Pathogenesis of Crohn’s Disease–Associated Fistula and Abscess

Introduction

Patients with Crohn's disease (CD) frequently suffer from fistula and abscess that can result from adverse sequelae of persistent complicated active disease or surgical intervention. Spontaneous fistulas associated with active disease including perianal, enteroenteric and enterocutaneous fistulas ranges from 17% to 50% in patients with CD. Recurrence of those fistulas after medical or surgical therapy is common.

It is generally believed that fistula results from ulcer or transmural fissure that gradually penetrates the surrounding soft tissue and eventually communicate with other bowel segments or organs such as bladder and vagina, or skin. Immune-mediated mechanisms likely play a primary role in the formation of spontaneous fistula. However, the pathogenesis of fistulas in CD is still poorly understood, despite recent understanding of the immune pathogenesis of CD and the molecular genetics underlying penetrating CD. To develop targeted and more effective therapeutic strategies, it is important to understand the pathogenesis of CD-associated fistula and abscess.

Definition

A fistula, a tubule or tube-like structure, represents a tract between two epithelial-lined surfaces. Fistulas affect up to 50% of CD patients, and the most common fistulas are perianal (54% of the total), enteroenteric (24%), and rectovaginal (9%). Defining Crohn's fistulas includes the diagnosis of CD, as well as the exclusion of infection, hidradenitis suppurativa, malignancy, and tuberculosis-induced fistula. Crohn's fistula/abscess, which results from active disease, is complicated with Crohn's pathological features including intestinal inflammation, stricture, and ulcers and, importantly, a history of CD.

Morphological Characterization of Crohn's Fistulas

A fistula tract, which is defined as a central fissure penetrating through the lamina propria and the muscularis mucosae into the deeper layers, may be identifiable macroscopically ( Fig. 4.1 ) and microscopically ( Fig. 4.2 ). Fistulas are often surrounded by granulation tissue and/or squamous epithelium and typically filled with debris, erythrocytes, and acute inflammatory cells. For a better understanding of the pathogenesis of CD fistulas, it is critical to define the histologic characteristics of CD fistulas and, in particular, the ways in which they differ from non-CD fistulas. In addition, more knowledge about the specific cell types and characteristics of the cells along, as well as surrounding, the fistula tracts are required.

The histologic features of Crohn's fistulas are largely nonspecific, which includes chronic inflammation, a multinucleate foreign body–type giant cell reaction, a granulomatous reaction, and fibrosis.

Granulomas may be present. Specific features of CD fistulas include a lining of flattened intestinal or narrow squamous epithelium, or epithelialization of the inner layer fistula track is common in CD ( Fig. 4.2 ). The epithelialization of the inner layer of the fistula track may explain why the complete healing is difficult with systemic medical therapy, even with aggressive therapy with various biological agents. This may also explain why the surgical or topical therapy for fistula is started with the debridement of fistula track first.

The fistula track is surrounded by granulation tissue. In patients with CD, the interior wall of the fistulas is usually infiltrated by T cells and macrophages, whereas the outer wall is infiltrated with B cells. In addition, CD fistulas may have areas with disordered myofibroblasts and fragmented basal membrane.