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The clinical management of patients with dysplasia in chronic inflammatory bowel disease (IBD) is currently guided by Riddell et al.'s grading system (negative, indefinite, low grade, high grade) from 1983 which was based primarily on nuclear cytoarchitectural characteristics. Although most dysplasia in IBD resembles sporadic adenomas morphologically, other distinctive potential cancer precursors in IBD have been described over time. Recognizing the need for a updated comprehensive classification for IBD-associated dysplasia, an international working group of pathologists with extensive clinical and research experience in IBD devised a new classification system and assessed its reproducibility by having each participant assess test cases selected randomly from a repository of electronic images of potential cancer precursor lesions. The new classification system now encompasses three broad categories and nine sub-categories: 1) intestinal dysplasia (tubular/villous adenoma-like, goblet cell deficient, crypt cell, traditional serrated adenoma-like, sessile serrated lesion-like and serrated NOS), 2) gastric dysplasia (tubular/villous and serrated), and 3) mixed intestinal-gastric dysplasia. In the interobserver analysis, 67% of the diagnoses were considered definitive and achieved substantial inter-rater agreement. The key distinctions between intestinal and gastric lesions and between serrated and non-serrated lesions achieved substantial and moderate inter-rater agreement overall, respectively, however, the distinctions among certain serrated sub-categories achieved only fair agreement. Based on the Riddell grading system, definite dysplasia accounted for 86% of the collective responses (75% low grade, 11% high grade). Based on these results, this new classification of dysplasia in IBD can provide a sound foundation for future clinical and basic IBD research., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Tumor budding (TB) is an adverse prognostic factor in colorectal cancer (CRC). International consensus on a standardized assessment method has led to its wider reporting. However, uncertainty regarding its clinical value persists. This study aimed to (1) confirm the prognostic significance of TB, particularly in stage II CRC; (2) to determine optimum thresholds for TB risk grouping; and (3) to determine whether TB influences responsiveness to chemotherapy., Methods: TB was assessed in CRC sections from 1575 QUASAR trial patients randomized between adjuvant chemotherapy and observation. Optimal risk group cutoffs were determined by maximum likelihood methods, with their influence on recurrence and mortality investigated in stratified log-rank analyses on exploratory (n = 504), hypothesis-testing (n = 478), and final (n = 593) data sets., Results: The optimal threshold for high-grade TB (HGTB) was ≥ 10 buds per 1.23 mm 2 . High-grade TB tumors had significantly worse outcomes than those with lower TB: 10-year recurrence 36% versus 22% (risk ratio, 2.00 [95% CI, 1.62-2.45]; 2P < .0001) and 10-year mortality 50% vs. 37% (risk ratio, 1.53 [95% CI, 1.34-1.76]; 2P < .0001). The prognostic significance remained equally strong after allowance for other pathological risk factors, including stage, grade, lymphovascular invasion, and mismatch repair status. There was a nonsignificant trend toward increasing chemotherapy efficacy with increasing bud counts., Conclusions: TB is a strong independent predictor of recurrence. Chemotherapy efficacy is comparable in patients with higher and lower TB; hence, absolute reductions in recurrence and death with chemotherapy should be about twice as large in patients with ≥ 10 than < 10 TB counts., Competing Interests: Conflict of Interest Statement The authors have no conflicts of interest to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Venous invasion (VI) is an independent predictor of hematogenous metastasis and mortality in colorectal cancer (CRC) yet remains widely underreported. Its detection may require recognition of subtle morphologic clues, which at times are only unmasked with an elastin stain. This study evaluates the impact of a knowledge transfer initiative (KTI) on VI detection in a "real-world" pathology practice setting. Following participation in an interobserver variability study of VI detection (Kirsch et al, 2013), 12 participants received educational materials highlighting key issues in VI detection. Eighteen months later, participants were invited to submit pathology reports from all CRC resections signed out 18 months prior to and 18 months following the KTI (n = 266 and n = 244, respectively). Nine pathologists participated. Reports were reviewed for VI and other established prognostic factors. Numbers of elastin stains and tumor-containing blocks were also recorded. Comparative analyses were adjusted for baseline differences in tumor, lymph node, and metastasis stage; tumor location; use of neoadjuvant therapy; and number of tumor-containing blocks. VI detection increased significantly post-KTI versus pre-KTI (39.3% versus 18.4%, adjusted odds ratio [OR] 2.86 [1.91-4.28], P < .001). Increased VI detection post-KTI was observed in both stage II (31.8% versus 12.5%, adjusted OR 3.27 [1.45-7.42], P = .004) and stage III CRC (62.4% versus 28.2%, adjusted OR 4.23 [2.37-7.55], P < .001). All pathologists demonstrated increased VI detection post-KTI. Use of elastin stains was significantly higher post-KTI versus pre-KTI (61.5% versus 5.3% of cases respectively, P < .001). This study demonstrates the effectiveness of knowledge transfer in increasing VI detection in routine pathology practice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Tumor budding is a well-established adverse prognostic factor in colorectal carcinoma (CRC). It may represent a form of epithelial-to-mesenchymal transition (EMT), although the underlying mechanisms remain unclear. High-temperature requirement A3 (HtrA3) is an inhibitor of the bone morphogenetic protein pathway, the suppression of which has been linked to EMT. Since HtrA3 is highly expressed in the desmoplastic stroma at the CRC invasive front, we sought to evaluate the relationship between tumor budding and HtrA3 expression in 172 stage II CRC resection specimens. All tumors were evaluated for tumor budding, with the highest budding slide selected for pan-keratin (CK) and HtrA3 immunohistochemistry. Representative areas of tumor core and invasive front, including budding and non-budding areas, were marked on CK stained slides, and then evaluated on HtrA3 stained slides. HtrA3 expression in tumor cells (tHtrA3) and peritumoral stroma (sHtrA3) was assessed for staining percentage and intensity (the product yielding a final score). Tumors with high-grade tumor budding (HGTB) showed increased expression of sHtrA3 in budding areas compared to non-budding areas at the invasive front (P<0.001). In addition, sHtrA3 expression at the invasive front was significantly higher in HGTB tumors compared to minimally budding tumors (P<0.05). tHtrA3 expression at the invasive front was significantly associated with high histological grade (P<0.05). Higher sHtrA3 expression in the tumor core (but not invasive front) was significantly associated with decreased 5-year overall survival on univariate analysis (P<0.05), but not multivariate analysis. HtrA3 expression in the peritumoral stroma of patients with stage II CRC is associated with HGTB and may be a novel marker of poor outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

Bone morphogenetic proteins (BMPs) are a group of growth factors with dual functions in cancer development and progression. Recently, certain tumor-promoting roles have been identified for selected antagonists/inhibitors (BMPIs) of this developmental pathway. A recent focus on the implication of BMP in colorectal cancer progression has emerged, mainly due to the presence of inactivating mutations in several members of the canonical signaling cascade. However, the detailed expression profiles of BMPIs remain largely unknown. Based on our previous work, whereby three specific BMPIs, gremlin-1 (GREM1), high-temperature requirement A3 (HTRA3) and follistatin (FST) were collectively overexpressed in desmoplastic cocultures of colorectal cancer (CRC), here, we undertook an immunohistochemical approach to describe the patterns of their expression in CRC patients. Two major characteristics described the BMPI expression signature: First, the synchronous and coordinated stromal and epithelial overexpression of individual BMPIs in desmoplastic lesions, which demonstrated that all three of them contribute to increasing levels of BMP antagonism in such areas. Second, the presence of microenvironmental polarity in the BMPI pattern of expression, which was indicated through the preferential expression of HTRA3 in the stromal, and the parallel FST/GREM1 expression in the epithelial component of the investigated sections. In addition, expression of HTRA3 in the epithelial compartment of the tumors demonstrated a significant predictive power to discriminate between tumor-budding-bearing and tumor-budding-free desmoplastic microenvironments. Together, these findings contribute to the understanding of signaling dynamics of BMP antagonism in the colorectal cancer desmoplastic invasion front., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Surveillance for neoplasia in colitis is the most challenging diagnostic colonoscopic procedure. The detection and treatment of colorectal dysplasia in inflammatory bowel disease remain problematic to the point that unsuspected colorectal cancers (CRCs) are still identified. Excellent bowel preparation and use of high-resolution colonoscopes with chromoendoscopy facilitate the detection and characterization of subtle neoplasia. This approach is superior to taking random biopsy specimens and should be the standard of care for surveillance but requires adequate training. Suspicious lesions should be assessed carefully and described using objective terminology. The terms dysplasia-associated lesions/masses and flat dysplasia are best avoided because they may be open to misinterpretation. Most suspicious lesions detected during surveillance can be removed endoscopically, precluding the need for surgery. Nevertheless, endotherapy in colitis can be difficult as a result of underlying inflammation and scarring. Lesions that are not endoscopically resectable need to be removed surgically, although the possibility that some lesions might be amenable to local resection (including lymphadenectomy) rather than subtotal colectomy may need to be re-evaluated. Despite surveillance programs, patients still present clinically with CRC. This may occur because lesions are missed (possibly because of the failure to use optimal techniques), lesions are not adequately removed, patients fail to return for colonoscopy, or CRCs arise rapidly in mucosa that is minimally dysplastic and the CRCs are not recognized as being potentially invasive even on biopsy. Future advances in, for example, stool DNA assays, use of confocal endomicroscopy, or use of endoscopic ultrasound, may help in the identification of high-risk patients and the assessment of dysplastic lesions., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Venous invasion (VI) is an independent prognostic indicator in colorectal cancer and may prompt consideration for adjuvant chemotherapy in patients with stage II tumors. Recent evidence suggests that VI is underreported in colorectal cancer and that detection may be enhanced by an elastin stain. This study aimed (1) to determine the impact of an elastin stain on VI detection and on interobserver agreement between gastrointestinal (GI) and non-GI pathologists, and (2) to identify factors associated with increased VI detection. Forty hematoxylin and eosin (H&E)-stained slides were circulated to 6 GI and 6 non-GI pathologists who independently assessed the VI status as positive, negative, or equivocal. Six weeks later, 40 corresponding Movat-stained slides were recirculated together with the original H&E slides and reassessed for VI status. Detection of VI was >2-fold higher with a Movat stain compared with an H&E stain alone (46.4% vs. 19.6%, P=0.001). GI pathologists detected VI more frequently than non-GI pathologists on both H&E (30.0% vs. 9.2%, P=0.029) and Movat (58.3% vs. 34.6%, P=0.018) stains. There was higher interobserver agreement in the case of a Movat stain, particularly for extramural VI (H&E: κ=0.23 vs. Movat: κ=0.41). A poststudy survey indicated that GI pathologists and non-GI pathologists applied similar diagnostic criteria but that GI pathologists more frequently applied "orphan arteriole" and "protruding tongue" signs as diagnostic clues to VI. This study confirms that VI is underdetected on H&E and highlights the role of elastin staining in improving VI detection and interobserver agreement. Strategies to improve VI detection are warranted.

Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010.  They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.

Tumor 'budding', loosely defined by the presence of individual cells and small clusters of tumor cells at the invasive front of carcinomas, has received much recent attention, particularly in the setting of colorectal carcinoma. It has been postulated to represent an epithelial-mesenchymal transition. Tumor budding is a well-established independent adverse prognostic factor in colorectal carcinoma that may allow for stratification of patients into risk categories more meaningful than those defined by TNM staging, and also potentially guide treatment decisions, especially in T1 and T3 N0 (Stage II, Dukes' B) colorectal carcinoma. Unfortunately, its universal acceptance as a reportable factor has been held back by a lack of definitional uniformity with respect to both qualitative and quantitative aspects of tumor budding. The purpose of this review is fourfold: (1) to describe the morphology of tumor budding and its relationship to other potentially important features of the invasive front; (2) to summarize current knowledge regarding the prognostic significance and potential clinical implications of this histomorphological feature; (3) to highlight the challenges posed by a lack of data to allow standardization with respect to the qualitative and quantitative criteria used to define budding; and (4) to present a practical approach to the assessment of tumor budding in everyday practice.

Aims: Venous invasion (VI) is a known independent prognostic indicator of recurrence and survival in colorectal cancer. The guidelines of the Royal College of Pathologists (RCPath) state that, in a series of resections, extramural VI should be detected in at least 25% of specimens. However, there is widespread variability in the reported incidence, and this may affect patient access to adjuvant therapy. This study aims to clarify the current practice patterns of pathologists regarding the assessment of VI and to identify factors associated with an increased self-reported VI detection rate., Methods: A population-based survey was mailed to 361 pathologists in the province of Ontario, Canada., Results: The overall response rate was 64.9%. Most pathologists were practicing in community-based centres (66.2%) and approximately half had been in practice for over 15 years (53.5%). A subspecialist interest in gastrointestinal (GI) pathology was declared by 27.3% of pathologists. The majority of pathologists (70.2%) reported that they detected VI in less than 10% of resection specimens, with only 9.1% reporting VI detection rates above 20%. Standardised reporting criteria were applied by 62.1%. Special stains were employed by 57.6% if VI was suspected on H&E-stained sections. Practice in a university-affiliated centre, a subspecialist interest in GI pathology and the acceptance of the 'orphan arteriole' sign were all independently associated with a self-reported VI detection rate above 10% on multivariate analysis., Conclusions: Self-reported VI detection rates are low among most pathologists. Even among specialist GI pathologists practicing in university-affiliated centres, few reported a detection rate close to that recommended by the RCPath. Strategies to increase the detection of VI may be required.

Aims: MYH is a DNA glycosylase in the base excision repair pathway. Germ-line biallelic mutations in the MYH gene are associated with the development of multiple colorectal adenomas and colorectal carcinoma (CRC). A slightly increased risk of CRC is suggested in monoallelic MYH mutation carriers. The aim was to characterize the histopathological features of carcinomas from biallelics and monoallelics., Methods and Results: Clinicopathological features of 57 colorectal carcinomas from 50 patients identified in familial CRC registries were recorded. These included 16 cancers from 14 MYH biallelics; 25 cancers from 22 MYH monoallelics; and 16 cancers from 14 controls. Carcinomas in biallelics demonstrated tubular, papillary or cribriform patterns as the predominant histological subtype, and main histological groups differed according to mutation status (P = 0.0053). All biallelic cancers were low grade, with high-grade tumours more common in monoallelics and controls (P = 0.002). Synchronous polyps were observed in 75% of biallelics, 33% of monoallelics and 43% of controls (P = 0.035). Serrated carcinoma was the predominant type in 12% (3/25) of the monoallelics but in none of the biallelics or controls. MYH immunohistochemistry failed to distinguish between groups., Conclusions: Neither pathological features nor immunohistochemistry could predict the MYH mutation status of CRCs in this study.

A roundtable consensus meeting was held to consolidate current knowledge on the etiology of colorectal cancer in patients with inflammatory bowel disease and to review current strategies, both diagnostic and preventive, specifically addressing the role of 5-aminosalicylic acid. Specific topics that were addressed included: the epidemiology of colorectal cancer, including an assessment of risk factors and the impact of colonoscopy on colorectal cancer incidence and mortality; the origin and evolution of dysplasia nomenclature and the natural history of dysplasia; review of the experience of St. Mark's Hospital (London) as gleaned from its surveillance database; mechanisms by which 5-aminosalicylic acid is thought to exert a chemopreventive effect; the potential future role of 5-aminosalicylic acid in chemopreventive strategies; chemoprevention in familial adenomatous polyposis; and other future research directions. This article provides a comprehensive overview of the issues discussed and should act as a guide to shaping the design of future studies in this area.

The reporting of colorectal cancer is facilitated by the provision of a checklist giving the features required for good patient care. However, the practicalities of applying such a checklist may not be straightforward. Familiar examples include finding the prescribed number of lymph nodes, distinguishing mesenteric tumor deposits from replaced lymph nodes, and deciding if a cluster of malignant cells in a lymph node sinus counts as metastasis. Checklists have traditionally focused on prognostic factors and, particularly, tumor stage. It is becoming increasingly clear that additional factors, whether morphological or molecular, will be needed for future clinical management. It is also evident that prognosis is strongly influenced by the surgical technique used, most notably by the introduction of total mesorectal excision in the case of rectal cancer. Adjuvant therapy is playing an increasingly important role in the management of colorectal cancer, and it is inevitable that morphological and molecular markers will be used to predict responses to the expanding range of therapeutic modalities. Neoadjuvant or preoperative radiotherapy is being offered to patients with advanced rectal cancer and can greatly modify the pathologic findings in operative specimens. For all the preceding reasons, the work of diagnostic pathologists has become increasingly complex and demanding. The 6th edition of the TNM classification fails to meet many of the challenges posed by the realities of modern cancer management. In fact, by changing the rules for staging without strong justification and introducing diagnostic criteria that are unhelpful and lack a good evidence base, there is a real danger that the community of pathologists will fail to engage with reporting recommendations in a standardized manner and that the quality of reporting will decline.

Purpose of Review: To examine and clarify the nomenclature and histologic lesions identified as serrated mucosal lesions of the colorectum, including serrated adenomas, sessile serrated polyps (also known as sessile serrated adenomas) and hyperplastic polyps. This is timely given the significant confusion in ascribing a microscopic diagnosis and clinical utility of such a diagnosis., Recent Findings: The emergence of sessile serrated polyps (or adenomas) as distinct histomorphologic lesions from serrated adenomas, as well as the appreciation of the possibility of different modes of dysplasia exhibited in serrated lesions., Summary: Clarification of the microscopic features, nomenclature and biology of serrated lesions are important for accurate histologic diagnosis, and in clinical terms for useful outcomes assessment, recommendations for follow-up and risk stratification.

In chronic ulcerative colitis, the object of surveillance is prevention of cancer or at least prevention of death from cancer by diagnosis at an early curable stage or by detection at a pre-malignant phase. Patients must be informed about their cancer risk as well as the limitations of endoscopic surveillance and the availability of surgical alternatives. Physicians must bear in mind the risks, benefits and costs of surveillance procedures. Patients at greatest risk of cancer for whom endoscopic surveillance is warranted are those with extensive colitis of greater than 8 years duration. Colonoscopy should be performed every 1 to 2 years at which time multiple biopsies are obtained from every 10-12 cm of normal-appearing mucosa. Targeted biopsies should also be obtained from areas where the surface appears raised as a broad-based polyp, low irregular plaque or villiform elevation, or from an unusual ulcer, particularly one with raised edges, or from a stricture. Typical inflammatory polyps need not be sampled. Colectomy is recommended in the presence of multifocal high-grade dysplasia if confirmed by an experienced pathologist. The identification of a mass lesion associated with any degree of overlying dysplasia is also a generally accepted indication for colectomy, while persistent low-grade dysplasia without a mass is somewhat more controversial. Recently introduced biomarkers may replace or supplement dysplasia in surveillance programmes as well as provide new information about malignant transformation.