139 How to approach the patient with colitis, type-unclassified: Diagnosis and management options Janneke van der Woude The Netherlands Learning objectives 1.The term indeterminate colitis (IC) is reserved for colectomy specimens. 2. The diagnosis of IC in a colectomy specimen may change to ulcerative colitis or Crohn’s disease. 3. The diagnosis colitis, type-unclassified or IC should not be regarded as a contra-indication for ileal pouch anal anastomosis. After this course the participant is able to 1. Describe factors leading to the diagnosis of colitis, type-unclassified. 2. Describe the management in the patient group. The management of patients with ulcerative colitis (UC) and Crohn’s disease (CD) may differ in terms of medical treatment, disease course and long-term prognosis and type of surgery. Most complicated are those cases where a colectomy is needed and the patient has rectal inflammation without a clear diagnosis of either UC or CD, because an ileal pouch anal anastomosis (IPAA) in CD is generally contraindicated due to a high risk of morbidity related pouch complications (fistulas) and pouch failure. Definitions In approximately two-third to three quarter of newly diagnosed patients a correct diagnosis of inflammatory bowel disease (IBD) can be made, and the additional endoscopic and clinical data allow a final diagnosis in the vast majority of patients (1). In 1978, Price introduced the term indeterminate colitis (IC) to refer to a subgroup of 10-15 % of IBD cases (mostly patients with severe inflammatory activity) in which there was difficulty to distinguish between UC and CD in the excised colon (2). After this publication the term IC was not only used for colectomy specimens but also used by gastroenterologist in patients of whom the diagnosis inflammatory bowel disease was clear but insufficient data was lacking to make a definite diagnosis. Because the term IC was originally proposed for colectomy specimens and not all diagnostic microscopic features can be assessed on endoscopic biopsy samples it was recommended to restrict the term IC to resected colon specimens and to use IBD unclassified (IBDU) for all other cases (3). Pathological features In the original description by Price, 90% of the patients diagnosed with IC had undergone urgent surgery and since this first publication others have also found that the dia- gnosis of IC more often is associated with urgent surgery for acute or fulminant colitis (4-6). In the acute phase pathological features of UC and CD can overlap. For example the presence of fissures can lead to confusion. The typical chronic fissures of CD are usually single serpiginous tract lined with inflammatory cells, but fissures can also be seen in fulminant disease. In Price’s IC paper, he described in areas of severe ulceration the presence of multiple, short, V-shaped fissures. Another paper described probably the same pathological features as deep slit-like fissures (7). Transmural inflammation which can be a feature of CD was present in most cases of IC, but only related to areas of severe ulceration, this was further specified by Lee et al (7). Transmural inflammation was defined as lymphocytes in an aggregated pattern in all layers of the colon, including the serosa. The presence of scattered mononuclear inflammatory cells in the muscularis mucosa adjacent to ulceration was regarded as a non-specific response of the colon, including the serosa. Serologic markers Serologic tests may be used for diagnostic purposes; however data on the value of these tests are conflicting. In a prospective study on patients with IBD unclassified, a 48% positive predictability of ASCA-/pANCA- was found for sustained IC (8). In contrast in a large population based study no substantial number of IC patients with this pattern was found (9). Common reasons for diagnosing IBD unclassified The most common reason for diagnosing IBD unclassified is in a patient with a fulminant colitis, when there is insufficient clinical, radiologic or pathological information, which stretches the importance to follow the guidelines for diagnosing IBD (10). Furthermore unu- Medical & Surgical Gastroenerology II Medical / surgical scenarios in ulcerative colitis Saturday, October 22 14:00 – 16:30 Key messages 140 Janneke van der Woude | How to approach the patient with colitis, type-unclassified: Diagnosis and management options Saturday, October 22 14:00 – 16:30 sual variants of UC and CD can be overlooked, such as UC patients demonstrating at endoscopy relative rectal sparing and backwash ileitis and at biopsies superficial fissures, granulomas related to ruptured crypts, or even skip lesions due to therapy effect. Furthermore the presence of a secondary disease can lead to difficult interpretation of biopsy specimens for example the UC patients with an intestinal co-infection. Unusual variants of UC and CD As depicted in the above paragraph there are different reasons leading to a diagnosis of IBD unclassified, some of these reasons are listed below: 1. Effect of oral and topical therapy: in both UC and CD features found in biopsies can be related to the effect of medical treatment. In UC patients followed over time endoscopic and histological patchiness of inflammation and rectal sparing was found in 59% of the patients (11). 2.Children with a newly diagnosed IBD: especially in children microscopic features used for the diagnosis of IBD are often not present in the early stage of disease. Atypical lesions at initial presentation of UC include absence of chronicity, mild active disease, and microscopic skip areas (12). 3. Backwash ileitis: patients with severe pancolitis may show a mid degree of active inflammation in the distal few centimetres of the terminal ileum. Occasionally this inflammation is confused with CD of the terminal ileum, also due to the fact that strict histolopathologic criteria are lacking. 4.Upper gastrointestinal tract involvement: gastroduodenal involvement, which is often used to be diagnostic of CD, may also occur in UC (13). Furthermore diffuse antral H pylori negative gastritis is of no value to distinguish between UC and CD, with diffuse acute duodenitis being more suggestive of UC (14, 15). 5. Perianal fistulas in UC: both low and high fistulas can be present in the absence of CD. Frequency and natural history In approximately 5% of IBD cases, a definite diagnosis of UC or CD cannot be established, it is estimated that the true nature of the patient’s underlying IBD usually becomes apparent within a few years (17). A recent meta-analysis found that in children more frequently the distinction between UC and CD could not be made when compared to adults (12,7% versus 6%, p<0.0001) (18). Large studies studying the natural history of IBD unclassified are scarce. In a study from Norway a large proportion of patients initially diagnosed with IBD unclassified, after one year were reclassified to UC, CD, and non-IBD (9, 18). A review of IC patients that underwent restorative proctocolectomy showed that the percentage of patients that subsequently develop CD varies from 0-15%, whilst a significant number of patients remain categorised as having IC (19). Management The medical management of IBD unclassified resembles the management of UC. This includes the initiation of 5-ASA in mild to moderate cases to anti-TNF inhibitors in severe refractory cases (20). Surgery is usually performed in a 2-step procedure, after a subtotal colectomy the colon will be thoroughly reviewed by the pathologist and in cases of persisted diagnosis of IBD unclassified (now IC) a pouch construction can be performed (20). Outcome pouch Some surgeons are reluctant to offer IPAA to IC patients due to the re- ported risk of pouch failure compared to UC in early small case series. However the general consensus is that there is no significant difference in pouch failure and functional outcome between UC and IC, but other postoperative complications such as pelvic sepsis and fistulae are more often seen in IC patients (21). Colorectal cancer It is known that colorectal cancer (CRC) can complicate IBD unclassified. In the Netherlands of 149 cases of CRC complicating IBD only one patient was diagnosed with IC and in another study conducted in a referral hospital with 57 IBD CRC patients only 2 patients had the diagnosis of IC (22-23). Conclusions The term IC should be reserved only for those cases where colectomy has been performed and a definitive diagnosis of CD or UC cannot be made. The current term for uncertain cases is IBD unclassified. Management of patients with IBD unclassified resembles the mangment of an UC patient, including undergoing an IPAA, although this can be related to postoperative complications such as pelvic sepsis and the forming of fistulas. Case presentation In the course a case of young male with unclassified will be presented and some of the challenges in treating a patient with colitis, type-unclassified will be discussed. References 1. Dejaco C, Osterreicher C, Angelberger S, et al. Diagnosing colitis: a prospective study on essential parameters for reaching a diagnosis. Endoscopy 2003; 35: 1004-1008. 2. Price AB. Overlap in the spectrum of non-specific inflammatory bowel disease-colitis indeterminate. J Clin Pathol 1978; 31: 567-176. 3. Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The MONTREALl classification of inflammatory disease: controversies, consensus and implications. Gut 2006; 55: 749753. 4. Brown CJ, MacLean AR, Cohen Z, et al. Crohn’s disease and indeterminate colitis and the ileal pouch-anal anastomosis: outcomes and patterns of failure. Dis Colon Rectum 2005; 48: 1542-1549. 5. Marcello PW, Schoetz DJ, Roberts PL, et al. Evolutionary changes in the pathologic diagnosis after ileoanal pouch procedure. Dis Colon Rectum 1997; 40: 263-269. 6. Swan NC, Geoghegan JG, O’Donoghue DP, et al. Fulminant colitis in inflammatory bowel disease: detailed pathologic and clinical analysis. Dis Colon Rectum 1998; 41: 1511-1515. 7. Lee KS, Medline A, Shockey S. Indeterminate colitis in the spectrum of inflammatory bowel disease. Arch Pathol Lab Med 1979; 103: 173-176. 8. Joossens S, Reinisch W, Vermeire S, et al. The value of antiSaacharomyces antibodies and perinuclear anti-neutrophil cytoplasmic antibodies in indeterminate colitis; a prospective follow-up study. Gastroenterology 2002; 122: 1242-1247. 9. Moum B, Vatn MH, Ekbom A, et al. Incidence of ulcerative colitis and indeterminate colitis in four counties of southeastern Norway, 1990-93. A prospective population-based study. Scand J Gastroenterol 1996; 31: 362-366. Medical & Surgical Gastroenerology II Medical / surgical scenarios in ulcerative colitis 10. Stange EF, Travis SPL, Vermeire S, et al. European evidencebased Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. Journal of Crohn’s and Colitis 2008; 2: 1–23. 11. Kim B, Barnett JL, Kleer CG, et al. Endoscopic and histological patchiness in treated ulcerative colitis. Am J Gastroenterol 1999; 94: 3258-3262. 12. Markowitz J, Kahn E, Grancher K, et al. Atypical rectosigmoid histology in children with newly diagnosed ulcerative colitis. Am J Gastroenterol 1993; 88: 2034-2037. 13. Tobin JM, Sinha B, Ramani P, et al. Upper gastrointestinal mucosal disease in pediatric Crohn’s disease and ulcerative colitis: a blinded, controlled study. J Pediatr Gastroenterol Nutr 2001; 32; 443-448. 14. Sasaki M, Okada K, Koyama S, et al. Ulcerative colitis complicated by gastroduodenal lesions. J Gastroenterol 1996; 31: 585-589. 15. Valdez R, Appelman HD, Bronner MP, et al. Diffuse duodenitis associated with ulcerative colitis. Am J Surg Pathol 2000; 24: 1407-1413. 16. Farmer M, Petras RE, Hunt LE, Janosky JE, et al. The importance of diagnostic accuracy in colonic inflammatory disease. Am J Gastroenterol 2000; 95: 3184-3188. 17. Prenzel F, Uhlig HH. Frequency of indeterminate colitis in children and adults with IBD- a metaanalysis. J Crohns Colitis 2009; 4: 277-281. 18. Moum B, Vatn MH, Ekbom A, et al. Incidence of inflammatory bowel disease in southeastern Norway. Evaluation of methods after one year of registration. Digestion 1995; 56: 377-381. 19. Mitchell PJ, Rabau MY, Haboubi NY. Indeterminate colitis. Tech Coloproctol 2007; 11: 91-96. 20. Travis SPL, Stange EF, Lémann M, et al. European evidencebased Consensus on the management of ulcerative colitis: Current management. Journal of Crohn’s and Colitis 2008; 2: 24–62. 21. Yu CS, Pemberton JH, Larson D. Ileal pouch-anal anastomosis in patients with indeterminate colitis. Long term results. Dis Colon Rectum 2000; 43: 1487-1496. 22. Lutgens MW, Vleggaar FP, Schipper ME, et al. High frequency of early colorectal cancer in inflammatory bowel disease. Gut 2008; 57: 1246–1251. 23. Rubio CA, Befrits R. Colorectal adenocarcinoma in Crohn’s disease: a retrospective histologic study. Dis Colon Rectum 1997; 40: 1072–1078. Policy of full disclosure Herewith I disclose the participation in advisory board of the following companies: MSD, Abbott labaratories, Shire. Unrestricted grant were obtained form: Ferring The netherlnad, Falk Benelux, MSD. Medical & Surgical Gastroenerology II Medical / surgical scenarios in ulcerative colitis 141 Saturday, October 22 14:00 – 16:30 How to approach the patient with colitis, type-unclassified: | Janneke van der Woude Diagnosis and management options