DNA flow cytometric and interobserver study of crypt cell atypia in inflammatory bowel disease

Abstract

Aims The pathological features and diagnostic reliability of crypt cell atypia (CCA) arising in inflammatory bowel disease (IBD) and its clinical significance are unknown. Methods and results DNA flow cytometry (FCM) was performed on 14 colon biopsies of CCA from seven IBD patients (male‐to‐female ratio, 5:2; mean age, 53 years; mean IBD duration, 15 years) using paraffin‐embedded tissue. Seven gastrointestinal pathologists were asked to diagnose each biopsy as negative for dysplasia (NEG), indefinite for dysplasia (IND), low‐grade dysplasia (LGD) or high‐grade dysplasia (HGD) by morphology alone, then again with knowledge of FCM results. Aneuploidy was detected in all 14 biopsies, and five of eight biopsies (63%) also showed strong and diffuse nuclear staining for p53 in the areas of CCA. Six (86%) patients developed HGD (n = 5) or adenocarcinoma (n = 1) in the same colonic segment where CCA had been diagnosed within a mean follow‐up time of 27 months. No follow‐up information was available in the remaining one patient. When diagnoses were grouped as NEG or ‘atypical’ (including IND, LGD or HGD), the overall agreement rate of 76% (kappa = 0.51) based on morphology alone improved to 90% (kappa = 0.81) with knowledge of FCM results. Even when categorised as NEG or dysplasia (LGD or HGD) with each of the IND diagnoses reclassified into three categories (NEG, LGD or HGD) based on the degree of suspicion for dysplasia, the overall agreement rate of 63% (kappa = 0.25) based on morphology alone improved to 73% (kappa = 0.46) with knowledge of FCM results. However, when grouped as NEG, LGD or HGD, the overall agreement rate was less than 40% (kappa < 0.09) regardless of knowledge of FCM results. Conclusions The presence of aneuploidy, p53 positivity and development of HGD or adenocarcinoma on follow‐up indicate that CCA likely represents a dysplastic lesion (at least LGD) and is a histological marker of neoplastic progression. Although the grading of CCA, largely based on cytological abnormalities, is subject to significant interobserver variability, CCA can be histologically identified and should lead to a recommendation of increased endoscopic surveillance, especially if aneuploidy is detected.

Non‐conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum

“…The neoplastic nature of this lesion is supported by the frequent detection of aneuploidy (100%) and p53 overexpression (63%) 102 . Although large studies are necessary to determine its natural history, one study showed that six (86%) of seven patients with crypt cell dysplasia developed high‐grade dysplasia or colorectal cancer within a mean follow‐up time of 27 months 102 …”

DNA aneuploidy with image cytometry for detecting dysplasia and carcinoma in oral potentially malignant disorders: A prospective diagnostic study

“…17 Of particular interest, the presence of DNA aneuploidy in inflammatory bowel disease determined by flow cytometry was also associated with development of dysplasia or colorectal cancer. 26 Our profile of DNA aneuploidy to some extent reflected that the malignant progression of OPMD is a typical multistep carcinogenesis processes with stepwise accumulations of DNA and genetic alterations. These findings suggest that DNA aneuploidy using brushing sample could be used as an indicator of disease before the appearance of clinical signs and symptoms in early OSCC patients.…”

Non-conventional dysplastic subtypes in inflammatory bowel disease: a review of their diagnostic characteristics and potential clinical implications

“…Although pathologists have a good grasp of the morphologic criteria of conventional dysplasia, several unfamiliar morphologic patterns of dysplasia (collectively known as "non-conventional" dysplasia) have been recently described in IBD. There are at least seven subtypes, including (1) hypermucinous dysplasia; (2) crypt cell dysplasia; (3) dysplasia with increased Paneth cell differentiation; (4) goblet cell deficient dysplasia; (5) SSL-like dysplasia; (6) TSA-like dysplasia; and (7) serrated dysplasia NOS [38,[41][42][43]. Although their clinicopathologic and molecular features are not fully characterized, in part due to the rarity of these subtypes and the likelihood that they are under-recognized, the recognition of these non-conventional subtypes is becoming increasingly important, as they often present as invisible/flat lesions, and at least some of them appear to have a higher malignant potential than conventional dysplasia or sporadic adenomas.…”

“…Crypt cell dysplasia accounts for approximately 4% of all dysplastic lesions in IBD patients (Table 1) [38], but it is likely an under-diagnosed entity. Most patients have a long history of IBD (mean duration: 15 years) and often have a concurrent history of PSC (43%) [38,42]. It is predominantly found in UC patients and shows a propensity for the left colon (79%).…”