A case report of anaplastic thyroid cancer and papillary thyroid cancer lymph node metastasis: an unusual presentation as an invasive hypopharyngeal mass.

Anaplastic thyroid carcinoma is a rare undifferentiated tumour of the thyroid follicular epithelium. It almost always develops from a pre-existing well-differentiated thyroid cancer with a co-existent thyroid malignancy varying from 5 to 17% . The co-existence of papillary thyroid cancer (PTC) with anaplastic thyroid cancer is a rare occurrence in metastases outside the primary thyroid lesion. Traditionally, this has been regarded as an aggressive form of cancer associated with a dismal prognosis. Recently, the focus has shifted to the development of novel therapies based on the availability of comprehensive genomic profiling platforms (CGP) with a rapid turn-around to identify molecular aberrations in tumours which acts as potential therapeutic targets. In the United Kingdom, we report the case of a 60-year-old woman with an unusual presentation of (metastatic) anaplastic thyroid carcinoma and concomitant papillary thyroid cancer metastasis within a contralateral lymph node. This was initially perceived as a left pyriform fossa mass involving and compressing her left hemi-larynx on clinical and radiological examination. Following the identification of BRAF V600E mutation on CGP, she was started on targeted therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib and demonstrated excellent clinical and radiological response following 7 months of treatment. She has subsequently undergone total thyroidectomy alongside with bilateral neck dissection, and is due to start radioactive iodine treatment to reduce the risk of recurrence of disease.

Fast investigative lung cancer pathway and endobronchial ultrasound procedure supported by rapid on-site evaluation.

INTRODUCTION: EBUS is a well-established tool for diagnosis and staging of lung cancer in a fast track investigative pathway. However, impact of ROSE in conjunction with EBUS on reduction of time to treatment decision (TTD) for cancer patients is less well known. AIMS: Our aim was to determine TTD which was defined as the number of working days from EBUS procedure to the discussion at sector lung multidisciplinary team meeting (MDT). Moreover, concordance of ROSE with final diagnosis was evaluated. METHODS: A retrospective analysis was performed of a prospective data collection in a busy teaching hospital over a four months study period (September to December 2018). RESULTS: Data from 112 patients was analyzed. There were 61 (54%) males. Mean age was of 70 years (range 43-91). WHO performance status was 0 in 20 (23%), 1 in 57 (51%), 2 in 22 (20%) and 3 in 7 (6%) patients. In total 522 needle passes were performed from 242 sampling sites. Average working days to discuss at MDT after optimal EBUS sampling was 2.087 (range 0-13 working days). ROSE concordance with final cytological diagnosis was 98.4%. The number of needle passes per site for adequate sample and diagnosis in malignant (4.929) vs non-malignant (2.776) involvement was significantly different (p value <0.0001). There was 100% sample adequacy for preliminary diagnosis, immunohistochemistry and predictive molecular testing. CONCLUSION: ROSE supported fast-investigative pathway by reducing the time to treatment decision (TTD) making at MDT. High concordance with final cytological diagnosis makes it an effective tool to inform meaningful decision making.

Synchronous uterine and bladder cancers detected in urine and vaginal samples by cytology.

Novel diagnostics for uterine cancer are urgently needed to reduce the burden of invasive testing for the majority of healthy women with postmenopausal bleeding. We have previously shown that uterine cancer cells can be detected by cytology in urine and vaginal samples with high diagnostic accuracy. Here, we demonstrate its potential to distinguish malignant cells of different aetiologies in the same urogenital biofluid sample according to their distinctive morphology and immunoprofiles. Synchronous tumours of the urogenital tract are uncommon but can cause diagnostic confusion, delays and poor outcomes. A 79-year-old woman presented to accident and emergency with postmenopausal bleeding. Voided urine and Delphi screener-collected vaginal samples were assessed by cytology and immunocytochemistry. Two malignant cell populations with distinct morphology and immunophenotypes consistent with synchronous uterine and urothelial tumours were identified. Subsequent routine diagnostics confirmed concurrent uterine carcinosarcoma and high-grade urothelial carcinoma of the bladder. This case demonstrates that cytology and adjunctive immunocytochemistry can simultaneously identify and phenotype cancers of different aetiologies from a single urogenital biofluid sample. This can help rationalise diagnostic pathways in complex, unusual cases of dual urogenital primaries.

DEveloping Tests for Endometrial Cancer deTection (DETECT): protocol for a diagnostic accuracy study of urine and vaginal samples for the detection of endometrial cancer by cytology in women with postmenopausal bleeding.

INTRODUCTION: Postmenopausal bleeding (PMB), the red flag symptom for endometrial cancer, triggers urgent investigation by transvaginal ultrasound scan, hysteroscopy and/or endometrial biopsy. These investigations are costly, invasive and often painful or distressing for women. In a pilot study, we found that voided urine and non-invasive vaginal samples from women with endometrial cancer contain malignant cells that can be identified by cytology. The aim of the DEveloping Tests for Endometrial Cancer deTection (DETECT) Study is to determine the diagnostic test accuracy of urine and vaginal cytology for endometrial cancer detection in women with PMB. METHODS AND ANALYSIS: This is a multicentre diagnostic accuracy study of women referred to secondary care with PMB. Eligible women will be asked to provide a self-collected voided urine sample and a vaginal sample collected with a Delphi screener before routine clinical procedures. Pairs of specialist cytologists, blinded to participant cancer status, will assess and classify samples independently, with differences settled by consensus review or involving a third cytologist. Results will be compared with clinical outcomes from standard diagnostic tests. A sample size of 2000 women will have 80% power to establish a sensitivity of vaginal samples for endometrial cancer detection by cytology of ≥85%±7%, assuming 5% endometrial cancer prevalence. The primary objective is to determine the diagnostic accuracy of urogenital samples for endometrial cancer detection by cytology. Secondary objectives include the acceptability of urine and vaginal sampling to women. ETHICS AND DISSEMINATION: This study has been approved by the North West-Greater Manchester West Research Ethics Committee (16/NW/0660) and the Health Research Authority. Results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and via charity websites. TRIAL REGISTRATION NUMBER: ISRCTN58863784.

Validation of ROS1 by immunohistochemistry against fluorescent in situ hybridisation on cytology and small biopsy samples in a large teaching hospital.

OBJECTIVE: Rearranged ROS1, present in 1%-2% of non-small cell lung cancer (NSCLC) patients, usually young, never or light smokers, is assessed by fluorescence in situ hybridization (FISH) to determine eligibility for tyrosine kinase inhibitors (TKI). Immunohistochemistry (IHC) for the protein product of ROS1 rearrangement, a cost-effective alternative, is validated on cytology and small biopsy samples. METHODS: From 1 March to 31 December 2019, cytology cell blocks and small biopsy samples from a selected cohort of NSCLC patients were concurrently tested for ROS1 gene rearrangement by Vysis 6q22 Break Apart FISH probe and IHC using Cell Signalling D4D6 antibody. Mismatch cases were tested by an RNA fusion next generation sequencing (NGS) panel. RESULTS: In a prospective population of 95 cases, 91 were negative and two were positive by both FISH and IHC. Both dual positive cases were female never smokers and benefited from TKI treatment. Another two cases were positive by FISH but negative by IHC and repeat by NGS showed one to be negative but one failed. Turnaround time for IHC was 0 to 8 days from request to authorisation, whilst that of FISH was 9 to 42 days at a cost of £51 and £159 respectively. CONCLUSION: IHC to assess for the protein product of ROS1 gene rearrangement on cytology cell blocks and small biopsy samples in a routine setting is a promising screening method to assess eligibility for TKI treatment with positive and indeterminate cases confirmed by FISH or NGS as it has good negative predictive value, faster turnaround time and is cost effective, with proven technical and clinical validation.

Diagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples.

Postmenopausal bleeding triggers urgent investigation by sequential invasive tests that are avoidable for the 90-95% of women who do not have endometrial cancer. A simple, non-invasive tool that accurately identifies cancer and safely reassures healthy women could transform patient care. Here we report, in a cross-sectional diagnostic accuracy study of 103 women with known cancer and 113 with unexplained postmenopausal bleeding, that urine and vaginal cytology has a combined sensitivity of 91.7% (95% CI 85.0%, 96.1%) and specificity of 88.8% (81.2%, 94.1%) for gynecological cancer detection. Cytology identifies 91 endometrial, two fallopian tube and one cervical cancer from 103 known cancer cases. In women with unexplained postmenopausal bleeding, cytology identifies all four endometrial cancers and three others (cervical, ovarian and bladder), for a 12/107 (11.2%) false positive rate. We show proof-of-principle that endometrial cancer can be detected in urine and vaginal fluid. Prospective validation of these findings will support incorporation of this non-invasive test into clinical practice.

EBUS-guided mediastinal lung cancer staging: monitoring of quality standards improves performance.

This audit examined key performance indices related to endobronchial ultrasound (EBUS)-guided mediastinal lung cancer staging before and after the introduction of defined quality standards, at four independent EBUS centres in one cancer network. Data from 642 procedures were prospectively collected and analysed. The introduction of standards was associated with a significant increase (p<0.001) in sampling of key mediastinal lymph node stations (4R, 4L and 7) and a reduction in the variability of staging sensitivity between centres. These data reinforce the requirement for an appropriate regulatory framework for EBUS-transbronchial needle aspiration provision that includes quality assurance and performance monitoring.

Forward and back aspiration during ST-elevation myocardial infarction: a feasibility study.

AIMS: The inability to optimise stent expansion fully whilst simultaneously preventing distal embolisation during ST-elevation myocardial infarction (STEMI) remains a clinical conundrum. We aimed to describe a newly devised angiographic strategy of "forward" and "back" aspiration that leads to more complete thrombus removal and prevention of distal embolisation, to allow high-pressure post-dilatation of the implanted stent to be performed. METHODS AND RESULTS: Forward aspiration was conducted with a conventional aspiration thrombectomy catheter, with bail-out aspiration thrombectomy for angiographically persistent thrombus utilising the larger bore 6 Fr (0.056") guide catheter extension system (GuideLiner; Vascular Solutions, Inc., Minneapolis, MN, USA). Back aspiration was undertaken with a deeply intubated GuideLiner or guide catheter with a vacuum induced within, extending to the inflated angioplasty balloon, to allow for proximal embolic protection during balloon deflation during all stages of the PCI procedure, including high-pressure post-dilatation of the stent to the visually estimated reference vessel diameter (RVD). Over a six-month period 30 consecutive cases were undertaken during working hours. Bail-out GuideLiner-assisted aspiration thrombectomy was performed in 9/30 cases because of inadequate thrombus removal with a conventional aspiration thrombectomy catheter. Back aspiration was performed in all cases. In 27/30 cases high-pressure post-dilatation of the stent was performed. The mean maximum post-dilatation balloon size and mean proximal reference vessel diameter did not significantly differ (3.60±0.41 mm vs. 3.65±0.45 mm, p=0.68). In all cases, implantation +/- post-dilatation of the stent to the visually estimated RVD was achievable without any deterioration in TIMI blood flow or myocardial blush grade. CONCLUSIONS: The strategy of forward and back aspiration to facilitate stent implantation and high-pressure post-dilatation during STEMI appears to be safe and effective. Randomised controlled trials are required to confirm the safety and efficacy of this newly devised angiographic strategy.

Adenosquamous carcinoma of the lung diagnosed by cytology?: a diagnostic dilemma.

Adenosquamous cell carcinomas of the lung are rare tumours and are associated with a poor prognosis compared to other non-small cell carcinomas. We report a case of a solitary lung carcinoma evaluated by bronchial brush and lavage cytology, bronchial biopsy and pleural fluid cytology. Cytological assessment of the pleural fluid demonstrated non-small cell carcinoma and immunohistochemical staining confirmed a metastatic lung adenocarcinoma. The bronchial brush and lavage specimens, however, demonstrated the cytomorphological features of squamous cell carcinoma, which was confirmed by the bronchial biopsy. The finding of a mixed squamous and glandular component predicts a poor prognosis for this patient. The identification of a squamous component with the non-small cell carcinoma is important as this excludes the patient from anti-VEGF monoclonal antibody treatment due to the increased risk of haemorrhage.

Automation-assisted versus manual reading of cervical cytology (MAVARIC): a randomised controlled trial.

BACKGROUND: The standard for reading cervical cytology is for a cytoscreener to manually search across an entire slide for abnormal cells using a conventional microscope. Automated technology can select fields of view to assess abnormal cells, which allows targeted reading by cytoscreeners. In the Manual Assessment Versus Automated Reading In Cytology (MAVARIC) trial, we compared the accuracy of these techniques for the detection of underlying disease. METHODS: For this randomised controlled trial, women aged 25-64 years undergoing primary cervical screening in Manchester, UK, were randomly assigned (1:2) to receive either manual reading only or paired reading (automation-assisted reading and manual reading), between March 1, 2006, and Feb 28, 2009. In the paired arm, two automated systems were used-the ThinPrep Imaging System and the FocalPoint GS Imaging System. General practices and community clinics were randomised to either ThinPrep or to SurePath (for the FocalPoint system) liquid-based cytology with block randomisation stratified by deprivation index. Samples were then individually randomised to manual reading only or paired reading only. Laboratory staff were unaware of the allocation of each slide and concealment was maintained until the end of the reporting process. The primary outcome was sensitivity of automation-assisted reading relative to manual reading for the detection of underlying cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in the paired arm. This trial is registered, number ISRCTN66377374. FINDINGS: 73,266 liquid-based cytology samples were obtained from women undergoing primary cervical screening; 24,688 allocated to the manual-only arm and 48,578 to the paired-reading arm. Automation-assisted reading was 8% less sensitive than manual reading (relative sensitivity 0·92, 95% CI 0·89-0·95), which was equivalent to an absolute reduction in sensitivity of 6·3%, assuming the sensitivity of manual reading to be 79%. Specificity of automation-assisted reading relative to manual reading increased by 0·6% (1·006, 95% CI 1·005-1·007). INTERPRETATION: The inferior sensitivity of automation-assisted reading for the detection of CIN2+, combined with an inconsequential increase in specificity, suggests that automation-assisted reading cannot be recommended for primary cervical screening.

Ancillary testing in liquid based cytology to distinguish cervical glandular neoplasia from tuboendometrial metaplasia in a young woman.

A 33-year old woman had a cervical sample taken at colposcopy clinic. Seven years prior to this, at the age of 26, she had had a cytological diagnosis of cervical glandular neoplasia (cytology descriptor indicated cells suspicious of endocervical neoplasia) and severe dyskaryosis. Confirmation and treatment were by LLETZ and knife cone, and, in keeping with England and Wales National Health Service guidelines, this woman was under follow-up by the colposcopy clinic. Intervening cytological follow-up included a number of negative cytological samples interspaced with one equivocal report. A recent repeat cytology which was rather cellular contained several hyperchromatic crowded cell groups (HCCG's). Careful examination revealed benign endometrial clusters, LUS, TEM and endocervical cells in strips showing pseudostratification and loss of polarity. Following an agar block, there was positive staining for p16 and Ki-67 in the abnormal groups whilst the benign TEM cells stained positive for bcl-2.

Differentiating between endocervical glandular neoplasia and high grade squamous intraepithelial lesions in endocervical crypts: cytological features in ThinPrep and SurePath cervical cytology samples.

A recent audit at our institution revealed a higher number of cases diagnosed as endocervical glandular neoplasia on ThinPrep (TP) cervical cytology samples (9 cases) as opposed to SurePath (SP) (1 case), which on histology showed only high-grade cervical intraepithelial neoplasia (CIN) with endocervical crypt involvement (CI). We attempted to ascertain the reasons for this finding by reviewing the available slides of these cases, as well as slides of cases diagnosed as glandular neoplasia on cytology and histology; cases diagnosed as high-grade squamous intraepithelial lesions (HSIL) on cytology which had CIN with CI on histology and cases with mixed glandular and squamous abnormalities diagnosed both cytologically and histologically. Single neoplastic glandular cells and short pseudostratified strips were more prevalent in SP than TP with the cell clusters in glandular neoplasia 3-4 cells thick, in contrast to the dense crowded centre of cell groups in HSIL with CI. The cells at the periphery of groups can be misleading. Cases with HSIL and glandular neoplasia have a combination of the features of each entity in isolation. The diagnosis of glandular neoplasia remains challenging and conversion from conventional to liquid based cervical cytology requires a period of learning and adaptation, which can be facilitated by local audit and review of the cytology slides in cases with a cytology-histology mismatch.

Metastatic transitional cell carcinoma causing a unilateral pleural effusion: a case report.

BACKGROUND: Transitional cell carcinoma (TCC) is a common neoplasm, but it is only rarely associated with serous effusions. The cytologic features of metastatic TCC in pleural effusions have been described only in occasional studies. One feature that raises the possibility of metastatic TCC in this setting is the presence of eosinophilic cytoplasmic inclusions (ECIs). CASE: Metastatic TCC was diagnosed in a pleural fluid from a 50-year-old man with a unilateral effusion. Two years previously he had been diagnosed with a poorly differentiated TCC of the urinary bladder (WHO grade 3, stage pT2 at least), and more recently he had also been diagnosed with an omental metastasis. Cytologic examination of the pleural fluid sample revealed numerous pleomorphic malignant cells, many of which were vacuolated. Numerous eosinophilic inclusions were identified within the malignant cells in the liquid based cytology (ThinPrep) preparation. Examination of the omental cake biopsy revealed similar appearances. CONCLUSION: ECIs within malignant pleural effusion fluid specimens should, if detected, raise the possibility of metastatic transitional cell carcinoma.