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ABSTRACT: Based on epidemiologic studies, 18 mucosal human papillomavirus (HPV) types have been classified as (probably) high-risk (HR) (i.e., HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82). Recognition of HR HPV at the individual type level may be valuable in clinical management of HR HPV-positive women.
The goal of this study was to evaluate the performance of the novel digene HPV Genotyping RH Test (digene RH Test), which uses type-specific probes for the 18 HR HPV genotypes, in comparison to the established in-house Reverse Line Blot (RLB) genotyping assay on PCR products generated with the clinically validated GP5+/6+-PCR method.
GP5+/6+ amplimers, generated from 493 digene High Risk HPV HC2 DNA Test (HC2)-positive and 95 HC2-negative cervical smears, were genotyped by both the digene RH Test and the RLB assay.
Both genotyping assays demonstrated high concordance for overall HR HPV detection (ú = 0.886) and type-specific identification of the 18 HR types (overall ú = 0.951, individual ú range 0.777 to 1.000) in 493 HC2-positive samples. The digene RH Test revealed positivity for one or more HR HPV type(s) in 86.6% of the HC2-positive women, and negativity was confirmed in 97.9% of the HC2-negative women.
The digene HPV Genotyping RH Test revealed a high genotyping agreement with the established RLB assay on GP5+/6+ amplimers. Accordingly, this assay following GP5+/6+-PCR could serve as a follow-up test in a clinical setting for women who are HC2-positive to identify the respective HR HPV genotype(s).
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 11/2009; 46 Suppl 3:S16-20. · 3.12 Impact Factor
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ABSTRACT: Epidemiologic studies have classified 18 genotypes of the human papillomavirus (HPV) as (probably) high-risk (HR) based on their association with cervical cancer, i.e., HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and 82. Given the fact that certain HR HPV types confer an increased risk of cervical (pre)cancer, type-specific identification might aid clinical management of women tested positive for HR HPV. Therefore, the development of robust, high-throughput genotyping assays is important.
An analytical comparison of the digene HPV Genotyping LQ Test (digene LQ Test), capable of identifying 18 HR types using bead-based xMAP suspension array technology, with the established Reverse Line Blot (RLB) genotyping assay was carried out on amplimers generated with the clinically validated GP5+/6+-PCR method.
GP5+/6+ amplimers, generated from 434 digene High Risk HPV HC2 DNA Test (HC2)-positive and 95 HC2-negative cervical smears, were genotyped by both the digene LQ Test and the RLB genotyping assay.
The genotyping assays revealed high agreement for overall HR HPV detection (ú = 0.884) and type-specific identification of the 18 HR HPV types (overall ú = 0.958, individual ú range 0.795 to 1.000). The digene LQ Test demonstrated a very good inter-laboratory reproducibility (ú = 0.987). Among the HC2-positive women, the digene LQ Test revealed positivity for one or more HR HPV type(s) in 85.9%, and negativity was observed in 97.9% of the HC2-negative women.
The digene LQ Test demonstrated a high genotyping agreement with the established RLB genotyping assay on GP5+/6+ amplimers. This novel assay allows for high-throughput genotyping following HR HPV testing by HC2.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 11/2009; 46 Suppl 3:S21-6. · 3.12 Impact Factor
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N Keita,
G M Clifford,
M Koulibaly,
K Douno,
I Kabba,
M Haba,
B S Sylla,
F J van Kemenade,
P J F Snijders, C J L M Meijer,
S Franceschi
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ABSTRACT: Background: Methods: Results: Conclusion: Materials and methods Results Discussion References Acknowledgements Figures and TablesBackground: Cervical cancer incidence in western Africa is among the highest in the world.
British Journal of Cancer 06/2009; 101(1):202-208. · 5.04 Impact Factor
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N Keita,
G M Clifford,
M Koulibaly,
K Douno,
I Kabba,
M Haba,
B S Sylla,
F J van Kemenade,
P J F Snijders, C J L M Meijer,
S Franceschi
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ABSTRACT: Cervical cancer incidence in western Africa is among the highest in the world.
To investigate human papillomavirus (HPV) infection in Guinea, we obtained cervical specimens from 831 women aged 18-64 years from the general population of the capital Conakry and from 77 locally diagnosed invasive cervical cancers (ICC). Human papillomavirus was detected using a GP5+/6+ PCR-based assay.
Among the general population, the prevalence of cervical abnormalities was 2.6% by visual inspection and 9.5% by liquid-based cytology. Fourteen of 15 high-grade squamous intraepithelial lesions were visual inspection-negative. Human papillomavirus prevalence was 50.8% (32.1% for high-risk types) and relatively constant across all age groups. Being single or reporting > or =3 sexual partners was significantly associated with HPV positivity. HPV16 was the most common type, both among the general population (7.3%) and, notably in ICC (48.6%). HPV45 (18.6%) and HPV18 (14.3%), the next most common types in ICC, were also more common in ICC than in HPV-positive women with normal cytology from the general population.
The heavy burden of HPV infection and severe cervical lesions in Guinean women calls for new effective interventions. Sixty-three per cent of cervical cancers are theoretically preventable by HPV16/18 vaccines in Guinea; perhaps more if some cross-protection exists with HPV45.
British Journal of Cancer 06/2009; 101(1):202-8. · 5.04 Impact Factor
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ABSTRACT: CD30 is expressed in various types of cutaneous lymphomas, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (C-ALCL), some cases of mycosis fungoides showing large cell transformation (MF-TR) and skin localizations of systemic anaplastic lymphoma kinase (ALK)-positive or ALK-negative ALCL. Differentiation between these entities is often not possible on the basis of histology alone, but several markers, including TRAF1, MUM1 and BCL2, have been reported to provide additional diagnostic information.
To evaluate the diagnostic and prognostic significance of these markers in a large group of cutaneous CD30-positive lymphoproliferations.
An immunohistochemical study on the expression of TRAF1, MUM1, BCL2 and CD15 was performed on skin biopsies from 28 patients with C-ALCL, 39 patients with LyP, 11 patients with CD30-positive MF-TR, two with ALK-positive ALCL and six with ALK-negative ALCL. In addition, the prognostic significance of these markers was evaluated.
TRAF1 was expressed in roughly 70-80% and MUM1 was expressed in 70-100% of all the groups of cutaneous CD30-positive lymphoproliferations. Highest levels of BCL2 were expressed in MF-TR (73%), in contrast to 21% in C-ALCL and 36% in LyP. Highest levels of CD15 were expressed in C-ALCL (43%), compared with 18% in LyP and 9% in MF-TR. A relationship with survival was not clear.
The results of the present study suggest that TRAF1, MUM1, BCL2 and CD15 cannot be considered as useful diagnostic or prognostic marker in cutaneous CD30-positive lymphoproliferations. Differentiation between these different conditions should be based on a combination of clinical, histological and immunophenotypical criteria.
British Journal of Dermatology 05/2009; 161(1):121-7. · 3.67 Impact Factor
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ABSTRACT: Increasing evidence points to a negative correlation between K-ras mutations and patient's response to, or survival benefit after, treatment with EGFR-inhibitors. Therefore, rapid and reliable assays for mutational analysis of the K-ras gene are strongly needed.
We designed a high resolution melting (HRM) technology-based approach followed by direct sequencing to determine K-ras exon 1 (codons 12/13) tumour genotype.
Reconstruction experiments demonstrated an analytical sensitivity of the K-ras exon 1 HRM assay following sequencing of 1.5-2.5% of mutated DNA in a background of wild-type DNA. Assay reproducibility and accuracy were 100%. Application of the HRM assay following sequencing onto genomic DNA isolated from formalin-fixed paraffin-embedded tumour specimens of non-small cell lung cancer (n=91) and colorectal cancer (n=7) patients revealed nucleotide substitutions at codons 12 or 13, including a homozygous mutation, in 33 (34%) and 5 (5%) cases, respectively. Comparison to conventional nested-PCR following cycle-sequencing showed an overall high agreement in genotype findings (kappa value of 0.96), with more mutations detected by the HRM assay following sequencing.
HRM allows rapid, reliable and sensitive pre-screening of routine diagnostic specimens for subsequent genotyping of K-ras mutations, even if present at low abundance or homozygosity, and may considerably facilitate personalized therapy planning.
Cellular oncology: the official journal of the International Society for Cellular Oncology 02/2009; 31(3):161-7. · 4.17 Impact Factor
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ABSTRACT: Sentinel Lymph Node (SLN) status is strongly related to clinical outcome in melanoma patients. In this study we investigated the possible association between the presence of activated and/or suppressive Tumour Infiltrating Lymphocytes (TILs) and SLN status in clinically stage I/II melanoma patients.
Diagnostic primary melanoma samples from 20 patients with a sentinel lymph node metastasis were compared to melanoma samples from 20 patients with a negative sentinel lymph node, who were matched for gender, age and Breslow thickness. Presence of activated Granzyme B positive (GrB+) TILs, presence of suppressive (FoxP3+) TILs and MHC class I antigen expression on tumour cells were analysed by immunohistochemistry.
FoxP3 and MHC-I expression had no direct bearing on the presence of melanoma metastases in the SLN. Whereas the presence of activated GrB+ TILs in the primary melanoma had no predictive value for SLN status either, their absence was strongly associated with the presence of metastasis in the SLN (p=0.001). While both GrB+ and FoxP3+ TILs could be detected in SLN metastases, a majority did not display MHC-I expression.
These data support a role for cytotoxic T cells in the prevention of early metastasis of melanoma to the draining lymph nodes.
Cellular oncology: the official journal of the International Society for Cellular Oncology 01/2009; 31(5):407-13. · 4.17 Impact Factor
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ABSTRACT: Increasing data from clinical trials support EGFR and K-ras mutation status as predictive markers of tumour response to EGFR-targeted therapies. Consequently, rapid and reliable mutation screening assays are demanded to guide rational use of EGFR-targeted therapies.
In this study, we describe the development of high resolution melting (HRM) technology-based assays with direct sequencing confirmation possibility for mutation screening of the EGFR gene (exons 19, 20 and 21) in routine diagnostic specimens, and compared assay findings to those of conventional nested-PCR following cycle-sequencing.
In reconstruction experiments, each HRM assay following sequencing demonstrated a sensitivity of < or =5% of mutated DNA in a background of wild-type DNA. The panel of EGFR HRM assays following sequencing applied to a series of genomic DNA samples isolated from 68 FFPE NSCLC specimens correctly identified all EGFR mutations that were previously found by nested-PCR following cycle-sequencing. The HRM approach additionally scored two mutations not detected by the conventional assay. Complementary HRM following sequencing for K-ras revealed three mutations. EGFR and K-ras mutations were mutually exclusive.
The panel of designed HRM assays with direct reflex sequencing possibility provides an effective method for mutation screening of EGFR and K-ras genes in routine diagnostic specimens, thereby allowing the selection of the treatment of choice in clinical practice.
Cellular oncology: the official journal of the International Society for Cellular Oncology 01/2009; 31(5):329-33. · 4.17 Impact Factor
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A T Hesselink,
M A P C van Ham,
D A M Heideman,
Z M A Groothuismink,
L Rozendaal,
J Berkhof,
F J van Kemenade,
L A F G Massuger,
W J G Melchers, C J L M Meijer,
P J F Snijders
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ABSTRACT: Using a case control approach, we performed a two-way comparison study between GP5+/6+-PCR and HPV SPF(10)-Line Blot 25 (SPF(10)) assays for detection of 14 types of high-risk human papillomavirus (hrHPV) in samples from women with normal cytology results who had or developed grade 3 cervical intraepithelial neoplasia (CIN 3). Samples were pooled from two cohorts, i.e., women participating in population-based screening and women attending a gynecological outpatient clinic. Cases (n = 45) were women with histologically confirmed CIN 3 diagnosed within a median follow-up time of 2.7 (range, 0.2 to 7.9) years. Control samples were from women (n = 264) who had developed CIN 1 lesions at maximum (median follow-up at 5.8 [range, 0 to 10] years). Identical numbers of cases tested positive for 1 or more of the 14 hrHPV types by both systems (40/45; McNemar; P = 1.0). Conversely, SPF(10) scored significantly more controls as hrHPV positive than did GP5+/6+-PCR (95/264 versus 29/264; McNemar; P < 0.001). Consequently, women with normal cytology results and an hrHPV GP5+/6+-PCR-positive test exhibited a risk of CIN 3 that was 4.5 times higher (odds ratio [OR], 65; 95% confidence interval [95%CI], 24 to 178) than that seen for women with an hrHPV-positive SPF(10) test (OR, 14; 95%CI, 5 to 38)). Similar results were obtained after analysis of both cohorts separately. Discrepancy analysis by viral load assessment for the most common discordant hrHPV types (HPV16, -18, and -52) showed that samples which were SPF(10) positive only for these types had viral loads significantly lower than those for samples that were positive by both assays (analysis of variance; P < or = 0.006). Our data indicate that GP5+/6+-PCR has a better clinical performance than SPF(10) for women who are diagnosed with CIN 3 after prior normal cytology results. The extra positivity scored by SPF(10) mainly involved infections characterized by low viral loads that do not result in CIN 3.
Journal of clinical microbiology 08/2008; 46(10):3215-21. · 4.16 Impact Factor
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ABSTRACT: A novel approach for primary prevention of cervical cancer has become available by the discovery of efficient prophylactic human papillomavirus (HPV) vaccines based on virus-like particles. This review elaborates on the progress in the field of prophylactic HPV vaccination achieved in the past decade, provides indications for prophylactic HPV vaccination, and discusses the impact on public health and the current secondary prevention system. In summary, with current vaccines, effective prevention and control of cervical cancer within the next decades requires an integrated vaccination-screening approach, including routine prophylactic vaccination to young women and adapted cervical screening for older women (> or =30 years).
BJOG An International Journal of Obstetrics & Gynaecology 07/2008; 115(8):938-46. · 3.41 Impact Factor
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ABSTRACT: Tumour necrosis factor (TNF)-receptor associated factor 2 (TRAF2) is an adaptor molecule involved in nuclear factor (NF)-kappaB activation, which is characteristic of in vitro activated B-cell (ABC)-like diffuse large B-cell lymphomas (DLBCL) and may result in expression of anti-apoptotic genes and poor response to chemotherapy. TRAF2 also has direct anti-apoptotic properties via interference with the apoptosis signalling cascade. The aim was to determine whether TRAF2 is preferentially expressed in ABC-like DLBCL, and whether expression correlates with clinical outcome.
TRAF2 was expressed in nine of 20 tested ABC-like DLBCLs and in only one of 13 tested germinal centre B-lymphocyte (GCB)-like DLBCLs. High TRAF2 expression was correlated with high International Prognostic Index at time of presentation, high chance of relapse and short progression-free survival time in 44 tested DLBCLs. Furthermore, when analysis was restricted to ABC-like DLBCL only, TRAF2 expression was significantly associated with poor progression-free survival time.
TRAF2 might be involved in activation of NF-kappaB in a subset of ABC-like DLBCL, and its expression is associated with a particularly poor outcome in primary nodal DLBCL patients. Because of its possible effect on to chemotherapy resistance, resistance, TRAF2 might be an attractive candidate as a molecular target for TRAF2+ DLBCL.
Histopathology 05/2008; 52(5):578-84. · 3.08 Impact Factor
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ABSTRACT: --Each year, 600-700 women in the Netherlands are diagnosed with cervical cancer. Over the last 10 years, an average of 250 women have died annually due to cervical cancer. --Gardasil, the first vaccine for Human papillomavirus (HPV), was recently approved in Europe for the prevention of cervical cancer. --The availability of a vaccine for HPV prompts the question whether it should be included in the Dutch National Immunisation Programme. --At the end of 2006, the Medicines Evaluation Board, the Health Council of the Netherlands and the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment organised a workshop for experts in the field to answer that question. --The HPV vaccine provides protection against HPV-16 and HPV-18, which cause approximately 70% of cervical cancers. --Because the efficacy of vaccination is only evident after many years, preserving good participation in the screening programme is essential. --The current screening could be improved by introducing an HPV test combined with self-sampling for women who do not participate in screening. --Vaccination is unarguably an important development. However, there are still several unanswered questions regarding vaccination and its actual protection, duration of protection, long-term safety and cost-effectiveness. --April 1st, 2008, the Health Council of the Netherlands had recommended including HPV vaccination in the National Immunisation Programme.
Nederlands tijdschrift voor geneeskunde 05/2008; 152(17):987-92.
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ABSTRACT: --Infection with high-risk genital Human papillomavirus (hrHPV) is necessary for the development of cervical cancer and its early stages. --Although it is widely accepted that infection with hrHPV is sexually transmitted, insight into the clinical manifestations of hrHPV infection in men is limited. --Flat penile lesions may be the hrHPV reservoir in men. --Their limited visibility with the naked eye explains why flat penile lesions may escape the attention of both the carrier and the clinician. The lesions can be visualized by the application of an acetic acid solution. They should be distinguished from papillary abnormalities occurring close to the frenulum and the pearl-shaped penile papulae around the coronary sulcus that do not accompany HPV. --Only flat penile lesions are associated with high numbers of HPV copies and therefore contribute to the sexual viral spread. --The use of condoms protects against sexual transmission of HPV.
Nederlands tijdschrift voor geneeskunde 05/2008; 152(17):993-8.
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A Bardin,
S Vaccarella,
G M Clifford,
J Lissowska,
M Rekosz,
P Bobkiewicz,
J Kupryjańczyk,
R Krynicki,
J Jonska-Gmyrek,
A Danska-Bidzinska,
P J F Snijders, C J L M Meijer,
W Zatonski,
S Franceschi
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ABSTRACT: Cervical cancer incidence and mortality in Poland is among the highest in Europe. To investigate infection with different human papillomaviruses (HPV) in Warsaw, Poland, we obtained cervical cell specimens from 834 women aged 18-59 years from the general population, and 88 cervical cancers. DNA of 44 HPV types was detected using a GP5+/6+-based PCR assay. HPV prevalence was 16.6% in the general female population, being highest (24.2%) in women aged 25-34 years, notably among unmarried women (37.3%). HPV prevalence fell to 8.6% at ages 55-59. High-risk HPV prevalence was 11.3%, with HPV16 being the most common type (3.7%). All but one cervical cancer were high-risk HPV-positive, although the importance of HPV16 (73%) was much greater, and multiple infections fewer (1%), than among HPV-positive women in the general female population. In summary, we report a relatively high burden of HPV infection in Warsaw, Poland, where 79% of cervical cancers are theoretically preventable by HPV16/18 vaccines.
European Journal of Cancer 04/2008; 44(4):557-64. · 5.54 Impact Factor
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ABSTRACT: We determined the prevalence of type-specific hrHPV infections in the Netherlands on cervical scrapes of 45 362 women aged 18-65 years. The overall hrHPV prevalence peaked at the age of 22 with peak prevalence of 24%. Each of the 14 hrHPV types decreased significantly with age (P-values between 0.0009 and 0.03). The proportion of HPV16 in hrHPV-positive infections also decreased with age (OR=0.76 (10-year scale), 95% CI=0.67-0.85), and a similar trend was observed for HPV16 when selecting hrHPV-positive women with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) (OR=0.76, 95% CI=0.56-1.01). In women eligible for routine screening (age 29-61 years) with confirmed CIN2+, 65% was infected with HPV16 and/or HPV18. When HPV16/18-positive infections in women eligible for routine screening were discarded, the positive predictive value of cytology for the detection of CIN2+ decreased from 27 to 15%, the positive predictive value of hrHPV testing decreased from 26 to 15%, and the predictive value of a double-positive test (positive HPV test and a positive cytology) decreased from 54 to 41%. In women vaccinated against HPV16/18, screening remains important to detect cervical lesions caused by non-HPV16/18 types. To maintain a high-positive predictive value, screening algorithms must be carefully re-evaluated with regard to the screening modalities and length of the screening interval.
British Journal of Cancer 03/2008; 98(3):646-51. · 5.04 Impact Factor
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ABSTRACT: Cervical screening, currently performed by cervical cytology, depends on the timely detection of malignant lesions for its success. The presence of high-risk human papillomavirus (hrHPV) is associated with an increased risk of subsequent high-grade cervical intra-epithelial neoplasia (CIN2/3) and cervical cancer. The aim of this study was to determine the extent to which hrHPV is present in cervical smears with a high a priori chance of being false negative (ie, in normal smears preceding CIN2/3).
Archival specimens of 187 women with CIN2/3 and preceding normal conventional smears were identified retrospectively. Of these specimens, 144 (77%) had adequate cytological samples for further HPV DNA testing.
Of 144 CIN2/3 lesions, preceding normal smears showed hrHPV positivity in 80% of cases. Of the hrHPV-positive smears, 69% were upgraded cytologically at rescreening compared with 24% of hrHPV-negative smears (p<0.001). Upgrading of smears was not associated with specific hrHPV types (p = 0.217). In over 90% of cases, type concordance in smear and CIN2/3 lesion was demonstrated.
hrHPV is present in a high proportion of normal archival smears preceding CIN2/3, and false-negative cytology was highly associated with the presence of hrHPV. This supports the current notion that hrHPV testing can be used as a primary cervical screening tool. If so, hrHPV-positive cervical smears should be carefully examined for cytological abnormalities to reduce false-negative cervical cytology.
Journal of clinical pathology 03/2008; 61(3):385-9. · 2.43 Impact Factor
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I S van Houdt,
J J Muris,
A T Hesselink,
D Kramer,
S A G M Cillessen,
L M Moesbergen,
W Vos,
E Hooijberg, C J L M Meijer,
J A Kummer,
J J Oudejans
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ABSTRACT: Inhibition of apoptosis is important in the pathogenesis of lymphomas. c-FLIP, a regulator of caspase 8-mediated apoptosis, plays an important role in protecting normal B and T cells from apoptosis and possibly also in lymphomas. Because of contradictory reports about immunohistochemical detection of c-FLIP expression, the aim was to test the specificity of four antibodies in c-FLIP-transfected cells and subsequently to investigate expression of c-FLIP in different types of lymphoma.
Two of four antibodies were specific. In primary lymphomas c-FLIP expression was restricted to Hodgkin's lymphomas (> 90%) and diffuse large B-cell lymphomas (44%). Burkitt lymphomas and indolent B-cell lymphomas were negative in all cases. No expression was detected in primary T-cell lymphomas, although expression was observed in one relapsed ALK+ anaplastic large cell lymphoma. Expression of c-FLIP was inversely correlated with caspase 8 activation.
c-FLIP is important in escape of B cells from apoptosis during normal follicle centre cell reaction and may thus be an important early event in the development of B-cell-derived lymphomas. Moreover, non-specific staining of frequently used antibodies might explain discrepancies in different reports of c-FLIP expression.
Histopathology 01/2008; 51(6):778-84. · 3.08 Impact Factor
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ABSTRACT: We aimed to link DNA methylation events occurring in cervical carcinomas to distinct stages of HPV-induced transformation. Methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) analysis of cervical carcinomas revealed promoter methylation of 12 out of 29 tumour suppressor genes analysed, with MGMT being most frequently methylated (92%). Subsequently, consecutive stages of HPV16/18-transfected keratinocytes (n=11), ranging from pre-immortal to anchorage-independent phenotypes, were analysed by MS-MLPA. Whereas no methylation was evident in pre-immortal cells, progression to anchorage independence was associated with an accumulation of frequent methylation events involving five genes, all of which were also methylated in cervical carcinomas. TP73 and ESR1 methylation became manifest in early immortal cells followed by RARbeta and DAPK1 methylation in late immortal passages. Complementary methylation of MGMT was related to anchorage independence. Analysis of nine cervical cancer cell lines, representing the tumorigenic phenotype, revealed in addition to these five genes frequent methylation of CADM1, CDH13 and CHFR. In conclusion, eight recurrent methylation events in cervical carcinomas could be assigned to different stages of HPV-induced transformation. Hence, our in vitro model system provides a valuable tool to further functionally address the epigenetic alterations that are common in cervical carcinomas.
British Journal of Cancer 12/2007; 97(10):1457-64. · 5.04 Impact Factor
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N W J Bulkmans,
J Berkhof,
L Rozendaal,
F J van Kemenade,
A J P Boeke,
S Bulk,
F J Voorhorst,
R H M Verheijen,
K van Groningen,
M E Boon,
W Ruitinga,
M van Ballegooijen,
P J F Snijders, C J L M Meijer
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ABSTRACT: Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented.
Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131.
8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups.
The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.
The Lancet 11/2007; 370(9601):1764-72. · 38.28 Impact Factor
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ABSTRACT: Differentiated vulvar intraepithelial neoplasia (VIN) is presumed to be the precursor of invasive squamous cell carcinoma (SCC) of the vulva. It is commonly assumed that differentiated VIN is related to lichen sclerosus (LS). However, evidence for this is limited to a small number of studies describing epithelial alterations adjacent to vulvar SCC.
To study the histology and human papillomavirus (HPV) status in patients with a history of both LS and VIN without coexistent SCC.
Original biopsy specimens and surgical specimens of patients retrieved from the pathology files were revised for the presence of LS, VIN and (early) invasive SCC, specifically focused on the two different types of VIN: differentiated and undifferentiated. Thereafter, VIN lesions were tested for the presence of HPV DNA.
Twenty-seven patients fulfilled the criteria for LS and VIN without SCC. In all 27 patients, LS was found to be related to undifferentiated VIN. Grading yielded the following results: VIN 1 (n=10), VIN 2 (n=11) and VIN 3 (n=6). Additionally, VIN lesions from 26 patients could be tested for the presence of HPV DNA. HPV DNA, predominantly type 16, was present in 8 (31%) of them. Seven of these eight patients had VIN 2 or 3. During follow-up, three patients progressed to (early) invasive carcinoma. In two of these patients, differentiated VIN was observed overlying early invasive SCC.
VIN related to LS without coexisting SCC is likely to be undifferentiated, in contrast to what was previously thought. HPV DNA was demonstrated in 31% of the lesions, and was strongly related to high-grade VIN.
Journal of Clinical Pathology 06/2007; 60(5):504-9. · 2.31 Impact Factor
