Interlaboratory agreement of different human papillomavirus DNA detection and typing assays in cervical scrapes.
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Cervix Uteri↗
Biomedical subjects
J M Walboomers
Publications and source records attributed to J M Walboomers.
Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses.
High-risk types of human papillomaviruses (hrHPVs) may be a necessary cause in cervical cancer and in some subtype of anal, vulvar, and penile cancers. Large studies aimed at characterizing hrHPV-associated and non-hrHPV-associated subtypes of anal carcinomas are, however, lacking. We searched for human papillomavirus type 16 and 13 other hrHPVs in tumor tissue by PCR and performed a systematic histological evaluation of specimens from 386 patients with anal cancer (86% invasive; 302 women and 84 men). Cancers in women and homosexual men were more often hrHPV positive (P < 0.01) and located in the anal canal (P < or = 0.01) than were cancers in heterosexual men. In both women and men, anal canal cancers contained hrHPV clearly more often than did perianal skin cancers, and increasing hrHPV positivity was seen with higher localization in the anal canal. Indeed, 95 and 83% of cancers involving the anal canal in women and men, respectively, were hrHPV positive versus 80 and 28% of perianal skin cancers (P-trend < 0.001). Basaloid feature, adjacent anal intraepithelial neoplasia, poor or absent keratinization, and a predominance of small or medium neoplastic cells were all strongly positively associated with hrHPV status. Like cancer of the uterine cervix, the development of cancer of the anal canal may require infection with hrHPV, whereas a dual etiology of perianal skin cancers bears parallels to vulvar and penile cancers.
Age Factors↗
Expression of CD3-zeta on T-cells in primary cervical carcinoma and in metastasis-positive and -negative pelvic lymph nodes.
Lymphocytic infiltrate is often present in cervical cancer lesions, possibly reflecting an ongoing, but ineffective, immune response to the tumour. Recently, evidence has accumulated for systemically impaired T-cell functions in cancer patients, associated with decreased expression of signal-transducing zeta (zeta) chain dimer molecules on circulating T-cells and NK-cells. Here, we report on the intralesional down-regulation of zeta chain expression on T-cells in cervical carcinoma. Paraffin-embedded or snap-frozen sections from 24 different cervical cancer specimens were studied. Paraffin-embedded tumour-positive (n = 7) and tumour-negative (n = 15) pelvic lymph nodes were also included in the study. Immunostaining was performed on consecutive sections with antibodies specific for CD3-epsilon or the CD3-associated zeta chain dimer. Antigen retrieval by sodium citrate/microwave treatment was essential for zeta staining of paraffin sections. The amount of zeta positive cells was quantitated and related to the number of CD3-epsilon+ cells in corresponding tumour areas. Of the 24 cervical cancer specimens studied, zeta chain dimer expression was reduced in seven cases and strongly reduced in the other 17 samples. In tonsil control sections, CD3-epsilon and CD3-zeta were always co-expressed in almost equal numbers. Also, both tumour-negative and -positive lymph nodes showed zeta chain expression which equalled that of CD3-epsilon expression. These data indicate that a decreased expression of signal-transducing zeta molecules on tumour-infiltrating T-cells is frequent in cervical cancer. The apparently unimpaired zeta chain expression within draining lymph nodes suggests that local tumour-derived factors at the primary site are instrumental in zeta chain down-regulation.
Adult↗
Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia. I. Differential T-helper and IgG responses in relation to HPV infection and disease outcome.
T-helper (Th) cell-dependent IL-2 production and plasma IgG responses to virus-like particles consisting of the human papillomavirus type 16 (HPV-16) major capsid protein L1 (L1-VLP) were determined in patients with cytological evidence of cervical intraepithelial neoplasia (CIN) participating in a non-intervention prospective cohort study. IgG responses were associated with HPV-16 persistence and high-grade CIN lesions, while high frequencies of Th responses were observed in patients with both virus clearance and virus persistence, irrespective of CIN grade. The IgG response was found in conjunction with an IL-2 response to L1-VLP in 87% of the patients. Recognition of the HPV-16 L1 Th epitope (amino acids 311-335) was found to be more closely associated than recognition of L1-VLP as a whole to HPV exposure and CIN development. Among the HPV-16+ patients included in this study, those showing a Th response to amino acids 311-335 were more likely to carry the HLA DRB1*11/DQB1*0301 haplotype, while those showing an IgG response to L1-VLP were more likely to carry DRB1*0101/DQB1*0501. However, neither cell-mediated nor humoral immune responses against HPV-16 L1 appear to be sufficient for the natural control of HPV infection and CIN development.
Adult↗
Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia. II. Systemic but not local IgA responses correlate with clearance of HPV-16.
To investigate whether there is an association between local or systemic IgG and IgA responses against human papillomavirus (HPV) type 16 virus-like particles (VLP) containing L1 and L2 and the possible influence of these responses on clearance of HPV-16 and its associated lesions, cervical mucus samples from 125 patients and plasma samples from 100 patients, all participating in a non-intervention cohort study of women with abnormal cytology, were analysed. The results show that local IgG and IgA HPV-16 VLP-specific antibodies do not correlate with virus clearance. However, systemic IgG responses were more frequently detected in patients with a persistent infection (11/24) compared with patients with cleared HPV-16 infections (3/28, P = 0.006). Furthermore, the ultimate development of high-grade lesions was associated with systemic VLP-specific IgG reactivity (P = 0.026). By contrast, systemic IgA responses were correlated with virus clearance (7/28 clearance compared with 1/24 persistence patients, P = 0.06). This correlation was statistically significant when only those clearance patients who tested HPV-16 DNA-positive at more than one visit were included in the analysis (5/11 compared with 1/24, P = 0.007). As these systemic IgA responses were not accompanied by local IgA responses, the systemic IgA responses in HPV-16 clearance patients are suggested to be a by-product of a successful cellular immune response induced at the local lymph nodes, mediated by cytokines.
Adolescent↗
[Sexually transmitted infection as a cause of anal cancer].
Interviews were carried out with 423 women and 93 men with invasive or in situ anal cancer in Denmark and Sweden in a search for clues to the aetiology of this neoplasm. Patients with rectal adenocarcinoma (n = 534) and persons drawn from the background population (n = 554) served as controls. Multivariate logistic regression analyses confirmed previous observations of a strong association between either male homosexual experience or a history of anogenital warts and the risk for anal cancer. Moreover, hitherto unknown, but strong and consistent associations were observed between measures of high heterosexual activity and the risk for anal cancer among both sexes. Polymerase chain reaction analysis revealed human papilloma-virus DNA in the majority (88%) of anal cancer specimens but in none of 20 examined rectal adenocarcinomas. It is concluded that most anal cancers appear to be caused by sexually transmitted types of human papillomaviruses and, consequently, that anal cancer is a potentially preventable neoplasm.
Adenocarcinoma↗
HPV 16 infection and progression of cervical intra-epithelial neoplasia: analysis of HLA polymorphism and HPV 16 E6 sequence variants.
High-risk human papillomavirus (HPV) infection plays an important role in cervical intra-epithelial neoplasia (CIN), but HPV infection alone is not sufficient for progression to cervical cancer. Several lines of evidence suggest that cellular immune surveillance is important in the control of HPV infection and the development of CIN. The presentation to T cells of target viral peptides in the context of HLA molecules is influenced by the genetic polymorphisms of both HPV and HLA and thereby influences the host immune response and clinical outcome of HPV infection. HLA class I and II polymorphism in susceptibility for HPV 16 infection, development and progression of CIN was analyzed in a group of 118 patients participating in a prospective study of women with initial abnormal cytology. Patients were stratified according to HPV status and course of the disease. HLA-B*44 frequency was increased in the small group of patients with a lesion that showed clinical progression during follow-up [OR = 9.0 (4.6-17.5), p = 0.007]. HLA-DRB1*07 frequency was increased among HPV 16-positive patients compared with patients who were negative for all HPV types [OR = 5.9 (3.0-11.3), p = 0.02]. Our results are consistent with the immunogenetic factors associated with disease progression being different from those associated with susceptibility to HPV 16 infection. Sequencing of the HPV 16 E6 and E7 open reading frames of a subset of these patients (n = 40) showed the frequency of HPV 16 variants to be similar to other studies. However, there was no significant correlation between variant incidence and disease progression or viral persistence and no significant correlation with any HLA allele. It appears that multiple HLA types can influence HPV 16-associated cervical dysplasia but the role of HPV 16 variants in disease progression and susceptibility in relation to HLA polymorphism remains unclear.
Adult↗
Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human papillomavirus DNA.
In this study, we investigated telomerase activity and human telomerase reverse transcriptase (hTERT) mRNA expression in relation to high-risk human papillomavirus (HPV) DNA presence in the spectrum of cervical premalignant lesions. Reconstruction experiments revealed that telomerase activity determined by the telomeric repeat amplification protocol assay and hTERT mRNA by reverse transcriptase-PCR could be detected in down to 100 and 1 SiHa cervical cancer cells, respectively. Telomeric repeat amplification protocol analysis on cervical tissue specimens revealed that none of the histomorphologically normal cervical samples (n = 8) and cervical intraepithelial neoplasia (CIN) grade I (n = 10) and grade II (n = 8) lesions had detectable telomerase activity. However, telomerase activity was shown in 40% of CIN grade III lesions (n = 15) and 96% of squamous cell carcinomas (n = 24). Despite the fact that hTERT mRNA was found at much higher frequencies, semiquantitative reverse transcriptase-PCR revealed that elevated hTERT mRNA levels were strongly correlated with detectable telomerase activity. Furthermore, telomerase activity and elevated hTERT mRNA levels were only detected in cases that contained high-risk HPV DNA. In contrast, low or undetectable hTERT mRNA levels were demonstrated in both high-risk HPV positive and negative cases. These data indicate that telomerase activity detectable with the assay used and concomitant elevated levels of hTERT mRNA reflect a rather late step in the CIN to squamous cell carcinoma sequence, which follows infection with high-risk HPV.
DNA, Viral↗
Different risk factor patterns for high-grade and low-grade intraepithelial lesions on the cervix among HPV-positive and HPV-negative young women.
Risk factors for cervical intraepithelial neoplasia have most often been studied in high-grade lesions. Furthermore, in a high proportion of the studies, human papillomavirus (HPV), the most significant risk determinant of cervical neoplasia, was not taken into account when evaluating other risk factors. To compare risk factors for ASCUS (atypical cells of undetermined significance), LSIL (low-grade squamous intraepithelial lesion) and HSIL (high-grade squamous intraepithelial lesion), we conducted a case-control study among 20 to 29 year-old women participating in a prospective cohort study in Copenhagen. It included 131 women with ASCUS, 120 women with LSIL, 79 women with HSIL and 1,000 randomly chosen, cytologically normal, control women. All participants had a personal interview and a gynecological examination including a Pap smear and cervical swabs for HPV DNA detection using general primer-mediated polymerase chain reaction. The most significant risk determinant of all 3 disease categories was the presence of genital HPV DNA. The risk factor pattern was nearly identical for ASCUS and LSIL, but differed significantly from that for HSIL. Stratified analysis by HPV-status showed that, apart from, respectively, smoking and parity among HPV-positive women, and smoking and number of sex partners among HPV-negative women, no additional risk factors were observed for ASCUS and LSIL. In contrast, among HPV-negative women with HSIL, long-term use of oral contraceptives was the most important risk factor. However, our result should be taken with great caution as it is based on very small numbers, and as it is unknown whether the HPV-negative lesions constitute a true entity. Among HPV-positive women, the risk of HSIL was associated with e.g., years of sex life without barrier contraceptive use, early age at first genital warts and smoking. Whether the risk factors that are applicable only to HSIL represent factors related to progression remains unknown.
Adult↗
Non-random allelic losses at 3p, 11p and 13q during HPV-mediated immortalization and concomitant loss of terminal differentiation of human keratinocytes.
To obtain a comprehensive overview of chromosomal alterations that may underlie human papillomavirus (HPV)-mediated immortalization, 4 foreskin keratinocyte cell lines generated by transfection with either HPV 16 (cell lines FK16A and FK16B) or HPV 18 (FK18A and FK18B) were subjected to chromosomal analysis using comparative genomic hybridization (CGH). Three cell lines were analyzed both in the mortal state during their extended lifespan and in the subsequent immortal state. From cell line FK18A, only immortal cells were tested. Chromosomal imbalances increased in number through the process of immortalization. Subsequent loss of heterozygosity (LOH) analysis, using a panel of 21 microsatellite markers selected on the basis of CGH losses, revealed no clonal LOHs in cells at the mortal stage. However, in the immortal descendants 67% of underrepresentations detected by CGH were expressed as clonal LOH at the respective loci. Clonal LOHs at 3p, 11p and 13q were detected in 2 cell lines each and were thus considered non-random. Immortal cells of 1 cell line (FK18B) revealed LOH at all 3 loci. Moreover, all immortal cell lines displaying allelic losses at one or more of these loci shared a severely dysplastic phenotype after organotypic culturing, as shown previously. Therefore, loss-of-function mutations of genes at these loci, eventually in combination, are potentially involved in the process of HPV-mediated immortalization that is attended by a loss of terminal differentiation. Since chromosomal changes at these loci are also found in HPV-associated carcinomas in vivo, the HPV-transfected cell lines seem to provide a valuable model system for studying HPV-mediated carcinogenesis.
Alleles↗
Differential T helper cell responses to human papillomavirus type 16 E7 related to viral clearance or persistence in patients with cervical neoplasia: a longitudinal study.
T-cell-mediated immune responses against oncogenic human papillomaviruses (HPVs) are believed to play a role in the prevention of cervical carcinogenesis. The in vitro production of interleukin 2 by CD4+ T helper (Th) cells in response to overlapping 20-mer peptides covering the HPV-16 E7 oncoprotein sequence was determined in 72 women with cytological evidence of premalignant cervical intraepithelial neoplasia (CIN) who participated in a nonintervention follow-up (FU) study. In addition, 15 HPV-16 + cervical carcinoma patients were tested. Positive Th cell reactivity was restricted to patients infected by HPV-16 and related types and showed a strong association with viral persistence and disease progression, as evidenced by the high frequency of positive responders among women with persistent HPV-16 infections who ended FU with high-grade CIN III lesions [14 of 15 (93%)]. Women with cervical carcinoma showed responses at a significantly reduced rate [7 of 15 (47%); P = 0.014]. Over the FU period (10-34 months), the level of E7-induced interleukin 2 production from the lymphocytes of CIN patients who had cleared HPV-16 infection showed an inverse correlation with time relative to the last positive HPV DNA test, with 8 of 13 of these patients showing positive responses after clearance. By contrast, among women with persistent HPV-16 infections and developing CIN III lesions (n = 8), there was a rise in Th cell activity over the course of FU. The majority of women responded to an immunogenic region in the carboxyl terminus of the E7 protein (amino acids 67-98). The observed HPV-16 E7-specific Th cell responses may develop as a consequence of increased antigen availability resulting either from clearance or from progression of cervical lesions.
Adult↗
The viral origin of cervical cancer in Rabat, Morocco.
In Northern Africa, cervical cancer is the second most common cancer among women. The diagnosis is usually made in advanced stages, and mortality is high, yet few studies have investigated the role of human papillomavirus (HPV) and other risk factors in the etiology of cervical cancer. A hospital-based case-control study was completed at the Institut National d'Oncologie (INO) in Rabat, Morocco. The study included 214 cases of invasive cervical cancer and 203 controls. A structured questionnaire was used to investigate known and suspected risk factors for cervical cancer. A GP 5+/6+ polymerase chain reaction system was used to detect the presence of HPV DNA and HPV type distribution. Probes for 30 HPV types were used in one research laboratory. HPV DNA was the central risk factor and accounted for the large majority of the cases. The adjusted odds ratio (ORa) for any HPV was 61.6 (95% CI, 29.2-130) and the corresponding HPV attributable fraction (AF) was 92%. Among cases of cervical cancer, HPV 16 was the most common type (67.7%) followed by HPV 18. The HPV type-specific prevalence was similar for squamous cell carcinomas and adenocarcinomas. In multivariate adjusted or HPV-stratified analyses, in addition to the strong effect of HPV, other risk factors identified were sexual intercourse with multiple partners before the age of 20 and low socio-economic status. Use of oral contraceptives for 5 or more years and high parity were also found to be related to cervical cancer. Screening was rare in this population but offered substantial protection against cervical cancer. In Morocco, cervical cancer is a late sequel of a viral infection with certain HPV types. Developing screening programs for preneoplastic cervical lesions is a public health priority. When available, HPV vaccination would offer a relevant alternative for preventing cervical cancer.
Adenocarcinoma↗
Specific HLA class I down-regulation is an early event in cervical dysplasia associated with clinical progression.
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Cohort Studies↗
Causes of cervical cancer in the Philippines: a case-control study.
BACKGROUND: Among the numerous human papillomavirus (HPV) types, only types 16 and 18 have been formally classified as human carcinogens. To evaluate the associations of 33 HPV types and other risk factors with squamous cell carcinoma and adenocarcinoma of the cervix, we performed a hospital-based, case-control study in the Philippines. METHODS: The study included 356 case subjects who had histologically confirmed cervical cancer (323 incident cases of squamous cell carcinoma and 33 incident cases of adenocarcinoma/adenosquamous carcinoma) and 381 control subjects. Information on risk factors was obtained by personal interview. HPV DNA was detected in exfoliated cervical cells and biopsy specimens by use of a polymerase chain reaction assay. RESULTS: HPV DNA was detected in 93.8% of case subjects with squamous cell carcinoma and in 90.9% of case subjects with adenocarcinoma/adenosquamous carcinoma compared with 9.2% of control subjects, giving age-adjusted odds ratios of 156 (95% confidence interval [CI] = 87-280) for squamous cell carcinoma and 111 (95% CI = 31-392) for adenocarcinoma/adenosquamous carcinoma. Fifteen different HPV types were detected in squamous cell carcinoma, and six different HPV types were detected in adenocarcinoma/adenosquamous carcinoma. Among HPV types other than types 16 and 18, the associations of HPV with risk of squamous cell carcinoma were strongest for HPV45. In addition to HPV, high parity, low socioeconomic status, and smoking were also associated with both types of cervical cancer. CONCLUSIONS: As has been shown for squamous cell carcinoma, HPV is the central cause of adenocarcinoma/adenosquamous carcinoma of the uterine cervix. The observed associations of less prevalent HPV types with cervical cancer have important implications for cervical cancer prevention strategies.
Adenocarcinoma↗
Risk factors for cervical cancer in Thailand: a case-control study.
BACKGROUND: Human papillomaviruses (HPV) types 16 and 18 are clearly involved in the etiology of cervical cancer, but the evidence for the carcinogenicity of other HPV types is limited. Cofactors involved in the progression from infection with HPV to high-grade precursors and cancer have not been clearly defined by the results of previous studies. METHODS: We conducted a hospital-based, case-control study of invasive cervical cancer to investigate risk in relation to HPV infection and its epidemiologic cofactors in Hat-Yai, Thailand. A total of 338 patients with squamous cell carcinoma, 39 patients with adenocarcinoma/adenosquamous carcinoma, and 261 control subjects were included in the study and were interviewed to obtain information with regard to cervical cancer risk factors. HPV DNA presence in cervical exfoliated cells or frozen biopsy specimens was determined by a polymerase chain reaction assay. RESULTS: HPV DNA was detected in 95% of patients with squamous cell carcinoma, 90% of those with adenocarcinoma/adenosquamous carcinoma, and 16% of control subjects. For patients with squamous cell carcinoma, the most common types of HPV found were type 16 (60% of the positives), type 18 (18%), type 58 (3%), type 52 (3%), and type 31 (2%). For patients with adenocarcinoma/adenosquamous carcinoma, the most common HPV types found were type 18 (60% of the positives), type 16 (37%), and type 45 (3%). The risk factors that remained associated with risk of both histologic types after adjustment for HPV and their mutual confounding effects were limited education, increasing number of sexual partners, history of venereal diseases, and interval since last Pap smear (i.e., cytologic) test. Among patients with squamous cell carcinoma, some association with smoking was also observed. CONCLUSION: New preventive strategies for cervical cancer will require the consideration of multiple HPV types.
Adenocarcinoma↗
Risk factors for HPV infection in women from sexually transmitted disease clinics: comparison between two areas with different cervical cancer incidence.
We have compared risk factors for human papillomavirus (HPV) infection in very sexually active women [attenders of clinics for sexually transmitted diseases (STDs)] living in 2 areas with a 4-fold difference in cervical cancer incidence, i.e., Greenland and Denmark. The results were compared with findings of HPV infection in men attending the STD clinics during the same period. Overall, 204 Greenlandic women (GW), 187 Danish women (DW), 103 Greenlandic men and 216 Danish men were included. A similar age distribution was found in the 2 female populations. The GW reported significantly more sexual partners, earlier first intercourse and more STDs, but HPV was less frequently detected in the GW (25%) than in the DW (35%). However, this could be explained by a difference in the age pattern of HPV prevalence seen in the 2 areas. In each geographical area, the age pattern of HPV prevalence in men was very similar to that seen in women. The most important risk factors for HPV detection were the same in both female populations, i.e., age, years since first sexual intercourse and number of partners in the last years. In conclusion, the pattern of risk factors for HPV infection was the same in STD women from a high-risk area and a low-risk area for cervical cancer. Our results also show that the use of an overall HPV prevalence for comparing populations is meaningless, even in populations with similar age distribution.
Adolescent↗
p53 expression above the basal cell layer in oral mucosa is an early event of malignant transformation and has predictive value for developing oral squamous cell carcinoma.
Epithelial dysplasia is usually used to establish the prognosis of oral premalignant lesions. Its assessment, however, is subjective and does not always correctly predict the outcome of the lesions in terms of malignant transformation. Early molecular alteration(s) that dictate the development of cancer should be identified and used to evaluate oral premalignant lesions. In this context, alterations in the expression of p53 were investigated. Thirty-five oral premalignant lesions and 11 carcinomas that developed from them in a period of 16 years were investigated for p53 expression by immunohistochemistry. Normal oral mucosa from healthy individuals and oral benign lesions were used as controls. In benign lesions and normal mucosa, p53 staining, when present, was confined to the basal cell layer. Seven out of 35 (20 per cent) premalignant lesions showed p53 expression clearly above the basal cell layer and six of these (86 per cent) developed carcinomas. Suprabasal p53 expression was found in three lesions with no or mild dysplasia that developed carcinomas. All carcinomas derived from premalignant lesions with p53 suprabasal expression showed p53 expression in neoplastic cells. The combined use of histological parameters (presence of moderate or severe dysplasia) with p53 expression patterns (p53 staining above the basal cell layer) showed the highest sensitivity for the detection of lesions that progressed to carcinoma (91 per cent). When used individually, the p53 expression pattern showed higher specificity than assessment of dysplasia (96 per cent vs. 54 per cent) and higher positive predictive value (86 per cent vs. 44 per cent) for correct prediction of the malignant transformation of the lesions. The results suggest that clear expression of p53 above the basal cell layer is an early event in oral carcinogenesis and an indicator of a developing carcinoma, even preceding morphological tissue alterations. However, since immunohistochemistry cannot always detect changes in p53 expression in lesions preceding carcinoma, p53 immunohistochemical analysis is strongly recommended in conjunction with histological parameters, to increase the sensitivity of detection of cases that will progress to carcinoma.
Adult↗