Hypermucinous dysplasia represents approximately 2% of all dysplastic lesions in IBD patients (Table 1) [38]. Most patients have a long history of IBD with a mean duration of 23 years. It is predominantly found in UC patients (86%) who often have a concurrent history of PSC (29%). Although the majority of hypermucinous dysplastic lesions have a polypoid endoscopic appearance with a mean size of 2.1 cm [38], up to 42% are endoscopically invisible or flat (unpublished results). Hypermucinous dysplasia shows a predilection for the left colon (57%).

Morphologically, hypermucinous dysplasia most often demonstrates a tubulovillous/villous architecture lined by tall, prominent mucinous cells representing>50% of the lesion (Fig. 3A, B) [38,41,43]. Although low-grade dysplastic features are usually present in crypts, the degree of atypia tends to decrease towards the surface epithelium due to prominent mucinous differentiation, so one must be careful not to miss hypermucinous dysplasia when evaluating superficial fragments with hypermucinous features but without significant nuclear atypia (Fig. 3B). The presence of high-grade nuclear features is relatively uncommon (29%). Hypermucinous dysplasia can present either as a ‘pure type’ or a ‘mixed type’ with either conventional or another non-conventional subtype (most often with a serrated subtype) [41]. However, to be categorized as the mixed type, the hypermucinous component should represent >50% of the lesion.

There is increasing evidence that hypermucinous dysplasia may be a marker of increased risk for advanced neoplasia. First, hypermucinous dysplasia was the most common non-conventional subtype (42%) found in a cohort of 58 IBD patients with CRC [41]. Second, a significant proportion of hypermucinous dysplastic lesions (57%) were associated with advanced neoplasia [38]. In another study, we demonstrated that 19 (49%) of 39 low-grade hypermucinous dysplastic lesions were correlated with subsequent detection of HGD (n=9, 23%) or adenocarcinoma (n=10, 26%) at the site of previous biopsy or in the same colonic segment within a mean follow-up time of 11 months (unpublished results). Third, hypermucinous dysplasia, even without cytologic atypia, has been shown to have a higher rate of KRAS mutations (61%) than conventional LGD (4%, p<.001) or HGD (29%, p>.05) [45]. Similarly, we reported that the frequency of aneuploidy in low-grade hypermucinous dysplasia (80%) is significantly higher than that of low-grade conventional dysplasia (8%) or sporadic adenomas (9%) (p<.001) [38]. In fact, its rate of aneuploidy (80%) is similar to that of invisible/flat HGD (93%) [37]. Overall, these results indicate that despite its low-grade morphology, hypermucinous dysplasia shares similar molecular features with conventional HGD, suggesting that it may represent at least a high-risk low-grade lesion, if not already HGD. These findings also suggest that KRAS mutations and/or aneuploidy may contribute to the development of tubulovillous/villous growth, larger size, and/or higher biologic grade in hypermucinous dysplasia [46]. Similar to conventional dysplasia, hypermucinous dysplasia most likely develops via the chromosomal instability pathway involving multiple genetic mutations (including KRAS, TP53, and APC genes) and altered regulation of Wnt/β-catenin pathway, as well as aneuploidy [47-50].

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%). It exclusively presents as an invisible/flat lesion. When endoscopically visible, it has been described as “mild inflammation,” “edema,” “erythema,” “friable,” or “scarring” [42].

Histologically, crypt cell dysplasia is characterized by mildly enlarged, round-to-oval or slightly irregular, crowded, hyperchromatic nuclei limited to the crypt base without surface involvement or significant architectural atypia (Fig. 3C, D) [38,42,43]. Increased mitoses at the base of crypts are common (Fig. 3D). Although a few scattered cells may show more than mild nuclear enlargement and/or focal loss of nuclear polarity, there is no unequivocal evidence of HGD. To avoid confusion with reactive changes, significant neutrophilic inflammation and/or ulceration should be absent. Immunohistochemical staining for p53 could be potentially useful to distinguish crypt cell dysplasia from reactive changes, as strong and diffuse p53 nuclear staining has been reported in up to 63% of crypt cell dysplastic lesions [42].

Similar to hypermucinous dysplasia, crypt cell dysplasia is considered a high-risk marker for advanced neoplasia. In support of this, we reported that six of seven patients (86%) with crypt cell dysplasia developed HGD (n=4, 57%) or CRC (n=2, 29%) in the same colonic segment within a mean follow-up time of 27 months [38,42]. Notably, all 14 biopsies with crypt cell dysplasia from the seven patients demonstrated aneuploidy [42]. This is consistent with our previous finding that invisible/flat dysplasia in IBD patients is characterized by the high rate of aneuploidy (41% for invisible/flat LGD and 93% for invisible/flat HGD) [37]. Taken together, these findings indicate that crypt cell dysplasia likely represents at least high-risk LGD, if not already HGD. Other investigators also reported that TP53 (43%) and KRAS (14%) mutations are common in crypt cell dysplasia, further confirming its dysplastic nature [47]. Of note, these results are very similar to what has been described in Barrett’s esophagus-related “crypt dysplasia,” which showed similar molecular alterations (i.e., aneuploidy and TP53 mutations) that are normally found in traditional dysplasia with surface involvement [51].

In practice, it may be difficult to diagnose and/or grade crypt cell dysplasia in a consistent manner on histologic grounds alone. In fact, we previously reported a poor interobserver agreement in the diagnosis and/or grading of crypt cell dysplasia [42]. Even though the majority of pathologists recognized its atypical morphology and diagnosed as IND, LGD, or HGD in 83% of their readings, a diagnosis of IND was made in 50% rather than either LGD (13%) or HGD (19%). As such, in challenging situations, we recommend that pathologists use the diagnostic term “crypt cell atypia” to describe similar changes and recommend a repeat colonoscopy within 3–6 months. If there is significant neutrophilic inflammation and/or ulceration in the areas of cytologic atypia, it may be more appropriate to make a diagnosis of IND and suggest a repeat colonoscopy within 3–6 months (Fig. 1B).

Dysplasia with increased Paneth cell differentiation is a common non-conventional subtype accounting for 51% of non-conventional dysplastic lesions and 13% of all dysplastic lesions in IBD patients (Table 1) [38]. The majority of affected patients have a long history of IBD (mean duration: 17 years), but a concurrent history of PSC is rare (9%). Dysplasia with increased Paneth cell differentiation most often presents as a polypoid lesion (70%) with a mean size of 1 cm. The right colon is most frequently involved (45%), and there appears to be a strong association with male sex (82%).

The defining histologic feature of dysplasia with increased Paneth cell differentiation is increased Paneth cell differentiation involving at least two contiguous dysplastic crypts in two different foci (beyond what is present in background mucosa) (Fig. 4A, B) [38,41,43]. It usually demonstrates a tubular architecture mostly lined by elongated, hyperchromatic nuclei involving both crypts and surface epithelial cells. Goblet cells may be reduced, but they are not absent or nearly-absent. Although scattered Paneth cells may be present in other dysplastic subtypes, they are not present in multiple crypts and in multiple foci as in dysplasia with increased Paneth cell differentiation, and the same degree of Paneth cell differentiation is always present in adjacent, non-dysplastic mucosa.

Unlike hypermucinous and crypt cell dysplasias, increased Paneth cell differentiation may be a marker of lower-risk lesions. In favor of this, we previously demonstrated that the risk of harboring advanced neoplasia in dysplasia with increased Paneth cell differentiation (15%) is compatible to that of conventional dysplasia (19%) (p=.523). Also, the rate of aneuploidy in lowgrade lesions (12%) is similar to that of low-grade conventional dysplasia (8%, p=0.715) or sporadic adenomas (9%, p=.823) [38]. These results are in agreement with our previous finding that dysplasia with increased Paneth cell differentiation was a rare non-conventional subtype (11%) found in a cohort of 58 IBD patients with CRC [41].

Interestingly, sporadic Paneth cell-containing adenomas have been described in the literature with the reported frequency of 0.2% to 39% [52-55]. Even though these earlier studies defined the presence of even one Paneth cell as histologic evidence of increased Paneth cell differentiation, sporadic Paneth cell-containing adenomas appear to share similar clinicopathologic features with their IBD-related counterpart. For instance, Pai et al. [55] reported that sporadic Paneth cell-containing adenomas are more likely to occur in the right colon (85% vs. 56% for non-Paneth cell-containing adenomas; p=.006) and in male individuals (89% vs. 56% for non-Paneth cell-containing adenomas; p=.002). Also, Mahon et al. [53] demonstrated that sporadic Paneth cell-containing adenomas in the proximal (p=.157) and distal colon (p=.797) are not significantly associated with subsequent detection of CRC, compared with non-Paneth cell-containing adenomas.

Goblet cell deficient dysplasia represents approximately 3% of all dysplastic lesions in IBD patients (Table 1) [38]. Most patients have a long history of IBD (mean duration: 17 years). Although a concurrent history of PSC is not uncommon (14%), it appears to be not as frequent as in patients with crypt cell dysplasia (43%) or hypermucinous dysplasia (29%). Goblet cell deficient dysplasia is often endoscopically invisible or flat (40%), but when endoscopically visible, it usually presents as a large polypoid lesion with a mean size of 1.9 cm. It is equally common in both right and left colon (40% each).

Morphologically, goblet cell deficient dysplasia is defined by a complete or near-complete absence of goblet cells, often leading to intensely eosinophilic cytoplasm (Fig. 4C, D) [38,41,43]. It predominantly shows a tubular architecture with low-grade dysplastic features involving both crypts and surface epithelial cells. However, up to 40% of goblet cell deficient dysplastic lesions may demonstrate HGD at diagnosis. Eosinophilic luminal secretion is another common histologic feature of goblet cell deficient dysplasia (Fig. 4C).

Similar to hypermucinous and crypt cell dysplasias, goblet cell deficient dysplasia may be another high-risk marker for advanced neoplasia. In support of this, as noted above, 40% of goblet cell deficient dysplastic lesions were associated with advanced neoplasia [38]. In another study, we demonstrated that 10 (59%) of 17 low-grade goblet cell deficient dysplastic lesions were correlated with subsequent detection of HGD (n=4, 24%) or adenocarcinoma (n=6, 35%) at the site of previous biopsy or in the same colonic segment within a mean follow-up time of 13 months (unpublished results). Also, low-grade goblet cell deficient dysplasia appears to have a higher rate of aneuploidy (25%) than lowgrade conventional dysplasia (8%) or sporadic adenomas (9%) [38]. Furthermore, other investigators reported the high rates of TP53 (44%), KRAS (22%), and PIK3CA (56%) mutations in goblet cell deficient dysplasia [47].

This category includes three distinct subtypes, including SSL-like dysplasia, TSA-like dysplasia, and serrated dysplasia NOS [38,41,43]. Serrated dysplastic lesions usually present as polypoid lesions with a mean size of 1.2 cm (Table 1) [38,56], and they are known to share similar clinicopathologic and molecular features with their sporadic counterparts [38,56-58]. For instance, while TSA-like dysplasia shows a propensity for the left colon, SSL-like dysplasia is more common in the right colon [38,56,57]. Ko et al. [56] also reported that low-grade serrated dysplasia in IBD patients often resembles sporadic TSA, occurs mainly in the left colon, and contains KRAS mutations (45%). In addition, serrated dysplasia, in particular SSL-like dysplasia, usually lacks aneuploidy, suggesting that an alternative serrated pathway (without resulting in aneuploidy) may be responsible for the development of at least a subset of SSL-like and TSA-like dysplastic lesions [38,58].

Histologically, SSL-like dysplasia is characterized by distorted serrated crypts with prominent basal crypt dilatation (i.e., dilated L- or inverted T-shaped crypts) at the interface with muscularis mucosa (Fig. 5A) [38,41,43]. TSA-like dysplasia most often demonstrates a tubulovillous/villous architecture lined by tall columnar cells with intensely eosinophilic cytoplasm and ectopic crypts (Fig. 5B) [38,41,43]. Serrated dysplasia NOS shows no definite features of SSL-like dysplasia or TSA-like dysplasia (Fig. 5C, D) [38,41,43]. Serrated dysplasia can co-exist with conventional dysplasia or another non-conventional subtype as a minor component, but to be classified as a specific serrated subtype, a serrated architecture should form the predominant feature representing >50% of the lesion [38,41].

Although the natural history of serrated dysplasia is not well defined in IBD patients, low-grade serrated dysplasia (which often resembles sporadic TSA) has been reported to have higher rates of advanced neoplasia (17% within 10 years, p=.020) and prevalent neoplasia (76%, p<.001) than serrated lesions without dysplasia (0% and 11%, respectively) [56]. Its 10-year rate of advanced neoplasia (17%) was similar to that of low-grade, non-serrated, conventional dysplasia (23%) [56]. Overall, these findings suggest that although serrated lesions that lack dysplasia seem to pose little risk for advanced neoplasia, those with LGD are associated with increased rates of synchronous and metachronous neoplasia. However, their risk of developing advanced neoplasia is probably compatible to that of conventional dysplasia (Table 1).