An increase in the awareness of the entity of microscopic colitis has resulted in it being recognized as a known cause of chronic watery diarrhea[2,13,23
]. Although the incidence of this disease seems to be rising, there has been very little documentation of this entity from our hospital. The importance of recognizing this condition is crucial, firstly, because chronic diarrhea is a debilitating illness, and secondly, treatment of this condition is no longer empirically based, as several recent randomized, double-blind, placebo-controlled trials have shown budesonide to be effective in the treatment of this disorder[24-27
Our study is novel in the sense that we reviewed all our non-malignant colon biopsies reported as normal or chronic inflammation, to identify patients with chronic diarrhea that might have had microscopic colitis. Using this bottom up approach, we focused on lymphocytic colitis. Neither the incidence nor the prevalence of this disease could be estimated using this approach, because our sample population did not consist of patients presenting exclusively with chronic diarrhea. Instead, we identified secondary causes of intraepithelial lymphocytosis that included diverticular disease, ulcerative colitis, and malignancy. These secondary causes need to be excluded before making a diagnosis of microscopic colitis[14
]. Other secondary causes of intraepithelial lymphocytosis, not identified in this study but described by Nielson, include Crohn’s disease, colonic infections and amyloidosis[14
]. According to Fenoglio-Preiser[28
], there have also been reports of lymphocytic-colitis-like histology in patients with constipation, which is similar to our findings. We have also identified patients with abdominal pain as another group presenting with lymphocytosis. Although the clinical symptoms of constipation and abdominal pain resolved in a few cases, others were later identified as having significant pathology. Our results suggest that any normal colonoscopy with a finding of intraepithelial lymphocytosis should be carefully monitored for future disease.
In the present study, the diagnosis of lymphocytic colitis was missed in five patients at the initial histological evaluation. It is particularly interesting to note that four of these patients were labeled as having IBS, in view of the biopsy being reported as normal. In a population-based cohort from Olmsted County, approximately one half of patients with microscopic colitis met the symptom-based criteria for IBS[29
]. It is therefore not surprising that there is symptomatic overlap between these two entities. The recommendations from the Olmsted County study are that patients with diarrhea-predominant IBS should undergo colonoscopy to exclude microscopic colitis[29
]. Similarly, Madisch et al[30
]have shown that 30% of patients with microscopic colitis had clinical symptoms that overlap with IBS. We can therefore conclude that patients with microscopic colitis can be misdiagnosed with IBS.
Even though there is very little inter- and intra-observer variability in the histological diagnosis[19
], the diagnosis of microscopic colitis can be challenging at times, especially due to the morphological heterogeneity described in microscopic colitis. Since the initial description of lymphocytic colitis in 1989, there have been several atypical forms of microscopic colitis described[15
], including a paucicellular variant[31
]. In this variant, patients still have the same clinical symptoms, but the IEL count is less, with only 10-12 IELs/100 enterocytes cited[32
]. We feel that, in these cases, immunostaining might be of more diagnostic value in determining a low IEL that is not so apparent by H and E staining. A recent study has challenged the notion of regarding paucicellular lymphocytic colitis as a variant of classical lymphocytic colitis, based on the demonstration of a distinct immunological difference[33
]. This group also has indirectly claimed that immunostaining displays a clear contrast between immunoreactive lymphocytes and negative epithelial cells. However, the comparison between H and E staining and immunohistochemistry was not directly evaluated in their study[33
]. Our study was not designed to identify cases of paucicellular lymphocytic colitis, but it is an area that requires further study.
As stated earlier, the prevalence of microscopic colitis is difficult to estimate from our study due to our selection criteria and referral bias. However, this study does indicate that microscopic colitis, especially the lymphocytic colitis subtype, is underdiagnosed at our institution (P
< 0.05). For a true estimate of the prevalence of this disorder, further studies are needed, combining data from all referral centers in the region. Other factors not taken into account in this study are the site of the biopsy and drug history. It is well known that lymphocytic colitis and collagenous colitis can be patchy in distribution, and the topographic gradient of IELs decreases from the right colon to the rectum[34
]. Therefore, representative biopsies should be taken from each part of the colon and submitted in a separate container. Concomitant drug use can cause or worsen drug-induced microscopic colitis. It is important to recognize these drugs because drug withdrawal may improve symptoms. Among the more common drugs implicated are non-steroidal anti-inflammatory drugs, lansoprazole, clozapine, ranitidine, ticlopidine, carbose and flutamide[32
]. Future studies at our institution need to take these factors into account.
We identified that intraepithelial lymphocytosis may be an early manifestation of a disease other than microscopic colitis within our defined population. IEL count alone is not specific for microscopic colitis and the biopsy findings need to be correlated with clinical information for a more specific diagnosis. In cases in which there is a history of chronic watery diarrhea, the use of CD3 immunohistochemistry may be of additional value in making the diagnosis of lymphocytic colitis. We suggest that patients with diarrhea-predominant IBS should have a routine colonoscopy and be evaluated for microscopic colitis.