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Shepherd, Neil A.

Biography
I am Professor of Gastrointestinal (GI) Pathology at Gloucestershire Cellular Pathology Laboratory, based in Cheltenham. I am a specialised GI pathologist and have, and have had, wide-ranging involvement in national and international GI pathological education, training, research, audit, publishing and service provision. I have given more than 150 invited lectures at national & international symposia on GI pathology. I am Lead Editor of Morson & Dawson's Gastrointestinal Pathology, the flagship UK textbook of GI pathology and have been Associate Editor for GI pathology for Histopathology, the leading UK journal for Cellular Pathology, for 19 years. I have authored seven other books, 40 chapters & more than 250 original articles & reviews. I am a past President, former General Secretary and former Councillor of the British Division of the International Academy of Pathology. My research interests focus on the pathology of Barrett's oesophagus, colorectal polyps, inflammatory bowel disease and colorectal cancer although I also undertake collaborative research, in conjunction with the University of Exeter, on spectroscopic methods for the identification of pre-cancerous changes at several sites in the GI tract.

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2020 - 202622
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    PublicationOpen Access
    British Society of Gastroenterology guidelines on colorectal surveillance in inflammatory bowel disease
    (BMJ Publishing Group, 2025-04-30) East, James Edward; Gordon, Morris; Nigam, Gaurav Bhaskar; Sinopoulou, Vassiliki; Bateman, Adrian; Din, Shahida; Iacucci, Marietta; Kabir, Misha; Lamb, Christopher Andrew; Wilson, Ana; Al Bakir, Ibrahim; Dhar, Anjan; Dolwani, Sunil; Faiz, Omar; Hart, Ailsa; Hayee, Bu’Hussain; Healey, Chris; Leedham, Simon John; Novelli, Marco; Raine, Tim; Rutter, Matthew; Shepherd, Neil; Subramanian, Venkataraman; Vance, Margaret; Wakeman, Ruth; White, Lydia; Trudgill, Nigel; Morris, John; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    Patients with inflammatory bowel disease (IBD) remain at increased risk for colorectal cancer and death from colorectal cancer compared with the general population despite improvements in inflammation control with advanced therapies, colonoscopic surveillance and reductions in environmental risk factors. This guideline update from 2010 for colorectal surveillance of patients over 16 years with colonic inflammatory bowel disease was developed by stakeholders representing UK physicians, endoscopists, surgeons, specialist nurses and patients with GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodological support. An a priori protocol was published describing the approach to three levels of statement: GRADE recommendations, good practice statements or expert opinion statements. A systematic review of 7599 publications, with appraisal and GRADE analysis of trials and network meta- analysis, where appropriate, was performed. Risk thresholding guided GRADE judgements. We made 73 statements for the delivery of an IBD colorectal surveillance service, including outcome standards for service and endoscopist audit, and the importance of shared decision- making with patients. Core areas include: risk of colorectal cancer, IBD- related post- colonoscopy colorectal cancer; service organisation and supporting patient concordance; starting and stopping surveillance, who should or should not receive surveillance; risk stratification, including web- based multivariate risk calculation of surveillance intervals; colonoscopic modalities, bowel preparation, biomarkers and artificial intelligence aided detection; chemoprevention; the role of non- conventional dysplasia, serrated lesions and non- targeted biopsies; management of dysplasia, both endoscopic and surgical, and the structure and role of the multidisciplinary team in IBD dysplasia management; training in IBD colonoscopic surveillance, sustainability (green endoscopy), cost- effectiveness and patient experience. Sixteen research priorities are suggested.
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    PublicationOpen Access
    British Society of Gastroenterology, Association of Upper Gastrointestinal Surgery of Great Britain and Ireland and Royal College of Pathologists Delphi consensus guidance on biopsy sampling during upper gastrointestinal endoscopy in adult patients
    (2025-11-12) Srinivasa, Amar; Bendall, Oliver; Babikir, Amira; Ahmed, Shahd; Griffiths, Helen; Haslam, Neil; Catton, James; Cripps, Neil; Oates, Beverly; Morris, Allan; Bhandari, Pradeep; Banks, Matthew; Shepherd, Neil; Osborn, Michael; Bateman, Adrian; Sultana-Miah, Farhana; Husbands, Nikki; Banerjee, Saswata; Trudgill, Nigel; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    These guidance statements represent a practical approach to tissue sampling in the upper gastrointestinal tract during endoscopy in adult patients, outlining instances when biopsies should and should not be taken. Analysis of data from the UK National Endoscopy Database has shown wide variations in biopsy practice among endoscopists. Endoscopy providers with high rates of post-endoscopy upper gastrointestinal cancer take more inappropriate and less appropriate biopsies during endoscopy. This guidance document was commissioned by the British Society of Gastroenterology (BSG) as part of its Upper Gastrointestinal Endoscopy Quality Improvement programme and developed in line with the BSG guidance methodology. A systematic literature review was performed to review the evidence base. However, due to the low quality of evidence in this area, application of GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was not possible and therefore Good Practice Statements, along with Expert Opinions, were used for recommendations. In total, 32 statements or recommendations were initially created and voted on by members of the Guidance Development Group on a five-point scale (strongly agree to strongly disagree). Statements achieving over 80% agreement were adopted. Following voting, one statement did not achieve consensus and was removed, and one statement was amended. All statements achieved over 80% agreement following a second round of voting. In formulating this guidance document, we hope that it will standardise biopsy practice for upper gastrointestinal endoscopy. Outlining when not to undertake tissue sampling will in turn reduce pressure on histopathology services, reduce costs in the National Health Service, and improve sustainability in endoscopy and pathology.
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    PublicationOpen Access
    Deep learning for automated scoring of immunohistochemically stained tumour tissue sections – Validation across tumour types based on patient outcomes
    (CellPress, 2024-07-15) Kidal, Wanja; Cyll, Karolina; Kalsnes, Joakim; Islam, Rakibul; Julbo, Frida; Pradhan, Manohar; Ersvaer, Elin; Shepherd, Neil; Vlatkovic, Ljiljana; Tekpli, Xavier; Garred, Oystein; Kristensen, Gunnar; Askautrud, Hanne; Hveem, Tarjei; Danielsen, Havard; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and β-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9–98.5 %) for the nuclear model, 85.6 % (73.3–96.6 %) for the cytoplasmic model, and 78.4 % (75.5–84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.
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    PublicationOpen Access
    System transferability of Raman-based oesophageal tissue classification using modern machine learning to support multi-centre clinical diagnostics
    (Springer Nature, 2024-07-23) Blake, Nathan; Gaifulina, Riana; Isabelle, Martin; Dorney, Jennifer; Rodriguez-Justo, Manuel; Lau, Katherine; Ohrel, Stephanie; Lloyd, Gavin; Shepherd, Neil; Lewis, Aaran; Kendall, Catherine; Stone, Nick; Bell, Ian; Thomas, Geraint; Shepherd, Neil A.; Lloyd, Gavin; Shepherd, Neil; Kendall, Catherine; Healthcare Scientists; Medical and Dental
    Background The clinical potential of Raman spectroscopy is well established but has yet to become established in routine oncology workflows. One barrier slowing clinical adoption is a lack of evidence demonstrating that data taken on one spectrometer transfers across to data taken on another spectrometer to provide consistent diagnoses. Methods We investigated multi-centre transferability using human oesophageal tissue. Raman spectra were taken across three different centres with different spectrometers of the same make and model. By using a common protocol, we aimed to minimise the difference in machine learning performance between centres. Results 61 oesophageal samples from 51 patients were interrogated by Raman spectroscopy at each centre and classified into one of five pathologies. The overall accuracy and log-loss did not significantly vary when a model trained upon data from any one centre was applied to data taken at the other centres. Computational methods to correct for the data during pre-processing were not needed. Conclusion We have found that when using the same make and model of spectrometer, together with a common protocol, across different centres it is possible to achieve system transferability without the need for additional computational instrument correction.
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    An international inter-rater agreement study in the challenging diagnosis of squamous dysplasia of the oesophagus
    (Wiley, 2025-07-08) Patil, Ameya; Jiezhen, Tracy; Kosiorek, Heidi; Brown, Ian; Carneiro, Fatima; Gill, Anthony; Kumarasinghe, Priyanthi; Kushima, Ryoji; Sheahan, Kieran; Shepherd, Neil; Slavik, Tomas; Srivastava, Amitabh; Lauwers, Gregory; Langner, Cord; Pai, Rish; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    Aims: There is a lack of published literature on the diagnostic reproducibility of oesophageal squamous dysplasia using a two-tiered grading system. Methods and results: We identified 75 oesophageal biopsies, which were reviewed by 10 international pathologists twice (1500 total observations) with a > 4-week washout period. Between rounds, a consensus meeting refining diagnostic criteria was held and an atlas was created to provide illustrations. Overall agreement was fair with kappa of 0.35 and 0.32 in round 1 and 2, respectively. Agreement was moderate to fair for negative for dysplasia (ND) (round 1 = 0.41 and round 2 = 0.34) and poor for indefinite for dysplasia (IND) and low-grade dysplasia (LGD) (kappa <0.2). Agreement for high-grade dysplasia (HGD) was good in both rounds (round 1 = 0.64; round 2 = 0.61). In round 1, majority diagnosis (MDx, ≥6 of 10 raters agreeing) was seen in 51 (68%) cases with the majority classified as ND (N = 27) or HGD (N = 18). MDx was rarely achieved for LGD (N = 6). In round 2, MDx was seen in 49 (65%) cases (20 ND, 1 IND, 11 LGD and 17 HGD). Of the 40 cases with MDx for both rounds, 39 were concordant (15 HGD, 6 LGD and 18 ND). Conclusions: Overall agreement among pathologists in diagnosing squamous lesions is fair; however, HGD had good agreement. This study fills an important gap in our knowledge of the inter-rater variability in the diagnosis of oesophageal squamous dysplasia.
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    The isolated caecal patch lesion: a clinical, endoscopic and histopathological study
    (BMJ Publishing Group, 2020-03) Ekanayaka, Anju; Anderson, John; Lucarotti, Michele; Valori, Roland; Shepherd, Neil; Shepherd, Neil A.; Ekanyaka, Anju; Anderson, John; Lucarotti, Michele; Valori, Roland; Shepherd, Neil; Medical and Dental
    Objective: To describe and investigate the potential causes of the isolated caecal patch lesion, a previously undescribed endoscopic phenomenon of a lesion fulfilling endoscopic and histopathological criteria for chronic inflammatory bowel disease but without evidence of similar inflammatory pathology elsewhere at colonoscopy. Methods: Cases were collected prospectively by one specialist gastrointestinal pathologist over a 10-year period. Full endoscopic and histopathological analysis was undertaken and follow-up sought to understand the likely cause(s) of the lesions. Results: Six cases are described. Two had very close links with ulcerative colitis, one predating the onset of classical distal disease and the other occurring after previous demonstration of classical distal ulcerative colitis. Two occurred in younger patients and we postulate that these lesions may predict the subsequent onset of chronic inflammatory bowel disease. Finally two can be reasonably attributed to the effects of non-steroidal inflammatory agent therapy. Conclusions: Caecal patch lesions can be demonstrated in isolation. Despite the strong association of caecal patch lesions with ulcerative colitis, solitary lesions may well have disparate causes but nevertheless possess a close relationship with chronic inflammatory bowel disease.
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    Vascular intrusion is a mimic of true vascular invasion inlarge bowel adenomatous polyps
    (Wiley, 2025-07) Wong, Newton; Loughrey, Maurice; Bateman, Adrian; Rodriguez-Justo, Manuel; Shepherd, Neil; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    Aims: 'Vascular intrusion' is a proposed but poorly recognised phenomenon of colorectal adenomas whereby dysplastic epithelium is forced into blood vessels. This study aimed to validate its existence and to characterise histological features that distinguish it from true vascular invasion. Methods and results: Three gastrointestinal pathologists independently assessed 38 colorectal polyps showing possible vascular intrusion as two cohorts. After the cohort A (15 cases) assessment, the pathologists met to decide upon diagnostic criteria and consensus diagnoses. They met again after the cohort B (23 cases) assessment to establish final consensus diagnoses. Histological features found to favour vascular intrusion were: absence of adenocarcinoma; presence of adjacent epithelial misplacement; low-grade cytology; crush artefact; and presence of lamina propria among the intravascular glands. The proportion of cases where all three pathologists independently agreed upon diagnoses of vascular intrusion versus vascular invasion increased from 53% for cohort A to 74% for cohort B. However, while there were final consensus diagnoses of vascular intrusion and vascular invasion for 21 and seven cases, respectively, the assessors were unable to agree upon either diagnosis for 10 cases. Follow-up of 17 patients who had undergone polyp resection > 3 years previously (including eight with consensus diagnoses of vascular intrusion) did not demonstrate recurrent or metastatic colorectal carcinoma. Conclusions: Vascular intrusion may be caused by forcing of adenoma into vessels as part of epithelial misplacement or during resection or laboratory processing of the polyp. Histological features of the intravascular glands and surrounding adenoma help to distinguish this benign/artefactual phenomenon from true vascular invasion.
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    Current dilemmas in the pathological staging of colorectal cancer: the results of a national survey
    (Wiley, 2020-11-05) Wong, Newton; Bracey, Tim; Mozayani, Behrang; Bateman, Adrian; Novelli, Marco; Shepherd, Neil; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    Aims: Accurate and consistent pathological staging of colorectal carcinoma (CRC) in resection specimens is especially crucial to guide adjuvant therapy. The aim of this study was to assess whether certain staging scenarios yield discordant opinions in the setting of current international and UK national guidelines. Methods and results: Members of the UK Gastrointestinal Pathology External Quality Assurance Scheme were invited to complete an anonymous, on-line survey that presented 15 scenarios related to pT or pR staging of CRC, and three questions about the respondent. The survey invitation was e-mailed to 405 pathologists, and 184 (45%) responses were received. The respondents had discordant opinions on whether and how CRC pT or pR staging is affected by: acellular mucin lakes and duration after short-course radiotherapy; the nature of the carcinoma at a resection margin or peritoneal surface; and microscopic evidence of perforation. This discordance was rarely related to the respondent's occupation type, and was not related to duration of work as a consultant or the staging guidelines used. Conclusions: This survey confirms that there remain several clinically critical but unresolved pT and pR staging issues for CRC. These issues therefore deserve attention in future versions of international and national staging guidelines.
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    The indications for biopsy in routine upper gastrointestinal endoscopy
    (Wiley, 2020-12-31) Loughrey, Maurice; Shepherd, Neil; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    This review describes the indications and contraindications for endoscopic biopsy, in routine practice, of the upper gastrointestinal (GI) tract. We accept that this review provides grounds for controversy, as our stance in certain situations is counter to some national guidelines. Nevertheless, we provide evidence to support our viewpoints, especially on efficiency and economic grounds. We describe the particular controversies concerning the biopsy assessment of Barrett's oesophagus, chronic gastritis and the duodenum in the investigation of coeliac disease. We accept that there are indications for more extensive upper GI biopsy protocols in children than in adults; the latter constitute our main focus in this article. We would encourage detailed discussion between pathologists and their endoscopy colleagues about the indications, or lack of them, for routine upper GI endoscopic biopsy, as studies have shown that adherence to agreed guidelines has resulted in a very considerable diminution in the biopsy workload without compromising patient management. Furthermore, where biopsy is indicated, we emphasise the importance of accompanying clinical information provided to the pathologist, in particular regarding biopsy site(s), and regular feedback to endoscopists to improve and maintain the quality of such information. Finally, local dialogue is also advised, when necessary, to indicate to endoscopists the need to appropriately segregate biopsies into separate, individually labelled specimens, to maximise the information that can be derived by pathological evaluation and thereby improve the quality of the final pathology report.
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    Microvesicular hyperplastic polyp and sessile serrated lesion of the large intestine: a biological continuum or separate entities?
    (BMJ Publishing Group, 2023-03-16) Bateman, Adrian; Booth, Adam; Gonzalez, Raul; Shepherd, Neil; Shepherd, Neil A.; Shepherd, Neil; Medical and Dental
    The range of lesions with a serrated appearance within the large intestine has expanded and become more complex over the last 30 years. The majority of these were previously known as metaplastic polyps but are today called hyperplastic polyps (HPs). HPs show two main growth patterns: microvesicular and goblet cell-rich. The former type shows morphological and molecular similarities (eg, BRAF mutations) to the more recently described sessile serrated lesion (SSL). In this review, we debate whether these lesions represent a biological spectrum or separate entities. Whichever view is held, microvesicular HPs and SSLs are distinct from the goblet cell-rich HP and the traditional serrated adenoma (TSA), which may themselves share molecular changes (eg, KRAS mutations), with the goblet cell-rich HP representing a precursor to the TSA. Both SSLs and the goblet cell-rich HP-TSA pathway are routes to colorectal cancer within the serrated pathway and overlaps between them can occur, for example, a (BRAF-mutated) TSA may arise from an SSL.