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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.)

Germline activating platelet-derived growth factor receptor alpha (PDGFRA) mutations have been described in four families. All the index patients have presented with multiple mesenchymal tumors of the gastrointestinal tract. We identified a fifth family with four first-degree relatives that harbor a PDGFRA exon 18 (D846V) germline mutation. The affected kindred have a unique phenotype including coarse facies and skin, broad hands and feet, and previously undescribed premature tooth loss. While the index patient presented with multiple small bowel inflammatory fibroid polyps (IFPs) and has a gastric gastrointestinal stromal tumor (GIST), no tumors have yet been identified in other family members. We describe the pathology, genetics, the incomplete penetrance and variable expressivity of the familial PDGFRA-mutation syndrome referencing the mouse knock-in Pdgfra model. We speculate on the role of the telocyte, a recently described CD34, PDGFRA+ stromal cell, in the development of inflammatory fibroid polyps and the somatic phenotype., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.)

Neuroendocrine tumors (NETs) account for 2% of tumors of the gastrointestinal tract, most occurring in the small intestine. A size of 2 cm is generally regarded as a cut-off point for risk of lymph node metastasis in intestinal neuroendocrine tumors in the absence of other high-risk features; however, metastatic disease has been reported in 12% of tumors of the jejunum and ileum measuring 1 cm or less. Archives from 2 institutions were searched for ileal NETs measuring 1 cm or less, and selected data were recorded. Twenty-one ileal NETs were identified measuring ≤1 cm. Six (29%) were multifocal and 7 (33%) had distant metastasis at diagnosis. Regional lymph nodes were examined in 14 cases (67%), and 10 of these cases (71%) showed lymph node metastasis. Mean primary tumor size in cases with nodal metastasis was 7.3 mm. In this series of ileal NETs ≤1 cm in size, the rate of lymph node metastasis was 48% overall and 71% for cases with regional lymph node resections. In addition, 33% showed distant metastasis at the time of diagnosis. Tumors as small as 3 mm and those confined to the submucosa can give rise to nodal metastasis, emphasizing the need for consideration of local resection with regional lymphadenectomy, even for subcentimeter ileal NETs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Following restorative proctocolectomy with an ileal pouch-anal anastomosis, the small bowel mucosa undergoes several specific histologic adaptions, which may be unrelated to the underlying disease or symptoms of pouchitis. An increase in intraepithelial lymphocytes (IELs) has not been described as part of this spectrum. Mucosal biopsies of the ileal pouch and afferent limb of 230 patients (mean age: 45.7y [18.3-74.7], gender [female/male]: 117/113) with a functioning ileal pouch-anal anastomosis (mean time since ileostomy closure: 10.8months) and associated clinically annotated outcome data were assessed for IELs/100 enterocytes. Forty-two patients (18.3%) showed an increase in IELs (≥20 IELs/100 enterocytes [range 20-39]), in pouch and/or afferent limb biopsies. Intraepithelial lymphocytosis was more commonly observed in afferent limb compared to pouch biopsies (18.8% vs 8.3%; P = .42) and in familial adenomatous polyposis compared to ulcerative colitis patients (16% vs 8%; P = 0.36), but neither difference reached statistical significance. No cases with increased IELs displayed severe villous blunting. Increased IELs were not significantly associated with age, sex, ethnicity, smoking history, time since ileostomy, use of antibiotics, biologic agents, anti-diarrheal agents or probiotics, C-reactive protein levels or differential white cell count. None of the 42 patients with increased IELs had positive celiac serology (anti-human tissue transglutaminase IgA [ELISA] with corresponding total serum IgA). Intraepithelial lymphocytosis in pouch biopsies may represent a subclinical response to an altered bacterial microenvironment. Pathologists should be aware that intraepithelial lymphocytosis is part of the spectrum of changes in pouch biopsies, and only rarely is due to celiac disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Anti-tumor necrosis factor α (anti-TNF-α) therapy can result in endoscopic healing, reduction of symptoms, and reduced need for surgery and hospitalization in many patients with Crohn's disease (CD). Earlier data suggested that anti-TNF-α therapy may be associated with fibrosis and stricturing. We sought to determine whether anti-TNF-α therapy affects histologic inflammation, fibrosis, and granuloma formation. Hematoxylin and eosin sections from 62 patients with CD treated with either infliximab or adalimumab and 80 controls undergoing the same surgery but without prior exposure to anti-TNF-α therapy were compared. All patients with CD had undergone surgery within 6 months of therapy; CD controls were matched for steroid exposure, procedure, and indication for surgery and were subcategorized and case matched. Blinded histologic assessment of all slides was performed using a semiquantitative scoring system to assess inflammatory changes and fibrosis in all bowel layers. Compared with controls, the group treated with anti-TNF-α showed a reduction in mucosal and submucosal inflammation (P < .05), a decrease in granuloma formation (P < .05), and an increase in duplication of the muscularis mucosae (P < .05). A notable feature was a distinct pattern of hyalinizing submucosal fibrosis that was often devoid of inflammatory cells and that started directly below the muscularis mucosae; this pattern was not observed in the control group (P < .05). Resection specimens from patients with CD treated with anti-TNF-α therapy showed (a) reduced mucosal and submucosal inflammation; (b) a decrease in granuloma formation; and (c) a distinct pattern of submucosal hyaline fibrosis, with increased fibrosis in the muscularis mucosae and muscularis propria., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

An immunohistochemical study of 34 pleomorphic adenomas of the major salivary glands demonstrated phenotypic differences among the various morphologic regions in these tumors. The phenotypes expressed were comparable to those of normal salivary gland cells. In the normal glands, myoepithelial cells were immunoreactive for glial fibrillary acidic protein (GFAP), S-100 protein, and keratin; acinic cells exhibited strong, predominantly nuclear S-100 staining and weaker keratin staining; intercalated ducts had both cytoplasmic and nuclear S-100 positivity; and several epithelial antigens were observed throughout the ductal system. In the tumors, the presence of classic epithelial markers (including carcinoembryonic antigen, epithelial membrane antigen, secretory component, and keratin) in the luminal cells of ducts and the intense immunoreactivity with GFAP (with weaker keratin and S-100 staining) in periductal and stromal cells indicated distinct epithelial and myoepithelial differentiation. Solid epithelioid areas consisted phenotypically of intercalated duct/acinic cells and/or myoepithelial cells, the former exhibiting predominant nuclear S-100 positivity. The presence of GFAP-like immunoreactivity in normal myoepithelial cells strongly supports the extensive involvement of this cell in pleomorphic adenomas. The spectrum of phenotypes expressed adds weight to existing evidence for pleomorphism rather than a mixed origin of this tumor. The combination of keratin, S-100, and GFAP immunostaining is particularly useful in identifying the component cells in pleomorphic adenomas of the salivary glands.

Assessment of epithelial dysplasia in ulcerative colitis has been hindered by inconsistencies in and disagreements about nomenclature and interpretation. To resolve these issues, pathologists from ten institutions participated in three exchanges of multiple slides and, following each exchange, in discussions of the results. A classification system for the epithelial changes that occur in ulcerative colitis was developed, which should be applicable to other forms of inflammatory bowel disease as well. The classification makes use of standardized terminology, addresses specific problem areas, and offers practical solutions. The reproducibility of the system was studied by means of examinations of both inter- and intra-observer variations. The clinical implications of the findings were incorporated into suggestions for patient management. The basis of the classification is that the term "dysplasia" is reserved for epithelial changes that are unequivocally neoplastic and may therefore give rise directly to invasive carcinoma. Specimens are categorized as negative, indefinite, or positive for dysplasia. The negative category includes all inflammatory and regenerative lesions and indicates that only continued regular surveillance is required. The indefinite category is applied to epithelial changes that appear to exceed the limits of ordinary regeneration but are insufficient for an unequivocal diagnosis of dysplasia or are associated with other features that prevent such unequivocal diagnosis. Clinically, it indicates that early repeat biopsy is often required to assess the changes more accurately. The positive category is divided into two subcategories: 1) high-grade dysplasia, for which colectomy should be strongly considered after confirmation of the diagnosis, and 2) low-grade dysplasia, which also requires confirmation and early repeat biopsy or colectomy, depending on other findings.

The solitary ulcer syndrome of the rectum is not rare but often remains unrecognised. A greater awareness of the condition will lead to more frequent diagnosis. The aetiology remains unproven but the evidence would suggest that a combination of prolapse, trauma and ischaemia, caused by excessive straining at stool may be important factors. The reasons for straining at stool are also obscure but in some cases a failure in the normal behaviour of the puborectalis may be involved. The history and clinical features of the condition are described, and the pathogenesis discussed.

Changes in the pattern of sulfomucin and sialomucin secretion and height of large bowel mucosa have been described adjacent to primary colonic adenocarcinomas and adenomas, and called "transitional" mucosa. These changes were initially thought to be specific preneoplastic changes. In this study "transitional" changes in colonic and rectal mucosa were found in some cases overlying benign mesenchymal tumors, metastatic tumors from noncolonic sites, and sites of endometriosis, as well as adjacent to primary colonic and rectal neoplasms. These findings suggest that although these changes may be found adjacent to primary large bowel neoplasms, they are frequently secondary reactive rather than primary preneoplastic phenomena. In addition, the thickness of the mucosa and the accompanying pattern of mucin secretion usually seen in transitional mucosa may be dissociated.