|Gert de Hertogh
Histopathologists have traditionally fulfilled three functions in Inflammatory Bowel Disease (IBD) care. First, they play a role in the initial diagnosis, together with gastroenterologists, endoscopists and radiologists. Second, they establish a differential diagnosis at clinical flares of the disease, resolving the question of whether there is reactivation of the IBD, a superinfection or an unrelated pathology. Third, they are involved in the screening of patients for premalignant lesions and cancer.
Quite recently, pathologists have also been asked to assess disease activity in endoscopic biopsies. The results of such evaluation may serve several functions. In conjunction with the clinical and the endoscopic findings, the pathology results describe the response to medical therapy in routine clinical care. Further, they may allow assessment of the risk of relapse and perhaps the risk for development of (pre)neoplasia in endoscopically inactive or mildly active disease. Lastly, microscopic assessment of disease activity is more and more frequently requested in order to document the effects of new medications in clinical trials. Indeed, while the traditional evaluation of disease activity has been clinical or by endoscopy, there is currently a tendency to include histological data, especially in Ulcerative Colitis (UC).
The targets for medical management of UC have shifted over time from clinical remission to endoscopic healing (first defined as a Mayo endoscopic subscore of 0 or 1, and later exclusively as a subscore of 0). Histological remission has been proposed most recently, but is still a controversial endpoint. According to the STRIDE consensus statement on treat-to-target recommendations in UC, histopathology is a sensitive measure of inflammation, but cannot yet be considered a target due to lack of evidence of clinical utility . On the other hand, the FDA draft guidance for endpoints in UC states that “A claim of mucosal healing would not be supported through endoscopy, that provides only an assessment of the visual appearance of the mucosa. Any claim related to findings on endoscopy, in the absence of a validated histological assessment of the mucosa, would be limited to the endoscopic appearance of the mucosa” . Clearly, there is thus a need for a validated histological index of disease activity in UC. Such an index, when approved for clinical trials, may eventually enter routine clinical practice.
The FDA guidance is underpinned by old and more recent data that histological remission in UC may effectively predict clinical outcome. First, it has long been established that the correlation between histological and endoscopic disease activity is better than for histology and clinical status, although it is not perfect . More recent data on large numbers of biopsies have shown that even patients with mild endoscopic disease (defined as a Mayo endoscopic subscore of 0 or 1) may have microscopic erosions or ulcerations, i.e. evidence of active inflammation, epithelial damage and loss of mucosal integrity . It is thus clear that histology provides different information from endoscopy. It has further been shown that specific histological parameters, namely the presence of neutrophils in the biopsy, crypt abscesses, a breached surface epithelium  and basal plasmacytosis , alone or in combination, predict an increased risk of disease relapse within 12 months of follow-up in patients with chronic quiescent UC or Mayo 0 at surveillance colonoscopy. Every histological UC activity index should therefore probably contain one or more of these parameters.
This is effectively the case with the so-called Geboes score, a categorical system containing seven microscopic features of UC . These histological parameters are ranked according to their link with disease activity and severity, and are graded separately. The highest obtained grade is retained as the overall score. The Geboes score has been extensively used in clinical trials. It is, however, less applicable outside a research setting, mainly because it requires sufficient training to use it in a reproducible way.
More recent efforts in this field have concentrated on a reduction in the number of histological features to be scored, the introduction of “weighted” parameters, and internal and cross-validation of indices. For example, the Nancy index is a simple, reproducible and validated grading system that is already used in routine clinical practice . The Robarts histopathology index (RHI) is a simplification of the initial Geboes score and retains only the reproducible and clinically relevant parameters, which are weighted relative to one another . These two indices have also been compared with each other and found to demonstrate near-perfect to good intra- and interobserver agreement. In fact, the Geboes score, the Nancy index and the RHI can all predict the Mayo endoscopic subscore and faecal calprotectin levels. It has already been demonstrated that elevations in faecal calprotectin in histologically active disease are mainly associated with neutrophils in the epithelium and with mucosal erosion and ulceration . Faecal calprotectin has also been identified as an independent predictor of histological inflammation . This seems logical as calprotectin is mainly found as a cytosolic protein in neutrophils. Although validation studies are ongoing, histological remission can thus be defined as a Geboes score <2B.0 (no neutrophils in the biopsy), a Nancy index ≤1 (idem) or an RHI score ≤3 (as long as there are no neutrophils in the biopsy). Further research will doubtlessly concentrate on defining appropriate cut-off values for faecal calprotectin levels and on the influence of bowel preparation and the extent of biopsy sampling on the definition of cut-offs for histological remission in UC.
In contrast to UC, histological scoring systems are far less commonly used in Crohn’s Disease (CD). There are a number of reasons for this, both practical and conceptual. For example, some bowel segments may be inaccessible during endoscopy due to stenosis. The treatment target is usually defined as absence of ulceration rather than mucosal healing. It is also unknown whether mucosal biopsies are representative for the ongoing disease process in the deeper bowel wall layers. Nevertheless, many different histological scoring systems have been developed in CD. One of the best known is the so-called D’Haens score (the GHAS index), which, however, has not been formally validated and is already used in several modifications . It has further been argued that the Nancy index and the RHI can also be used for CD biopsies, and attempts to do this are already underway.
In conclusion, histology may measure the response to medical therapy and predict the clinical disease course in IBD. To this end, over the last few years several validated histological activity indices have been developed, at least for UC. Definitions for histological remission have been proposed. The correlation between faecal calprotectin levels and endoscopic remission has been investigated. A real demonstration of the independent value of histology may, however, require a large-scale clinical trial with treatment decisions based on histology in comparison with other existing targets, including faecal calprotectin levels.