Our understanding of serrated colorectal polyps has increased dramatically over the past two decades and has led to a modern classification scheme for these lesions. Sessile serrated polyps with ...dysplasia represent the most clinically significant serrated polyp; however, the morphologic heterogeneity of dysplasia in sessile serrated polyps has only recently been recognized and correlated with MLH1 immunohistochemistry. Detailed morphologic analysis of traditional serrated adenomas has led to the recognition of flat and early forms of this polyp. Robust data on the risk of metachronous lesions in patients with serrated polyps are also beginning to emerge. This review will summarize our current understanding of serrated polyps and associated carcinomas with a focus on diagnostic criteria, morphologic heterogeneity, molecular findings, and natural history. Controversial issues in the diagnosis and classification of these polyps are also discussed.
Histologic evaluation of disease activity in the setting of inflammatory bowel disease is gaining interest within the gastroenterology community. Recent data suggests that histologic measurements of ...inflammation in ulcerative colitis are more sensitive at detecting disease activity and perform better than endoscopic measurements in predicting clinical outcomes. Histologic measurements are also increasingly used in ulcerative colitis clinical trials to assess response to new therapies. Histologic measurements of disease activity are less well studied in Crohn’s disease, but are gaining attention. Current published treatment algorithms in inflammatory bowel disease do not take into consideration histologic activity; however, this may change in the near future. In order for histologic measurements to be included in clinical decision-making, validated, reliable, and responsive histologic scoring systems are needed. In this review, the recent literature on the significance of histologic activity in both ulcerative colitis and Crohn’s disease is summarized. Histologic scoring systems are also briefly discussed.
Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative ...indices, and defining thresholds for histologic response and remission after treatment.
An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting.
Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations.
These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.
Assessment of disease activity is essential for developing and determining appropriate therapy in patients with ulcerative colitis (UC). Validated clinical and endoscopic scoring systems have been ...established to accurately define disease activity. Clinical and endoscopic treatment targets have also been proposed, with gastroenterologists encouraged to optimize medical therapy to achieve these targets. Recently, histology has been recognized as an important prognostic factor and potential treatment target in patients with UC.
This review summarizes the recent literature regarding histologic scoring indices in UC and offers practical guidance to gastroenterologists on how to interpret histologic data.
Substantial evidence indicates that histology accurately predicts clinical relapse, hospitalization, corticosteroid use, and development of dysplasia. Furthermore, compared with endoscopy, findings suggest that histology may be more predictive of these outcomes. Because microscopic disease activity can persist in the absence of clinical or endoscopic disease activity, histology may be the ideal marker of inflammation. Standardized definitions of histologic response and remission and a biopsy procurement protocol are needed to guide clinical decision making. It is recommended that overall assessment of disease severity be determined according to the worst affected biopsy fragment. Crypt architectural distortion, basal plasmacytosis, and neutrophilic activity should be reported. A 5-category classification system based on disease chronicity/activity and basal plasmacytosis is proposed. It is not yet necessary to report on the degree of mucosal eosinophilia or use a validated scoring system, although the latter may aid in determining therapeutic response.
Although rarely used to measure inflammation and guide therapy, histologic disease activity is predictive of important clinical outcomes in UC. Randomized controlled trials are needed to determine whether histology should function as a treatment target.
Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to ...conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.
BACKGROUND:The American Joint Committee on Cancer and the College of American Pathologists provide guidelines for reporting pathologic response to neoadjuvant treatment of rectal cancer. The clinical ...relevance of these tumor regression grading guidelines is undefined.
OBJECTIVE:This study evaluates the prognostic significance of the American Joint Committee on Cancer/College of American Pathologists regression grading.
DESIGN:This is a retrospective cohort study based on data from a prospectively maintained colorectal cancer database. The cohorts were defined by American Joint Committee on Cancer/College of American Pathologists tumor regression grade.
SETTING:This study was performed at a single tertiary referral center.
PATIENTS:Five hundred thirty-eight patients with primary rectal adenocarcinoma who underwent neoadjuvant therapy between 1992 and 2012 were identified.
MAIN OUTCOME MEASURES:The primary outcome measures were overall and disease-free survival, cancer-specific mortality, and cumulative recurrence rate.
RESULTS:Five hundred thirty-eight patients were included, 105 of whom (19.5%) were American Joint Committee on Cancer/College of American Pathologists grade 0, 153 patients (28.4%) were grade 1, 181 patients (33.6%) were grade 2, and 99 (18.4%) were grade 3. Kaplan-Meier analysis revealed that American Joint Committee on Cancer/College of American Pathologists grade was associated with significant differences in overall survival (p < 0.001), disease-free survival (p < 0.001), and cumulative recurrence (p < 0.001). No local recurrences were observed in American Joint Committee on Cancer/College of American Pathologists grade 0 patients. Five-year overall survival rates were 89%, 74%, 63%, and 40% (p < 0.001); 5-year disease-free survival rates were 85%, 64%, 54%, and 33% (p < 0.001); and 5-year recurrence rates were 7%, 18%, 25%, and 33% (p <0.001) for American Joint Committee on Cancer/College of American Pathologists grades 0, 1, 2, and 3. After adjusting for significant covariates, including pathologic stage, American Joint Committee on Cancer/College of American Pathologists grade remained an independent predictor of overall survival (p < 0.001), disease-free survival (p < 0.001), and cumulative recurrence (p < 0.001) in Cox regression analyses.
LIMITATIONS:This was a retrospective study. There was a low local recurrence rate in our population, limiting the sensitivity of recurrence analyses.
CONCLUSIONS:This is the first study to delineate American Joint Committee on Cancer/College of American Pathologists regression grade as an independent oncologic prognostic factor. This information can be used in discussions with patients who have rectal cancer.
OBJECTIVE:To evaluate the independent prognostic ability of the American Joint Committee on Cancer (AJCC) tumor regression scores within pathologic stage II and III rectal cancers.
...BACKGROUND:Response to neoadjuvant chemoradiation (nCRT) has been debated as a biologic surrogate for tumor biology and prognosis in rectal cancer. AJCC regression scores have been shown to correlate with prognosis.
METHODS:Patient demographics, tumor characteristics, and AJCC scores (0 = complete response; 1 = isolated tumor cells remaining; 2 = residual cancer outgrown by fibrosis; 3 = extensive residual cancer) were assessed from 545 rectal cancer patients treated by nCRT followed by surgery at a single institution. Patients were classified as responders (score 0–2) or nonresponders (score 3). Survival analyses were performed using Cox proportional hazards models.
RESULTS:Of 545 cases, 123 and 182 were pathologic stage II and III, respectively. Median follow-up was 4.9 years. AJCC regression scores were not independently prognostic within stage II cancers. However, AJCC scores were strongly associated with prognosis within stage III cancers (nonresponse 5-year overall survival OS 27% vs 67%, P < 0.001). Stage III responders (N = 139, 76.4%) had similar outcomes to stage II (5-year OS 67% vs 74%, P = 0.89). Conversely, stage III nonresponders (N = 43, 23.6%) approached stage IV outcomes (5-year OS 27% vs 18%, P = 0.09). On multivariable analysis, nonresponse (hazard ratio 3.2, 95% confidence interval 1.7–6.2), along with positive margin, abdominoperineal resection, and no adjuvant chemotherapy administration were independently associated with worse OS.
CONCLUSIONS:AJCC response score after nCRT is a novel prognostic factor in pathologic stage III rectal cancer and may guide surveillance and adjuvant therapy decisions.
Neoadjuvant therapy is increasingly used to treat patients with a wide variety of malignancies. Histologic evaluation of treated specimens provides important prognostic information and may guide ...subsequent chemotherapy. Neoadjuvant therapy is commonly employed in the treatment of locally advanced rectal adenocarcinoma, hepatic colorectal metastases, esophageal/esophagogastric junction carcinoma, and pancreatic ductal adenocarcinoma. Numerous tumor regression schemes have been used in these tumors and standardized approaches to evaluate these specimens are needed. In this review, the various tumor regression scoring systems that have been used in these organs are described and their associations with clinical outcomes are discussed. Recommendations regarding how to handle and report the histologic findings in these resections specimens are provided.
Lynch syndrome accounts for roughly 1 of every 35 patients with colorectal carcinoma, making it the most common hereditary form of colorectal carcinoma. Identifying patients at risk for Lynch ...syndrome is essential, as these patients can develop additional Lynch syndrome–related tumors, and patients and their relatives benefit from genetic counseling. The hallmark of Lynch syndrome–associated neoplasms is DNA mismatch repair protein deficiency. In most instances, the pathologist is the first to identify patients at risk for Lynch syndrome and is tasked with communicating these results to treating clinicians and genetics counselors. This review will attempt to provide the tools for pathologists to identify patients at risk for Lynch syndrome through evaluation of tumors of the gastrointestinal tract and provide up-to-date knowledge on evaluating mismatch repair protein deficiency in tumors of the gastrointestinal tract.
Aims
To develop and validate a deep learning algorithm to quantify a broad spectrum of histological features in colorectal carcinoma.
Methods and results
A deep learning algorithm was trained on ...haematoxylin and eosin‐stained slides from tissue microarrays of colorectal carcinomas (N = 230) to segment colorectal carcinoma digitised images into 13 regions and one object. The segmentation algorithm demonstrated moderate to almost perfect agreement with interpretations by gastrointestinal pathologists, and was applied to an independent test cohort of digitised whole slides of colorectal carcinoma (N = 136). The algorithm correctly classified mucinous and high‐grade tumours, and identified significant differences between mismatch repair‐proficient and mismatch repair‐deficient (MMRD) tumours with regard to mucin, inflammatory stroma, and tumour‐infiltrating lymphocytes (TILs). A cutoff of >44.4 TILs per mm2 carcinoma gave a sensitivity of 88% and a specificity of 73% in classifying MMRD carcinomas. Algorithm measures of tumour budding (TB) and poorly differentiated clusters (PDCs) outperformed TB grade derived from routine sign‐out, and compared favourably with manual counts of TB/PDCs with regard to lymphatic, venous and perineural invasion. Comparable associations were seen between algorithm measures of TB/PDCs and manual counts of TB/PDCs for lymph node metastasis (all P < 0.001); however, stronger correlations were seen between the proportion of positive lymph nodes and algorithm measures of TB/PDCs. Stronger associations were also seen between distant metastasis and algorithm measures of TB/PDCs (P = 0.004) than between distant metastasis and TB (P = 0.04) and TB/PDC counts (P = 0.06).
Conclusions
Our results highlight the potential of deep learning to identify and quantify a broad spectrum of histological features in colorectal carcinoma.
PDF
