Tropical 2011;32(2):87–93

Editorial : The scope of the scopes in nomenclature and diagnosis

S. Datta Gupta

Department of Life-long learning is the hall-mark of professional education. This is often the result of All India Institute of Medical Sciences experiences shared by our colleagues world-wide, of common clinical conditions that present New Delhi - 110029, India in an unusual manner. Correspondence: The two major constituents of inflammatory bowel disease: Crohn’s disease (CD) and Dr. S. Datta Gupta ulcerative colitis (UC) have several overlapping features and their distinction in difficult Email: [email protected] cases is a true accreditation of the skills of a gastroenterologist. Indistinguishable cases are aptly labeled as indeterminate colitis. In certain countries such as India, additionally, colonic tuberculosis (TB) is a close differential of colonic Crohn’s disease mainly because both are recognized to show patchy involvement and granulomatous . In this issue of the journal, Shah SN, Amarapurkar AD, Thiruvengadam NR, Nistala S and Rathi PM1 highlight unusual presentations of ulcerative colitis that may make the diagnosis otherwise difficult. Non-contagious diarrheal diseases have been apparent to over centuries having been described by Aretaeus (A.D. 300) and Soranus (A.D. 117).2 Sir Samuel Wilks in 18593 has been credited with introducing the term “ulcerative colitis” to a disease that was less understood then and perhaps even lesser understood today. It is likely that several clinically similar diseases may have been considered under this term. Thus it has been suggested that in 1745 Prince Charles, the Young Pretender to the throne, cured himself of ulcerative colitis by adopting a milk-free diet!2,4 Excellent descriptions have been provided by the Surgeon General of the Union Army (describing the medical history of the American Civil War), Wilks & Moxon (1875), Allchin (1885) and Hale-White (1888). By 1909, around 300 cases were collected from various London hospitals and described at a symposium of the Royal Society of .2 Ulcerative colitis has been defined as an inflammatory disease of unknown origin, characterized clinically by recurrent attacks of bloody , and pathologically by a diffuse inflammation of the wall of the large bowel. The inflammatory changes spread proximally from the rectum; and are confined to (or most severe in) the colonic and rectal mucosa.2 Nevertheless at one time it was suggested that an accurate definition is not possible since the etiology is largely unknown.5 Whether this is true even today is a matter of personal opinion. To match the definition, it appears that the diagnosis of ulcerative colitis follows a unique rule. Unlike several conditions, the final diagnosis of ulcerative colitis is anything but histological! The histological features of chronic colitis may be present as early as 1 week after the onset of clinical symptoms; are usually well established after 3–4 weeks time; and are relatively non- specific (several other colitis such as infective, ischemic, drug induced or toxic, apart from Crohn’s disease show similar features). Hence, in routine practice, clinical, imaging and conventional sigmoidoscopic and colonoscopic features are correlated to arrive at a diagnosis. The accuracy of individual methods of diagnosis is difficult to determine since very few studies have looked into these aspects critically. However, in one study the performance of clinical impression in recognizing disease activity, as determined by endoscopy, was relatively poor (sensitivity = 56.0%, negative predictive value = 56.8%, kappa coefficient = 0.35) while

© Tropical Gastroenterology 2011 88 Tropical Gastroenterology 2011;32(2):87–93 histological evaluation in recognizing disease activity was limited sample at a single point in time. One of the reasons for markedly better (sensitivity = 93.5%, negative predictive value problems is the over-zealous diagnosis of ulcerative colitis, = 89.1%, kappa coefficient = 0.70).6 Conventionally, endoscopy based on a single rectal biopsy that contains some crypt (sigmoidoscopy and colonoscopy) is considered an extension, abscesses. Crypt abscesses are seen in both acute and chronic if not a part of clinical examination, especially if the evaluating colitis including Crohn’s disease, bacterial infection, is a gastroenterologist. Thus endoscopy has a lymphocytic colitis and Clostridium difficile-related toxic special role in the diagnosis of ulcerative colitis. Several damage. In bacterial infection crypt abscesses are superficial.18 endoscopic activity grading schemes are available (Matts, The differential diagnosis can be narrowed down with help of Schroeder or Mayo, Baron, Blackstone, Rashmilewitz and their a history of long duration (typically of bloody diarrhea over six modifications).7 Endoscopy alone may not be able to provide a month duration). Thus a properly filled requisition form specific diagnosis in nearly 70% of cases especially if non- accompanying the specimen is invaluable. Histological features specific features such as only hyperemia or aphthous ulcers of chronicity include crypt branching and Paneth cell are observed.8 However once a diagnosis is rendered there is metaplasia. Of the two, crypt branching is more reliable a fairly acceptable concordance between endoscopic and especially if the branches are at irregular angles and parallel to histological assessment of activity.9 In general, endoscopic the muscularis mucosae. It is worth noting that since Paneth assessments and agreements are better with training and cells may extend into the proximal colon in adults and some experience.7,10,11 To enhance the accuracy of diagnosis, several distance further in pediatric patients, their presence in non-invasive methods have been introduced over the years. rectosigmoid biopsies is excellent proof of chronic damage. Most of these are of use in differentiating Crohn’s disease and Thus biopsies must be submitted properly labeled with regard ulcerative colitis or in assessing activity of illness in diagnosed to their site and not aggregated together in one specimen bottle ulcerative colitis.12-15 Here, mention needs to be made that or submitted unlabeled. Inflammation is typically imaging techniques are gradually gaining a place in lymphoplasmacytic, confined to the lamina propria, extends complementing other non-invasive and endoscopic methods throughout its thickness with relative sparing of the intercryptal of diagnosis. However, their role in differentiating Crohn’s surface epithelium. In bacterial colitis the inflammation is not disease from ulcerative colitis appears more appropriate by uniform,19 whereas in lymphocytic colitis and collagenous virtue of detecting small intestinal involvement than colitis the inflammation is usually limited to the top half of the demonstrating specific diagnostic features of ulcerative lamina propria (“top heavy”). The intercryptal surface colitis.13,16 epithelium is damaged in ischemic damage, C. difficile toxin, Despite acceptance of the consensus that ulcerative colitis and lymphocytic and collagenous colitis. The muscularis should be diagnosed after a reasonable collation and mucosa is often thickened in inflammatory bowel disease. In assessment of clinical, endoscopic, imaging and histological addition, in collagenous colitis there is a thick, irregular collagen data; due to various reasons and limitations reliance on one or band under this surface epithelium.20 Lymphocytic and more observations is resorted to. Thus, for obvious reasons, collagenous colitis are important because they can produce the diagnosis of acute severe ulcerative colitis that has an chronicity similar to inflammatory bowel disease, although there immense bearing on immediate and critical management are clinical and endoscopic differences. Granulomatous decisions is based purely on clinical and laboratory data.17 inflammation undoubtedly points to Crohn’s disease (and Even if such special situations are excluded, more often than wherever relevant to tuberculosis). Granulomas may not, there is an undue reliance on histological features, perhaps occasionally be found as a reaction to mucin extruded from as a tribute to the traditional method of final diagnosis whenever crypt abscesses (“crypt granulomas”). It must be emphasized a tissue sample is available. Thus, as discussed in a recent that there may be instances wherein unusual findings are excellent review,18 endoscopic biopsies play a major role in the present. The article by Shah et al in this issue1 lists unusual establishment of a diagnosis of idiopathic inflammatory bowel histological features that include a predominance of disease despite the fact that it is clearly not possible to be polymorphs in 38% and eosinophils in 6.3% cases. Such consistently certain of the presence of inflammatory bowel observations have been recorded in both inflammatory bowel disease (as opposed to infection, toxin, and the like) on a single disease and infective colitis. A recent interesting report Ulcerative colitis 89 reiterates that such findings are associated with active colitis.21 Despite similarities with other conditions, one of the time- Histological changes in ulcerative colitis can be graded similar tested characteristic that assists in the diagnosis ulcerative to clinical features.22 colitis is a diffuse continuous involvement of the colon. Therefore, communication between the attending clinician, Typically, the rectum is always involved and is a clinical and gastroenterologist or surgeon and the histopathologist should pathologic hallmark of ulcerative colitis especially in patients be a top prerequisite for making a diagnosis of inflammatory at initial presentation. Very often the rectum is the most severely bowel disease.18 It is essential to make an accurate distinction inflamed.27-29 Even the incidence of cancer has been reported between various types of colitis especially between ulcerative to be more frequent in the rectum and sigmoid colon in ulcerative colitis and Crohn’s disease. This is more than an academic colitis in comparison to Crohn’s disease.30,31 Thus, sparing of exercise. Current therapeutic options available make it more rectum is considered as an important feature against diagnosis relevant to differentiate between Crohn’s disease and ulcerative of ulcerative colitis. colitis than to make a diagnosis of inflammatory bowel disease The pathogenesis of ulcerative colitis is replete with or no diagnosis at all! An ileal pouch anal anastomosis (IPAA, theories that includes genetic susceptibility, infection “pouch” procedure) is generally contradicted in CD due to a (antibiotics are nevertheless unhelpful as therapeutic agents) high risk of morbidity related to pouchitis, fistulas, incontinence and inappropriate immune reaction.32 Additionally factors such or anastomosis leak. as stress, smoking, diet and a history of appendicectomy (which However, even in the best of hands, in certain situations it is protective) are known to be associated with ulcerative colitis.33 is indeed difficult to differentiate the two conditions (and In general, ulcerative colitis is considered to be a result of an several others actually) due to the tremendous overlap of inappropriate, exaggerated activation of the mucosal immune features, both clinical and investigative. In addition, unusual system by bacteria that may be normally resident in the features may confound differentiation even further. This has intestinal tract. This pathological response is likely to be resulted in the acceptance of another entity, indeterminate associated with defects in epithelial barrier function and of the colitis. Originally, indeterminate colitis (IC, IND, or IndC) was immune system, which are in part, genetically determined.34,35 proposed by pathologists for colectomy specimens, usually If the pathogenesis of ulcerative colitis is enigmatic then the from patients operated on for severe colitis, showing reason for an almost universal rectal involvement is a greater overlapping features of ulcerative colitis and Crohn’s disease. mystery. Interestingly, abnormality in the normally protective However in later years with the wide-spread use of endoscopy, mucus (associated with goblet cell depletion) which is more the same terminology was used for patients showing no clear marked in the recto-sigmoid region than elsewhere has been clinical, endoscopic, histologic, and other features allowing a observed in ulcerative colitis.36-38 This, undoubtedly is not the diagnosis of either UC or CD. Thus the necessity of examining final explanation for rectal involvement in ulcerative colitis and a colectomy specimen did not appear to be mandatory to make is also difficult to conclude whether this is a cause or an effect this diagnosis. This confusion and ambiguity was settled after of the pathogenetic mechanisms involved, since an alteration an international working group in 2005 suggested that in mucus promotes bacterial colonization of the mucosa. indeterminate colitis (IC) be restricted to such diagnosis made Shah et al1 have identified in a series of 110 newly diagnosed on colectomy specimens and the term “IBD unclassified” cases of ulcerative colitis, rectal sparing in 12 (10.9%) and (IBDU), be used for all other cases.23 Another terminology that patchy involvement of the colon (skip-lesions) in 24 (21.8%) has made its way is “colitis of uncertain type or etiology” patients. The authors have thus highlighted the problem of (CUTE) as an alternative term for IC in resected specimens.24 using these features to decide for or against a diagnosis of One of the outcomes of such nomenclature is to appreciate the ulcerative colitis. Although ulcerative colitis is more common difficulty in making a specific diagnosis in some cases. Thus than Crohn’s disease, with more reports of Crohn’s disease around 5% of all cases of IBD would be classified as IBDU.25 being reported in countries such as India, such observations However of these, a majority (around 80% in 8 years) are proven are indeed important if over-zealous diagnosis of Crohn’s to be ulcerative colitis.26 Therefore of the inflammatory bowel disease are to be avoided.39 diseases, ulcerative colitis is more likely to show unusual Surprisingly, other reports also seem to indicate that the features than Crohn’s disease. ‘rule of thumb’, regarding lack of rectal sparing and patchy 90 Tropical Gastroenterology 2011;32(2):87–93 colonic involvement in ulcerative colitis is not necessarily patients with no inflammation in the rectum and sigmoid colon, absolute!40 Rectal sparing or patchy lesions have been 40% had inflamed mucosa in the descending colon or the more relatively well-recognized in three situations: pediatric age proximal portion.53 group (rectal sparing in 21% and patchy in 26%),41,42 fulminant Thus is it true that the time has come when we should colitis (rectal sparing in 13% on endoscopy)43 and following change our perception of ulcerative colitis and certain basic treatment (around 60% especially with steroid enemas).44-46 Of concepts that have been propagated over the years? Such these, rectal sparing and patchy disease is best recognized in drastic changes need to be sipped from the goblet of untreated pediatric patients, so much so that it has been observations after the froth has settled. suggested that these features should not favor a diagnosis of Most of the observations of rectal sparing and patchy Crohn’s disease over ulcerative colitis (as is conventional) in ulcerative colitis are based on evaluation of clinical features, pediatric patients.47 The importance of recognizing these endoscopic findings and mucosal biopsies. It is obvious that unusual features of ulcerative colitis have a tremendous bearing the presence or absence of inflammation is the deciding factor not only on the diagnosis but also on subsequent treatment to determine whether any portion of the colonic mucosa is and outcome.48 involved in ulcerative colitis. It also stands to reason that Unlike naïve pediatric patients of ulcerative colitis, in adults, microscopic changes in the mucosa (not to mention changes treated cases tend to show rectal sparing more often than at a cellular or molecular level) would precede gross untreated cases. Kim et al found that in 47 (27%) follow-up abnormalities and perhaps clinical features. Gross abnormalities endoscopies in 19 (59%) patients, there was either patchy are easily identified by the experienced endoscopist who has disease, rectal sparing, or both sometime during the course of the advantage of observing the living unfixed colonic mucosa disease with treatment.44 In the classic description of Oedze et under magnification. It must be reiterated that endoscopy al46 36% of patients treated with enemas had rectal sparing in findings with limited mucosal biopsies have been one of the comparison to 12% who did not. While this is statistically primary reasons for recording unusual manifestations of significant, it must be appreciated that the rectum was not ulcerative colitis as has been indicated earlier. It is therefore involved in some untreated patients also. Interestingly, the pertinent to determine whether resected specimens show similar appendix has been reported to be a site of skip-lesion relatively features. Hence let us recall the experience of those who have frequently in ulcerative colitis.46,50. Ulcerative colitis presents had an opportunity to evaluate the mucosal changes in greater as a disease limited to the left-side of the colon in 65% and detail or by using a colectomy specimen as the gold standard. then spreads to involve the proximal portions in 29-58% cases. One of the most neglected aspects (unfortunately even by This proximal extension may be either sharp or gradual. In these histopathologists) of histological diagnosis of ulcerative colitis latter cases the transitional areas may appear patchy and give is the appreciation of the fact that changes may not be typical the impression of “skip lesions”. Further, in almost 75% of in all biopsies and hence the diagnosis may be missed these patients the caecum and appendix may show altogether. In one study that examined this problem, biopsy inflammation.51,52 A recent study53 has also indicated that specimens were assessed by three pathologists and ascribed sigmoidoscopy alone may miss several cases of ulcerative to one of four categories: normal; borderline abnormality (one colitis, including patients who present for the first time. In 545 or more minor nonspecific abnormalities which, when combined, patients, 59% had maximum inflammation in the rectum, 14% in did not fulfill the minimal acceptable criteria for a diagnosis of the sigmoid colon, 13% in the descending colon, and 14% on ulcerative colitis); minimal features of chronic ulcerative colitis; the oral side of the splenic flexure. Severe inflammatory activity and unequivocal ulcerative colitis. Despite a confident (Mayo 3) was observed more frequently in patients who had previous diagnosis, surprisingly 46% of 24 patients of long maximum activity in the descending colon or the more proximal standing ulcerative colitis had a rectal biopsy specimen that portion than those who had this in the rectum or sigmoid colon was devoid of the acceptable attributes on which a diagnosis (42% vs. 25%, p<0.0001). The first-attack patients were is established.54 In an elegant study, Robert et al55 examined significantly more frequently found in patients with maximum the issue of complete rectal sparing in 28 resected specimens severity in the descending colon or the proximal side of splenic of ulcerative colitis. Complete rectal sparing (defined as normal flexure than those with maximum severity in the rectum or mucosa) was not seen in specimens from the group of 28 sigmoid colon (p=0.016). Moreover, among approximately 25% patients. Five (31%) of 16 patients with rectal and more proximal Ulcerative colitis 91 biopsies had relative rectal sparing, with lower scores for calls for a greater uniformity and agreement amongst branching (3/5), subcryptal plasma cells (1/5), lamina propria gastroenterologists and histopathologists in the relative plasma cells (4/5), cryptitis (4/5), and epithelial injury (2/5) in weightage of each modality or criteria for making a meaningful the rectum than in more proximal sites in the same patient. The diagnosis. There is a need to evaluate the number of biopsies authors found that in 4 (14%) of 28 had no crypt branching, 4 that need to be examined and also to provide biopsies from (16%) of 25 had no subcryptal plasma cells (3 biopsy specimens seemingly normal mucosa on endoscopy in separate were poorly orientated), 5 (18%) of 28 had a score of 0 or 1 for containers to the histopathologist. The histopathologist also lamina propria plasma cells, and 1 (4%) of 28 had no evidence needs to appreciate that when gross findings are minimal it is of cryptitis or epithelial injury. Although all rectal biopsy very unlikely that microscopy would show florid changes. It is specimens received overall chronicity scores of at least 1 (of a here that the communication between the gastroenterologist possible 9), low overall chronicity scores (1-2) were present in and the histopathologist overrides all modalities of 4 (16%) of 25 cases.55 investigation to arrive at a consensus. More recently Joo and Oedze56 evaluated 56 UC patients, It is reasonable to expect that diagnosis of ulcerative colitis including those who were treated by standard regimens, all of would continue to depend on clinical, endoscopic and histologic whom had at least one preoperative endoscopy with biopsies, evidence with findings of additional imaging and other non- and who subsequently underwent a colectomy for non- invasive modalities wherever appropriate. Undoubtedly, it neoplastic complications. Rectal sparing and patchy would be tempting to bite the fruits of several recent advances inflammation in biopsies and resection specimens, categorized in technology. Biochemical tests are very unlikely to help in as either absolute or relative, were graded for their inflammatory distinguishing ulcerative colitis with or without rectal sparing activity on a 5-point scale. Overall, the mean colitis score in or patchy disease since these generally detect markers of biopsies was significantly lower than in resection specimens inflammation or immune response. Nevertheless, they would (2.7+/-0.9 vs. 3.2+/-0.8, p<0.01). Evidence of rectal sparing and be helpful in distinguishing major types of inflammatory bowel patchy disease occurred in 32.1% and 30.4% of patients by disease. Imaging, including MRI, also have a similar role but endoscopy, and 30.4% and 25% of patients by analysis of features diagnostic of ulcerative colitis are generally not biopsies. Only 3 patients (5.4%) showed rectal sparing, and all discernible.57 This is not surprising since ulcerative colitis is a of these were considered “relative” after evaluation of the mucosal disease. Perhaps the role of PET may be more helpful patients’ colectomy specimens. Six (10.7%) showed patchiness in these circumstances.58 Thus, it remains to be seen if the of disease in the colon resection specimen, 4 of which were newer endoscopy techniques that enhance image quality and absolute. After evaluation of all of the patients’ pre-resection give a near-histology picture of the mucosa such as biopsy specimens and colectomy specimens, none of the chromoendoscopy and narrow-band and multi-band imaging59 patients (0%) showed complete absence of rectal involvement as well as techniques that allow a wider view of the mucosa (absolute rectal sparing) after all of the tissue sections were such as wireless-capsule endoscopy,60 can improve the quality evaluated even in treated patients. A significant correlation of overall evaluation of difficult cases. While these techniques was noted between endoscopic and biopsy findings and have been in vogue for several years now, most of the available between biopsy and colectomy findings, but poor correlation data relate more to their use in early detection of colonic was noted between the patients’ endoscopic features and the malignancies and pre-malignant lesions than inflammatory- pathologic features of their colectomy specimens.56 bowel disease per se. In developing countries, costs and Therefore “true” rectal sparing and patchiness in ulcerative training may preclude wide-spread use of these techniques for colitis is indeed rare [if it does occur at all] and their true some time currently, but it is expected that these would be incidence is difficult to conclude. The observations are more commonly available in the future. confounded by the fact that colectomy specimens are rarely Thus it is indeed worthwhile to realize that while in some available to provide a gold standard of gross and microscopic cases of ulcerative colitis the scope of diagnosis is often limited evaluation. Nevertheless it is humbling to appreciate that both by the scope of evaluation by the endoscope and the histological and endoscopic features, the current mainstay of microscope, there is indeed a tremendous scope for routine diagnosis, may be minimal or “non-diagnostic”. It also improvement in diagnosis of such difficult cases! 92 Tropical Gastroenterology 2011;32(2):87–93

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