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Background: High-risk human papillomavirus (hrHPV) testing on self-collected samples has potential as a primary screening tool in cervical screening, but real-world evidence on its accuracy in hrHPV-based screening programmes is lacking., Methods: In the Netherlands, women aged 30-60 years invited for cervical screening can choose between sampling at the clinician's office (Cervex Brush) or self-sampling at home (Evalyn Brush). HrHPV testing is performed using Roche Cobas 4800. We collected screening test results between January 2017 and March 2018 and histological follow-up until August 2019. The main outcome measures were mean cycle threshold (Ct) value, cervical intraepithelial neoplasia (CIN) grade 3 or cancer (CIN3+) and CIN grade 2 or worse (CIN2+)., Findings: 30,808 women had a self-collected and 456,207 had a clinician-collected sample. In hrHPV-positive women with adequate cytology, Ct values were higher for self-collection than clinician-collection with a mean Ct difference of 1·25 (95% CI 0·98-1·52) in women without CIN2+, 2·73 (1·75-3·72) in CIN2 and 3·59 (3·03-4·15) in CIN3+. The relative sensitivity for detecting CIN3+ was 0·94 (0·90-0·97) for self-collection versus clinician-collection and the relative specificity was 1·02 (1·02-1·02)., Interpretation: The clinical accuracy of hrHPV testing on a self-collected sample for detection of CIN3+ is high and supports its use as a primary screening test for all invited women. Because of the slightly lower sensitivity of hrHPV testing on a self-collected compared to a clinician-collected sample, an evaluation of the workflow procedure to optimise clinical performance seems warranted., Funding: National Institute for Public Health and the Environment (the Netherlands) and the European Commission., Competing Interests: FI and JB report grants from the European Commission (RISCC, grant number 847845) during the conduct of the study. CA, IdK, and JB report grants from the Dutch National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM) during the conduct of the study. DAMH is minority shareholder of Self-screen B.V., a spin-off company of VUmc, which develops, manufactures and licences hrHPV and methylation marker assays for cervical cancer screening and holds patents on these tests. DAMH has been on the speakers’ bureau of Qiagen and serves occasionally on the scientific advisory boards of Pfizer and Bristol-Myers Squibb. All other authors declare no competing interests., (© 2021 The Authors.)

International surveys find HPV-negativity in up to 30% of cervical adenocarcinomas. We investigated the pathological diagnosis by expert consensus with immunohistochemistry and the presence of somatic mutations in recognised tumour genes in HPV-positive and negative cervical adenocarcinomas (CADC). A sample was selected of 45 paraffin-embedded cervical blocks diagnosed locally as usual cervical adenocarcinoma from a global study. These represented different diagnoses made at previous diagnostic review and HPV status. All were suitable for analysis for somatic tumour associated gene mutations. Three pathologists examined H/E slides and immunohistochemistry for p16, progesterone receptor and p53 and classified the cases. L1 genes from high-risk HPVs and low-risk HPVs were analysed by SPF10 PCR-DEIA-LiPA25 version 1 in whole tissue sections and microdissected tumour and retested by PCR for E6/E7 genes of hrHPVs if negative. Cases were analysed for microsatellite instability and next-generation sequencing mutation analysis. From the 45 cases, 20 cases of usual CADC were confirmed of which 17 (85%) were HPV-positive in tumour cells. The other 25 cases were reclassified as endometrial, serous, clear-cell and gastric-type adenocarcinomas and all were HPV-negative in tumour cells. Careful retesting for HPV DNA and IHC leads to more accurate identification of HPV-positive usual cervical adenocarcinomas. Endometrioid endometrial adenocarcinomas, other uterine adenocarcinoma with multiple somatic mutations were important in misclassification of HPV-negative cases locally managed as cervical adenocarcinoma, as was gastric-type adenocarcinoma with germline STK11 mutation in East Asia. Few consensuses confirmed HPV-negative usual cervical adenocarcinomas showed somatic tumorigenic mutations also seen in some HPV-positive usual CADC., (© 2020 UICC.)

Objective: A hospital-based multicenter, retrospective study was conducted to compare the distribution of human papillomavirus (HPV) in squamous cell carcinoma (SCC) and cervical adenocarcinoma (CADC) in China., Methods: Paraffin-embedded tissue blocks diagnosed as SCC and CADC across China were collected, as well as the total number of diagnosed invasive cervical cancer of the 9 selected centers. DNA enzyme immunoassay, reverse hybridization, and multiplex type-specific polymerase chain reaction were used for HPV genotyping., Results: The ratios of CADC to SCC were increasing from 2005 to 2010, in parallel with HPV prevalence in CADC. In 630 patients with SCC (mean ± SD age, 45.40 ± 10.30) and 718 patients with CADC (mean ± SD age, 46.09 ± 10.59) recruited, HPV prevalence rates were 97.6% and 74.5%, respectively. Human papillomavirus viral load for SCC is significantly higher than that for CADC. Most common HPV types distributed in SCC and CADC were HPV-16 (78.5%, 75.1%-81.6%; 47.1%, 42.9%-51.3%), HPV-18 (8.0%, 6.1%-10.4%; 41.1%, 37.0%-45.3%), HPV-52 (2.3%, 1.4%-3.8%; 5.6%, 4.0%-7.9%), and HPV-45 (1.1%, 0.6%-2.3%; 3.9%, 2.6%-5.9%). Different diagnostic mean ± SD age for HPV-16/HPV-18 versus other high-risk HPV types were observed: SCC (44.5 ± 9.94 vs 51.0 ± 10.83, p < .05) and CADC (44.1 ± 9.44 vs 47.4 ± 10.41, p = .006). For HPV-negative cases, mean ± SD age was 46.1 ± 10.73 in SCC and 50.3 ± 11.85 in CADC, which were older than the positive (45.4 ± 10.31, 44.5 ± 9.64). HPV-16 and HPV-18 were the most frequent HPV types in both histological types, and HPV-18 was more frequent in CADC than in SCC., Conclusions: Human papillomavirus infection was identified more often in SCC than in CADC. Women with HPV-associated cancers, especially HPV-16/HPV-18, were of a younger age at diagnosis when compared with non-HPV-associated cancers.

Background: Two etiologic pathways for vulvar squamous cell carcinoma (SCC) are described: in a background of lichen sclerosus and/or differentiated vulvar intraepithelial neoplasia and related to high-risk human papillomavirus (HPV) infection with high grade squamous intraepithelial lesion (HSIL) as precursor. The aim was to compare the predilection site and survival of HPV-related to non HPV-related vulvar SCCs., Methods: Data of patients treated for primary vulvar SCC at the Radboudumc between March 1988 and January 2015 were analyzed. All histological specimens were tested for HPV with the SPF 10 /DEIA/LiPA 25 system assay and p16 INK4a staining was performed using CINtec® histology kit. Vulvar SCCs were considered HPV-related in case of either >25% p16 INK4a expression and HPV positivity or >25% p16 INK4a expression and HSIL next to the tumor without HPV positivity. Tumor localization, disease specific survival (DSS), disease free survival (DFS) and overall survival (OS) of patients with HPV-related and non HPV-related vulvar SCC were compared., Results: In total 318 patients were included: 55 (17%) had HPV-related (Group 1) and 263 (83%) had non HPV-related vulvar SCC (Group 2). Tumors in Group 1 were significantly more often located at the perineum compared to Group 2, 30% and 14%, respectively (p=0.001). The DSS, DFS and OS were significantly better in HPV-related than in non HPV-related vulvar SCC patients., Conclusion: HPV-related vulvar SCCs are more frequently located at the perineum and have a favorable prognosis compared to non HPV-related vulvar SCCs. Both localization and HPV-relation could explain this favorable prognosis. HPV-related vulvar SCC seems to be a separate entity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV., (© 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.)

Anal condylomata are common in HIV-positive individuals and among men who have sex with men (MSM). Generally attributable to infection by low-risk human papillomaviruses (HPVs), condylomata are considered benign low-grade squamous intraepithelial lesions (SILs). However, anal condylomata have occasionally been linked to high-grade SIL and to oncogenic, high-risk HPVs. Here we describe the range of intraepithelial lesions and of the associated HPVs in heterosexual men and women and MSM. Perianal and anal condylomata were collected from 243 patients (56 heterosexual women, 61 heterosexual men and 126 MSM, including 41 HIV-positive MSM). We assessed lesion histology and HPV genotype. Prevalence estimates and Poisson models were used. Irrespective of HIV infection status, MSM showed a higher proportion of condylomata as high-grade SILs compared to heterosexual men/women. High-grade SILs were also more prevalent in anal than in perianal lesions in all patient groups. HIV-positive MSM exhibited increased prevalence ratio (4.6; 95% confidence interval 2.1-10.0) of perianal low-grade SILs containing only high-risk HPVs compared to HIV-negative MSM. In addition, more than 64% of anal SILs with a high-grade component, regardless of HIV infection, were exclusively associated with low-risk HPVs. In anal condylomata, both high-grade and low-grade SILs can be associated with high-risk and/or low-risk HPVs. Particularly, low-grade perianal SILs associated with high-risk HPVs were common in HIV-positive MSM, while presence of only low-risk HPVs in high-grade SILs were common in both MSM groups. Our findings sound a note of caution for the common clinical practice for the treatment of anal condylomata as benign lesions in MSM and HIV-positive patients., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy., (Copyright © 2014. Published by Elsevier B.V. All rights reserved.)

Knowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3,103 women were diagnosed with HG-CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions., (Copyright © 2012 UICC.)

A comparison of two PCR-based human papillomavirus (HPV) DNA detection and genotyping systems (PGMY LBA and SPF(10) LiPA) was conducted in two laboratories. Both systems are based on broad-spectrum PCR for the detection of HPV DNA, followed by reverse hybridization with type-specific probes. A total of 400 selected cervical scrape specimens in PreservCyt solution (55% normal cytology, 18% atypical squamous cells of unknown significance, 14.8% low-grade squamous intraepithelial lesions [SIL], and 12.5% high-grade SIL) were tested for the presence of HPV DNA. In this selected group of specimens, the overall agreement between the two methods for the detection of any HPV DNA was high (kappa = 0.859). When the 20 common HPV genotypes identified by both methods were considered (HPV types 6, 11, 16, 18, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 56, 58, 59, 66, and 68), compatible genotype-specific results were observed in 96.5% of the samples, even when multiple HPV genotypes were present. However, for some specific HPV genotypes, there were significant differences in HPV detection by the two methods. PGMY LBA detected more HPV type 42 (P = 0.002), HPV type 56 (P = 0.039), and HPV type 59 (P < 0.001), whereas SPF(10) LiPA detected more HPV type 31 (P < 0.001) and HPV type 52 (P = 0.031). For the remaining genotypes, including HPV types 16 and 18, the results obtained by the two methods were not significantly different. In general, both genotyping methods are highly suitable for clinical and epidemiological studies.

The neurofibromatosis Type 2 tumor suppressor gene is implicated in the hereditary tumor syndrome NF2, hallmarked by bilateral vestibular schwannomas, meningiomas, and ocular non-neoplastic features. The gene product has characteristics of a membrane cytoskeleton-linking protein but the mechanism of tumor suppression by the NF2 protein remains to be elucidated. The NF2 gene is widely expressed in mouse and rat tissues. In humans, most of the expression data have accumulated through Northern blot analysis, RT-PCR and, more recently, Western blot analysis, providing information on whole tissues and organs rather than on specific cell types. We report here an extensive survey of NF2 gene expression in human tissues using a combination of mRNA in situ hybridization (mRNA ISH) and immunohistochemistry (IH) with a panel of monoclonal antibodies (MAbs) supplemented by tissue immunoprecipitation experiments with affinity-purified polyclonal antibodies. Expression was observed in many different cell types, most of which appear functionally normal in individuals affected by NF2. Surprisingly, expression could not be consistently documented in Schwann cells and arachnoidal cells by IH or by mRNA ISH in formalin-fixed tissue. However, consistent immunostaining of Schwann cells was seen in frozen sections. (J Histochem Cytochem 47:1471-1479, 1999)

We have isolated a gene, called MN1, which resides on chromosome 22 and which was found to be disrupted by a balanced translocation (4;22) in meningioma 32. The MN1 gene spans about 70 kb and consists of at least two large exons of approximately 4.7 kb and 2.8 kb. The MN1 cDNA codes for a protein of 1319 amino acids when the first methionine in the open reading frame is used. The MN1 cDNA contains two CAG repeats, one of which codes for a string of 28 glutamines. The t(4;22) disrupts the 5'-exon within the open reading frame. In meningioma 32 no expression of the MN1 mRNA is observed. These results suggest that inactivation of the MN1 gene in this tumour may contribute to its pathogenesis.

A method for the efficient rescue of lac operator containing plasmids from transgenic mouse genomic DNA is described. The method is based on the high affinity of the LacI repressor protein for the lac operator sequence. Using the LacI repressor protein conjugated to magnetic beads, more than 95% of plasmid sequences could be purified from restriction enzyme digested genomic DNA. After circularization, the plasmids were introduced into Escherichia coli by means of electroporation. Since the plasmid was cloned into a bacteriophage lambda vector, the efficiency of plasmid rescue could easily be compared with in vitro packaging. Our results indicate that plasmid rescue is about 25 times more efficient. Application of this method should be especially useful with transgenic mouse models harboring LacZ plasmid shuttle vectors for studying spontaneous or induced mutations in vivo.