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Sejben A, Bàthori Á, Hegedűs F, Vasas B, Lauwers GY, Kővári B. Gastric-like (pseudopyloric and pseudofoveolar) metaplasia and Paneth cell hyperplasia-neglected histological features of chronic ileal inflammation. Virchows Arch 2024:10.1007/s00428-024-03954-x. [PMID: 39496819 DOI: 10.1007/s00428-024-03954-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/01/2024] [Accepted: 10/15/2024] [Indexed: 11/06/2024]
Abstract
Architectural distortion and basal plasmacytosis are the most widely recognized histologic features of chronic ileal inflammation. However, these features might be difficult to assess in small, poorly oriented, or superficial biopsies. Additional features of chronic mucosal damage, including pseudopyloric or pseudofoveolar metaplasia and Paneth cell hyperplasia, have been less commonly reported, and their broader appreciation could facilitate the diagnosis of chronic ileal inflammatory conditions. The prevalence of gastric-like (pseudopyloric and pseudofoveolar) metaplasia and Paneth cell hyperplasia was evaluated in 102 ileal biopsies obtained from patients with Crohn's disease (n = 47), ulcerative colitis with endoscopically normal ileum (n = 20) or with backwash ileitis (n = 20), and nonsteroidal anti-inflammatory drugs- (NSAIDs-) induced ileitis (n = 15). Gastric-like metaplasia was identified in 23% of CD and 13% of NSAID-induced ileitis cases, whereas it was absent among all ulcerative colitis cases. Pseudopyloric metaplasia, pseudofoveolar metaplasia, or a combination of both was documented in 13%, 2%, and 9% of Crohn's disease cases, respectively. NSAID-associated cases showed only pseudopyloric metaplasia. Paneth cell hyperplasia was detected in 43% of Crohn's disease cases, 13% of NSAID-induced ileitis cases, and 5% of backwash ileitis cases. Accordingly, pseudofoveolar metaplasia, pseudopyloric metaplasia, and Paneth cell hyperplasia are not uncommon in conditions causing chronic ileal inflammation. They are most frequently detected in Crohn's disease, but may also be present in NSAID-induced ileitis, whereas they are significantly less common in backwash ileitis and absent in normal ileum. Given the surface localization of pseudofoveolar metaplasia, its identification can be particularly helpful when dealing with poorly oriented or superficial samples.
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Affiliation(s)
- Anita Sejben
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, 2 Állomás Utca, Szeged, Hungary, 6725
| | - Ágnes Bàthori
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, 2 Állomás Utca, Szeged, Hungary, 6725
| | - Fanni Hegedűs
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, 2 Állomás Utca, Szeged, Hungary, 6725
| | - Béla Vasas
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, 2 Állomás Utca, Szeged, Hungary, 6725
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA
| | - Bence Kővári
- Department of Pathology, Mass General Brigham, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
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Bahceci D, Alpert L, Storozuk T, Liao X, Yozu M, Westerhoff M, Kővári BP, Lauwers GY, Choi WT. Dysplasia Detected in Patients With Serrated Epithelial Change Is Frequently Associated With an Invisible or Flat Endoscopic Appearance, Nonconventional Dysplastic Features, and Advanced Neoplasia. Am J Surg Pathol 2024; 48:1326-1334. [PMID: 38907614 DOI: 10.1097/pas.0000000000002271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/24/2024]
Abstract
The significance of serrated epithelial change (SEC), defined as endoscopically invisible hyperplastic polyp (HP)-like mucosal change identified in patients with inflammatory bowel disease (IBD), remains unclear. Although some studies reported an increased risk of synchronous and/or metachronous colorectal neoplasia in patients with SEC, including advanced neoplasia (high-grade dysplasia or colorectal cancer), the development of SEC is not significantly associated with increased colonic inflammation. This contrasts with the reported positive correlation between increased colonic inflammation and the risk of colorectal neoplasia in ulcerative colitis, arguing against the notion that SEC may represent a form of dysplasia. As such, this study aimed to characterize the features of synchronous and metachronous dysplasia detected in patients with SEC to identify factors contributing to the increased risk of colorectal neoplasia, including advanced neoplasia, observed in a subset of these patients. Clinicopathologic features of 46 IBD patients with SEC (n=109) and synchronous and/or metachronous dysplasia (n=153) were analyzed. All dysplastic lesions were subtyped as either conventional or nonconventional dysplasia. As controls, 45 IBD patients with endoscopically visible or polypoid HP (n=75) and synchronous and/or metachronous dysplasia (n=87) were analyzed. The SEC group included 28 (61%) men and 18 (39%) women with a mean age of 58 years and a long history of IBD (mean duration: 23 years). The majority of patients (n=34; 74%) had ulcerative colitis, and 12 (26%) had Crohn's disease. Thirty-nine (85%) patients had a history of pancolitis, and 2 (4%) had concomitant primary sclerosing cholangitis. Twenty-seven (59%) patients had multifocal SEC. SEC was predominantly found in the left colon (n=52; 48%) and rectum (n=34; 31%). Dysplasia in the SEC group was often endoscopically invisible or flat (n=42; 27%) and demonstrated nonconventional dysplastic features (n=49; 32%). Six nonconventional subtypes were identified in the SEC group, including 17 (11%) dysplasia with increased Paneth cell differentiation, 12 (8%) hypermucinous dysplasia, 8 (5%) crypt cell dysplasia, 7 (5%) goblet cell deficient dysplasia, 3 (2%) sessile serrated lesion-like dysplasia, and 2 (1%) traditional serrated adenoma-like dysplasia. Advanced neoplasia was detected in 11 (24%) patients. The SEC group was more likely to have nonconventional dysplasia (32%, P <0.001), invisible/flat dysplasia (27%, P <0.001), and advanced neoplasia (24%, P <0.001) than the control group (7%, 2%, and 0%, respectively). High-risk nonconventional subtypes (ie, hypermucinous, crypt cell, and goblet cell deficient dysplasias) accounted for 18% of all dysplastic lesions in the SEC group, which were not seen in the control group ( P <0.001). The SEC group (n=35; 76%) also had a higher rate of concordance between the location of SEC and the area of synchronous/metachronous dysplasia than the control group (n=22; 49%) ( P =0.007). In conclusion, dysplasia detected in patients with SEC is often endoscopically invisible/flat (27%), nonconventional (32%, including the high-risk subtypes), and found in the same colonic segment as SEC (76%), which may in part explain why some patients with SEC are associated with an increased risk of colorectal neoplasia, including advanced neoplasia. The finding of SEC may warrant a careful follow-up colonoscopy with increased random biopsy sampling, especially in the segment of colon with SEC.
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Affiliation(s)
- Dorukhan Bahceci
- Department of Pathology, University of California at San Francisco, San Francisco, CA
| | - Lindsay Alpert
- Department of Pathology, University of Chicago, Chicago, IL
| | | | - Xiaoyan Liao
- Department of Pathology, University of Rochester, Rochester, NY
| | - Masato Yozu
- Histopathology Department, Middlemore Hospital, Auckland, New Zealand
| | | | - Bence P Kővári
- Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL
| | | | - Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, CA
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Zhang R, Wang D, Lauwers GY, Choi WT. Increased Active Inflammation in the Colon is Not a Reliable Predictor of an Elevated Risk of Dysplasia in Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis. Am J Surg Pathol 2024; 48:1154-1163. [PMID: 38809303 DOI: 10.1097/pas.0000000000002255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2024]
Abstract
Although the increased risk of colorectal neoplasia in patients with both primary sclerosing cholangitis (PSC) and ulcerative colitis (UC; termed PSC-UC) is well documented, the mechanism through which concomitant PSC increases the risk of colorectal neoplasia remains unclear. Given that the risk of colorectal neoplasia in UC is positively correlated with increased histologic inflammation, this study sought to investigate whether increased histologic inflammation could be used to stratify the risk of dysplasia development in patients with PSC-UC. Twenty patients with PSC-UC and dysplasia were compared with 30 control patients with PSC-UC who had no history of neoplasia. For each patient, all surveillance biopsies were scored using a 4-point scoring system: (1) no epithelial neutrophils = 0, (2) cryptitis only = 1, (3) cryptitis plus crypt abscess in <50% of crypts = 2, and (4) crypt abscess in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration = 3. A score was designated for each biopsy, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores derived from all colonoscopies for each patient were used to determine the patient's overall mean, maximum, and inflammation burden scores. In both the dysplasia and control groups, the 3 summative inflammation scores were calculated independently for the entire colon, right colon, and left colon. The dysplasia group consisted of 14 (70%) men and 6 (30%) women, with a mean age of 27 years at UC diagnosis and a long history of pancolitis (mean duration: 17 y). A total of 49 dysplastic lesions were detected in the dysplasia group, and 8 (40%) of the 20 patients had multifocal dysplasia. The majority of dysplastic lesions belonged to nonconventional subtypes (n = 28; 57%) and were located in the right colon (n = 37; 76%). Irrespective of the colon segment, there was no significant difference in the 3 summative inflammation scores between the dysplasia and control groups ( P > 0.05). However, in each group, the 3 summative inflammation scores were significantly higher in the right colon than in the left colon ( P < 0.05). In conclusion, patients with PSC-UC exhibit increased histologic inflammation in the right colon compared with the left colon, regardless of the presence of dysplasia. Although this may provide an explanation for the predominance of right-sided colorectal neoplasia in patients with PSC-UC, increased histologic inflammation does not reliably predict an elevated risk of dysplasia in patients with PSC-UC. These findings reinforce the current recommendation for annual endoscopic surveillance for all patients with PSC-UC, irrespective of the extent and severity of inflammation.
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Affiliation(s)
- Ruth Zhang
- Department of Pathology, University of California, San Francisco, CA
| | - Dongliang Wang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Won-Tak Choi
- Department of Pathology, University of California, San Francisco, CA
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Bahceci D, Wang D, Lauwers GY, Choi WT. The Development of Serrated Epithelial Change in Ulcerative Colitis is not Significantly Associated With Increased Histologic Inflammation. Am J Surg Pathol 2024; 48:719-725. [PMID: 38584461 DOI: 10.1097/pas.0000000000002216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Serrated epithelial change (SEC) in inflammatory bowel disease is most often defined as hyperplastic polyp-like mucosal change detected on random biopsies. Although SEC has been reported to be associated with an increased risk of synchronous and/or metachronous colorectal neoplasia, it remains unknown if SEC represents a form of dysplastic lesion despite the lack of morphologic evidence of dysplasia. Since the risk of colorectal neoplasia in ulcerative colitis (UC) is positively correlated with increased histologic inflammation, this study investigated if increased colonic inflammation is an independent risk factor for SEC. A cohort of 28 UC patients with SEC was analyzed and compared with 51 control UC patients without SEC. None of these patients had a history of colorectal neoplasia. For each patient with SEC, all biopsies conducted before and at the time of SEC diagnosis (versus all biopsies for each control patient) were scored by using a 4-point scoring system: no activity (no epithelial infiltration by neutrophils=0); mild activity (cryptitis only=1); moderate activity (cryptitis plus crypt abscess formation in <50% of crypts=2); and severe activity (crypt abscess formation in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration=3). Each biopsy was designated a score, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores of all colonoscopies for each patient were used to assign the patient's overall mean, maximum, and inflammation burden scores. The SEC cohort included 12 (43%) men and 16 (57%) women with a mean age of 47 years at the time of the first SEC diagnosis and a long history of UC (mean: 13 y). The majority of patients (n=21; 75%) had pancolitis, and only 1 (4%) patient had primary sclerosing cholangitis. A total of 37 SEC were identified in the 28 patients, 4 (14%) of whom had multifocal SEC. SEC was predominantly found in the left colon (n=32; 86%). In the multivariate analysis, none of the 3 summative inflammation scores, including overall mean (odds ratio [OR] 1.9, P =0.489), maximum (OR 0.4, P =0.259), and inflammation burden scores (OR 1.2, P =0.223), were significantly associated with the development of SEC. Similarly, no other potential risk factors, including age, gender, ethnicity, and duration and extent of UC, were significantly correlated with the detection of SEC ( P >0.05). In conclusion, the development of SEC in UC is not significantly associated with increased histologic inflammation. Given the reported association of SEC with an increased risk of synchronous and/or metachronous colorectal neoplasia, along with the presence of molecular alterations in some cases (such as TP53 mutations and aneuploidy), SEC may represent an early morphologic indicator of segmental or pan-colonic molecular abnormalities that have not advanced enough to result in colorectal neoplasia, as opposed to being a form of dysplasia.
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Affiliation(s)
- Dorukhan Bahceci
- Department of Pathology, University of California at San Francisco, San Francisco, CA
| | - Dongliang Wang
- Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Won-Tak Choi
- Department of Pathology, University of California at San Francisco, San Francisco, CA
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Harpaz N, Itzkowitz SH. Pathology and Clinical Significance of Inflammatory Bowel Disease-Associated Colorectal Dysplastic Lesions. Gastroenterol Clin North Am 2024; 53:133-154. [PMID: 38280745 DOI: 10.1016/j.gtc.2023.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2024]
Abstract
Timely diagnosis and effective management of colorectal dysplasia play a vital role in preventing mortality from colorectal cancer in patients with chronic inflammatory bowel disease. This review provides a contemporary overview of the pathologic and endoscopic classification of dysplasia in inflammatory bowel disease, their roles in determining surveillance and management algorithms, and emerging diagnostic and therapeutic approaches that might further enhance patient management.
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Affiliation(s)
- Noam Harpaz
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai; Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, Annenberg Building 5-12L, 1468 Madison Avenue, New York, NY 10029, USA.
| | - Steven H Itzkowitz
- Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, Annenberg Building 5-12L, 1468 Madison Avenue, New York, NY 10029, USA
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Choi WT. Characteristics, Reporting, and Potential Clinical Significance of Nonconventional Dysplasia in Inflammatory Bowel Disease. Surg Pathol Clin 2023; 16:687-702. [PMID: 37863560 DOI: 10.1016/j.path.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2023]
Abstract
The term nonconventional dysplasia has been coined to describe several underrecognized morphologic patterns of epithelial dysplasia in inflammatory bowel disease (IBD), but to date, the full recognition of these newly characterized lesions by pathologists is uneven. The identification of nonconventional dysplastic subtypes is becoming increasingly important, as they often present as invisible/flat dysplasia and are more frequently associated with advanced neoplasia than conventional dysplasia on follow-up. This review describes the morphologic, clinicopathologic, and molecular characteristics of seven nonconventional subtypes known to date, as well as their potential significance in the clinical management of IBD patients.
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Affiliation(s)
- Won-Tak Choi
- Department of Pathology, University of California at San Francisco, 505 Parnassus Avenue, M552, Box 0102, San Francisco, CA 94143, USA.
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Harpaz N, Goldblum JR, Shepherd NA, Riddell RH, Rubio CA, Vieth M, Wang HH, Odze RD. Colorectal dysplasia in chronic inflammatory bowel disease: a contemporary consensus classification and interobserver study. Hum Pathol 2023; 138:49-61. [PMID: 37247824 DOI: 10.1016/j.humpath.2023.05.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 05/22/2023] [Indexed: 05/31/2023]
Abstract
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.
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Affiliation(s)
- Noam Harpaz
- Department of Pathology, Molecular and Cell-Based Medicine and Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - John R Goldblum
- Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH, 44195, USA.
| | - Neil A Shepherd
- Gloucestershire Cellular Pathology Laboratory, Gloucester, GL53 7AN, UK.
| | - Robert H Riddell
- Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Toronto, M5G 1X5, Canada.
| | - Carlos A Rubio
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, 171 64, Sweden.
| | - Michael Vieth
- Institute of Pathology, Bayreuth Clinic, Bayreuth, 95445, Germany.
| | - Helen H Wang
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
| | - Robert D Odze
- Department of Pathology and Laboratory Medicine, Tufts University School of Medicine, Boston, MA, 02111, USA.
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Waters KM, Singhi AD, Montgomery EA. Exploring the spectrum of serrated epithelium encountered in inflammatory bowel disease. Hum Pathol 2023; 132:126-134. [PMID: 35753410 PMCID: PMC11186602 DOI: 10.1016/j.humpath.2022.06.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 06/17/2022] [Indexed: 02/07/2023]
Abstract
Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer. Currently, dysplasia is the best marker of CRC risk. Assessing dysplasia is a challenging task for pathologists as the longstanding inflammation causes marked reactive cytologic changes and architectural distortion. Recent descriptions of nonconventional types of dysplasia in IBD have added to the complexity. In this review, we focus on the clinical, endoscopic, histologic, and molecular findings in lesions with serrated epithelium. Serrated epithelial change (SEC), sessile serrated lesion (SSL)-like, serrated lesion-not otherwise specified (SL-NOS), and traditional serrated adenoma (TSA)-like lesions all typically occur in patients with longstanding IBD with mean ages in the fifth-sixth decade. SEC is often encountered in nontargeted biopsies while the others form visible polyps. While serrated lesions have significant histologic overlap, subtle differences can help pathologists separate them. SEC has markedly distorted architecture with crypts losing perpendicular orientation to the muscularis mucosae. The crypts are goblet cell-rich and have irregular serrations that involve the full length of the crypt. SSL-like lesions are goblet cell poor and have microvesicular cytoplasm. Like their sporadic counterpart in non-IBD patients, these lesions have lateral growth at the crypt bases. TSA-like lesions are characterized by their villous architecture, ectopic crypts, pink cytoplasm, and hyperchromatic elongated nuclei. We also explore molecular findings that help in distinguishing these lesions, current knowledge on the association of each of these lesions with dysplasia and CRC, and future research needed to better characterize these entities.
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Affiliation(s)
- Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Li Y, Wang HL. Influence of SCENIC recommendations on terminology used for histopathologic diagnosis of inflammatory bowel disease-associated dysplasia. World J Gastrointest Oncol 2022; 14:1375-1387. [PMID: 36160744 PMCID: PMC9412923 DOI: 10.4251/wjgo.v14.i8.1375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/18/2022] [Accepted: 08/06/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Published in 2015, the International Consensus Recommendations on Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients (SCENIC) recommended abandoning the use of diagnostic term "dysplasia-associated lesion or mass (DALM)" for polypoid dysplastic lesions detected in patients with inflammatory bowel disease (IBD). The aim of this study was to investigate whether this recommendation had any influence on diagnostic terminologies used by pathologists in their practice. METHODS We retrospectively reviewed all pathology reports for surveillance colonoscopic biopsies from ulcerative colitis (UC) patients in our institution during 1/2012-12/2014 (pre-SCENIC) and 1/2016-12/2018 (post-SCENIC). These included 1203 biopsies from 901 UC patients during the pre-SCENIC period and 1273 biopsies from 977 UC patients during the post-SCENIC period. Their corresponding endoscopic findings and histopathologic diagnoses were recorded. Clinical indications for total colectomy for UC patients and corresponding histopathologic findings in colectomy specimens were also recorded and compared. RESULTS A total of 347 and 419 polyps/polypoid lesions were identified during the pre-SCENIC and post-SCENIC periods, among which 60 and 104 were dysplastic/adenomatous, respectively. More polypoid dysplastic lesions were simply diagnosed as "adenoma" during the post-SCENIC period in comparison with the pre-SCENIC period (97.1% vs 65.0%; P < 0.001). The number of cases with a comment in pathology reports regarding the distinction between DALM and sporadic adenoma was also significantly decreased during the post-SCENIC period (5.8% vs 38.3%; P < 0.001). In addition, the term "dysplasia" was more consistently used for random biopsies during the post-SCENIC period. Furthermore, the terms "sessile serrated adenoma/polyp" (SSA/P) and "serrated epithelial change" (SEC) were more consistently used for polypoid lesions and random biopsies, respectively, during the post-SCENIC period, although these were not specifically addressed in the SCENIC recommendations. The indications for colectomy remained unchanged, however, despite the standardization of diagnostic terminologies. CONCLUSION The SCENIC recommendations relieve pathologists from the burden of distinguishing DALM from sporadic adenoma in IBD patients, which helps the standardization of diagnostic terminologies used by pathologists. The consistent use of the diagnostic terminologies may help reduce potential confusions to clinicians and patients.
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Affiliation(s)
- Yuan Li
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
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10
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Mitra S, Paramaguru R, Das P, Katti SV. Preneoplastic Lesions and Polyps of the Gastrointestinal Tract. SURGICAL PATHOLOGY OF THE GASTROINTESTINAL SYSTEM 2022:593-698. [DOI: 10.1007/978-981-16-6395-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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11
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Rath E, Haller D. Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury. Mucosal Immunol 2022; 15:595-604. [PMID: 35534699 PMCID: PMC9259489 DOI: 10.1038/s41385-022-00514-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/16/2022] [Accepted: 04/05/2022] [Indexed: 02/07/2023]
Abstract
The intestinal epithelium represents the most regenerative tissue in the human body, located in proximity to the dense and functionally diverse microbial milieu of the microbiome. Episodes of tissue injury and incomplete healing of the intestinal epithelium are a prerequisite for immune reactivation and account for recurrent, chronically progressing phenotypes of inflammatory bowel diseases (IBD). Mitochondrial dysfunction and associated changes in intestinal epithelial functions are emerging concepts in the pathogenesis of IBD, suggesting impaired metabolic flexibility of epithelial cells affects the regenerative capacity of the intestinal tissue. Next to rendering the intestinal mucosa susceptible to inflammatory triggers, metabolic reprogramming of the epithelium is implicated in shaping adverse microbial environments. In this review, we introduce the concept of "metabolic injury" as a cell autonomous mechanism of tissue wounding in response to mitochondrial perturbation. Furthermore, we highlight epithelial metabolism as intersection of microbiome, immune cells and epithelial regeneration.
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Affiliation(s)
- Eva Rath
- grid.6936.a0000000123222966Technical University of Munich, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany
| | - Dirk Haller
- grid.6936.a0000000123222966Technical University of Munich, Chair of Nutrition and Immunology, Freising-Weihenstephan, Germany ,grid.6936.a0000000123222966Technical University of Munich, ZIEL Institute for Food & Health, Freising-Weihenstephan, Germany
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12
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Montgomery EA, Arnold CA, Lam-Himlin DM, McDonald OG, Poveda JC, Salimian KJ, Voltaggio L, Waters KM, Wood LD, Singhi AD. Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture. Am J Surg Pathol 2022; 46:e1-e14. [PMID: 33284191 DOI: 10.1097/pas.0000000000001637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Laura D Wood
- Department of Pathology, Johns Hopkins, Baltimore, MD
| | - Aatur D Singhi
- Department of Pathology, The University of Pittsburgh, Pittsburgh, PA
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13
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Arpa G, Vanoli A, Grillo F, Fiocca R, Klersy C, Furlan D, Sessa F, Ardizzone S, Sampietro G, Macciomei MC, Nesi G, Tonelli F, Capella C, Latella G, Ciardi A, Caronna R, Lenti MV, Ciccocioppo R, Barresi V, Malvi D, D'Errico A, Rizzello F, Poggioli G, Mescoli C, Rugge M, Luinetti O, Paulli M, Di Sabatino A, Solcia E. Prognostic relevance and putative histogenetic role of cytokeratin 7 and MUC5AC expression in Crohn's disease-associated small bowel carcinoma. Virchows Arch 2021; 479:667-678. [PMID: 33963925 PMCID: PMC8516779 DOI: 10.1007/s00428-021-03109-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/28/2021] [Accepted: 04/21/2021] [Indexed: 01/27/2023]
Abstract
Most Crohn's disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies.
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Affiliation(s)
- Giovanni Arpa
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy
| | - Alessandro Vanoli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy.
| | - Federica Grillo
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University Hospital and Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | - Roberto Fiocca
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University Hospital and Ospedale Policlinico San Martino IRCCS, Genova, Italy
| | - Catherine Klersy
- Service of Clinical Epidemiology & Biometry, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Daniela Furlan
- Anatomic Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Anatomic Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | | | | | | | - Gabriella Nesi
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Francesco Tonelli
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Carlo Capella
- Anatomic Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy
| | - Roberto Caronna
- Surgical Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine, Fondazione IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico G.B. Rossi, University of Verona, Verona, Italy
| | - Valeria Barresi
- Section of Anatomical Pathology, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Deborah Malvi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Antonietta D'Errico
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Fernando Rizzello
- Intestinal Chronic Bowel Disease Unit, Department of Medical and Surgical Sciences, Sant'Orsola Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Gilberto Poggioli
- Surgery of the Alimentary Tract, Department of Medical and Surgical Sciences, Sant'Orsola - Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Claudia Mescoli
- Pathology Unit, Department of Medicine DIMED, University of Padua, Padova, Italy
| | - Massimo Rugge
- Pathology Unit, Department of Medicine DIMED, University of Padua, Padova, Italy
| | - Ombretta Luinetti
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy
| | - Marco Paulli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine, Fondazione IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy
| | - Enrico Solcia
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Via Carlo Forlanini 16 -, 27100, Pavia, Italy
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14
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Parian AM, Limketkai BN, Chowdhury R, Brewer GG, Salem G, Falloon K, Selaru F, Melia J, Lazarev MG. Serrated Epithelial Change Is Associated With High Rates of Neoplasia in Ulcerative Colitis Patients: A Case-controlled Study and Systematic Review With Meta-analysis. Inflamm Bowel Dis 2021; 27:1475-1481. [PMID: 33295614 DOI: 10.1093/ibd/izaa312] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Patients with long-standing ulcerative colitis (UC) are at an increased risk of colorectal cancer. Risk stratification is important to identify patients who require more frequent endoscopic surveillance. Serrated epithelial change (SEC) found in patients with long-standing colitis may be associated with neoplasia and serve as a marker to stratify patients at higher risk of colorectal cancer (CRC). METHODS A case-control study was performed to compare the rates of neoplasia between UC patients with SEC and UC patients without SEC who were matched for age, disease duration, and disease extent. Paired tests, conditional logistic regression, and Kaplan-Meier analyses were used to compare groups. A systematic review with meta-analysis was performed, combining our local data with previously published data. RESULTS This study included 196 UC patients without prior neoplasia, 98 with SEC and 98 without SEC. Ulcerative colitis patients with SEC had a significantly higher rate of synchronous or metachronous neoplasia than UC patients without SEC (26.5% vs 3.1%; P < 0.001). Synchronous or metachronous high-grade dysplasia and CRC were found more frequently in UC patients with SEC than UC patients without SEC (11.2% vs 2.0%; P = 0.02). A meta-analysis was consistent with these findings, showing a higher rate of neoplasia in patients with SEC compared with those without SEC (16.4% vs 3.9%; P < 0.001). CONCLUSION Serrated epithelial change is associated with a significantly increased risk of synchronous and metachronous neoplasia including high-grade dysplasia and CRC in patients with UC. Histopathological findings of SEC should warrant closer endoscopic surveillance for CRC.
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Affiliation(s)
- Alyssa M Parian
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Berkeley N Limketkai
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA.,Vatche & Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, USA
| | - Reezwana Chowdhury
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Gala Godoy Brewer
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - George Salem
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Katie Falloon
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH, USA
| | - Florin Selaru
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Joanna Melia
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Mark G Lazarev
- Department of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
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15
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Singhi AD, Waters KM, Makhoul EP, Parian A, Lazarev MG, Proksell SS, Dueker JM, Schwartz MB, Wald AI, Nikiforova MN, Montgomery EA. Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia. Hum Pathol 2021; 112:9-19. [PMID: 33727167 PMCID: PMC10113803 DOI: 10.1016/j.humpath.2021.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022]
Abstract
Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.
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Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Elias P Makhoul
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Alyssa Parian
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Mark G Lazarev
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Siobhan S Proksell
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Jeffrey M Dueker
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Marc B Schwartz
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Elizabeth A Montgomery
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, 21205, USA; Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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16
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Brcic I, Dawson H, Gröchenig HP, Högenauer C, Kashofer K. Serrated Lesions in Inflammatory Bowel Disease: Genotype-Phenotype Correlation. Int J Surg Pathol 2021; 29:46-53. [PMID: 33030071 DOI: 10.1177/1066896920963798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) and hyperplastic/serrated polyposis have an increased risk of colorectal cancer. The aim of our study was to elucidate the nature of serrated lesions in IBD patients. MATERIALS AND METHODS Sixty-five lesions with serrated morphology were analyzed in 39 adult IBD patients. Lesions were classified according to the WHO 2019 criteria or regarded as reactive, and molecular analysis was performed. RESULTS 82.1% of patients had ulcerative colitis, 17.9% had Crohn's disease; 51.3% were female, and the mean age was 54.5 years. The duration of IBD varied significantly (16.7 ± 11.4 years). Endoscopy showed polypoid lesions in 80.3%; the size ranged from 2 to 20 mm. A total of 21.6% of the lesions were located in the right colon. Five lesions were classified as inflammatory pseudopolyps, 28 as hyperplastic polyp, 21 and 2 as sessile serrated lesion without and with dysplasia, respectively, and 9 as traditional serrated adenoma with low-grade dysplasia. Analysis of all true serrated lesions revealed 31 mutations in KRAS and 32 in BRAF gene. No mutations were identified in inflammatory pseudopolyps. In the right colon BRAF mutations were more frequent than KRAS (16 vs 3), while KRAS mutations prevailed on the left side (28 vs 16, P < .001). One patient with traditional serrated adenomas progressed to an adenocarcinoma after 61 months. CONCLUSION The molecular analysis could help discriminate true serrated lesions (IBD-associated or not) from reactive pseudopolyps with serrated/hyperplastic epithelial change. These should help in more accurate classification of serrated lesions.
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Affiliation(s)
- Iva Brcic
- Medical University of Graz, Graz, Austria
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17
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Batts KP, Atwaibi M, Weinberg DI, McCabe RP. Significance of serrated epithelial change in inflammatory bowel disease. Postgrad Med 2020; 133:66-70. [PMID: 32746680 DOI: 10.1080/00325481.2020.1802138] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVES The clinical significance of hyperplastic polyp-like histologic changes in random biopsy samples ('serrated epithelial change' or SEC) from patients with inflammatory bowel disease (IBD) remains uncertain, with some studies suggesting an increased risk of dysplasia and even carcinoma. Controlled studies are few. We studied the significance of SEC on the development of dysplasia in follow-up surveillance of IBD patients in our system. METHODS We identified 94 IBD patients with SEC and 187 IBD patients without SEC identified in index biopsy samples, and retrospectively collated results of follow-up surveillance samples in each group, with the development of dysplasia and/or adenocarcinoma as study endpoints. RESULTS IBD patients with SEC had a 12.8% likelihood of developing dysplasia of any type within IBD-affected areas vs a 4.3% likelihood in non-SEC patients (follow-up in the 1-4 year range for each group). This was significant in univariate analysis (p = 0.013) but not in multivariate analysis, likely due to increased frequency of follow-up sampling in the SEC patients. One cancer developed in each group (p = NS). CONCLUSION Our data, in the context of other studies, neither prove nor conclusively exclude an increased risk of dysplasia in IBD patients with SEC. But cancer risk appears low and continued surveillance at usual intervals seems reasonable.
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Affiliation(s)
- Kenneth P Batts
- Department of Pathology and Lab Medicine, Hospital Pathology Associates, PC , Minneapolis, MN, USA.,Virginia Piper Cancer Institute , Minneapolis, MN, USA
| | | | - David I Weinberg
- Virginia Piper Cancer Institute , Minneapolis, MN, USA.,Department of Gastroenterology, MNGI Digestive Health , Minneapolis, MN, USA
| | - Robert P McCabe
- Virginia Piper Cancer Institute , Minneapolis, MN, USA.,Department of Gastroenterology, MNGI Digestive Health , Minneapolis, MN, USA
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18
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Nonconventional dysplasia in patients with inflammatory bowel disease and colorectal carcinoma: a multicenter clinicopathologic study. Mod Pathol 2020; 33:933-943. [PMID: 31822800 DOI: 10.1038/s41379-019-0419-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/19/2019] [Accepted: 11/05/2019] [Indexed: 02/06/2023]
Abstract
Several types of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). However, strict morphologic criteria are lacking, and their clinicopathologic features (including potential association with conventional dysplasia and/or colorectal cancer [CRC]) are poorly understood. A total of 106 dysplastic or serrated lesions in 58 IBD patients with CRC were retrospectively identified from five institutions. Thirty-six cases of nonconventional dysplasia were identified in 26 (45%) of the 58 patients and occurred with similar frequency in men and women (58% and 42%, respectively), with a mean age of 54 years (range: 24-73) and a long history of IBD (mean: 17 years, range: 2-43). Six morphologic patterns were recognized. Hypermucinous dysplasia (n = 15; 42%) presented as either a 'pure type' (n = 5; 14%) or a 'mixed type' with either conventional or another nonconventional subtype (n = 10; 28%). Serrated lesions, as a group, were equally common (n = 15; 42%) and included three variants: traditional serrated adenoma-like (n = 10; 28%), sessile serrated lesion-like (n = 1; 3%), and serrated lesion, not otherwise specified (n = 4; 11%). Dysplastic lesions with increased Paneth cell differentiation (n = 4; 11%) and goblet cell deficient dysplasia (n = 2; 6%) were rare. Twelve (46%) of the 26 patients had only nonconventional dysplasia, whereas the remaining 14 patients (54%) had both nonconventional and conventional dysplasias. Nonconventional dysplasia was most often graded as low-grade dysplasia (81%), which was less common in conventional dysplasia (37%) (p = 0.003). When present alone, nonconventional dysplasia was predominantly found in the left colon (81%, p = 0.006) as a polypoid or raised lesion (75%, p < 0.001) compared with when it occurred simultaneously with conventional dysplasia (35% and 50%, respectively). When both nonconventional and conventional dysplasias occurred simultaneously, they were found in the same colonic segment in all but 3 patients (79%). Nonconventional dysplasia was also commonly detected in the same colonic segment as CRC or immediately adjacent to the CRC at a rate (85%) similar to conventional dysplasia (96%). CRC occurring in patients with only nonconventional dysplasia was more likely to be high-grade (poorly differentiated; 36%) than CRC that occurred in association with conventional dysplasia (10%) (p = 0.026). In conclusion, nonconventional dysplasia is common in IBD patients with CRC. It appears to develop in the same field of carcinomatous development, and it is not uncommonly associated with conventional dysplasia.
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19
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Gui X, Köbel M, Ferraz JGP, Iacucci M, Ghosh S, Demetrick DJ. Newly recognized non-adenomatous lesions associated with enteric carcinomas in inflammatory bowel disease - Report of six rare and unique cases. Ann Diagn Pathol 2019; 44:151455. [PMID: 31862522 DOI: 10.1016/j.anndiagpath.2019.151455] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 12/05/2019] [Indexed: 01/26/2023]
Abstract
It is the current view that the inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous (with classic cytologic dysplasia) and non-adenomatous (without frank cytologic dysplasia), and the latter ones are in various histomorphologies including serrated, mucinous, eosinophilic (goblet cell deficient), and differentiated (dysplasia with terminal epithelial differentiation) types. By retrospectively reviewing the surgically resected IBD-associated colorectal and ileal carcinomas (×53), analyzing the background epithelial changes/lesions in the mucosa surrounding and adjacent to invasive carcinomas, and testing the key molecular profile (KRAS, BRAF, PIK3CA, NRAS, p53, mismatch repair proteins, and SAT-B2) known to be involved in colorectal carcinogenesis, we identified 6 representative, rare and unique cases, in which non-adenomatous lesions were clearly in vicinity and in transition to invasive carcinomas. Furthermore, we identified certain colonic carcinoma-related molecular alterations, and thus further confirmed the neoplastic nature of various non-adenomatous lesions. It was also revealed that non-adenomatous lesions are heterogeneous in both morphology and molecular alterations, and that it is common to have more than one type of lesions be associated with a carcinoma. Moreover, mixed focal adenomatous dysplasia was common, which may be the necessary step in the malignant transformation of the non-adenomatous lesions.
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Affiliation(s)
- Xianyong Gui
- Department of Pathology and Laboratory Medicine, University of Calgary, Canada; Alberta Precision Laboratories, Calgary, Canada; Department of Pathology, University of Washington School of Medicine, USA.
| | - Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Canada; Alberta Precision Laboratories, Calgary, Canada
| | - Jose G P Ferraz
- Division of Gastroenterology and Hepatology, University of Calgary, Canada
| | - Marietta Iacucci
- Division of Gastroenterology and Hepatology, University of Calgary, Canada; NIHR Biomedical Research Centre, Institute of Translational Medicine, University of Birmingham, UK
| | - Subrata Ghosh
- Division of Gastroenterology and Hepatology, University of Calgary, Canada; NIHR Biomedical Research Centre, Institute of Translational Medicine, University of Birmingham, UK
| | - Douglas J Demetrick
- Department of Pathology and Laboratory Medicine, University of Calgary, Canada; Alberta Precision Laboratories, Calgary, Canada
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20
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Gui X, Köbel M, Ferraz JG, Iacucci M, Ghosh S, Liu S, Ou Y, Perizzolo M, Winkfein RJ, Rambau P, Demetrick DJ. Histological and molecular diversity and heterogeneity of precancerous lesions associated with inflammatory bowel diseases. J Clin Pathol 2019; 73:391-402. [PMID: 31801800 DOI: 10.1136/jclinpath-2019-206247] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 01/08/2023]
Abstract
AIMS Inflammatory bowel disease (IBD)-associated precancerous lesions may be adenomatous or non-adenomatous with various histomorphologies. We aim to validate the newly proposed classification, to explore the neoplastic nature of the non-adenomatous lesions and to elucidate the molecular mechanisms underlying the different histomorphologies. METHODS 44 background precursor lesions identified in 53 cases of surgically resected IBD-associated colorectal and ileal carcinomas were reviewed for the histomorphological features (classified into adenomatous, mucinous, sessile serrated adenoma (SSA)-like, traditional serrated adenoma-like, differentiated, eosinophilic and serrated not otherwise specified (NOS)) and analysed for a key panel of colonic cancer-related molecular markers. RESULTS Approximately 60% of the lesions were adenomatous, of which some had mixed serrated, mucinous or eosinophilic changes. The remaining non-adenomatous lesions, including all other types except SSA-like type, mostly showed mixed features and focal adenomatous dysplasia. KRAS mutation and p53 mutant-type expression were found in about half cases across all types, while PIK3CA mutation only in some of adenomatous and eosinophilic lesions and MLH1/PMS2 loss in a subset of adenomatous, mucinous and eosinophilic but not in differentiated and serrated lesions. SAT-B2 or PTEN loss and IMP3 overexpression were seen in a small subset of lesions. No BRAF, NRAS or EGFR gene mutation was detected in any type. Certain molecular-morphological correlations were demonstrated; however, no single or combined molecular alteration(s) was specific to any particular morphological type. CONCLUSIONS IBD-associated precancerous lesions are heterogeneous both histologically and molecularly. True colitis-associated adenomatous lesions are unlikely conventional adenomas. Non-adenomatous lesions without frank cytologic dysplasia should also be regarded as neoplastic.
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Affiliation(s)
- Xianyong Gui
- Pathology, University of Washington School of Medicine, Seattle, Washington, USA .,Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Martin Köbel
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Jose Gp Ferraz
- Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Marietta Iacucci
- NIHR Biomedical Research Centre, Institute of Translational Medicine, University of Birmingham, Birmingham, Birmingham, UK
| | - Subrata Ghosh
- NIHR Biomedical Research Centre, Institute of Translational Medicine, University of Birmingham, Birmingham, Birmingham, UK
| | - Shuhong Liu
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Young Ou
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Marco Perizzolo
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Robert J Winkfein
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Peter Rambau
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Douglas J Demetrick
- Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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21
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Karamchandani DM, Zhang Q, Liao XY, Xu JH, Liu XL. Inflammatory bowel disease- and Barrett's esophagus-associated neoplasia: the old, the new, and the persistent struggles. Gastroenterol Rep (Oxf) 2019; 7:379-395. [PMID: 31857901 PMCID: PMC6911999 DOI: 10.1093/gastro/goz032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/30/2019] [Accepted: 06/04/2019] [Indexed: 12/30/2022] Open
Abstract
Early diagnosis of and adequate therapy for premalignant lesions in patients with inflammatory bowel disease (IBD) and Barrett's esophagus (BE) has been shown to decrease mortality. Endoscopic examination with histologic evaluation of random and targeted biopsies remains the gold standard for early detection and adequate treatment of neoplasia in both these diseases. Although eventual patient management (including surveillance and treatment) depends upon a precise histologic assessment of the initial biopsy, accurately diagnosing and grading IBD- and BE-associated dysplasia is still considered challenging by many general as well as subspecialized pathologists. Additionally, there are continuing updates in the literature regarding the diagnosis, surveillance, and treatment of these disease entities. This comprehensive review discusses the cancer risk, detailed histopathological features, diagnostic challenges, and updates as well as the latest surveillance and treatment recommendations in IBD- and BE-associated dysplasia.
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Affiliation(s)
- Dipti M Karamchandani
- Department of Pathology, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Qin Zhang
- Department of Pathology, The Third Central Hospital of Tianjin, Tianjin, China
| | - Xiao-Yan Liao
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Jing-Hong Xu
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiu-Li Liu
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA
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Kamarádová K, Vošmiková H, Rozkošová K, Ryška A, Tachecí I, Laco J. Non-conventional mucosal lesions (serrated epithelial change, villous hypermucinous change) are frequent in patients with inflammatory bowel disease—results of molecular and immunohistochemical single institutional study. Virchows Arch 2019; 476:231-241. [DOI: 10.1007/s00428-019-02627-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/11/2019] [Accepted: 07/15/2019] [Indexed: 12/13/2022]
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Kamarádová K, Vošmiková H, Rozkošová K, Ryška A, Tachecí I, Laco J. Morphological, immunohistochemical and molecular features of inflammatory bowel disease associated colorectal carcinoma and associated mucosal lesions - Single institution experience. Pathol Res Pract 2019; 215:730-737. [PMID: 30679085 DOI: 10.1016/j.prp.2019.01.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 12/23/2018] [Accepted: 01/05/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patients with inflammatory bowel disease (IBD) - ulcerative colitis (UC) and Crohn's disease (CD) have an elevated risk of developing colorectal carcinoma (CRC). Major risk factor in IBD patients is the continuous chronic inflammation leading to development of dysplasia and carcinoma. Nevertheless, other types of non-conventional but suspicious mucosal changes serrated change/dysplasia, NOS and villous hypermucinous change, have also been reported in IBD patients. Preneoplastic potential of these lesions is still not well elucidated. AIMS The aim of this study was identification of IBD-associated CRCs focusing on finding related precursor lesions in the surgical specimen or in archival biopsy samples followed by a detailed morphological, immunohistochemical and molecular evaluation. For the purpose of the study the mucosal lesions were divided into conventional IBD-associated dysplasia and non-conventional lesions that were merged under a provisory term of putative preneoplastic lesions (PPL). METHODS A total of 309 consecutive IBD colectomy specimens diagnosed during a 10-year period were reviewed. Detailed morphological evaluation, immunohistochemical analysis of mismatch repair (MMR) proteins, p53 and O6-methylguanine DNA methyltransferase (MGMT) expression and molecular analysis for KRAS, NRAS and BRAF gene mutation were performed in the retrieved CRC cases as well as in the detected dysplasia and PPLs of these patients. RESULTS We identified 11 cases of morphologically heterogenous IBD-associated CRCs, occurring in 5 males and 6 females, aged 26-79 years (mean 44 years). A total of 22 mucosal lesions were revealed in 8 CRC patients comprising conventional IBD-associated dysplasia (4 lesions), PPLs as serrated change/dysplasia NOS (11 lesions), villous hypermucinous change (5 lesions), and two true serrated lesions (one sessile serrated adenoma and one traditional serrated adenoma). More than one type of lesion was found in 6 patients. Seven CRC cases harbored mutation of KRAS/NRAS and one case of BRAF. Two patients with KRAS-mutated CRC showed the same mutation in PPL in the same specimen (one serrated change NOS and one TSA with high-grade dysplasia). Similarly, one BRAF-mutated carcinoma case presented the same mutation in serrated change/dysplasia, NOS in the same specimen. Of the CRCs, two showed deficient MMR system profile, six presented with loss of MGMT expression, and six showed aberrant p53 expression. PPLs showed deficient MGMT expression (14 cases) and aberrant p53 (10 cases) as well. CONCLUSION IBD-associated CRCs are very heterogeneous entities. Besides conventional IBD-related dysplasia, other types of mucosal lesions may be associated with long lasting IBD and CRC e.g. villous hypermucinous change and serrated change/dysplasia, NOS. Since these lesions share certain genetic or immunohistochemical changes with the related CRC, a suspicion is raised that these lesions may also have preneoplastic potential. Awareness of these changes is necessary to prevent their missing and under-reporting, and further studies of these lesions should be carried out.
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Affiliation(s)
- Kateřina Kamarádová
- The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic.
| | - Hana Vošmiková
- The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic.
| | - Kateřina Rozkošová
- The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic.
| | - Aleš Ryška
- The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic.
| | - Ilja Tachecí
- 2nd Department of Internal Medicine-Gastroenterology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic.
| | - Jan Laco
- The Fingerland Department of Pathology, Charles University Faculty of Medicine and University Hospital Hradec Králové, Sokolská 581, Hradec Králové, 500 03, Czech Republic.
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Zhang L, Wu TT. Inflammatory Bowel Disease. SURGICAL PATHOLOGY OF NON-NEOPLASTIC GASTROINTESTINAL DISEASES 2019:373-424. [DOI: 10.1007/978-3-030-15573-5_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yang C, Tarabishy Y, Dassopoulos T, Nalbantoglu ILK. Clinical, Histologic, and Immunophenotypic Features of Serrated Polyps in Patients With Inflammatory Bowel Disease. Gastroenterology Res 2018; 11:355-360. [PMID: 30344807 PMCID: PMC6188039 DOI: 10.14740/gr1064w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022] Open
Abstract
Background Colorectal serrated polyps (SP), which include hyperplastic polyps (HP), sessile serrated adenomas/polyps (SSA/P), and traditional serrated adenomas, are not uncommon and have been implicated to play a role in the pathogenesis in a subset of sporadic colorectal carcinomas; however, their significance in patients with prolonged inflammatory bowel disease (IBD) remains unclear. Methods We retrospectively studied the clinicopathologic features, BRAF and β-catenin immunohistochemistry staining patterns in 36 SPs from 28 patients with IBD compared with 40 SPs in patients without IBD. Results Eleven SSA/Ps and 25 HPs from IBD and site-matched controls were included. SSA/Ps in the study group were slightly more commonly seen in males (55% vs. 41%, P = 0.7) and older patients (55.2 vs. 47.8 years, P = 0.2) compared to patients with HP. They were moderately larger (7.13 mm vs. 4.83 mm, P = 0.14) and more likely located on the right (63.6% vs. 32%, P = 0.46). Smaller percentage of SSA/Ps showed BRAF staining compared to controls (55.6% vs. 73.3%, P = 0.41) and HPs showed similar features (52.0% vs. 54.2%, P = 1). β-catenin was negative in all cases. During follow-up, only one patient in the SSA/P group developed carcinoma 42 months after at the same site and two developed adenoma-like low-grade dysplasia but no patients with HPs had such findings. Conclusions Our findings show that SPs in IBD share similar clinicodemographic and immunophenotypical features with sporadic SPs. However, patients with SSA/Ps may have a slight increase in risk of developing dysplasia compared to patients with HPs in IBD.
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Affiliation(s)
- Chen Yang
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | | | - Themistocles Dassopoulos
- Baylor University Medical Center, Baylor Scott and White Center for Inflammatory Bowel Diseases, Dallas, TX, USA
| | - ILKe Nalbantoglu
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
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Choi WT, Wen KW, Rabinovitch PS, Huang D, Mattis AN, Gill RM. DNA content analysis of colorectal serrated lesions detects an aneuploid subset of inflammatory bowel disease-associated serrated epithelial change and traditional serrated adenomas. Histopathology 2018; 73:464-472. [DOI: 10.1111/his.13652] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/11/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Won-Tak Choi
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
| | - Kwun Wah Wen
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
| | | | - Danning Huang
- Department of Public Health and Preventive Medicine; SUNY Upstate Medical University; Syracuse NY USA
| | - Aras N Mattis
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
| | - Ryan M Gill
- Department of Pathology; University of California at San Francisco; San Francisco CA USA
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Pierce ES. Could Mycobacterium avium subspecies paratuberculosis cause Crohn's disease, ulcerative colitis…and colorectal cancer? Infect Agent Cancer 2018; 13:1. [PMID: 29308085 PMCID: PMC5753485 DOI: 10.1186/s13027-017-0172-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 12/12/2017] [Indexed: 01/07/2023] Open
Abstract
Infectious agents are known causes of human cancers. Schistosoma japonicum and Schistosoma mansoni cause a percentage of colorectal cancers in countries where the respective Schistosoma species are prevalent. Colorectal cancer is a complication of ulcerative colitis and colonic Crohn’s disease, the two main forms of idiopathic inflammatory bowel disease (IIBD). Mycobacterium avium subspecies paratuberculosis (MAP), the cause of a chronic intestinal disease in domestic and wild ruminants, is one suspected cause of IIBD. MAP may therefore be involved in the pathogenesis of IIBD-associated colorectal cancer as well as colorectal cancer in individuals without IIBD (sporadic colorectal cancer) in countries where MAP infection of domestic livestock is prevalent and MAP’s presence in soil and water is extensive. MAP organisms have been identified in the intestines of patients with sporadic colorectal cancer and IIBD when high magnification, oil immersion light microscopy (×1000 total magnification rather than the usual ×400 total magnification) is used. Research has demonstrated MAP’s ability to invade intestinal goblet cells and cause acute and chronic goblet cell hyperplasia. Goblet cell hyperplasia is the little-recognized initial pathologic lesion of sporadic colorectal cancer, referred to as transitional mucosa, aberrant crypt foci, goblet cell hyperplastic polyps or transitional polyps. It is the even lesser-recognized initial pathologic feature of IIBD, referred to as hypermucinous mucosa, hyperplastic-like mucosal change, serrated epithelial changes, flat serrated changes, goblet cell rich mucosa or epithelial hyperplasia. Goblet cell hyperplasia is the precursor lesion of adenomas and dysplasia in the classical colorectal cancer pathway, of sessile serrated adenomas and serrated dysplasia in the serrated colorectal cancer pathway, and of flat and elevated dysplasia and dysplasia-associated lesions or masses in IIBD-associated intestinal cancers. MAP’s invasion of intestinal goblet cells may result in the initial pathologic lesion of IIBD and sporadic colorectal cancer. MAP’s persistence in infected intestines may result in the eventual development of both IIBD-associated and sporadic colorectal cancer.
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Svrcek M. [Histoseminar on Inflammatory Bowel Diseases (IBD): Cases no. 07 and 08]. Ann Pathol 2017; 37:308-315. [PMID: 28760372 DOI: 10.1016/j.annpat.2017.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Accepted: 06/19/2017] [Indexed: 10/19/2022]
Affiliation(s)
- Magali Svrcek
- Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, GH HUEP, AP-HP, 184, rue du faubourg Saint-Antoine, 75582 Paris cedex 12, France; Sorbonne-Université, université Pierre-et-Marie-Curie - Paris 6, Paris, France.
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Grolleau C, Pote NM, Guedj NS, Zappa M, Theou-Anton N, Bouhnik Y, Panis Y, Cazals-Hatem DL. Small bowel adenocarcinoma complicating Crohn's disease: a single-centre experience emphasizing the importance of screening for dysplasia. Virchows Arch 2017; 471:611-617. [PMID: 28421339 DOI: 10.1007/s00428-017-2125-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 03/29/2017] [Accepted: 04/07/2017] [Indexed: 12/19/2022]
Abstract
Small bowel adenocarcinoma (SBA) complicating Crohn's disease (CD) is rare and generally found incidentally on surgical specimens. We report our experience in CD-associated SBA observed this last decade in a tertiary referral centre in order to update its incidence, clinical presentation and pathological features. All SBAs diagnosed in patients who underwent surgery for CD between 2006 and 2016 were retrospectively included. Clinico-pathological characteristics were reviewed, and follow-up was updated. SBA was diagnosed in 9 (1.7%) of 522 patients who underwent SB resection(s) after a median CD duration of 15 years [0-32]. The median age at diagnosis was 46 years. Seven (78%) patients had obstructive symptoms refractory to medical treatment. Pre-operative biopsy revealed neoplasia in five (56%) patients (dysplasia in three and SBA in two) justifying the surgery. Two (29%) of the seven patients with imaging had features suggestive of cancer. In all specimens, SBA developed in active ileitis with adjacent dysplasia. Stage I low-grade tubulo-glandular adenocarcinoma was observed in 33% of patients. Stage IV high-grade adenocarcinoma was observed in 56% of patients, and mucinous/signet ring cell differentiation predominated in 44% of patients. Molecular analysis showed no BRAF mutation, a KRAS mutation in one case and a microsatellite instability phenotype suggestive of Lynch syndrome in one case. After a median follow-up of 24 months [7-82], four (44%) patients died with advanced stage IV SBA. This surgical series confirms that CD-associated SBA is rare with an incidence of 1.7%. Adjacent dysplasia was present in all specimens and was identified before surgery in all patients who benefit from ileal biopsies. This strengthens the importance of screening all longstanding CD by endoscopy if surgery is not considered.
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Affiliation(s)
- Chloé Grolleau
- Department of Pathology, AP-HP, Hôpital Beaujon, 92110, Clichy, France
| | - Nicolas M Pote
- Department of Pathology, AP-HP, Hôpital Beaujon, 92110, Clichy, France.,University Paris Diderot, Sorbonne Paris Cité, 75018, Paris, France
| | - Nathalie S Guedj
- Department of Pathology, AP-HP, Hôpital Beaujon, 92110, Clichy, France.,University Paris Diderot, Sorbonne Paris Cité, 75018, Paris, France
| | - Magaly Zappa
- Department of Radiology, AP-HP, Hôpital Beaujon, 92110, Clichy, France
| | | | - Yoram Bouhnik
- University Paris Diderot, Sorbonne Paris Cité, 75018, Paris, France.,Department of Gastroenterology, AP-HP, Hôpital Beaujon, 92110, Clichy, France
| | - Yves Panis
- University Paris Diderot, Sorbonne Paris Cité, 75018, Paris, France.,Department of Colorectal Surgery, AP-HP, Hôpital Beaujon, 92110, Clichy, France
| | - Dominique L Cazals-Hatem
- Department of Pathology, AP-HP, Hôpital Beaujon, 92110, Clichy, France. .,Service d'Anatomie-Pathologie, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110, Clichy, France.
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Jackson WE, Achkar JP, Macaron C, Lee L, Liu X, Pai RK, Lopez R, Burke CA, Allende DS. The Significance of Sessile Serrated Polyps in Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:2213-20. [PMID: 27508509 DOI: 10.1097/mib.0000000000000895] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND The significance of serrated lesions in inflammatory bowel disease (IBD) remains unclear. We aim to characterize synchronous and metachronous lesions in IBD patients with an index serrated polyp and compare them to sporadic subjects with SSP. METHODS Serrated lesions in patients with IBD were identified from a pathology database and, after review, were reclassified as hyperplastic (HP), sessile serrated (SSPs), or serrated polyps unclassifiable (SPU). RESULTS One hundred thirty-four IBD patients were found to have 147 serrated polyps at index colonoscopy. SSPs were more likely to be located in the right colon: SSP (76.0%), SPU (41.7%) and HP (27.8%); P = 0.002. Synchronous multifocal visible dysplasia occurred more frequently in the SSP or SPU groups (44.5% and 66%) compared to the HP group (12%); P = 0.031. Among 13 IBD patients with index SSP followed over a median of 6 years, 61.5% developed metachronous visible dysplasia or additional SSPs. Larger index SSP size was associated with higher risk of developing subsequent visible dysplasia with a 10% increase for every 1 mm increase in size (HR = 1.1; P = 0.028), but was not associated with developing subsequent SSP (P = 0.50). The risk of subsequent SSP or visible dysplasia was no different between the IBD and non-IBD groups, but there was a trend suggesting SSP may be a marker of increased early risk of metachronous visible dysplasia in IBD patients. CONCLUSIONS IBD patients with an index SSP and SPU have a heightened risk of synchronous multifocal visible dysplasia. Additionally, IBD patients with SSP may be at risk of early metachronous visible dysplasia.
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Affiliation(s)
- Whitney E Jackson
- *Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio; †Section of Gastroenterology, Department of Veterans Affairs, Louis Stokes Cleveland Medical Center, Cleveland, Ohio; ‡Department of Pathology and Laboratory Medicine, North Shore-Long Island Jewish Health System, New Hyde Park, New York; §Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio; ‖Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona; and ¶Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
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Parian A, Koh J, Limketkai BN, Eluri S, Rubin DT, Brant SR, Ha CY, Bayless TM, Giardiello F, Hart J, Montgomery E, Lazarev MG. Association between serrated epithelial changes and colorectal dysplasia in inflammatory bowel disease. Gastrointest Endosc 2016; 84:87-95.e1. [PMID: 26709112 PMCID: PMC5555397 DOI: 10.1016/j.gie.2015.12.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 12/06/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Serrated epithelial change (SEC) is a histologic finding in longstanding colitis that may be associated with dysplasia. Our primary aim was to determine the incidence of dysplasia and colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients with SEC. Secondary aims were to determine the rate of location concordance between SEC and dysplasia/CRC and to identify other risk factors associated with dysplasia in IBD patients with SEC. METHODS A retrospective, descriptive, observational study was performed by searching the Pathology Data System at a single tertiary referral center for a histologic finding of "serrated epithelial change." The patient's first pathology specimen with SEC was designated the index SEC. All subsequent pathology reports were evaluated for the occurrence and location of dysplasia or CRC. Univariable and multivariable logistic regression were performed to identify predictors of dysplasia. RESULTS There were 187 patients with confirmed IBD and 1 or more histologic findings of SEC without prior dysplasia. Mean IBD duration was 16 years, and median follow-up time was 28 months. The rate of high-grade dysplasia or CRC was 17 per 1000 patient-years. Thirty-nine of 187 patients (21%) had synchronous or metachronous dysplasia or CRC. Location concordance was 68%. Multivariable analysis found SEC on follow-up examinations, older age at IBD diagnosis, male gender, and a first-degree relative with CRC were associated with dysplasia in IBD patients with SEC. CONCLUSIONS This uncontrolled study describes a high frequency of dysplasia in patients with a histologic finding of SEC. SEC seen on successive endoscopic examinations further increased the risk of dysplasia. Further controlled studies are needed to determine if SEC is a precancerous lesion in IBD patients and if SEC can be endoscopically identified.
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Affiliation(s)
- Alyssa Parian
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Joyce Koh
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Berkeley N. Limketkai
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA,Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Swathi Eluri
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - David T. Rubin
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Steven R. Brant
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Christina Y. Ha
- Division of Gastroenterology, University of California Los Angeles, Los Angeles, California, USA
| | - Theodore M. Bayless
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Francis Giardiello
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - John Hart
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Elizabeth Montgomery
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Mark G. Lazarev
- Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Serrated colorectal polyps in inflammatory bowel disease. Mod Pathol 2015; 28:1584-93. [PMID: 26403785 DOI: 10.1038/modpathol.2015.111] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 08/14/2015] [Accepted: 08/15/2015] [Indexed: 01/09/2023]
Abstract
Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively (P<0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different (P=0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.
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Shen J, Gibson JA, Schulte S, Khurana H, Farraye FA, Levine J, Burakoff R, Cerda S, Qazi T, Hamilton M, Srivastava A, Odze RD. Clinical, pathologic, and outcome study of hyperplastic and sessile serrated polyps in inflammatory bowel disease. Hum Pathol 2015; 46:1548-56. [DOI: 10.1016/j.humpath.2015.06.019] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 06/11/2015] [Accepted: 06/17/2015] [Indexed: 12/25/2022]
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Akinrinde AS, Olowu E, Oyagbemi AA, Omobowale OT. Gastrointestinal protective efficacy of Kolaviron (a bi-flavonoid from Garcinia kola) following a single administration of sodium arsenite in rats: Biochemical and histopathological studies. Pharmacognosy Res 2015; 7:268-76. [PMID: 26130939 PMCID: PMC4471654 DOI: 10.4103/0974-8490.157978] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Revised: 02/18/2015] [Accepted: 06/02/2015] [Indexed: 11/26/2022] Open
Abstract
Background: Arsenic intoxication is known to produce symptoms including diarrhea and vomiting, which are indications of gastrointestinal dysfunction. Objective: We investigated whether Kolaviron (KV) administration protected against sodium arsenite (NaAsO2)-induced damage to gastric and intestinal epithelium in rats. Materials and Methods: Control rats (Group I) were given a daily oral dose of corn oil. Rats in other groups were given a single dose of NaAsO2 (100 mg/kg; intraperitoneal) alone (Group II) or after pretreatment for 7 days with KV at 100 mg/kg (Group III) and 200 mg/kg (Group IV). Rats were sacrificed afterward and portions of the stomach, small intestine and colon were processed for histopathological examination. Hydrogen peroxide, reduced glutathione, malondialdehyde (MDA) concentrations as well as activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione S-transferase (GST) and myeloperoxidase (MPO) were measured in the remaining portions of the different gastrointestinal tract (GIT) segments. Results: NaAsO2 caused significant increases (P < 0.05) in MDA levels and MPO activity, with significant reductions (P < 0.05) in GST, GPX, CAT and SOD activities in the stomach and intestines. KV significantly reversed the changes (P < 0.05) in a largely dose-dependent manner. The different segments had marked inflammatory cellular infiltration, with hyperplasia of the crypts, which occurred to much lesser degrees with KV administration. Conclusion: The present findings showed that KV might be a potent product for mitigating NaAsO2 toxicity in the GIT.
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Affiliation(s)
- Akinleye S Akinrinde
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Ebunoluwa Olowu
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Ademola A Oyagbemi
- Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Olutayo T Omobowale
- Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
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Moussata D, Boschetti G, Chauvenet M, Stroeymeyt K, Nancey S, Berger F, Lecomte T, Flourié B. Endoscopic and histologic characteristics of serrated lesions. World J Gastroenterol 2015; 21:2896-904. [PMID: 25780286 PMCID: PMC4356908 DOI: 10.3748/wjg.v21.i10.2896] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 08/25/2014] [Accepted: 10/14/2014] [Indexed: 02/07/2023] Open
Abstract
In recent years, a second pathway for colonic carcinogenesis, distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp, characterised by a serrated appearance of the crypts: hyperplastic polyps (HP), sessile serrated adenomas (SSA) or lesions, and traditional serrated adenomas. Each lesion has its own genetic, as well as macroscopic and microscopic morphological features. Because of their flat aspect, their detection is easier with chromoendoscopy (carmin indigo or narrow-band imaging). However, as we show in this review, the distinction between SSA and HP is quite difficult. It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia. These different types of lesion are described in detail in the present review in general population, in polyposis and in inflammatory bowel diseases patients. This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.
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Boudreau MD, Mellick PW, Olson GR, Felton RP, Thorn BT, Beland FA. Clear evidence of carcinogenic activity by a whole-leaf extract of Aloe barbadensis miller (aloe vera) in F344/N rats. Toxicol Sci 2013; 131:26-39. [PMID: 22968693 PMCID: PMC3537128 DOI: 10.1093/toxsci/kfs275] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Accepted: 09/03/2012] [Indexed: 12/16/2022] Open
Abstract
Aloe barbadensis Miller (Aloe vera) is an herbal remedy promoted to treat a variety of illnesses; however, only limited data are available on the safety of this dietary supplement. Drinking water exposure of F344/N rats and B6C3F1 mice to an Aloe vera whole-leaf extract (1, 2, and 3%) for 13 weeks resulted in goblet cell hyperplasia of the large intestine in both species. Based upon this observation, 2-year drinking water studies were conducted to assess the carcinogenic potential of an Aloe vera whole-leaf extract when administered to F344/N rats (48 per sex per group) at 0.5, 1, and 1.5%, and B6C3F1 mice (48 per sex per group) at 1, 2, and 3%. Compared with controls, survival was decreased in the 1.5% dose group of female rats. Treatment-related neoplasms and nonneoplastic lesions in both species were confined primarily to the large intestine. Incidences of adenomas and/or carcinomas of the ileo-cecal and cecal-colic junction, cecum, and ascending and transverse colon were significantly higher than controls in male and female rats in the 1 and 1.5% dose groups. There were no neoplasms of the large intestine in mice or in the 0 or 0.5% dose groups of rats. Increased incidences of mucosa hyperplasia of the large intestine were observed in F344/N rats, and increased incidences of goblet cell hyperplasia of the large intestine occurred in B6C3F1 mice. These results indicate that Aloe vera whole-leaf extract is an intestinal irritant in F344/N rats and B6C3F1 mice and a carcinogen of the large intestine in F344/N rats.
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Affiliation(s)
- Mary D Boudreau
- Division of Biochemical Toxicology, Food and Drug Administration, Jefferson, Arkansas 72079, USA.
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Abstract
Until very recently, there was general acceptance in the pathology community that all serrated lesions of the colon and rectum without overt cytologic dysplasia were hyperplastic polyps and had no malignant potential. Although there are still several unanswered questions in regard to the relationship between the various serrated lesions, there is a better understanding of the relationship of sessile serrated adenoma to carcinoma. This article discusses hyperplastic polyps, sessile serrated adenoma, traditional serrated adenoma, mixed polyps, and serrated lesions in such conditions as idiopathic inflammatory bowel disease and mechanical trauma. The major focus of the content is on diagnostic features of these lesions.
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Affiliation(s)
- Dale C Snover
- Department of Pathology, Fairview Southdale Hospital, 6401 France Avenue South, Edina, MN 55435-2199, USA; Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, Mayo Mail Code 609, 420 Delaware Street SE, Minneapolis, MN 55455, USA
| | - Kenneth P Batts
- Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, Mayo Mail Code 609, 420 Delaware Street SE, Minneapolis, MN 55455, USA; Department of Pathology and Laboratory Medicine, and Virginia Piper Cancer Center, Abbott Northwestern Hospital, 800 East 28th Street, Minneapolis, MN 55407, USA; Hospital Pathology Associates, PA, 2345 Rice Street, Suite 160, Saint Paul, MN 55113-3769, USA.
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Odze RD, Maley CC. Neoplasia without dysplasia: lessons from Barrett esophagus and other tubal gut neoplasms. Arch Pathol Lab Med 2010; 134:896-906. [PMID: 20524867 DOI: 10.5858/134.6.896] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Classic pathology teaching emphasizes that neoplastic lesions of the gastrointestinal tract are characterized by architectural and cytologic abnormalities that distinguish it from normal tissue. Recent studies suggest that many important-and in some cases clonal-molecular abnormalities that lead to dysregulation of cell proliferation and differentiation (neoplasia) occur before morphologic expression of dysplasia. OBJECTIVE To summarize the biologic and pathologic features of preneoplastic conditions of the tubal gut that reveal evidence of neoplastic alteration, but without the traditional morphologic features of dysplasia, in order to provide guidance on how to identify these lesions. Particular attention is given to Barrett esophagus, a chronic inflammatory condition in which early molecular and morphologic events that drive carcinogenesis are best understood. DATA SOURCES Selected references and abstracts were obtained by a PubMed (US National Library of Medicine) search by using the search headings neoplasia, preneoplasia, dysplasia, adenoma, serrated polyps, and Barrett's esophagus between the years 1980 and 2009. CONCLUSIONS Many types of lesions throughout the tubal gut fulfill the most basic and classic principles of a neoplastic precursor lesion but lack conventional morphologic evidence of dysplasia and/or maintain the capacity for cell differentiation and maturation. All of these lesions, such as squamous dysplasia of the esophagus, dysplasia in Barrett esophagus, and hyperplastic/serrated polyps of the colon, represent early neoplastic precursor lesions but without conventional histologic features of dysplasia. It is important for pathologists to be aware of these lesions, both for diagnostic and prognostic purposes, but also so that future studies can be performed with regard to risk stratification of patients.
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Affiliation(s)
- Robert D Odze
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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Kumarasinghe MP, Quek TP, Chau CYP, Mustapha NRN, Luman W, Ooi CJ. Endoscopic biopsy features and diagnostic challenges of adult Crohn's disease at initial presentation. Pathology 2010; 42:131-7. [PMID: 20085514 DOI: 10.3109/00313020903494979] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIMS Endoscopic biopsy diagnosis of Crohn's disease (CD) is problematic due to lack of specific microscopic features and patchy involvement. There is no documentation of the pattern and severity of microscopic features of CD at initial presentation in adults or children. We aimed to assess the initial mucosal biopsy features of CD in adults and to identify any specific features to confirm the diagnosis. METHODS Thirty sets of initial, adult endoscopic biopsies suspected to be CD with subsequent resections, repeat biopsies with long-term follow-up, and/or other confirmatory laboratory results were analysed by three gastrointestinal pathologists, blinded for the final diagnosis for mucosal architectural changes, epithelial abnormalities, chronic and active inflammation and changes of muscularis mucosae and submucosa. There were 25 cases of CD and five cases of non-CD for comparison (3 tuberculosis and 2 right-sided diverticular disease and associated colitis). Cases confirmed as ulcerative colitis were excluded, as diagnostic challenges are already well established. RESULTS The majority of initial biopsies (96%) of CD were abnormal with active chronic ileocolitis with a very high proportion (80%) showing the classic combination of abnormal mucosal architecture, epithelial abnormalities and active chronic inflammation. The most sensitive feature was lamina proprial chronic inflammation (sensitivity 92.7%). Sensitivity for other features was as follows: active inflammation 87.8%, basal plasmacytosis 82.1%, architectural changes 80.5% and epithelial abnormalities 70.7%. Abnormalities were found in 94% of ileal and 76% of colonic biopsies. No feature was specific as all tuberculosis and diverticular disease cases showed the classic combination. Granulomata were seen in 10 of 41 CD, in all five tuberculosis and in no diverticular disease biopsies. Small, tight, well defined granulomata characterised CD over large coalesced ganulomata of tuberculosis. Paneth cell and pseudopyloric metaplasia was seen only in CD (2/25). CONCLUSIONS Initial endoscopic biopsies of adult CD are significantly abnormal and a majority shows active chronic ileocolitis. The features are sufficiently important to suspect CD at initial presentation in the appropriate clinical setting. Tuberculosis and diverticular disease associated colitis are two important mimics to consider in addition to ulcerative colitis.
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Affiliation(s)
- M P Kumarasinghe
- Singapore General Hospital and National University of Singapore, Singapore.
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Abstract
Serrated polyps of the large intestine comprise a heterogeneous group of mucosal lesions that includes nondysplastic polyps, such as hyperplastic polyps and sessile serrated polyps, and polyps that show overt cytologic dysplasia, namely serrated adenomas and mixed hyperplastic/adenomatous polyps. These polyps have received increased recognition over the past 2 decades, as emerging evidence suggests that a subset may be precursors to colorectal carcinomas that lack chromosomal instability. Several investigators have proposed the concept of the "serrated neoplastic pathway" according to which nondysplastic serrated lesions develop progressively severe dysplasia culminating in the development of microsatellite unstable carcinomas that show DNA hypermethylation and BRAF mutations. A subset of hyperplastic polyps and sessile serrated polyps show mutations in the BRAF gene and abnormal DNA methylation, which can, ultimately, affect the promoter regions of key DNA-repair and tumor suppressor genes, such as MLH1 and MGMT, leading to their decreased transcription and microsatellite instability. On the basis of this hypothesis, many authors have proposed that sessile serrated polyps should be treated and surveilled similar to conventional adenomas, although prospective data are lacking. This review describes the clinicopathologic and molecular features of serrated polyps and discusses the current data regarding their biologic significance.
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Hyperplastic/serrated polyposis in inflammatory bowel disease: a case series of a previously undescribed entity. Am J Surg Pathol 2008; 32:296-303. [PMID: 18223333 DOI: 10.1097/pas.0b013e318150d51b] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Herein, we describe the clinical, pathologic, immunohistochemical, and molecular features of 3 unique patients with long standing inflammatory bowel disease, all of whom developed numerous discrete hyperplastic/serrated colonic polyps similar to those described in the hyperplastic/serrated polyposis syndrome. The 3 patients (2 with ulcerative colitis and 1 with Crohn ileo-colitis) were evaluated for a variety of clinical, histologic (including the type, location and number of polyps in the colon), and immunohistochemical features [MLH-1, MSH-2, MGMT (O(6)-methylguanine-DNA methyltransferase), beta-catenin, and p53]. KRAS and BRAF mutation analysis was also performed on a subset of polyps from 2 patients. All patients had moderate-severe pancolitis of more than 10 years duration and had >20 colonic polyps. None had polyps in the upper gastrointestinal tract. Pathologically, a combination of conventional hyperplastic polyps and sessile serrated polyps (adenomas) were present in the 3 cases. In addition, serrated adenomas were present in 2 and conventional adenomas in 1. Two patients also had synchronous adenocarcinoma. All 3 cases showed retention of MLH-1 and MSH-2, and a membranous beta-catenin staining pattern. However, 2 cases showed loss of MGMT in several serrated polyps, and one also in adjacent colitic mucosa. KRAS mutations were detected in 5/11 serrated polyps. However, BRAF mutations were not present in any of the polyps tested. These findings suggest the possibility of a serrated pathway of carcinogenesis in inflammatory bowel disease characterized by silencing of MGMT, most likely by gene promoter methylation, KRAS mutations, and possibly other, as yet, uncharacterized molecular alterations, resulting eventually in progression to adenocarcinoma.
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Nathanson JW, Yadron NE, Farnan J, Kinnear S, Hart J, Rubin DT. p53 mutations are associated with dysplasia and progression of dysplasia in patients with Crohn's disease. Dig Dis Sci 2008; 53:474-80. [PMID: 17676397 DOI: 10.1007/s10620-007-9886-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2006] [Accepted: 05/21/2007] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mutations in the tumor suppressor gene p53 are associated with neoplasia in ulcerative colitis, but little is understood of their significance in Crohn's disease (CD). PURPOSE To explore p53 expression as a marker of neoplasia in CD patients. METHODS This is a retrospective review of CD patients who underwent p53 IHC staining in our center between 1995 and 2003. The p53 status was correlated to the presence and grade of neoplasia at the time of staining and in subsequent follow-up. RESULTS Fourteen CD patients had p53 assessment: eight were p53 positive and six were p53 negative. Seven of eight p53+ had dysplasia (six LGD, one HGD); one of six p53-had dysplasia (LGD) (P = 0.03). Four p53+ patients with follow-up had persistent dysplasia and two had progression to a higher grade. Three p53- patients with follow-up remained free of dysplasia. CONCLUSIONS This limited study shows that p53 over expression in CD patients is associated with dysplasia that may progress to a higher grade of neoplasia over time.
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Affiliation(s)
- Jeffrey W Nathanson
- Reva and David Logan Gastrointestinal Clinical Research Center at the University of Chicago, Chicago, IL, USA
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Lee DH, Esworthy RS, Chu C, Pfeifer GP, Chu FF. Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases. Cancer Res 2006; 66:9845-51. [PMID: 17047045 DOI: 10.1158/0008-5472.can-06-0732] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mice deficient in two glutathione peroxidases (GPX), Gpx1 and Gpx2, [Gpx1/2-double knockout (DKO) mice] are prone to ileocolitis on a mixed C57BL/6 and 129S1/SvJ (B6.129) genetic background. We reported previously that approximately 25% of B6.129 Gpx1/2-DKO mice develop ileocolonic tumors by 6 to 9 months of age, when their non-DKO littermates [having at least one wild-type (WT) Gpx1 or Gpx2 allele] rarely have inflammation and none have tumors. Because genetic background affects tumor susceptibility, we have generated a B6 Gpx1/2-DKO colony and discovered that these mice have fewer inflammatory cells, milder ileocolitis, and low mortality, and only 2.5% of B6 mice developed tumors. The mutant frequency of a cII reporter gene was about 2- to 3-fold higher in 28-day-old Gpx1/2-DKO and 4-fold higher in 8-month-old Gpx1/2-DKO ileal mucosa than in controls in both genetic backgrounds. In contrast, mutant frequencies in the unaffected B6 liver were not significantly different between WT and Gpx1/2-DKO mice. The mutant frequency of 8-month-old B6.129 Gpx1/2-DKO ileum was 38.94 +/- 15.5(-5), which was not significantly higher than the age-matched B6 ileum, 25.54 +/- 10.33(-5). The mutation spectra analysis has shown that B6 Gpx1/2-DKO ileum had a 3-fold increase in small nucleotide deletions at mononucleotide repeats over control B6, which are a signature mutation associated with oxidative stress. Unexpectedly, B6 Gpx1/2-DKO mice had fewer C to T transitions at CpG dinucleotides than the WT B6 (18.0% versus 40.1%; P < 0.001). Our results suggest that inflammation drives gene mutations, which leads to neoplastic transformation of intestinal epithelium in the B6.129 Gpx1/2-DKO mice but rarely in the B6 Gpx1/2-DKO mice.
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Affiliation(s)
- Dong-Hyun Lee
- Department of Biology and Department of Radiation Biology, City of Hope Cancer Center, Duarte, California 91010, USA
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Lomo LC, Blount PL, Sanchez CA, Li X, Galipeau PC, Cowan DS, Ayub K, Rabinovitch PS, Reid BJ, Odze RD. Crypt Dysplasia With Surface Maturation. Am J Surg Pathol 2006; 30:423-35. [PMID: 16625087 DOI: 10.1097/00000478-200604000-00001] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Little is known regarding the significance of esophageal biopsies that show dysplasia-like atypia limited to the bases of the crypts, without involvement of the surface epithelium in Barrett's esophagus (BE). The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (BCDA) with surface maturation in surveillance endoscopic mucosal biopsies to gain insight into its biologic significance. The Seattle Barrett's Esophagus Project is a prospective cohort study in which patients and their biopsies have been evaluated prospectively for clinical, pathologic, and molecular markers. As part of continued surveillance of the cohort, 206 consecutive BE patients were evaluated prospectively for BCDA between July 1, 2001 and August 13, 2003; 15 patients had BCDA (prevalence rate = 7.3%). These 15 patients were evaluated for clinical, pathologic, and immunohistochemical (p53 and MIB-1) features during the study period (2001-2003) as well as associations with clinical, pathologic, and molecular markers [17p(TP53) loss of heterozygosity (LOH), 9p(p16) LOH, tetraploidy, and aneuploidy] that were detected previously in the same patients in the cohort study (1983-2001). All BE patients with BCDA (male-to female ratio, 12:3; mean age, 72 years; mean length of BE, 7.0 cm; mean duration of BE, 95.1 months), except 2 (87%), had dysplasia or adenocarcinoma detected in biopsies either prior to or concurrent to the one that contained BCDA. In contrast, only 112 of 191 (59%) controls had neoplasia during the same time period (59%, P = 0.05). The difference between BCDA and controls was particularly significant with regard to the association with high-grade dysplasia (P = 0.004). Compared with adjacent nonatypical and nondysplastic (metaplastic) BE, areas of BCDA showed a significantly elevated prevalence rate of p53 positivity (60% vs. 13%, P<0.02) and a significantly elevated total crypt and basal crypt MIB-1 proliferation rate (P<0.001). Indeed, the MIB-1 proliferation rate in the basal portion of the crypts in BCDA was similar to that detected in conventional low- or high-grade dysplasia. Patients with BCDA showed a significantly increased rate of 17p(TP53) LOH (P = 0.016), aneuploidy (P = 0.004), and a trend in increased 9p(p16) LOH (P = 0.08), compared with control patients without BCDA. The clinical, pathologic, immunohistochemical, and molecular abnormalities were similar in BCDA cases that were considered low-grade versus those considered high-grade by histologic evaluation, except that high-grade cases tended to be older (79 years vs. 68 years, P = 0.06). BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or adenocarcinoma. Based on these findings, BCDA warrants further investigation as a possible subtype of true dysplasia despite the morphologic appearance of surface maturation.
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Affiliation(s)
- Leslie C Lomo
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Affiliation(s)
- Jean-François Flejou
- Anatomie pathologique, Hôpital Saint Antoine, 184, rue du Faubourg Saint Antoine, 75571 Paris Cedex 12
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Abstract
This review summarizes current diagnostic problems and advances with regard to patterns of inflammation and dysplasia in ulcerative colitis and Crohn's disease. Ulcerative colitis and Crohn's disease have a variety of characteristic but non-specific pathologic features. In approximately 5% of inflammatory bowel disease cases, a definite diagnosis of ulcerative colitis or Crohn's disease cannot be established, in which case the term "indeterminate" colitis is used. Most cases of indeterminate colitis are related to fulminant colitis, a condition in which the classic features of ulcerative colitis or Crohn's disease may be obscured by severe ulceration with early superficial fissuring ulceration, transmural lymphoid aggregates, and relative rectal sparing. Approximately 20% of patients with indeterminate colitis develop severe pouch complications, which is intermediate in frequency between ulcerative colitis (8-10%) and Crohn's disease (30-40%). In order to establish a diagnosis of ulcerative colitis or Crohn's disease, it is important to evaluate pathologic material in conjunction with clinical, laboratory, radiologic, and endoscopic features and to recognize the variety of changes that may be seen in fulminant ulcerative colitis. There are a number of exceptions to the classic principles of inflammatory bowel disease pathology that may lead to diagnostic confusion. For instance, apparent skip lesions on biopsy analysis may occur in patients with ulcerative colitis in the following settings; long term oral or topical therapy, focal ascending colon, cecum and/or appendiceal involvement in patients with left sided ulcerative colitis, upper gastrointestinal involvement in patients with ulcerative colitis, and at initial presentation of ulcerative colitis in pediatric patients. In all of these circumstances, the finding of patchy disease and/or rectal sparing should not be misinterpreted as either evidence against a diagnosis of ulcerative colitis, or as representing skip areas characteristic of Crohn's disease. Patients with ulcerative colitis and Crohn's disease are at increased risk for the development of dysplasia and carcinoma. Recent studies suggest that given a similar duration and extent of disease, patients with Crohn's disease have a similar risk of dysplasia and cancer as patients with ulcerative colitis. Dysplasia in ulcerative colitis may be classified as flat or elevated (dysplasia associated lesion or mass [DALM]). Patients with flat high grade dysplasia are generally treated with colectomy. However, there is recent evidence to suggest that patients with flat low grade dysplasia, particularly if detected at the time of initial endoscopic exam, or if its multifocal or synchronous, should also be treated with colectomy. Elevated lesions in ulcerative colitis (DALM) are subdivided into "adenoma-like" and "non-adenoma-like" lesions based on their endoscopic appearance. Recent data suggests that adenoma-like lesions, regardless of the grade of dysplasia, or the location of the lesion (i.e., inside or outside areas of established colitis) may be treated adequately by polypectomy if there are no other areas of flat dysplasia in the patient. Although there are some histologic and molecular features that can help differentiate sporadic adenomas from adenoma-like polypoid dysplastic lesions related to ulcerative colitis, none of these adjunctive techniques can help distinguish these lesions definitively in any single patient. Patients with a non-adenoma-like DALM, (irregular, broad based, or strictured lesion) should be treated with colectomy because of the high probability of adenocarcinoma. The surveillance and treatment options for patients with flat and elevated dysplasia in ulcerative colitis are reviewed in detail.
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Affiliation(s)
- Robert Odze
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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Odze RD, Brien T, Brown CA, Hartman CJ, Wellman A, Fogt F. Molecular alterations in chronic ulcerative colitis-associated and sporadic hyperplastic polyps: a comparative analysis. Am J Gastroenterol 2002; 97:1235-42. [PMID: 12014733 DOI: 10.1111/j.1572-0241.2002.05696.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES There is growing interest in the biological and molecular features and neoplastic potential of colonic hyperplastic polyps because of the recent finding of K-ras mutations in many of these lesions. Hyperplastic polyps may also develop in chronic ulcerative colitis (CUC), but it is unclear if these are biologically similar to the sporadic type. The aim of this study was to evaluate and compare the molecular profile of CUC-associated hyperplastic polyps with sporadic hyperplastic polyps of the colon. METHODS Thirty-nine hyperplastic polyps from 26 CUC patients, 39 sporadic hyperplastic polyps from 29 age- and sex-matched patients without CUC, and 26 colonic mucosal biopsies from 22 patients with CUC but without hyperplastic polyps were analyzed by polymerase chain reaction for loss of heterozygosity of APC, 3p, p53, and p16 and for mutations in codons 12, 13, and 61 of the K-ras gene. Immunohistochemical evaluations for the proliferation-associated nuclear peptide Ki67 (MIB-1) and p27 were also performed on a subset of hyperplastic polyps. RESULTS CUC-associated hyperplastic polyps showed a proportion of genetic alterations (47%) similar to that of sporadic hyperplastic polyps (33%) (p > 0.05), and neither significantly differed from chronically inflamed mucosae in CUC patients without hyperplastic polyps. Furthermore, in a small group of CUC patients in which informative tissue was available from both their hyperplastic polyps and adjacent flat colitic mucosae, the polyps contained mutations that were not present in the underlying mucosa. Loss of heterozygosity of APC, 3p, p53, p16, and K-ras mutations were present in 21%, 40%, 27%, 20%, and 19% of CUC patients with hyperplastic polyps, respectively, and in 0%, 11%, 20%, 13%, and 13% of non-CUC patients with sporadic polyps, respectively. Both CUC-associated and sporadic hyperplastic polyps showed a substantial number of cases (46% and 64% of cases, respectively) with loss of p27 expression, and both types of lesions showed similar MIB-1 proliferation indices. CONCLUSIONS These data suggest that CUC-associated hyperplastic polyps are genotypically similar to the sporadic type. This study adds to the expanding list of molecular alterations that have been discovered in hyperplastic polyps, and lends further support to the controversial theory that these lesions may have neoplastic potential.
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Affiliation(s)
- Robert D Odze
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
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