Abstract
Microscopic colitis is a diagnostic term that describes two distinct but clinically overlapping entities: collagenous colitis and lymphocytic colitis. Both conditions are characterised by the triad of chronic, non-bloody/watery diarrhoea, macroscopically normal or near-normal colorectal mucosa at endoscopy and diagnostic histopathological findings. With increasing clinical recognition, the incidence of microscopic colitis has risen over the last two decades and it is now a major cause of chronic diarrhoea, especially in elderly females. This chapter presents a brief history of these diagnostic terms, along with a current understanding of epidemiology relating to microscopic colitis and a brief discussion of possible pathogenetic mechanisms and common clinical features. It then describes in detail the microscopic features of collagenous and lymphocytic colitis, including variant forms, with a description of clinical and pathological differential diagnoses, key histological features used to discriminate between these diagnoses, and tips to avoid diagnostic pitfalls. The chapter then considers the association between microscopic colitis and chronic inflammatory bowel disease, and the features of small intestinal involvement by microscopic colitis. Finally, there is a brief discussion of the treatment and natural history of these diseases.
Introduction
Microscopic colitis is a diagnostic term that describes two distinct but clinically overlapping entities: collagenous colitis and lymphocytic colitis. Both are characterised by the triad of chronic, non-bloody/watery diarrhoea, macroscopically normal or near-normal colorectal mucosa at endoscopy, and diagnostic histopathological findings (Fact Sheet 20.1). Endoscopic biopsy is necessary to distinguish microscopic colitis from irritable bowel syndrome. With increasing clinical recognition, the incidence of microscopic colitis has risen over the last two decades and it is now a major cause of chronic diarrhoea, especially in elderly women.
This chapter presents a brief history of these diagnostic terms, along with a current understanding of the epidemiology relating to microscopic colitis and a summary of possible pathogenetic mechanisms and common clinical features. It then describes in detail the microscopic features of collagenous and lymphocytic colitis, including variant forms, with a description of clinical and pathological differential diagnoses, key histological features used to discriminate between these diagnoses, and tips to avoid diagnostic pitfalls. The chapter then considers the association between microscopic colitis and chronic inflammatory bowel disease (IBD), and the features of small intestinal involvement by microscopic colitis. Finally, there is a brief discussion of the treatment and natural history of these diseases.
History of Microscopic Colitis
The term ‘collagenous colitis’ was first applied by Lindstrom in 1976, in a case report of a middle-aged woman with chronic watery diarrhoea and a subepithelial collagen band on rectal biopsy.1 Similar reports followed, but uptake of the term was slow. Read et al. were the first, in 1980, to use the term ‘microscopic colitis’, describing a series of patients with chronic diarrhoea in whom investigations, including endoscopy, failed to reveal a diagnosis.2 Kingham et al. first employed microscopic colitis as a diagnostic term in 1982, in a similar series of patients, but with more description and illustration of the accompanying histology.3 Microscopic colitis evolved to become an umbrella term encompassing both collagenous colitis and lymphocytic colitis.4
Epidemiology
A recent systematic review and meta-analysis of European and North American population-based studies estimated that the pooled incidence rates were 4.14 per 100,000 person-years for collagenous colitis and 4.85 for lymphocytic colitis.5 Most studies examining temporal trends have reported an increasing incidence. In some recent studies, there is a plateau in incidence.5 These apparent increases in incidence almost certainly relate to an increase in endoscopy rates and more frequent routine sampling of normal colonic mucosa in the appropriate clinical setting in consideration of microscopic colitis.6 Ageing populations and increasing use of drugs that can cause microscopic colitis may also be contributing.
Collagenous colitis and lymphocytic colitis are predominantly, but not exclusively, diseases of elderly women. Estimates of the female/male incidence ratio include 3.05 for collagenous colitis and 1.92 for lymphocytic colitis.5 The median age at diagnosis for both conditions is 60–65 years. Although microscopic colitis is very rare in childhood, 25% of patients are less than 45 years of age at presentation. Therefore, the diagnosis should be a consideration over a broad age range and in both sexes (Fact Sheet 20.2).7, 8
Information about the environmental risk factors for the development of microscopic colitis is not extensive, but several reports identify an association with smoking.9, 10 There is also an association between microscopic colitis of both types and a range of autoimmune diseases, including coeliac disease, diabetes mellitus, hypothyroidism, psoriasis, and rheumatoid disease. In one large cohort, 4.3% of patients with coeliac disease also had microscopic colitis.11 The association with coeliac disease is stronger for lymphocytic colitis than for collagenous colitis, and up to 25% of patients with lymphocytic colitis could have coeliac disease.12–15 Therefore, European guidelines have advocated testing for coeliac disease in all patients diagnosed with microscopic colitis, especially lymphocytic colitis.16 This is particularly important in microscopic colitis patients who have symptoms of malabsorption, including significant weight loss, and in those who fail to respond to the usual therapies for microscopic colitis.17
Pathogenesis
Understanding of the pathogenesis of microscopic colitis is incomplete, but an abnormal immune reaction to various unknown luminal antigens in predisposed hosts is one possibility. The primary cause of the immune dysfunction is unknown. Some studies have identified specific enteric infectious agents as the potential trigger in certain cases of microscopic colitis, but this remains unproven.18, 19
Drug-Induced Microscopic Colitis
Several drugs may cause or exacerbate microscopic colitis.17 Non-steroidal anti-inflammatory drugs (NSAIDs) were among the first to be suspected.20, 21 Proving drug causality is extremely laborious, requiring consideration of the time between drug exposure and onset of symptoms, of the response in symptoms after discontinuation of the drug, and of the clinical course after resumption.
The best clinical clue that microscopic colitis is drug-related is the sudden onset of symptoms, usually starting within several months of commencing the causative drug although sometimes taking longer to appear. One review applied a scoring system that incorporated these considerations, and identified drugs with a high likelihood of inducing microscopic colitis.17 These included aspirin, other NSAIDs, lansoprazole, ranitidine, sertraline, and ticlodipine. Case-control studies may implicate many drugs without establishment of a definite cause–effect relationship.22, 23 Many of these drugs are in common usage, and yet associations between drug use and onset of microscopic colitis are rare. Therefore, it is likely that any adverse effect represents an idiosyncratic hypersensitivity reaction.24
Clinical Features
Microscopic colitis is characterised by the predominant symptom of chronic, non-bloody or watery diarrhoea. Occasionally there are additional symptoms, including abdominal pain, making clinical distinction from irritable bowel syndrome impossible without biopsy.25 Symptomatology does not reliably distinguish collagenous colitis from lymphocytic colitis. In contrast to chronic idiopathic IBD, weight loss is unusual.
Endoscopic Features
As the term microscopic colitis implies, no endoscopic abnormality is evident in most patients with either collagenous colitis or lymphocytic colitis. However, there is increasing recognition of a range of subtle endoscopic changes in some patients. These include mucosal vascular pattern abnormalities (Figure 20.1), red spots or nodules, and a spectrum of mucosal defects described as lacerations. The latter include so-called ‘cat scratch colon’, ulcerations, longitudinal fractures, and thin or thick scar-like ridges.26–28 Ulceration in association with collagenous colitis may be linked with NSAIDs.29
Figure 20.1 Colonoscopic image from the transverse colon of a 53-year-old woman with collagenous colitis on biopsy, demonstrating mild mucosal oedema and erythema. There is increasing recognition of subtle endoscopic abnormalities in patients with microscopic colitis.
Mucosal abnormalities are considerably more common in collagenous colitis than lymphocytic colitis but can occur in both conditions.27 One large series has described mucosal abnormalities in 37% of patients with collagenous colitis and in 25% of patients with lymphocytic colitis.27 This increasing recognition of endoscopic abnormalities calls into question the suitability of the term microscopic colitis.
Most of the macroscopic changes probably reflect increased mucosal fragility and decreased flexibility. This is probably the result of subepithelial collagen deposition in collagenous colitis, although the reason for its occurrence in lymphocytic colitis is less obvious. However, none of the endoscopic abnormalities is specific for microscopic colitis as they are also seen in the normal colon (attributed to barotrauma from excessive colonoscopic insufflation) and in a variety of other clinical settings.30, 31 Thus, the diagnosis of microscopic colitis relies heavily on characteristic histology.
Microscopic Features
The microscopic features of collagenous colitis and lymphocytic colitis overlap significantly but there are important differences. They share the following features:
The overall mucosal architecture is normal, with regular, well-oriented, and parallel tubular crypts that demonstrate no significant distortion or atrophy.
There is expansion of the inflammatory content of the lamina propria. Evaluation of this feature must consider the anatomical segment of biopsy, as the normal inflammatory content of the right colon exceeds that of the left colon.32
There is an increase in surface intraepithelial inflammatory cells, typically but not exclusively lymphocytes. This feature also depends partly on anatomical location.
The key diagnostic difference between collagenous colitis and lymphocytic colitis is the presence of a subepithelial collagen band in collagenous colitis but not lymphocytic colitis. Assessment of these features requires further consideration (Fact Sheets 20.3 and 20.4).
In both collagenous colitis and lymphocytic colitis, but particularly lymphocytic colitis, the expanded lamina propria is usually appreciable on low magnification. The increased cellularity, comprising mainly mononuclear cells, imparts a ‘blue’ low- or medium-power appearance that is often the first indication of an abnormality (Figure 20.2). If prominent, the subepithelial collagen band of collagenous colitis may also be visible on low- or medium-power magnification in association with the expanded lamina propria (Figure 20.3). Higher magnification demonstrates the mixed composition of the lamina propria inflammatory infiltrate, with mononuclear cells always prominent, eosinophils often conspicuous, and occasional neutrophils not uncommon (Figure 20.4). One large series reported scattered cryptitis and/or crypt abscess formation in up to one-third of patients with collagenous colitis or lymphocytic colitis.33 However, such active inflammation should be mild and patchy. If it is more prominent, a diagnosis of microscopic colitis is unlikely. Architectural irregularity is rare, and surface ulceration very rare, in both collagenous colitis and lymphocytic colitis.33
Figure 20.2 Lymphocytic colitis. Low-power examination of descending colonic mucosal biopsies demonstrates a normal crypt architecture but increased lamina propria cellularity, imparting a ‘blue’ appearance.
Figure 20.3 Collagenous colitis. Preserved crypt architecture, lamina propria expansion, and even a patchy subepithelial collagen band are visible at this magnification.
The average thickness of the normal subepithelial collagen table is approximately 3 μm.34 There is no agreement on a minimum thickness of collagen band required to indicate a diagnosis of collagenous colitis but the collagen band typically exceeds 10 μm in thickness, at least focally (Figure 20.4).16 Collagen deposition is usually most obvious immediately deep to the surface epithelium, and does not usually extend around crypts. Variability in the degree of collagen deposition along the colon is a common feature of collagenous colitis.35 Hence, adequate colonic mucosal sampling from various anatomical segments is important. Quality of the collagen deposition is at least as important as quantity. The collagen band should be irregular and should entrap capillaries within the superficial lamina propria. This is usually visible on haematoxylin and eosin (H&E)-stained sections, but a collagen stain, such as Masson trichrome or van Gieson (Figure 20.5), may assist interpretation if the collagen band is not conspicuous (Practice Points 20.1).
(A) The subepithelial collagen deposition can be highly variable, even within a single mucosal fragment. Note the artefactual detachment and loss of surface epithelium.
(B) A histochemical stain for collagen (which stains pink on van Gieson staining) can assist the H&E interpretation.
Figure 20.5 Collagenous colitis.
Artefactual loss of the surface mucosa, secondary to the collagen deposition, is a useful clue to the diagnosis of collagenous colitis (Figure 20.5). However, evaluation of surface intraepithelial inflammation requires the presence, at least focally, of intact surface epithelium. A collagen band unaccompanied by inflammation within the surface epithelium and/or lamina propria is not sufficient alone for a diagnosis of collagenous colitis and merits consideration of an alternative diagnosis (see Differential Diagnoses). Awareness of the requirement for lamina propria inflammation when diagnosing microscopic colitis also reduces the likelihood of misinterpreting a zone of eosinophilic subnuclear cytoplasm or a thickened basement membrane as collagenous colitis.
As discussed earlier, lymphocytic colitis shares many of the microscopic features of collagenous colitis but lacks significant subepithelial collagen deposition. A small amount of collagen table thickening (<10 μm) is acceptable in lymphocytic colitis, especially if not accompanied by capillary entrapment. Surface intraepithelial lymphocytosis is a requirement for the diagnosis and is usually much more prominent in lymphocytic colitis than in collagenous colitis (Figure 20.6). The intraepithelial lymphocytes are typically small and round and may have a characteristic surrounding ‘halo’. Often there are associated degenerative features within the epithelium, such as flattening, mucin depletion, or vacuolation.36 There is general agreement that a diagnosis of lymphocytic colitis should require a diffuse increase of surface intraepithelial lymphocytes of more than 20 per 100 epithelial cells.16 This figure applies to the assessment of sections stained with H&E. Immunohistochemistry for T lymphocytes, such as CD3, may assist in interpretation of borderline cases but is not usually necessary for routine diagnosis of lymphocytic colitis (Figure 20.7). There is no agreement on the upper limit of normality for surface intraepithelial lymphocyte counts when assessed by immunohistochemistry, but the number will be significantly greater than 20 per 100 epithelial cells. The normal epithelium overlying mucosal lymphoid follicles has a high intraepithelial lymphocyte count and accordingly is unsuitable for assessment of lymphocyte numbers.36
Figure 20.6 Lymphocytic colitis. The normal crypt architecture is preserved but there is superficial lamina propria expansion by mononuclear cells and diffuse surface intraepithelial lymphocytosis.
Figure 20.7 Lymphocytic colitis. CD3 immunostaining highlights the diffuse surface intraepithelial T-cell population.
Infrequently, variants on the classical features of collagenous colitis or lymphocytic colitis occur (Fact Sheet 20.5). Awareness of these potential variations is important and helps to avoid misdiagnosis.37 Pseudomembranes, resulting from accumulation of surface mucosal purulent exudate, occur rarely in association with collagenous colitis, and the appearance that they cause is sometimes termed ‘pseudomembranous collagenous colitis’.38 Only a few such cases have had coexistent Clostridioides difficile infection (the most common cause of pseudomembranes), and the pathogenesis is not usually related to superimposed infection. Clinical behaviour of pseudomembranous collagenous colitis is similar to that of classical collagenous colitis. Therefore, pseudomembranes should prompt the pathologist to seek the features of collagenous colitis before making a definite diagnosis of pseudomembranous colitis.
‘Pseudomembranous collagenous colitis’
Pseudomembranes
Typical features of collagenous colitis also present
Microscopic colitis with giant cells
May be a feature of collagenous or lymphocytic colitis
Microscopic colitis with granulomas
May be a feature of collagenous or lymphocytic colitis
‘Cryptal lymphocytic colitis’
Increase in intraepithelial lymphocytes confined to the crypts, with no increase in surface epithelium
Microscopic colitis of both types may rarely be associated with multinucleated giant cells (Figure 20.8) or non-necrotic granulomas in the lamina propria.39, 40 In all reported cases the clinical and endoscopic pictures were typical of microscopic colitis, and none of those with follow-up developed Crohn’s disease.39 Given the rarity of such reports, the clinical significance of these findings in microscopic colitis is unclear.
Figure 20.8 Giant cell rich variant of lymphocytic colitis. In addition to the classical features of lymphocytic colitis, an almost linear band of subepithelial giant cells is evident. Clinically this case was typical of microscopic colitis.
In some cases of lymphocytic colitis, intraepithelial lymphocytes may be more conspicuous in cryptal epithelium than in surface epithelium (Figure 20.9), and in one small series the intraepithelial lymphocytosis was exclusively cryptal, without surface lymphocytosis.41 The term ‘cryptal lymphocytic colitis’ may be applicable. These cases were otherwise typical of lymphocytic colitis. No patient had a history of coeliac disease and none developed coeliac disease subsequently. Therefore, a search for lymphocytosis within cryptal epithelium in addition to surface epithelium is important.
Topography
The histological features of both collagenous colitis and lymphocytic colitis may not affect the colon and rectum uniformly. This has implications for the optimisation of mucosal sampling at flexible sigmoidoscopy or colonoscopy in the clinical setting of possible microscopic colitis (Practice Points 20.2).
Although the histological changes of both collagenous colitis and lymphocytic colitis are often uniform throughout the large bowel, there may be some variation
The diagnosis or exclusion of microscopic colitis is most likely to be accurate if there are separate endoscopic samples from the ascending or transverse colon and from the descending colon
Rectal biopsies may be uninformative
Many studies show that features of microscopic colitis in colonic biopsies are often absent from rectal biopsies. Therefore, rectal biopsies are not recommended as a means of evaluating or excluding the diagnosis.42, 43 Some studies show that the features of microscopic colitis, particularly collagenous colitis, are less pronounced in distal than in proximal colonic mucosa, suggesting that proximal colonic sampling is necessary to exclude a diagnosis of microscopic colitis confidently.35, 44 One study of collagenous colitis found that only 66% of specimens from the rectosigmoid were diagnostic, that the transverse colon yielded the largest percentage of diagnostic biopsy specimens (83%), and that samples from the remaining right colon and the left colon were less likely to be diagnostic.35
Larger, more recent studies have reported much better concordance between histology of right and left colonic biopsies in diagnosing collagenous colitis and lymphocytic colitis.45–47 In one study, 95% of patients with collagenous colitis and 98% of patients with lymphocytic colitis had diagnostic features of microscopic colitis in both right colonic and left colonic samples.47 However, left colonic biopsies may show less collagen band deposition than right colonic biopsies in the setting of microscopic colitis.43, 47 Therefore, assessment of exclusively left-sided biopsies may allow a diagnosis of microscopic colitis but could result in misclassification of some cases as lymphocytic colitis rather than collagenous colitis. Although the management of collagenous colitis and lymphocytic colitis is similar, their aetiology and subsequent clinical behaviour may differ.
The assessment of mucosal biopsies from the descending colon, usually obtainable at flexible sigmoidoscopy, is almost always sufficient for confident diagnosis or exclusion of microscopic colitis, but patients with chronic diarrhoea are most appropriately evaluated by full colonoscopy which allows examination of the entire colon for more sinister pathology. Therefore, the question is not how to investigate chronic diarrhoea, but rather what samples are necessary for the exclusion of microscopic colitis if endoscopy is normal or nearly normal.48 As discussed, rectal biopsies have a limited role. Non-specific inflammatory changes, often related to diverticular disease, are frequent in the sigmoid colon and a subepithelial collagen band similar to the band seen in collagenous colitis occasionally accompanies these changes. Therefore, given that the features of microscopic colitis may be less obvious in the sigmoid colon than proximally, sampling that is limited to the sigmoid colon could result in a false negative or a false positive diagnosis. For these reasons, sampling to exclude microscopic colitis at flexible sigmoidoscopy should be from the most proximal colon reached during the procedure, typically the descending colon.44, 49 If these biopsies demonstrate features suggestive, but not diagnostic, of microscopic colitis, or if the features are equivocal for subtype of microscopic colitis, the pathology report should recommend further sampling at full colonoscopy.
Considering the extensive available evidence on topographical variation in the histological features of microscopic colitis, major national guidelines from the United States and United Kingdom have recently recommended that all patients undergoing colonoscopy for investigation of chronic diarrhoea should have sampling from right and left colon as a minimum, to exclude microscopic colitis.49, 50 Separate labelling of these samples is very important, given the normal variation in lamina propria cellularity between right and left colonic mucosa.32 Random colonic sampling from throughout the colon, but submitted in one container without an indication of biopsy site or sites, can cause particular diagnostic difficulty for the pathologist and increases the risk that an equivocal report will be issued, in turn necessitating further investigation.
Incomplete Microscopic Colitis
In some cases, there are clinical features of microscopic colitis and histological features suggestive but not diagnostic of either collagenous colitis or lymphocytic colitis. The question of how to report such cases then arises. Typically, these cases demonstrate a normal mucosal architecture and inflammatory expansion of the lamina propria. In addition, there is either some subepithelial collagen deposition that is insufficiently abnormal in quality and quantity for a diagnosis of collagenous colitis, or some intraepithelial lymphocytosis that is insufficient for a diagnosis of lymphocytic colitis (i.e. fewer than 20 lymphocytes per 100 epithelial cells).
Various possible terms for these cases include incomplete microscopic colitis and paucicellular lymphocytic colitis.47, 51–54 Of these terms, incomplete microscopic colitis appears to be in favour currently.8, 47, 55 However, it remains a controversial diagnosis with poor uptake in routine pathology practice, for two reasons. First, strong evidence of topographical variation in the histological features of microscopic colitis (see earlier) raises the possibility that any diagnosis of incomplete microscopic colitis simply represents undersampled microscopic colitis. Therefore, a diagnosis of incomplete microscopic colitis is possible only after extensive colonic sampling. Second, the minimum criteria for diagnosing incomplete collagenous colitis or incomplete lymphocytic colitis are not clear, potentially leading to overdiagnosis and overtreatment of patients. One study proposes, without good evidence, that, in addition to lamina propria inflammation, a diagnosis of incomplete collagenous colitis should require a collagen band greater than 5 μm in thickness and a diagnosis of incomplete lymphocytic colitis should require more than 10 intraepithelial lymphocytes per 100 epithelial cells.55
The term ‘microscopic colitis not otherwise specified’ may refer to borderline cases and/or to cases that are difficult to classify as lymphocytic or collagenous.
Differential Diagnosis
Many causes of chronic diarrhoea produce no colonic mucosal histological abnormality. These include irritable bowel syndrome, bile salt malabsorption, and pancreatic insufficiency. By excluding a diagnosis of microscopic colitis, normal colonic histology increases the likelihood of these alternative causes, which may then need further investigation and confirmation according to the clinical setting. Therefore, the first histological diagnosis to consider in the differential of microscopic colitis is one of normality. The most common and relevant questions to ask in this regard are listed in Practice Points 20.3.
Is the inflammatory content of the lamina propria appropriate for the anatomical segment sampled?
Is there any significant intraepithelial lymphocytosis?
Is there any significant subepithelial collagen deposition?
Is the architecture within normal limits?
Evaluation of the normal cellular composition of the lamina propria for each anatomical segment of the colon requires experience of looking at sufficient numbers of cases, normal and abnormal, to give a confident judgement. In brief, more cellularity is allowable within the right colon than left colon.32
‘Significant’ lymphocytosis and subepithelial collagen deposition have been described above. Immunohistochemistry for the T-cell marker CD3 is not usually necessary but can be helpful in borderline cases, especially when colonic sampling has been minimal. Assessment of lymphocytosis should avoid the epithelium overlying mucosal lymphoid aggregates, which often shows localised lymphocytosis (Figure 20.10). A thick section may also create the impression of intraepithelial lymphocytosis, and a clue to this explanation for apparent intraepithelial lymphocytosis is the presence of crowding of epithelial nuclei. In this circumstance, examination of a further, thin (4 μm), H&E-stained section usually confirms normality and CD3 immunohistochemistry may again be helpful (Practice Points 20.4).
Figure 20.10 Surface lymphocytosis should not be assessed near discrete mucosal lymphoid aggregates, which commonly demonstrate overlying intraepithelial lymphocytes.
Histochemical staining to help assess collagen deposition is not usually necessary. However, it can be informative when attempting to distinguish between a genuine collagen band and eosinophilic subnuclear cytoplasm within surface enterocytes (Figure 20.11). This distinction is usually obvious on H&E examination once the pathologist is familiar with the phenomenon. In addition, a thickened basement membrane may mimic the band of collagenous colitis. A thickened basement membrane should retain a linear configuration and, unlike the band of collagenous colitis, should not encircle capillaries within the superficial lamina propria. Absence of other features of microscopic colitis can assist with the interpretation.
Figure 20.11(A) Subnuclear cytoplasm within surface enterocytes can mimic a collagen band to the unwary but the absence of the inflammatory features of collagenous colitis should guard against misdiagnosis. Closer examination at higher power microscopy usually makes the distinction.
(B) A collagen stain may also help when interpretation is difficult.
Assessment of normal colonic mucosal crypt architecture can be difficult if there are problems with tissue orientation and if there is insufficient awareness of the range of normality. The classical description of normal colonic mucosa is of parallel rows of ‘test tubes’, which may appear as fully elongated tubular structures in a well oriented section or as rounded or ovoid structures in a horizontally or tangentially cut section (Figures 20.11 and 20.12). Regardless of orientation, evenly spaced crypts and repetitive shape pattern are good indications of normality.
