Case 2 -

Thickening of the Collagen Table Lisa Yerian, John Hart and Amy Noffsinger

Collagenous Colitis The diagnosis "collagenous colitis" was introduced in 1976 by Lindstrom [1] to describe patients who suffered from chronic, watery diarrhea and who had accumulations of a collagenous ground substance containing amorphous proteins, and immunoglobulins in the subluminal colonic basement membrane, at the lamina propria interface. Collagenous colitis demonstrates a marked female predominance with the female:male ratio ranging from 6-20:1 [2, 3]. This female predominance and its association with other autoimmune diseases suggests the possibility of an autoimmune etiology [2]. The median age at which collagenous colitis presents is 58-68 years, but the age range is wide [4]. The disorder sometimes affects children [5] and is sometimes familial [6, 7]. A significant percentage of patients with collagenous colitis have a history of using non-steroidal anti-inflammatory drugs [8, 9, 10]. Other agents such as lansoprazole, ticlopidine and flutamide have also been suspected, but a definite association has not been proven [11, 12, 13]. Pathophysiology: Surface epithelial damage appears to cause secretory diarrhea, whereas the thickened subepithelial collagen table appears to represent a variable response to the surface damage. The injury in collagenous colitis may result from bile acid malabsorption [14], mast cell infiltration [15, 16], NSAIDs [9, 10, 17] and possibly, other drugs. The development of clinical symptoms correlates with the thickness of the collagen deposits and the total epithelial surface area involved [18, 19]. Clinical Features: Symptoms include watery, nonbloody diarrhea with up to 20 stools per day. The diarrhea can last for months, or even years. Colicky abdominal pain occurs in up to three quarters of patients [2]. Nausea, vomiting, flatulence, urgency, incontinence, and weight loss vary in frequency. Joint disease, including chronic arthritis, affects some patients [20, 21, 22]. Abnormal thyroid function [2, 23, 24], the CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, telangiectasia) [25], and discoid lupus [26] are also associated with collagenous colitis. Autoantibodies such as antinuclear and antireticulin antibodies or rheumatoid factor occur in some patients [27, 28]. Pathologic Findings: The colon appears grossly and endoscopically normal, although mild erythema may sometimes be seen. The histologic hallmark of collagenous colitis is mucosal chronic inflammation associated with a broad, continuous, hypocellular, eosinophilic, linear, subepithelial, fibrous band immediately subjacent to the surface epithelium. In collagenous colitis, the subepithelial collagen band measures greater than 10 µm in thickness, and contains entrapped capillaries, red blood cells and inflammatory cells. There is little if any extension of the thickened collagen table around the crypts. The thickened subepithelial layer stains light pink with PAS and green with the Masson trichrome stain. The changes are most marked in the proximal colon with the distal portion being spared. The changes are often continuous, but may also exhibit a patchy distribution. Additional histologic findings in collagenous colitis include the presence of epithelial vacuolization and desquamation, as well as an intraepithelial lymphocytosis. The intraepithelial lymphocytosis seen in collagenous colitis, however, is not as dramatic as that seen in lymphocytic colitis [29]. Focally, the superficial lamina propria contains slightly to moderately increased numbers of lymphocytes, plasma cells, and mast cells admixed with variable numbers of eosinophils and neutrophils. Eosinophils can be focally prominent. Damaged epithelial cells appear flattened, mucin-depleted, vacuolated, and irregularly oriented. Focally, small strips of interglandular surface epithelium lift off their basement membrane and a subepithelial cleft filled with neutrophils and eosinophils forms. Despite all of these changes, the crypt epithelium appears relatively normal. Frank ulceration and active inflammation may be signs of NSAID-associated injury [30]. Treatment and Prognosis: Collagenous colitis exhibits spontaneous remissions and relapses; occasionally the disease resolves spontaneously. In other patients, symptoms resolve following treatment with bismuth subsalicylate. Refractory patients may respond to treatment with octreotide, methotrexate, cyclosporine or antibiotics [3]. Fecal stream diversion can induce clinical and histopathologic remission of collagenous colitis [31]. Collagenous colitis may rarely contribute to patient mortality. Differential Diagnosis: Subepithelial collagen thickening occurs in various diseases. As a result, the diagnosis of collagenous colitis can only be made in the proper clinical and histologic settings. Tangential sectioning of normal colonic mucosa results in artifactual thickening of the basement membrane and such cases can be incorrectly interpreted as collagenous colitis. If biopsies lack the characteristic inflammatory pattern, a tangentially cut thick basement membrane should be ignored. The key to a correct diagnosis of collagenous colitis is analyzing the summation of various inflammatory changes plus the subepithelial collagenization. The differential diagnosis of collagenous colitis includes lymphocytic colitis, NSAID injury, inflammatory bowel disease, ischemic colitis, radiation colitis, amyloidosis, progressive systemic sclerosis, acute infectious colitis, mucosal prolapse syndrome and diverticular disease. Biopsies with increased subepithelial collagen deposition from patients without characteristic clinical symptoms generally come from the rectum or rectosigmoid. Since collagenous colitis generally affects the proximal colon more severely, the most reliable biopsies for the diagnosis of collagenous colitis come from that region. Features that distinguish the diseases that mimic collagenous colitis are listed below. Distinguishing Features of Diseases that Mimic Collagenous Colitis Collagenous colitis Subluminal collagen thickening; intraepithelial lymphocytosis; inflammation in upper mucosa Lymphocytic colitis Intraepithelial lymphocytosis, increased lymphocytes and plasma cells in lamina propria; no collagen table thickening NSAID injury Subluminal collagen thickening may occur, superimposed acute inflammation, erosion or ulceration Radiation colitis Mucosal telangiectasia, submucosal vascular changes, atypical fibroblasts, fibrosis IBD Diffuse continuous process with numerous crypt abscesses, cryptitis, glandular destruction, and signs of chronicity; no subluminal collagen thickening. Infectious colitis Diffuse lamina propria inflammation, significant neutrophils in lamina propria; usually no subluminal collagen thickening. Mucosal prolapse Glandular distortion, mucosal ulceration, mucosal hyperplasia, mucosal fibrosis, perpendicular smooth muscle fibers in lamina propria Ischemic colitis Coagulative necrosis, fibrin thrombi, architectural distortion if disease chronic, mucosal fibrosis, glandular dropout Amyloidosis Perivascular, muscular, or lamina propria eosinophilic deposits; positivity with Congo red stains Progressive Fibrosis along all basement membranes, including crypts systemic sclerosis Diverticulosis Chronic inflammation, thickened basement membranes Lymphocytic Colitis Patients with lymphocytic colitis, like those with collagenous colitis, present with chronic watery diarrhea that can be intermediate or continuous, ranging in duration from 2 months to 25 years. Related symptoms may include mild crampy abdominal pain, moderate weight loss, and an essentially normal physical examination [29]. Up to one-third of patients with histologic evidence of celiac disease in the small bowel exhibit lymphocytic colitis [32, 33, 34]. An association also exists between lymphocytic colitis and tropical sprue [35]. Patients with lymphocytic colitis exhibit a more variable age range than those with collagenous colitis; it occurs at all ages. The disorder affects both men and women [36, 37]. Arthritis often coexists with lymphocytic colitis. Autoantibodies, such as antinuclear antibody and rheumatoid factor, are found in up to 50% of patients with lymphocytic colitis [38]. The most distinctive feature of lymphocytic colitis is the presence of increased intraepithelial lymphocytes, particularly at the luminal surface. The lamina propria contains increased numbers of lymphocytes, eosinophils, or neutrophils. Other prominent features of lymphocytic colitis include surface epithelial damage with cellular loss and epithelial detachment, infiltration of the surface epithelium with eosinophils and neutrophils, and minimal crypt distortion or active cryptitis. Unlike collagenous colitis, the histologic features of lymphocytic colitis are usually uniform throughout the large bowel. Comparison of Collagenous Colitis and Lymphocytic Colitis Feature Collagenous colitis Lymphocytic colitis Patient age Mean Age 54 Any Age Female/male ratio 6-20:1 1:1 Increased collagen table +++ - Intraepithelial lymphocytosis + +++ Distribution Proximal colon, patchy Diffuse Associations Autoimmune diseases + + Celiac disease - + Changes in small intestine + + Changes in stomach + + NSAID Induced Injury Several forms of colitis are associated with NSAID use. The most common is nonspecific in nature and difficult to distinguish from ulcerative colitis early in its natural history. The likelihood of a drug association increases if there is prominent apoptosis and increased intraepithelial lymphocyte counts. Collagenous colitis, eosinophilic colitis and pseudomembranous colitis can also be seen. NSAID-associated collagenous colitis often shows prominent neutrophilic infiltrates and areas of erosion or ulceration in addition to typical features of collagenous colitis. Chronic Colitis of Diverticular Disease A clinical syndrome of chronic colitis sometimes develops in the sigmoid colon harboring diverticula. Diverticular disease associated colitis affects older individuals and histologically has features that resemble IBD or collagenous colitis. The lamina propria is expanded by an infiltrate of mononuclear cells. Basal lymphoplasmacytosis, crypt distortion, cryptitis and crypt abscesses, surface epithelial sloughing, basal lymphoid aggregates, and mucin granulomas may all be present, mimicking ulcerative colitis. The mucosa lining diverticula may appear hyperplastic or it may appear to have a thickened collagen table mimicking collagenous colitis. This resemblance may be further accentuated if there is a mild colitis associated with the thickened collagen table. Diverticular disease associated colitis tends not to cause diagnostic dilemmas when one receives a resection specimen with obvious diverticulosis. However, given the frequency with which diverticulosis is encountered in the population and the frequency of colonic biopsies, diverticular disease-associated colitis may cause unrecognized diagnostic difficulties when interpreting biopsy specimens. Knowledge of the endoscopic findings is critical to proper interpretation of the biopsy. The endoscopic findings are usually characteristic and include the presence of a patchy, confluent granularity and friability surrounding diverticular ostia. Mucosal Prolapse Mucosal prolapse is more common in women than men, and tends to occur most often in the fifth decade. Prolapse also occurs in infants, but is uncommon in childhood and early adulthood. The incidence again increases after age 40. Prolapse complicates a number of disorders including cystic fibrosis, acute diarrheal diseases, IBD, chronic constipation and motility disorders. Presenting symptoms include straining during defecation, a sense of obstruction, defecatory pain, fecal incontinence, mucous discharge, pruritus, rectal bleeding, a sense of incomplete rectal evacuation, perineal or intervaginal pressure, and the need to digitally disimpact the rectum. Patients may have a palpable mass on digital examination. Endoscopically, one sees mucosal reddening, ulceration, edema or a mass lesion. Lesions associated with prolapse are usually single and confined to the lower portion of the sigmoid and rectum. Histologically, the earliest manifestation of rectal prolapse may consist of nothing more than mucosal erosions or ulcers, or even just nonspecific inflammation with thickening of the collagen table producing changes mimicking collagenous colitis. Ulceration is heralded by capillary dilatation and congestion beneath the surface epithelium. Later, the lamina propria shows fibrosis and the presence of smooth muscle cells and fibroblasts arranged entirely at right angles to the muscularis mucosae. The overlying epithelium appears regenerative with mucin depletion, branching, and hyperplasia. Radiation Injury Even though the colon and rectum are relatively radioresistant, they exhibit a high incidence of radiation damage due to both the large radiation doses used to treat tumors arising in the pelvic area and the fixed position of the sigmoid colon. Mucosal biopsies are generally performed in cases of suspected radiation injury in order to confirm the presence of the colitis or exclude the presence of recurrent tumor or the presence of an opportunistic infection. Histologic changes of radiation injury may mimic those seen in chronic ulcerative colitis, ischemic or collagenous colitis, particularly if only a superficial biopsy is examined. Acute effects consist of cryptitis, prominent submucosal edema, variable ulceration, inflammatory polyps, and sometimes ischemic changes. More chronic features include architectural distortion with variable atrophy, vascular ectasia, and thickening of the collagen layer beneath the surface and crypt epithelium. These changes mimic collagenous colitis. Features that suggest the diagnosis of radiation damage include the patchy nature of the process, marked telangiectasia, and, if one is lucky enough to get the submucosa, typical vascular changes sometimes associated with characteristic atypical radiation fibroblasts. In other cases, the tissue appears nonspecifically chronically damaged. Collagenous Enteritis and Gastritis Collagenous enteritis, or collagenous sprue, typically affects patients with a long history of celiac disease, but has been regarded by some as a distinct entity. The typical clinical history is of a patient with celiac disease who initially responded to a gluten free diet, but subsequently becomes refractory to treatment. The small bowel biopsy shows variable villous atrophy and other features typical of celiac disease. In addition, a prominent subepithelial collagen band is present. This thickened collagen table can be highlighted with the use of a trichrome stain. Collagenous gastritis is a rare form of gastritis that develops in the gastric body in the setting of chronic gastritis. Collagenous gastritis consists of a characteristic thickening of the subepithelial collagen table lying beneath the surface foveolar cells coexisting with gastritis. It resembles the subepithelial fibrosis that develops in the small intestine and in the colon. The etiology of collagenous colitis is unknown and its relationship to collagenous enteritis and collagenous colitis remains to be defined. References: Lindstrom CG. "Collagenous colitis" with watery diarrhoea—a new entity? Pathol Eur 1976;11:87-9. Fernandez-Banares F, et al. Collagenous and lymphocytic colitis: evaluation of clinical and histological features, response to treatment and long-term follow-up. Am J Gastroenterol 2003;98:340-7. Pardi DS, et al. Lymphocytic colitis: clinical features, treatment and outcomes. Am J Gastroenterol 2002;97:2829-33. 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