statistically significant. The mean age of the HPV 18 group was 37 years, compared to 49 years for the HPV 16 group. Similarly, among Stage IB cancers, nodal involvement was associated with 60% of HPV 18 cases (3 of 5) as compared with 36% of HPV 16 cases (4 of 11). These observations suggest that HPV 18 may be associated with a more aggressive form of cervical cancer than other HPV types.     

Clinical significance of serum human papillomavirus DNA in cervical carcinoma

OBJECTIVE: To study the association between serum human papillomavirus (HPV) deoxyribonucleic acid (DNA) and clinicopathologic prognostic factors and the clinical usefulness of serum HPV DNA in early-stage cervical cancer. METHODS: Deoxyribonucleic acids extracted from cervical tissues and sera of patients with stage IB or IIA cervical cancer and 40 controls including patients with cervical carcinoma in situ or benign disease were examined for HPV DNA with L1 consensus and types 16- and 18-specific E7 primers. Multivariable logistic regression was used to determine significant correlates of positive serum HPV DNA, and the receiver operating characteristic curve was applied in risk-factor assessment. RESULTS: Human papillomavirus DNA was not detected in sera from patients with carcinoma in situ or benign disease. Among the 112 patients with cervical cancer, we detected 27 positive samples (24.1%) in serum. Positive HPV DNA in serum was significantly associated with lymphovascular invasion and deep stromal invasion with or without parametrial extension (P <.001 for both conditions), pelvic lymph nodal metastasis (P =.001), large tumor size, and elevated levels of serum squamous cell carcinoma antigen (P <.001 for both conditions). When serum HPV DNA was used to predict high-risk patients who require adjuvant therapy, a sensitivity of 45.2%, a specificity of 88.6%, a positive predictive value of 70.4%, and a negative predictive value of 72.9% were obtained. CONCLUSION: The presence of serum HPV DNA in patients with early-stage cervical cancer was correlated with poor prognosis factors that warrant adjuvant therapy.     

不典型鳞状细胞的临床意义及HPV检测的分流作用

目的　探讨不典型鳞状细胞(ASC)的临床意义、进一步处理措施以及HPV检测的分流作用。方法　对宫颈细胞学诊断为ASC的12 6例患者,分别进行阴道镜检查、宫颈组织学检查及HPV检测。结果　细胞学检查中不能明确意义者7 94 % ,倾向于良性反应性改变者74 6 0 % ,倾向于上皮内瘤变者17 4 6 % ;②阴道镜下,倾向于良性反应性者多表现为正常转化区(44 6 8% ,P <0 0 0 5 ) ,倾向于上皮内瘤变者,以醋酸白色上皮最多见(36 36 % ) ,但与其余各种阴道镜表现比较,差异无统计学意义;③宫颈组织学检查发现宫颈癌4例(3 17% ) ,高度病变8例(6 35 % ) ,高度病变及宫颈癌均出现于倾向于上皮内瘤变一组。④HPV的检出率随病变程度的加重而上升(P <0 0 0 5 )。结论　对于ASC患者必须要有足够的重视,对其中不明意义的、倾向于上皮内瘤变者或HPV检测阳性患者建议行阴道镜检查,其余可用宫颈细胞学随访。     

人乳头瘤病毒L1壳蛋白在筛查宫颈鳞状上皮内病变中的应用

目的:探讨人乳头瘤病毒(HPV)L1壳蛋白筛查HPV阳性妇女宫颈脱落细胞中宫颈鳞状上皮内病变的应用价值。方法:选取2012年5月至2014年12月就诊于温州市人民医院的妇女212例,收集宫颈脱落细胞并行HPV L1壳蛋白检测、HPV DNA分型、TCT(液基细胞学)及阴道镜下活检,比较HPV阳性妇女的宫颈脱落细胞中HPV L1壳蛋白的表达情况。结果:212例细胞学标本中HPV L1壳蛋白阳性率为33.9%,其中未见上皮内病变/恶性细胞组(NILM)、无明确诊断意义的鳞状上皮细胞病变组(ASCUS)、低度鳞状上皮内病变组(LSIL)、不能排除高度鳞状上皮内病变组(ASC-H)、高度鳞状上皮内病变组(HSIL)中阳性率分别为47.1%、35.1%、54.2%、29.2%、16.1%,各组比较差异有统计学意义(P0.05);两两比较,HSIL组与LSIL组和NILM组比较,差异均有统计学意义(P均0.005);进行数据合并后,LSIL/ASCUS组与ASC-H/HSIL组比较差异有统计学意义(P=0.001)。178例宫颈细胞学异常患者中,宫颈低级别病变和宫颈高级别病变的HPV L1壳蛋白阳性率比较,在ASCUS组(P=0.000)、LSIL组(P=0.004)中均有差异,在ASC-H组(P=0.127)、HSIL组(P=0.515)中均无差异。HPV 16/18感染患者的HPV L1壳缺失同宫颈高级别病变有更紧密的关系(P=0.003)。结论:子宫颈脱落细胞HPV L1壳蛋白检测在HPV阳性妇女的子宫颈病变筛查中具有一定的价值,可能成为一种合适的分流方法。     

Evaluation of antibodies to human papillomavirus as prognostic markers in cervical cancer patients

OBJECTIVES: We wished to evaluate whether the presence of antibodies to HPV or to the HPV oncoproteins E6 and E7 or type of HPV DNA is related to prognosis among cervical cancer patients. METHODS: Blood samples were drawn from 313 patients with incident, untreated cervical cancer on admission to two hospitals in Sweden. Patients were followed from enrollment in 1984-1991 until death or up to June 1999. Clinical information was obtained from a review of medical records. Survival and cause of death were ascertained from both medical records and population-based cancer registries. The correlation of survival with antibodies to HPV16, to oncoproteins E6 and E7, and to type of HPV DNA was evaluated using multivariate Cox regression analysis, including stage, age, histology, and hospital in the model. RESULTS: Stage was the only significant prognostic factor influencing cervical cancer patient survival (OR = 3.62, 95% CI = 2.71-4.83). Age over 50 was associated with increased death rate among stage I-IIa patients (OR = 2.29, 95% CI = 1.12-4.68). Presence of antibodies to the oncoproteins E6 and E7 or to the HPV16 capsid or type of HPV DNA did not associate significantly with disease prognosis. CONCLUSIONS: Antibodies to HPV16 capsids and to oncoproteins E6 and E7 or type of HPV DNA do not appear to be useful as indicators of cervical cancer prognosis.     

人乳头瘤病毒检测在宫颈疾病诊断中的意义

目的探讨人乳头瘤病毒（human papillomavirus，HPV）联合宫颈液基细胞学（thin-prep cytology test，TCT）检测在宫颈病变诊断中的临床意义，以及HPV负荷量与宫颈病变程度的相关性。方法对我院妇科2350名患者行宫颈TCT和高危型HPV检测。结果①HPV高危阳性患者共895例，阳性检出率为38．09％，TCT结果正常组内：正常、轻度炎症、中度炎症、重度炎症HPV阳性率分别为17．06％、28．30％、36．43％和30．30％；②TCT结果为正常组、ASCUS、ASC—H、LSIL、HSIL中，HPV阳性率分别为27．60％、52．30％、61．31％、86．11％、91．25％。③将HPV负荷量由低至高行数量分级后，TCT异常率分别为12．92％、25．93％、41．38％、50．52％和65．74％。结论在TCT异常者中，病变程度越高，高危型HPV感染率越高。随着病毒负荷量增加，宫颈病变发生，率增加，其病变程度也越重。     

Human papillomavirus status in advanced cervical cancer: predictive and prognostic significance for curative radiation treatment

Human papillomavirus (HPV) infection plays a major role in oncogenesis of squamous cell carcinoma of the cervix. This study was performed to investigate if HPV status and E2 gene integrity are prognostic parameters for clinical outcome and predictive for radiation response. Forty women with locally advanced cervical cancer treated with curative radiotherapy were analyzed for HPV infection and E2 gene integrity by multiplex polymerase chain reaction. Statistical analyses were performed for overall survival, disease-free survival (DFS), local progression-free survival, and treatment response (clinical complete remission). Twenty-eight (70%) of 40 carcinomas were HPV positive. The only significant factor for a better overall survival, DFS, and local progression-free survival was HPV positivity (P < 0.02, P= 0.02, and P < 0.05, log-rank, respectively). HPV-positive tumors had a significantly better clinical complete remission (67% vs 33%, P= 0.04, Fisher's exact test). An intact E2 gene region showed a trend for a better DFS (P= 0.1, log-rank). This study reveals HPV as an independent prognostic parameter for outcome and radiation response. Integration of the virus genome into host cell DNA might be a molecular target to determine the treatment response of HPV-positive cancers.     

Clinical and prognostic significance of concanavalin-Ainduced suppressor cell activity in malignant cervical neoplasia

Summary. Peripheral blood lymphocytes from patients with different stages of cancer of the uterine cervix were analysed for concanavalin-A induced suppressor cell activity. All cancer patients had high levels of suppressor activity, the increase corresponding to tumour load. Radiotherapy resulted in further increase of suppressor activity. About six months after radiotherapy, patients who remained disease free returned to pretreatment levels of suppressor cell activity and later showed even lewer levels of suppression. On the other hand, patients who developed recurrent disease maintained sustained high levels of suppression and for all stages they always had higher suppressor activity than the patients who remained disease free in the corresponding stage. These results stress the importance of a possible deranged immune system in these patients and also shows the clinical and prognostic significance of the assay.     

Clinical and prognostic significance of concanavalin-A-induced suppressor cell activity in malignant cervical neoplasia

Peripheral blood lymphocytes from patients with different stages of cancer of the uterine cervix were analysed for concanavalin-A-induced suppressor cell activity. All cancer patients had high levels of suppressor activity, the increase corresponding to tumour load. Radiotherapy resulted in further increase of suppressor activity. About six months after radiotherapy, patients who remained disease free returned to pretreatment levels of suppressor cell activity and later showed even lewer levels of suppression. On the other hand, patients who developed recurrent disease maintained sustained high levels of suppression and for all stages they always had higher suppressor activity than the patients who remained disease free in the corresponding stage. These results stress the importance of a possible deranged immune system in these patients and also shows the clinical and prognostic significance of the assay.     

Phenotypic features with p53 alterations related to human papillomavirus and prognostic evaluation in cervical cancer

Cervical cancer is one of the most common tumor affecting women worldwide. Human papillomavirus (HPV) was found to have a causal relationship with cervical cancer and its precursors. The interaction between HPV E6 protein and p53 was identified in in vitro studies. The aim of the study was to evaluate the prevalence of p53 alterations related to HPV infection and the prognostic significance of p53 alterations in cervical cancer. Studies were identified by a MEDLINE search, and all relevant articles were retrieved from 1991 to March 2004. The prevalence of p53 mutations is a rare event in cervical cancer. The correlation between p53 mutations and HPV or prognosis is controversial. Loss of heterozygosity (LOH) of p53 is more commonly found in cervical cancer and is related with the prognosis of this disease. There is no significant correlation between p53 polymorphism and development of cervical cancer. The p53 mutations were not commonly found in cervical cancer. LOH of p53 may contribute to the progression of this malignancy. p53 polymorphism failed to be an independent prognostic factor in predicting the outcome of patients with cervical cancer. Further, epidemiologic surveys should be undertaken in larger populations and in different geographical regions.     

The evaluation of human papillomavirus DNA testing in primary screening for cervical lesions in a large Japanese population

To examine the utility of human papillomavirus (HPV) DNA testing for the screening of cervical cancer and its precursors, a prospective cohort study was performed in which a total of 8156 women with a median age of 36 years were enrolled. Two smear samples scraped from the uterine cervix were served for Papanicolaou test and HPV DNA testing (Hybrid Capture-II system). HPV-positive samples were further examined for HPV subtype using a DNA microarray chip. Women with cytologic abnormality or those with high-risk HPV DNA were further examined by colposcopy to determine histologic diagnosis. High-risk HPV DNA was detected in 11% of the general population, with higher prevalence of specific types, including 52, 16, 58, 51, 56, and 18. As expected, younger women were likely to have increased frequency of HPV infection. Notably, HPV DNA testing detected all 45 cases of cervical intraepithelial neoplasia (CIN) 3, while cytologic findings were negative in 6 of these cases. It is of particular interest that CIN was commonly associated with multiple HPV types, while invasive cancers had a single type of HPV. In terms of both sensitivity and positive predictive value in detecting the CIN, HPV DNA testing is superior to cytology. However, most importantly, HPV DNA testing in combination with cytology significantly improved the efficacy to CIN screening.     

The prognostic significance of leukocytosis in cervical cancer

Cervical cancer is a frequent tumor with established prognostic factors such as FIGO stage and hemoglobin levels among others. Despite the fact that paraneoplastic leukocytosis is relatively common in many solid tumors, only isolated cases of cervical cancer patients presenting this abnormality have been published; hence, the clinical significance of leukocytosis is unknown in this tumor type. Retrospective review on the medical records of 294 consecutive newly diagnosed and untreated locally advanced cervical cancer patients who received radiotherapy and concurrent cisplatin was conducted. Leukocytosis was defined as a persistent white blood cell count exceeding 10,800/microL, determined at least twice before commencing chemoradiation providing that patients were free of any active acute or chronic infection or any other condition known to elevate the leukocyte count. The frequency of leukocytosis and their correlation with clinicopathologic features were investigated, as well as their impact on tumor response and survival. Leukocytosis with a median value of 13,300/microL (11,100-28,800) was observed in 35 (11.9%) patients at diagnosis. Leukocytosis was statistically associated only with advanced stages. Clinical complete response was observed in 57% versus 86% of the patients with and without leukocytosis, respectively. In the univariate analysis, leukocytosis, stage, and hemoglobin levels were significant predictors of survival; however, only leukocytosis and the hemoglobin level remained significant predictors of survival in the multivariate analysis. Leukocytosis is common in cervical cancer patients and has a negative prognostic significance.     

Detection of human papillomavirus deoxyribonucleic acid in exfoliated cervicovaginal cells as a predictor of cervical neoplasia in a high-risk population

Specific types of human papillomavirus are currently implicated as etiologic agents of precancerous and cancerous lesions of the cervix. We have previously described the use of cervicovaginal lavage and molecular hybridization to detect human papillomavirus infections of the cervix. We report here the predictive value of this method of human papillomavirus detection to identify women with biopsy proved dysplastic and cancerous lesions of the cervix. One hundred ninety-one women from a city hospital colposcopy clinic underwent concurrent Papanicolaou smear, cervicovaginal lavage, and coloposcopically directed cervical biopsy. Human papillomavirus deoxyribonucleic acid was detected in 114 (59.7%) of these women. Of the positive results, human papillomavirus type 16 accounted for 23.7%, human papillomavirus type 18 for 10.5%, human papillomavirus type six or 11 for 6.2%, related human papillomavirus types for 52.6%, and 7.0% contained more than one type. The distribution of human papillomavirus types was similar in both women younger than 40 years of age and in older women. Eighty-nine of 128 (69.5%) women less than 40 years old with cervical lesions had positive findings of human papillomavirus, and 18 of 29 (62.1%) older women with cervical lesions had positive findings of human papillomavirus. Detection of human papillomavirus types 16 and 18 identified only 35 of 157 (22.3%) women with cervical lesions. The sensitivity of detecting all types of human papillomavirus as a predictor of a biopsy proved lesion (68.0%) was comparable with the sensitivity of cytologic examination alone (74.0%). However, human papillomavirus detection combined with the Papanicolaou smear provided an increased overall sensitivity of 89.3% (p less than 0.01). In fact, women either positive for human papillomavirus or having abnormal cytologic findings were 11.8 times more likely to have a biopsy proved cervical lesion than human papillomavirus-negative women with negative cytologic results (95% confidence interval for odds ratio: 5.3 to 26.6). We conclude that the sensitivity of cytologic examination plus human papillomavirus detection is superior to the use of either cytologic studies or human papillomavirus detection alone in identifying patients with cervical lesions.     

Cofactors in human papillomavirus infection and cervical carcinogenesis

Objective

This study aimed to identify the effect of various risk factors as the promoters of HPV infection, and to identify which HPV-positive women may have an increased risk of developing cervical cancer.

Methods

Smear preparations were examined and classified according to the Bethesda system. HPV-DNA detection and genotyping was carried out using polymerase chain reaction combined with reverse hybridization line-probe assays. Age, smoking habit, age at first sexual intercourse, number of sexual partners, number of term births, contraceptive method, progesterone therapy, history of sexually transmitted diseases, history or existence of warts and existence of cervical infection were recorded.

Results

642 women (96 women with abnormal cervical cytology and 546 women with normal cytology) provided cervical samples. Smoking habit, number of sexual partners, number of term births, history of sexually transmitted diseases, history or existence of warts and existence of cervical infection were identified as the promoters of HPV infection. History of sexually transmitted diseases, history or existence of warts and existence of cervical infection were identified as cofactors affecting progression from HPV infection to cervical cancer. Neither of contraceptive methods studied was related to HPV infection or coexistence with malign transformation to cervical cancer.

Conclusion

Information gathered from this study could be used to prioritize limited screening and treatment services to woman who have specific characteristics that may put them at an increased risk of HPV infection. Additionally, by identifying which women have a higher risk of cervical cancer; it may be possible to reduce the number of unnecessary colposcopies.     

Evaluation of a human papillomavirus assay in cervical screening in Zimbabwe

Objective To determine the utility of an assay for high risk genital human papillomavirus (HPV) in cervical screening in Zimbabwe, Africa.
Design Cross-sectional study.
Setting Harare, Zimbabwe.
Population Zimbabwe women (   n = 2140  ), 25 to 55 years old, recruited in clinics in Chitungwiza and Greater Harare.
Methods Genital specimens were assessed for HPV, using the HPV DNA test Hybrid Capture II (probe B). Further assessment of the women was conducted using colposcopy and biopsy as indicated. High grade squamous intraepithelial lesions were diagnosed in 215 women. Colposcopy and/or biopsy showed low grade lesions in 346 women.
Results The overall prevalences were: 42.7% for HPV, 10% for high grade squamous intraepithelial lesions and 16% for low grade lesions. Prevalence for HPV decreased significantly with increase in age (   P for trend < 0.0001  ) and increased significantly with increasing disease severity, from 35% in normal women, to 53% in women with low grade lesions and 81% in women with high grade lesions (   P for trend < 0.001  ). In specimens positive for HPV, the amount was 14-fold higher in women with high grade lesions compared with normal women. In screening for high grade lesions the assay for HPV had a sensitivity of 81% (CI 75%–86%); sensitivity for low grade lesions was 64% (CI 60%–68%). Specificity was 62% (CI 59%–64%) for high grade lesions and 65% (CI 62%–67%) for low grade lesions. The positive predictive value was 19% (CI 17%–22%) for high grade lesions and 39% (CI 36%–42%) for low grade lesions.
Conclusion For high grade squamous intraepithelial lesions the sensitivity of the Hybrid Capture II HPV DNA test was high, but the specificity was relatively low. The test may therefore be most useful in conjunction with other screening tests.