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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. [Extracted from the article]

Objective: The use of testing for human papillomavirus (HPV) is now recognized as an efficient means of triaging women with low-grade cytological abnormalities to either immediate referral to colposcopy or return to routine recall. We aimed to determine the sensitivity and specificity of each of four newer tests for HPV relative to the Qiagen Hybrid Capture 2 (HC2) assay in order to determine whether they could be approved for use in triage in the NHS cervical screening programme. Methods: We compared the performance of each of four different HPV assays (Abbott M2000, Roche Cobas, Hologic Cervista and Gen-Probe APTIMA) with that of HC2 in order to determine the sensitivity and specificity of each test relative to HC2 for the detection of cervical intraepithelial neoplasia (CIN) grade 2 or worse, using routine cytology samples reported as borderline (atypical squamous cells) or mild dyskaryosis (low-grade squamous intraepithelial lesion) from six laboratories in England. All women who were found to be HPV positive on any test were referred to colposcopy. Results: Between 2072 and 4217 tests were performed with each assay. All four assays were shown to have a relative sensitivity of no worse than 95% compared with HC2 when a cut-off of 2 relative light units (RLU) was used. All assays had higher relative specificity than HC2 for both borderline and mild cytology referrals (1.06-1.61). Conclusions: All assays tested met the criteria required. Consequently, all have now been approved for use in HPV triage in the NHS cervical screening programme. [ABSTRACT FROM AUTHOR]

Objectives To identify whether recurrences were picked up by cytology alone after radical vaginal trachelectomy and to determine the false-positive rate of abnormal cytology. Methods Retrospective collection of patients from the cancer registry since radical vaginal trachelectomy was first performed in Bristol in 1999. All cytology results were collated and re-reviewed by a senior consultant cellular pathologist at the cytopathology centre in Southmead Hospital, Bristol. Cytology results and pathology and survival data are discussed, and any downgrading or upgrading of reports is reviewed. Results Eighteen women were identified and 80 isthmic cytology samples were reviewed. Only one recurrence has occurred. Lower uterine segment sampling was apparent in 25 samples and other endometrial cells in 21 samples: thus 58% showed endometrial cell sampling. Odd metaplastic cells from the newly formed transformation zone were found in 25 samples (31%). Fifteen (19%) showed significant inflammation, two with actinomyces. After cytology review, seven of 80 reports were changed: two between negative and inadequate, two borderline changes in endocervical cells and one mild dyskaryosis were downgraded to negative, and two cases reported as ?glandular neoplasia were changed to squamous cell carcinoma and negative, respectively. Conclusions Cytology reporting may be challenging after trachelectomy. Cytology in our series did not add to the diagnosis of recurrence in the one case in which it occurred. We propose a pragmatic follow-up regime, and discuss the importance of the centralization of cytology reporting in these patients. [ABSTRACT FROM AUTHOR]

The British Society for Clinical Cytology Code of Practice on fine needle aspiration cytology complements that on exfoliative cytopathology, which was published in the last issue ( Cytopathology 2009; 20:211–23). Both have been prepared with wide consultation within and outside the BSCC and have been endorsed by the Royal College of Pathologists. A separate code of practice for gynaecological cytopathology is in preparation. Fine needle aspiration (FNA) cytology is an accepted first line investigation for mass lesions, which may be targeted by palpation or a variety of imaging methods. Although FNA cytology has been shown to be a cost-effective, reliable technique its accurate interpretation depends on obtaining adequately cellular samples prepared to a high standard. Its accuracy and cost-effectiveness can be seriously compromised by inadequate samples. Although cytopathologists, radiologists, nurses or clinicians may take FNAs, they must be adequately trained, experienced and subject to regular audit. The best results are obtained when a pathologist or an experienced and trained biomedical scientist (cytotechnologist) provides immediate on-site assessment of sample adequacy whether or not the FNA requires image-guidance. This COP provides evidence-based recommendations for setting up FNA services, managing the patients, taking the samples, preparing the slides, collecting material for ancillary tests, providing rapid on-site assessment, classifying the diagnosis and providing a final report. Costs, cost-effectiveness and rare complications are taken into account as well as the time and resources required for quality control, audit and correlation of cytology with histology and outcome. Laboratories are expected to have an effective quality management system conforming to the requirements of a recognised accreditation scheme such as Clinical Pathology Accreditation (UK) Ltd. [ABSTRACT FROM AUTHOR]

Objective: To describe our experience in recognizing an unusual presentation of severe dyskaryosis at two large cytology centres using ThinPrep liquid-based cytology (LBC). LBC has been introduced in England following successful pilot studies. It is clear that LBC improves visualization and preservation of cells, and that sensitivity for high-grade dyskaryosis is at least as good as for conventional cytology, and may be better. Several variants of high-grade dyskaryosis have been described on conventional cytology, including small and pale cell dyskaryosis. These are also seen on LBC. We are reporting a new variant of dyskaryosis which in our experience is seen only in LBC specimens prepared by the Thinprep® method, which we have named bland dyskaryosis. This has not to our knowledge been previously described. Bland dyskaryosis is characterized by cells with a high nuclear/cytoplasmic ratio, nuclear hyperchromasia and is present in groups with a chaotic architecture. The chromatin pattern appears bland at low power screening examination. On high power examination, however, the chromatin pattern can be seen to be subtly abnormal. Nuclear membranes are smooth. These changes mimic endocervical cells or immature squamous metaplasia at low power. Method: Identification and description of cytological appearances observed in routine practice and correlation with histological diagnosis. Conclusion: The features of bland dyskaryosis should be disseminated through teaching activities. Recognition of this previously undescribed variant will prevent false negative reporting of LBC samples. [ABSTRACT FROM AUTHOR]

The BSCC terminology was originally published in 1986 and although highly successful, requires revision. Through a process of professional consensus and literature review this has been undertaken by the BSCC. The revision takes account of recent developments and improvements in understanding of morphology and disease process and is compatible with other terminologies in use elsewhere, whilst still maintaining a focus on practice in the UK cervical screening programmes. [ABSTRACT FROM AUTHOR]

Objective: One of the key performance measures in the monitoring of the NHS cervical screening programme is the targeting of laboratories with very high or low percentages (outside the 10th–90th percentile) of adequate smears that have moderate dyskaryosis or worse. These laboratories are assumed to include those laboratories that may have extremes of sensitivity and specificity. A clear limitation with this methodology is that laboratories do not examine smears from women with the same underlying risk, age distribution or screening interval and adjustment for these factors should considerably improve the method. Methods: This paper describes a method that allows for these confounding variables and a new age-risk-interval adjusted moderate dyskaryosis or worse rate (ARI-adjusted mod+ rate) can be calculated. The adjusted rate is the rate of moderate or worse dyskaryotic smears that the laboratory would have detected had it been screening women with an English ‘average’ age-risk-interval. All laboratories can therefore be compared using this method. Results: The methodology is illustrated using data from the NHSCSP South West Region. The particularly low percentage of moderate or worse smears detected by one or two laboratories can be shown to be due to a local screened population with a very low risk because of a high mean age, relatively short screening interval and census variables associated with a low risk, rather than any under-calling by the associated laboratories. Conclusions: The ARI-adjusted mod+ rate requires to be calculated for all laboratories in England if it is to be used as a primary performance indicator. Alternatively, it can be used to further examine laboratories that are deemed to be outliers using the current methodology. [ABSTRACT FROM AUTHOR]

In recent years every aspect of the practice of cytology has come under close scrutiny. It is perhaps surprising therefore that very little has been published on the subject of training in cytology. Whilst training is an issue in all aspects of diagnostic cytology, this review will concentrate on cervical cytology. [ABSTRACT FROM AUTHOR]

The terminology used for reporting cervical samples in the UK is the BSCC classification, which has evolved over many years. In 2002 the BSCC held a consensus conference to review the BSCC classification, with the intention of providing clearer results for women, improving concordance with other terminologies and facilitating consistency with new scientific developments and technologies. The consensus conference was well attended and robust. In the intervening years there have also been other further advances on morphometry, data on outcomes, data from EQA and other sources. Liquid Based cytology (LBC) has been implemented by the NHS CSP. All of these developments have impacted on the proposed classification, which will be presented in full. The term ‘dyskaryosis’ will be retained and several of the current reporting categories will be relatively unchanged, though additional information on LBC will be provided. The major proposed changes are: (1) A move to a single category of ‘High Grade Dyskaryosis’ to replace the existing categories of moderate and severe dyskaryosis. (2) Sub-division of Borderline change into three categories. Borderline change in glandular cells Borderline change ?high grade Borderline change, NOS (3) The current grades of Mild Dyskaryosis and Borderline change with Koilocytosis to be merged. Details of these proposals, together with illustrations and the evidence base for change will be presented. [ABSTRACT FROM AUTHOR]

Liquid based cytology (LBC) has improved cell visualization and preservation in cervical cytology. There has been a reduction in inadequate rate and some data to suggest an increase in sensitivity for dyskaryosis. Training for LBC has focused on differences in distribution of abnormal cells, but in most cases the morphological appearance of the dyskaryotic cells themselves is similar to that seen in conventional cytology. We are describing a new presentation of dyskaryosis which may be a cause of false negative cytology. We have referred to this as ‘Bland dyskaryosis’ because cells appear deceptively bland on low power examination, and can be misinterpreted as metaplastic or endocervical cells. Bland dyskaryosis cells are seen in groups. The architecture of the group is very disorganized, and adjacent cells show variation in size. Cells have a high nuclear/cytoplasmic ratio and smooth nuclear membranes. Chromatin is finely granular and evenly distributed. This is an unusual presentation of high-grade dyskaryosis and we feel that there is a learning curve in laboratories converting to liquid based cytology. The spectrum of appearances of squamous dyskaryosis needs to be delineated to allow further increases in sensitivity for dyskaryosis. [ABSTRACT FROM AUTHOR]