Indeterminate Colitis

Najib Haboubi

Powerpoint File

Introduction

The distinction between Crohn’s Disease and Ulcerative Colitis is made in the majority of cases on the basis of clinical, radiological, endoscopic and pathological information. Unfortunately in some patients the distinction cannot be easily made. The term Indeterminate Colitis has been used to describe such cases, but since the term was introduced it has been used with varying definitions, which has led to considerable confusion.

The accurate diagnosis of inflammatory bowel disease is of paramount importance in terms of medical treatment, prognosis and surgical intervention. The aim of this review is to clarify the term ‘Indeterminate Colitis’, its clinical presentation, pathology, natural history and implications regarding pouch surgery. This report will help both pathologists and clinicians, by removing the confusion that surrounds the definition and surgical management of Indeterminate Colitis.

Definition and Incidence

Price first introduced the term Indeterminate Colitis (IC) in 1978 [1]. He found that in 9% of resected colons the definitive diagnosis of either Crohns disease (CD) or Ulcerative Colitis (UC) was not possible due to overlapping pathological features. In 90% of these cases the patient had undergone urgent surgery. Since then it has been estimated that 9-20% of cases of inflammatory bowel disease are categorised as IC [1,2,3] however, the term has been used with varying definitions. The Mayo Clinic defined the condition as ‘the unequivocal diagnosis of chronic UC preoperatively, but inconclusive histology on examination of the pathological specimens [4]. Koltun et al defined the condition as ‘inflammatory colitis containing features on macroscopic and microscopic evaluation of the colon that were consistent with both CD and chronic UC’ [5]. The term IC has also been used by clinicians for patients who present with both clinical and endoscopic features of inflammatory bowel disease, but in whom the histological diagnosis does not allow exact diagnosis of either UC or CD [6]. Therefore there has been much confusion regarding the appropriate use of this term. The Montreal Working Party addressed this issue in 2006, returning to the original definition of Price. They recommended that the term IC ‘should be reserved only for those cases where colectomy has been performed and pathologists are unable to make a definitive diagnosis of either crohn’s disease or ulcerative colitis after full examination’ [7]. In cases where clinical and endoscopic examination reveals colonic inflammatory bowel disease, but where histology is unable to classify as either CD or UC, the term ‘inflammatory bowel: type unclassified’ should be used instead [7]. If all pathologists and clinicians were to follow these recommended definitions, perhaps the confusion surrounding the term IC would be removed. This would in turn allow for more accurate follow-up studies of such cases in the future.

Pathological Features of IC.

In the original description by Price, 90% of patients diagnosed with IC had undergone urgent surgery. This contrasts with only 30% of patients in whom UC or CD was confidently diagnosed. Macroscopically there was a total colitis in most cases, often with either relative rectal sparing or a pattern of intermittent ulceration. On microscopic examination the dominant features were those of severe ulceration, non-specific transmural inflammation, and foci of myocytolysis. Islands of surviving mucosa were present with minimal inflammation, a regular glandular pattern and mucin preservation. Acute fissures were common [1].

Since Price numerous reports have also found that the diagnosis of IC more commonly follows urgent surgery for acute or fulminant colitis [8,9,10,11]. This may be due to the fact that the pathological features of UC and CD are often seen to overlap in the acute phase of disease. Rudolph however suggests that alternatively the intense steroid treatment of fulminant disease may have led to the appearance of IC, or that the very nature of fulminant disease may present a greater challenge to the histopathologist [10]. Swan et al reported 67 cases of fulminant colitis where the macroscopic appearance of the colon was of little help in discriminating between CD and UC. Microscopically he found the presence of granulomas and lymphoid aggregates (without associated mucosal ulceration) as the most specific markers of CD [12]. The failure to recognise characteristic signs of CD such as granulomas and transmural inflammation often leads to errors in pathological interpretation of inflammatory bowel disease [3]. Interestingly, Price found no granulomas during the analysis of specimens taken from patients diagnosed as IC [1].

The presence of fissures can lead to confusion in diagnosis. Some regard acute fissures as a feature typical of CD, while others consider them as part of the spectrum of severe UC [3,13] Swan et al regarded acute fissures as characteristic of fulminant disease [12], whereas Price was clear to distinguish two distinct forms of fissuring. The typical chronic fissure of crohns disease is usually a single serpiginous tract lined with inflammatory cells and penetrating intact muscle, whereas the multiple, short, V shaped fissures seen in the IC cases by Price are often seen in areas of severe ulceration [1].

Unusual patterns of UC may not be recognized, leading to the diagnosis of CD or IC. Some patients with UC of the left colon may show patchy inflammation of the caecum or ascending colon. This will therefore give the appearance of a skip lesion hence indicating CD [14]. The clinical significance of this right-sided patch of inflammation in left sided UC patients appears to be of no relevance in terms of their natural history [15]. However it is vital in terms of correct and accurate diagnosis of UC. Backwash ileitis is thought to occur due to severe colonic disease and an incompetent ileoceacal valve, resulting in retrograde flow of colonic contents into the terminal ileum, causing inflammation. Most commonly there will be a mild inflammatory response with neutrophils and cryptitis. Granulomas and fissuring ulceration are not seen in the terminal ileum except in cases of CD. Therefore mild inflammation of the ileum may be considered as part of the spectrum of UC provided that changes are mild, superficial and confined to the distal few centimeters of ileum. [16]

Interobserver variability further compounds the problem of accurately diagnosing inflammatory bowel disease. Theodossi et al addressed this issue by studying the variability among ten observers all of whom had a special interest in gastrointestinal pathology. Biopsy slides of ‘true’ cases of UC and CD were reviewed, but agreement between observers was only 65-76%. There was agreement in discriminating between normal bowel and inflammatory bowel disease, but ‘true’ CD was often thought to be UC [17]. Farmer et al studied the difference between general and specialist gastrointestinal pathologists, in relation to inflammatory bowel disease diagnosis in colectomy and biopsy specimens. In his study the gastrointestinal pathologist diagnosis differed from the initial diagnosis in 45% of colectomy specimens and 54% of biopsy specimens [3]. Swan et al also noted a change in diagnosis of 22% on re-evaluation of colectomy specimens in fulminant colitis [12]. The quality and quantity of examined material is vital for accurate diagnosis by the pathologist. In the diagnosis of IC, biopsy specimens are inadequate for accurate diagnosis. As recommended by the Montreal Working Party group in 2006, the diagnosis of ‘inflammatory bowel: type unclassified’ should be used if uncertainty exists on biopsy specimen [7]. Mucosal biopsies are of a very superficial nature and provide limited information on the depth of disease activity, types of ulcers present and the presence or absence of transmural inflammation [16]. Cases of IC are by their own definition difficult cases to diagnose having both features of UC and CD present, therefore diagnosis from mucosal biopsies is to be avoided. Variation has also existed in the number of paraffin blocks used per colectomy specimen [3]. This is another potential source of inaccuracy. Nine to twelve blocks should be obtained per colectomy specimen, including two sections from every 10cm of colon, in addition to both the proximal and distal margin sections. As detailed above, the presence of fulminant or acute disease, unusual patterns of UC and CD and the ability to recognise them, interobserver variability, variations in the material available for examination and the absence of clinico-radiological information can all lead to inaccuracies in the diagnosis of inflammatory bowel disease. The initial definition of IC by Price should be re-emphasised in that it should only apply to colectomy specimens in which the features are not sufficient to allow definitive diagnosis of either UC or CD. The addition of information available from the clinician, endoscopist and radiologist, along with a greater knowledge of the rarer forms of UC and CD will undoubtedly help in the accurate diagnosis of inflammatory bowel disease.

IC and Pouch Surgery

Ileal pouch-anal anastomosis (IPAA) has become the surgical treatment of choice for significant number of patients with UC. This is a major operation with significant complications, which requires careful patient selection and preoperative counselling. The accurate diagnosis of inflammatory bowel disease and subsequent categorisation are of vital importance in the selection of patients for such an IPAA procedure. Concerns have been raised, with studies reporting pouch failure rates of 30-50% in CD [8,9,28,29,30]. However, patients with colonic CD who have no small bowel manifestations, perineal involvement or clinical features of CD have been reported to have satisfactory outcomes after IPAA [31,32]. In addition to the high rate of pouch failure, the incidence of pelvic sepsis and fistulae are both significantly increased in patients with CD and therefore IPAA is generally not recommended [8,9,28,29,30]. Although experience has demonstrated that IC does not necessarily follow the same clinical course as CD, some surgeons are reluctant to offer IPAA to IC patients due to the risk of increased complications, pouch failure and evolution into CD. Marcello and colleagues [9] studied 53 patients with IC who underwent IPAA. They reported an increased rate of pouch failure in 12% of their IC patients compared with 2% of the UC patients. Similarly they noted increased perineal complications in IC patients (44% IC vs. 23% UC). Other published series by Koltun, Atkinson and Bodzin and their colleagues [5,33,34] have reported on a small series of IC patients. They all noted increased rates of pouch complications and failure in IC compared to UC.

Conversely, several larger and more recently published reports have shown more encouraging results. The largest published series by Delaney et al [11] from the Cleveland Clinic, Ohio, reported on the results of IPAA surgery in 115 patients diagnosed with IC following analysis of colectomy specimen. They found no difference in the pouch failure rate between IC and UC patients (3.4% IC vs. 3.5% UC). There was however, a significant increase in pelvic abscesses and perineal fistulae in IC patients compared to the UC group. 6% of the IC patients later converted to CD. The Mayo Clinic reported their long-term results of IPAA for IC in 2000 [4]. They studied 82 patients with IC and found that on follow up at ten years, these patients had significantly more episodes of pouch failure (27% IC vs. 9% UC, P<0.001), pelvic sepsis (17% vs. 7%, P<0.001) and pouch fistulae (31% vs. 9%, P<0.001). During the follow up period, CD was subsequently diagnosed in 12 of the 82 IC patients (15%), but only 2% of the UC patients (P<0.005). When these ‘converted cases’ were removed from the sample, the remaining IC patients had an identical outcome to the UC patients in terms of pouch failure and pelvic sepsis. However the IC group, were still more likely than the UC group to develop pouch fistulae. [4]. Therefore, one may be cautious with patients with non or ill defined diagnosis of UC who present with severe attack which requires surgery. In such patients, staged proctocolectomy (subtotal colectomy, end ileostomy with preservation of the rectum) should be considered in order that a definite diagnosis may be obtained from the whole specimen.

Dayton et al studied a series of 79 IC patients undergoing IPAA. They found no statistical significance in terms of pouch failure (2.5% IC vs. 1.2%UC) when compared with UC. There were an increased number of pouch complications in the IC group when compared to the UC group, but none of these e.g. stricture, leak, or fistula reached statistical significance [35]. Rudolph et al reported a series of 35 patients undergoing IPAA. After a mean follow up of 54 months, pouch failure had not occurred in any IC patient. However, the incidence of pouch fistulae was found to be more common in patients with IC when compared to both UC and CD cases [10]. Smaller studies reported by Brown, Pezim and Pishoris and their colleagues [8,36,37] have found no difference between IC and UC in terms of pouch failure.

Some authors have tried to study IC cases in more detail in an attempt to predict factors that may lead to an increased risk of pouch failure and poor outcome. Tekkis et al [38] reviewed all patients at St Marks, London who underwent restorative proctocolectomy for CD or IC. The 52 patients were then divided into two groups, the first group being IC or IC favouring UC, and the second being patients with CD or IC favouring CD. Patients were allocated into the later group if they had specific features suggestive of CD including the presence of anal disease; colonic histopathology (granulomas, transmural inflammation, rectal sparing) and disease distribution suggestive of CD such as skip lesions. Pouch failure occurred in 11.5% of the first group, compared to 57.7% of the second group. Fistulae were also more common in the CD/IC favouring CD group (61.5% vs. 19.2%). Gramlich et al [39] divided their surgical specimens from 115 IC patients into three pathological subgroups; IC favouring UC, ‘true’ IC and IC favouring CD. Although no pathological subgroup of IC had a significantly different rate of pouch failure, further subgroup analysis found that patients with specimens containing deep ulcers extending into the muscularis propria had a significantly increased risk of pelvic abscess, complex perianal fistulae and development of pathologically proven CD. The results of the main published series of IC patients undergoing IPAA are displayed in Table 1.

Functional outcome following IPAA surgery is often assessed in terms of bowel frequency and episodes of incontinence. When comparing IC and UC patients post IPAA, the frequency of bowel movements is similar [4,8,10,11,36]. The frequency of incontinence is also similar, although Yu et al found that IC patients were more likely to experience incontinence during the daytime [4].

IPAA should not be performed on patients with CD due to high rates of pouch failure and complications. The early reports of pouch surgery in IC found the rate of pouch failure to be higher than in UC patients. However in these studies the percentage of IC patients who converted into CD during follow up ranged from 8 – 15%. Larger, more recent studies of IPAA in IC have demonstrated no difference when compared with UC in terms of pouch failure. The percentage of patients who converted into CD was much lower in these more recent reports (0-6%), suggesting that subjects may have been selected on the basis of clinical and pathological evidence as to be unlikely to progress into CD. Whilst the general consensus is that there is no significant difference between IC and UC in terms of pouch failure and functional outcome, other postoperative complications such as pelvic sepsis and fistulae have been well documented in the literature. Attempts have been made to identify factors that accurately predict postoperative complications and some suggestions have been made, including the presence of deep ulcers. In addition, those patients with IC who have features either clinically or on pathological analysis that may be suggestive of CD appear more likely to suffer pouch complications. However, this evidence is limited and further research is required. Although IC is not a contraindication for IPAA, the patient who wishes to undergo restorative proctocolectomy should be counselled regarding the increased risk of complication and should receive very careful evaluation of the remainder of their gastrointestinal tract and previous histopathology, in an attempt to minimize the risk of future conversion of IC to CD.

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