The epidemiology, healthcare and societal burden of basal cell carcinoma in Wales 2000-2018: a retrospective nationwide analysis.

BACKGROUND: Basal cell carcinoma (BCC) represents the most commonly occurring cancer worldwide within the white population. Reports predict 298 308 cases of BCC in the UK by 2025, at a cost of £265-366 million to the National Health Service (NHS). Despite the morbidity, societal and healthcare pressures brought about by BCC, routinely collected healthcare data and global registration remain limited. OBJECTIVES: To calculate the incidence of BCC in Wales between 2000 and 2018 and to establish the related healthcare utilization and estimated cost of care. METHODS: The Secure Anonymised Information Linkage (SAIL) databank is one of the largest and most robust health and social care data repositories in the UK. Cancer registry data were linked to routinely collected healthcare databases between 2000 and 2018. Pathological data from Swansea Bay University Health Board (SBUHB) were used for internal validation. RESULTS: A total of 61 404 histologically proven BCCs were identified within the SAIL Databank during the study period. The European age-standardized incidence for BCC in 2018 was 224.6 per 100 000 person-years. Based on validated regional data, a 45% greater incidence was noted within SBUHB pathology vs. matched regions within SAIL between 2016 and 2018. A negative association between deprivation and incidence was noted with a higher incidence in the least socially deprived and rural dwellers. Approximately 2% travelled 25-50 miles for dermatological services compared with 37% for plastic surgery. Estimated NHS costs of surgically managed lesions for 2002-2019 equated to £119.2-164.4 million. CONCLUSIONS: Robust epidemiological data that are internationally comparable and representative are scarce for nonmelanoma skin cancer. The rising global incidence coupled with struggling healthcare systems in the post-COVID-19 recovery period serve to intensify the societal and healthcare impact. This study is the first to demonstrate the incidence of BCC in Wales and is one of a small number in the UK using internally validated large cohort datasets. Furthermore, our findings demonstrate one of the highest published incidences within the UK and Europe.

Genetic and Epigenetic Intra-tumour Heterogeneity in Colorectal Cancer.

INTRODUCTION: Colorectal cancer (CRC) is a highly heterogeneous disease, with pathologically similar cancers having completely different responses to treatment and patient survival. Intra-tumour heterogeneity (defined as distinct morphological and phenotypic differences) has recently been demonstrated to be an important factor in the development and behaviour of cancer cells and can be used to determine response to anticancer therapy. METHOD: Patients with resected CRC had DNA extracted from eight defined tumour areas which were analysed for two genetic mutations (BRAF and KRAS) and one epigenetic trait (CpG island methylator phenotype/CIMP). Normal adjacent tissue was studied as control. RESULTS: Twelve patients with CRC were included. Intra-tumoural heterogeneity for KRAS mutation was seen in 2 patients (17%). There was no statistical evidence of CIMP status heterogeneity (p = 0.85), but 6 of the 12 patients (50%) demonstrated at least one heterogeneous area within the tumour. DISCUSSION: Intra-tumoural heterogeneity for both genetic and epigenetic factors in CRC is more prevalent than previously thought in Stage II and Stage III CRC. This study provides new insight into epigenetic heterogeneity of CRC and supports the development of a more targeted biopsy strategy to support expansion of personalised treatment.

Mirtazapine-induced steatosis
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Mirtazapine is a commonly used drug indicated for the treatment of severe depression. It works as a presynaptic α2-adrenoreceptor antagonist that increases central noradrenergic and serotonergic neurotransmission, and it is metabolized by the p450 cytochrome oxidase system. There is evidence within the literature to suggest a link between antidepressants and increased liver enzymes, although case reports demonstrating a link between mirtazapine specifically and steatosis are sparse. Here, we present a case of mirtazapine-induced steatosis in a 48-year-old office worker. She presented with painless jaundice of 2 days duration and generalized lethargy and peripheral edema present for 3 weeks beforehand. Extensive investigations were undertaken to identify the cause of her jaundice but no biochemical, blood-borne, or anatomical cause could be found. Mirtazapine was subsequently stopped, and her liver function, both clinically and biochemically, improved rapidly. She made a full recovery after discontinuation of her mirtazapine.
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Clinicopathological characteristics of colorectal cancer presenting under the age of 50.

OBJECTIVE: Previous studies suggest that colorectal cancer (CRC) presenting at a young age tends to be advanced, proximally located and associated with a poor outcome. The aim of this study was to analyse characteristics of CRC in a cohort under the age of 50. METHOD: A single centre retrospective cohort study of consecutive patients under the age of 50 receiving potentially curative resection was performed. Clinical and pathological data was collected from a prospectively maintained cancer registry database. Of 2799 patients having CRC resections between 2002 and 2013, 103 patients (3.6%) were under 50, with full survival data available on 98 (3.5%). An additional 7 patients under 50 had inoperable disease. The proportion of patients under 50 was constant throughout the study period. A group of 98 consecutive patients over the age of 50 undergoing surgery for colorectal cancer in the same centre was used for comparison. Just 7 patients (7%) had pathologically verified FAP or Lynch syndrome, although there was a high suspicion of Lynch syndrome in further 3 patients. CONCLUSION: There was a higher proportion of rectal cancer in the under 50s (p < 0.0001), although there was no significant difference in the staging of the disease or lymph node positivity. There was a greater incidence of poor differentiation in the younger patients, but there was no effect on 5-year overall survival (71.4%) which is much higher than in the reported literature. The majority of colorectal cancers presenting under the age of 50 were sporadic, and a higher proportion of rectal cancer was observed compared with the older patients, and as compared to the published literature on younger CRC patients. This paper adds to the literature by demonstrating that despite advanced stage at presentation of colorectal cancer requiring extended surgery and multimodal treatment, this young age group experienced good overall survival.

Revisiting basal cell carcinoma clinical margins: Leveraging natural language processing and multivariate analysis with updated Royal College of Pathologists histological reporting standards.

INTRODUCTION: Data supporting the current British Association of Dermatologists guidelines for the management of basal cell carcinoma (BCC) are based on historic studies and do not consider the updated Royal College of Pathologists (RCPath) histological reporting standards. The aim of this study was to use natural language processing (NLP)-derived data and undertake a multivariate analysis with updated RCPath standards, providing a contemporary update on the excision margins required to achieve histological clearance in BCC. METHODS: A validated NLP information extraction model was used to perform a rapid multi-centre, pan-specialty, consecutive retrospective analysis of BCCs, managed with surgical excision using a pre-determined clinical margin, over a 17-year period (2004-2021) at Swansea Bay University Health Board. Logistic regression assessed the relationship between the peripheral and deep margins and histological clearance. RESULTS: We ran our NLP algorithm on 34,955 BCCs. Out of the 1447 BCCs that met the inclusion criteria, the peripheral margin clearance was not influenced by the BCC risk level (p = 0.670). A clinical peripheral margin of 6 mm achieved a 95% histological clearance rate (95% confidence interval [CI], 0.93-0.98). Tumour thickness inversely affected deep-margin histological clearance (OR 0.720, 95% CI, 0.525-0.991, p < 0.05). Depth level 2 had a 97% probability of achieving deep-margin histological clearance across all tumour thicknesses. CONCLUSION: Updated RCPath reporting standards minimally impact the peripheral margin histological clearance in BCC. Larger clinical peripheral margins than those indicated by current guidelines may be necessary to achieve excision rates of ≥95%. These findings emphasise the need for continuous reassessment of clinical standards to enhance patient care.

An unusual delayed rectal metastasis from prostate cancer masquerading as primary rectal cancer.

INTRODUCTION AND IMPORTANCE: Rectal metastasis of prostate cancer origin is exceedingly rare. Its clinical presentation, endoscopic morphology, and histopathology are similar to primary rectal cancer. Misdiagnosis may lead to inappropriate treatment. CASE PRESENTATION: We report a case of a gentleman in his 80's with a history of treated prostate cancer T3aN0M0 with radical prostatectomy sixteen years ago. He presented with one-year complaints of altered bowel habits and weight loss. Physical and rectal examination was unremarkable. Colonoscopy manifested some inflammatory changes in the rectum. The pelvis magnetic resonance imaging (MRI) showed an abnormal posterior rectal wall thickening 2 cm above the anal canal. Biopsy confirmed poorly differentiated adenocarcinoma of prostate origin. The staging workup was negative for other distant metastasis. After a multidisciplinary decision, the patient was started on androgen deprivation therapy and given palliative radiotherapy to the rectum. Six weeks later, the patient was stable with mild radiation proctitis. CLINICAL DISCUSSION: Management of rectal metastasis varies depending on the patient's choice, the extent of metastatic burden, symptoms, age, life expectancy, quality of life and comorbidities. While surgery remains the standard of care, other option including radiotherapy, hormonal therapy and chemotherapy has been documented in the literature with survival of few weeks to 2 years. CONCLUSION: Delayed rectal metastasis of prostate cancer after radical prostatectomy is a rare entity. Its clinical presentation and endoscopic and histopathological findings of rectal metastasis are similar to primary colorectal cancer, making diagnosis more demanding.

Feasibility and economic assessment of chromocolonoscopy for detection of proximal serrated neoplasia within a population-based colorectal cancer screening programme (CONSCOP): an open-label, randomised controlled non-inferiority trial.

BACKGROUND: Most post-colonoscopy interval colorectal cancers are proximal; serrated polyps are often precursors to these cancers and are considered difficult to detect. We assessed the safety, feasibility, and economic effect of chromocolonoscopy on detection of proximal serrated neoplasia. METHODS: We did an open-label, multicentre, randomised, controlled non-inferiority trial including patients from Bowel Screening Wales centres. Participants who tested positive for faecal occult blood and who were eligible for and considered fit to have colonoscopy (patients with known cases of polyposis syndromes, Lynch syndrome, and chronic inflammatory disease were excluded) were randomly assigned (1:1; with the use of minimisation, stratified by centre with an 80:20 random element) to either standard white light colonoscopy (standard group) or chromocolonoscopy (indigo carmine dye [0·2%]; chromocolonoscopy group) using a secure, internet-based, computerised, randomisation system that used centralised, dynamic allocation. Participants were followed up for 1 year and data from index colonoscopies and associated clearance procedures were analysed. All proximal polyps were reviewed by an expert pathologist panel. The main outcome on which power was based was time taken to perform the colonoscopy procedure, defined as from the time when the scope was inserted to withdrawal from the anus, assessed in the per-protocol population. The non-inferiority margin was 15 min. This trial is complete and is registered with ClinicalTrials.gov, number NCT01972451. FINDINGS: Between Nov 20, 2014, and June 16, 2016, 741 (72%) of 1031 patients screened were eligible and consented: 360 were randomly assigned to white light colonoscopy and 381 to chromocolonoscopy. In the chromocolonoscopy group, the procedure took a mean of 36·8 min (SD 15·0), compared with a mean of 30·6 min (13·7) in the standard group (mean difference 6·3 min [95% CI 4·2-8·4] longer with chromocolonoscopy than in the standard group). The mean difference was within the prespecified non-inferiority margin. Detection rates for proximal serrated lesions were significantly higher in the chromocolonoscopy group than in the control group (45 [12%] of 381 patients vs 23 [6%] of 360 patients; odds ratio 1·96 [95% CI 1·16-3·32]; p=0·012). Serious adverse events (four cases of postpolypectomy bleeding [two in each group], and one case of anxiety and hyperventilation [in the chromocolonoscopy group]), colonoscopy quality measures, comfort scores, and sedation were similar between groups. INTERPRETATION: Chromocolonoscopy is feasible within a population-based colorectal cancer screening programme, is safe, and has significantly increased detection of proximal serrated neoplasia and other polyp types compared with standard colonoscopy. Larger randomised trials of chromocolonoscopy, powered for improved detection of significant serrated polyps and for longer-term follow-up to investigate the effect on reduction of interval cancers within screening populations, are warranted. FUNDING: Health and Care Research Wales (RfPPB-1021).

DNA hypermethylation as a predictor of extramural vascular invasion (EMVI) in rectal cancer.

PURPOSE: DNA hypermethylation in gene promoter regions (CpG islands) is emerging as an important pathway in colorectal cancer tumourigenesis. Whilst genetic mutations have been associated with extramural vascular invasion (EMVI) in rectal cancer, no such association has yet been made with epigenetic factors. METHODS: 100 consecutive neoadjuvant-naïve patients undergoing curative surgery for rectal were classified according to the presence or absence of EMVI on histopathological examination. DNA was extracted from tumours and subjected to bisulfite conversion and methylation-specific PCR to determine CIMP status (high, intermediate, or low; according to a validated panel of 8 genes). CIMP status was correlated with EMVI status, histopathological, clinical, and demographic variables, in addition to overall (OS) and disease free (DFS) survival. RESULTS: 51 patients were characterised as CIMP-low, 48 CIMP-intermediate, and one patient CIMP-high. EMVI-positivity was associated with CIMP-intermediate epigenotype (p < 0.001). Patients with EMVI-positive tumours were found to have significantly more advanced disease by pT, pN, and pAJCC categorisation (p = 0.002, p < 0.001, and = p < 0.001, respectively). EMVI-positivity was significantly associated with the requirement for adjuvant chemotherapy (p < 0.001), and worse DFS but not OS (p = 0.012 and p = 0.052). CONCLUSIONS: Given the association between CIMP-intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients' cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer.

Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: Influence of the CpG island methylator phenotype.

AIM: To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer. METHODS: Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed. RESULTS: There were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced "T" stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence. CONCLUSION: We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.

A pathologist's survey on the reporting of sessile serrated adenomas/polyps.

AIM: The purpose of this survey was to ascertain reporting habits of pathologists towards sessile serrated adenomas/polyps (SSA/P). METHODS: A questionnaire designed to highlight diagnostic criteria, approach and clinical implications of SSA/P was circulated electronically to 45 pathologists in the UK and North America. RESULTS: Forty-three of 45 pathologists agreed to participate. The vast majority (88%) had a special interest in gastrointestinal (GI) pathology, had great exposure to GI polyps in general with 40% diagnosing SSA/P at least once a week if not more, abnormal architecture was thought by all participants to be histologically diagnostic, and 11% would make the diagnosis if a single diagnostic histological feature was present in one crypt only, while a further 19% would diagnose SSA/P in one crypt if more than one diagnostic feature was present. The vast majority agreed that deeper sections were useful and 88% did not feel proliferation markers were useful. More than one-third did not know whether, or did not feel that, their clinicians were aware of the implications of SSA/P. CONCLUSIONS: 98% of pathologists surveyed are aware that SSA/P is a precursor lesion to colorectal cancer, the majority agree on diagnostic criteria, and a significant number feel that there needs to be greater communication and awareness among pathologists and gastroenterologists about SSA/P.

Coeliac disease presenting as chronic cough in an 8-year-old child.

Patients with the 'classical' gastrointestinal symptoms of coeliac disease (CD) are usually readily diagnosed and treated with a gluten exclusion diet. However, the advent of sensitive serological investigations has revealed that over half of childhood CD remains asymptomatic or presents with more subtle non-gastrointestinal symptoms, with a significant risk to the health of undiagnosed children. In view of its changing presentation there is an increasing need for clinicians to have a low threshold to investigate patients for this disease. Rare cases of CD associated with respiratory symptoms have been reported. The authors report an interesting case presenting as chronic cough in an otherwise asymptomatic 8-year-old girl. As a result of having a low threshold of suspicion for underlying CD, a diagnosis has been made and the long-term health risks of undiagnosed disease have been improved in both the patient and her immediate family.