Crohn disease (CD) is an idiopathic, chronic regional enteritis that most commonly affects the terminal ileum but has the potential to affect any part of the gastrointestinal tract from mouth to anus. This condition was first described by Crohn, Ginzburg, and Oppenheimer in 1932, but it was not clinically, histologically, or radiographically distinguished from ulcerative colitis until 1959. [1, 2]
Untreated Crohn disease is characterized by transmural (full-thickness) inflammation, involvement of discontinuous segments of the intestine (skip areas), and, in a proportion of cases, by non-necrotizing granulomas composed of epithelioid histiocytes. Patients present with a range of symptoms, including crampy abdominal pain and diarrhea, which may be complicated by intestinal fistulas, particularly after surgical intervention, by intramural abscesses, and by bowel obstruction.
The diagnosis of Crohn disease can be difficult, and the proper clinical separation of this entity from ulcerative colitis has important therapeutic implications. Consequently, a thorough understanding of the clinical, radiologic, endoscopic, and pathologic features of Crohn disease, as well as effective communication between the pathologist and the managing clinicians, is essential to diagnostic accuracy.
Below are examples of some gross features of Crohn disease.
The prevalence of Crohn disease (CD) ranges from 0.7 to 56 cases per 100,000 persons and is more commonly seen in white individuals living in Western industrialized nations. [3, 4] In the United States, approximately 7 per 100,000 persons are affected; those of European (Ashkenazi) Jewish heritage have a 3-5 times higher prevalence than members of the general population.
The incidence and prevalence of the disease (especially colonic Crohn disease) are steadily increasing, mainly in northern climates and urban areas, but Crohn disease is also becoming more common in regions such as Africa, South America, and Asia. Although this condition can occur at any age, there are 2 peaks of incidence, one in early adulthood (range, teens–20s) and another in the 60-70 year age group. Males and females are affected, but there is a slight female predilection for the disease.
The precise etiology of Crohn disease (CD) is unknown, but there are several known risk factors, including family history, smoking, use of oral contraceptives, diet, and ethnicity. A combination of factors, including aberrant mucosal immune responses, intestinal epithelial dysfunction, and defects of host interactions with intestinal microbes likely contribute to Crohn disease. 
There is a clear genetic predisposition for Crohn disease. First-degree relatives have a 13-18% increase in incidence, and there are concordance rates of 50% in monozygotic twins. Classic Mendelian inheritance is not seen, implying a polygenic basis of the disease. [6, 7]
Molecular linkage analyses of affected families have identified NOD2 (nucleotide-binding domain 2) as a susceptibility gene in Crohn disease. [8, 9] NOD2 encodes a protein that binds to intracellular bacterial peptidoglycans, subsequently activates NF-kB (nuclear factor-kappaB), and may be involved both in preventing excessive immune activation and in combating luminal microbes. However, fewer than 10% of individuals carrying NOD2 mutations develop the disease, and genomic screening has identified linkage to multiple chromosomes, including chromosomes 3, 7, 12, and 16. [10, 11, 12]
Other genes of interest include ATG16L1 (autophagy-related 16-like) and IRGM (immunity-related GTPase M), both of which are involved in autophagy and the clearance of intracellular bacteria. IL23R (interleukin-23 receptor) may also be involved, as it is a regulatory cytokine receptor that plays a role in the initiation of the innate and adaptive immune activation in the intestinal mucosa. [13, 14, 15, 16]
Go to Crohn Disease and NOD2/CARD15 for complete information on this topic.
Environmental factors, especially cigarette smoking and diet, are also clearly involved in this disease. Tobacco smoking doubles the risk of both initial and recurrent Crohn disease, unlike the apparent protective effect of tobacco seen in ulcerative colitis. Improved food storage conditions and decreased food contamination may also contribute to the increase in incidence. 
This so-called "hygiene hypothesis" suggests that the reduction in enteric infections in developed countries has resulted in inadequate development of the regulatory processes that limit mucosal immune responses.  Pathogens that otherwise might cause only self-limited disease instead may trigger overwhelming inflammatory responses in susceptible individuals. Although more data are required, the observations that episodes of acute gastritis often precede the onset of Crohn disease in humans and that helminthic infections can prevent disease development in animal models lend support to this idea. 
Given the success of treatment of peptic ulcer disease with the discovery of Helicobacter pylori as the causative agent, there have been multiple studies attempting to link an infectious agent with inflammatory bowel disease.  Although decreased numbers of native lactobacilli and overgrowth of enteric bacteria are postulated to trigger excessive inflammation seen in Crohn disease, a single causative infectious agent has not been identified. Mycobacteria have been studied extensively in this context, given the histopathologic similarities between intestinal tuberculosis and Crohn disease, but the suggestion that mycobacteria play an etiologic role has been largely disputed. [20, 21]
Similarly, although both a measleslike virus and the measles vaccine have been implicated in the pathogenesis of Crohn disease, epidemiologic evidence has failed to support either as a causative agent. [22, 23, 24, 25] The search for an infectious cause of inflammatory bowel disease continues, but it seems more likely that the ultimate cause is polyfactorial. 
Mucosal immune response and epithelial damage
A variety of epithelial defects have been described in both Crohn disease and ulcerative colitis, including tight junction barrier function, defective transepithelial transport, extracellular matrix barrier proteins, and Paneth cell antibacterial peptides.  In addition, polarization of T cells to the T-helper cell type 1 (TH1) type is a well-recognized feature of Crohn disease, and emerging data indicate that TH17 cells also contribute to disease pathogenesis, whereas IL-23 receptor polymorphisms may confer protection from Crohn disease. [27, 28]
It has also been proposed that neutrophil dysfunction may play a role in altered innate immunity early in the development of Crohn disease. [29, 30] At this point in time, the exact defects and mechanisms involved in disease pathogenesis are yet to be elucidated, and research is ongoing. Immunosuppression remains the mainstay of Crohn disease therapy, and it is likely that a combination of derangements that alter mucosal immunity and suppress immunoregulation is crucial in the development of this disease.
Affected Anatomic Sites
Unlike ulcerative colitis, Crohn disease (CD) can occur at any point along the gastrointestinal tract. The most commonly involved sites at presentation are the terminal ileum, ileocecal valve, and cecum.
Disease is limited to the small intestine in approximately 40-50% of cases, whereas another 30-40% of cases involve both the small intestine and the colon. The remaining cases involve only the colon. 
Extraintestinal features are common and include the following:
Ocular manifestations (uveitis, recurrent iritis, and episcleritis)
Dermal manifestations (erythema nodosum, pyoderma gangrenosum, and Sweet syndrome)
Inflammatory seronegative arthropathies (sacroiliitis, ankylosing spondylitis, psoriatic arthritis, and reactive arthritis) 
The liver and bile ducts can be also be involved; the incidence of primary sclerosing cholangitis is increased by approximately 10% in patients with a history of Crohn disease. 
Regardless of the location of disease, Crohn disease (CD) usually follows a chronic, indolent course and tends to relapse and remit. Patients commonly present with symptoms due to ileocecal inflammation, [36, 37] including the following:
Crampy, lower right quadrant or periumbilical pain that is often relieved by defecation – Some patients report more diffuse and constant pain.
Prolonged nonbloody diarrhea with accompanying weight loss and possible malabsorption syndromes – If the colon is involved, the diarrhea may contain blood, mucus, and pus.
Low-grade fever and feeling of general fatigue and malaise
In pediatric patients, unexplained growth failure in addition to the above symptoms
Fissures, fistulas, and abscesses
Chronic, transmural inflammation can lead to fissures in the bowel wall with ensuing fistulas and abscesses. Fistulas may develop between the bowel and other organs, including enteroenteric fistulas, enterogastric, enterovaginal, enterocutaneous, and enterovesical fistulas. These can present as feculent vomiting or vaginal discharge, frequent urinary tract infections, pneumouria, fecaluria, and feculent soiling of skin lesions. Fistulas are significantly more common in postsurgical patients, an important reason why surgical intervention is deferred in favor of medical intervention, whenever possible. Retroperitoneal, intraperitoneal, and perianal/perirectal abscesses are common.
A retrospective study evaluated the clinico-pathological characteristics of patients who underwent surgery due to stricturing or non-perineal fistulizing Crohn's disease. The study concluded that no specific clinical feature was found to differentiate patients with the stricturing form of Crohn's disease from the fistulizing form. However, the authors also add that histopathological analysis of the resected specimens revealed significant differences in some parameters between the two disease forms. The L3 localization (Montreal Classification) was detected significantly more often in the non-perineal fistulizing group than in the stricturing group. 
Patients may also present with symptoms of obstruction, including the following:
Cramping, borborygmus, and postprandial bloating due to edema of the bowel wall
Possible ensuing constipation and obstipation, as the bowel wall becomes chronically thickened and the lumen narrows
Occurrence of complete obstruction as the result of stricture formation and progressive bowel wall thickening
Extraintestinal features may involve the mouth, anus, eyes, skin, joints, liver, and bile ducts. Aphthoid ulcers and erosions of the mouth, anal fissures, abscesses, ulceration around stomas and skin tags are common features of the disease. Uveitis and episcleritis as well as pyoderma gangrenosum and constitutional eczema are also quite common. [39, 40] The arthropathies tend to be migratory and asymmetrical, and there may be an associated ankylosing spondylitis. [41, 42]
Liver function test abnormalities are common, but severe hepatic pathology such as pericholangitis and primary sclerosing cholangitis are not as clearly associated with Crohn disease as with ulcerative colitis. 
Dysplasia and carcinoma
Patients with Crohn colitis are at increased risk to develop intraepithelial neoplasia, also known as dysplasia, and colonic adenocarcinoma.  Patients should begin periodic regular colonoscopic surveillance for dysplasia and carcinoma beginning approximately 8-10 years after the diagnosis of Crohn colitis. Patients with concomitant primary sclerosing cholangitis are thought to be at increased risk for colorectal neoplasia compared with other Crohn patients, but the relative risk is better defined for patients with ulcerative colitis and primary sclerosing cholangitis.  In addition, strictures may harbor malignancy.
The biopsy strategy for surveillance includes 4-quadrant biopsies taken at intervals of every 10 cm of colon involved by the colitis, beginning 10 cm proximal to the area of involvement, and extending 10 cm distally. If there is pancolitis, at least 33 biopsies are recommended, and biopsies at 5-cm intervals of the rectum are included. Biopsies should also include any nodules or masses, as well as the flat mucosa adjacent to the masses, clearly designated as such, and submitted separately. 
NOTE: Extreme care should be taken to avoid labeling the patient with Crohn disease at first biopsy. It is preferable in this clinical context to provide a descriptive diagnosis with a differential diagnosis. Appropriate clinical follow-up and subsequent biopsies will usually resolve the diagnostic dilemma.
Gross Features of Crohn Disease
Rigid thickening of the involved segment of bowel wall is typical in Crohn disease, as seen in the image below.
Hyperplasia of the subserosal and mesenteric adipose tissue, leading to the appearance of "creeping fat," is highly characteristic of the serosal surface of the specimen (see the following image). Serosal fibrosis, congestion, and adhesions are also common. [45, 46, 47]
Strictures, especially single, long segment strictures in the terminal ileum (leading to the string sign of Kantor on computed tomography [CT] scan) are classic, but multiple shorter strictures can also be seen.  See the image below.
The mucosal surface shows patchy lesional distribution with sharply delineated areas of disease surrounded by normal mucosa. Even in extensive disease, there are nearly always intervening patches of normal bowel with careful examination. In addition, linear and serpiginous mucosal ulcers with intervening mucosal edema lead to a classic gross "cobblestoned" appearance of the mucosa, as shown in the images below.
Deep ulcers, vertical fissures, and fistula tracts are commonly seen. In particular, vertical fissuring can be especially helpful in the distinction between Crohn disease and ulcerative colitis.  In addition, small, pinpoint hemorrhages and shallow ulcers with white bases (aphthoid ulcers) are frequent along the periphery of the involved segments of mucosa. 
Microscopic Features of Crohn Disease
Many of the classic microscopic findings were described in cases of bowel resection and in an era before the advent of immunosuppressive therapy. Pathologists currently face the challenge of rendering a pathologic diagnosis based on limited superficial mucosal biopsy samples obtained at endoscopy, often in the setting of previous treatment with anti-inflammatory medications.
The following are the most characteristic classically described histologic findings:
Areas of chronic inflammation, comprising increased lamina propria plasma cells and lymphocytes, in association with chronic architectural distortion with patchy, mild to severe, neutrophilic inflammation, including neutrophilic cryptitis, crypt abscesses, or erosions/ulcers
Skip lesions comprising focal, patchy erosions or ulcers, vertical fissures, and fistulas
The hint of "skip lesions" – Mucosal fragments from the same level of the colon have variable microscopic findings.
Transmural inflammation with multiple lymphoid aggregates
Submucosal fibrosis and neuromuscular hyperplasia of submucosa
The fissures are often longitudinally oriented, knifelike clefts lined by granulation tissue, epithelioid histiocytes, and giant cells, as depicted in the following images.
Focal, transmural inflammation consisting of lymphocytes, plasma cells, and neutrophils with large lymphoid aggregates is classic for Crohn disease. Cryptitis and crypt abscesses are common. The lymphoid aggregates are usually noted in the mucosa and submucosa, although they can be located throughout the bowel wall and are characteristically seen in the subserosal fat, following the vasculature.  See the images below.
The granulomas consist of non-necrotizing, well-circumscribed groups of epithelioid histiocytes, with or without accompanying giant cells of the Langerhans type (see the following images).  When present, granulomas are extremely helpful in securing the diagnosis of Crohn disease, but they are absent in 50-60% of cases. Moreover, granulomas are also seen in tuberculosis, yersiniosis, and can even be seen in ulcerative colitis in association with ruptured crypts. In general, caution must be employed when using granulomas as a diagnostic feature.
The granulomas of Crohn disease can be found throughout the bowel wall, and they are commonly associated with areas of ulcer, or along lymphatic spaces in the submucosa and subserosa, and, less frequently, with small blood vessels. [52, 53]
Granulomas are more commonly seen in the large bowel and anal region than in the small intestine; they are also more prominent in younger patients with a shorter disease duration than in patients with longstanding disease. 
Lymph nodes in the mesentery will often contain similar granulomas, but it is exceptional for granulomas to be present only in lymph nodes (see the image below). An alternate diagnosis should be strongly considered in such cases. 
Bowel wall thickening consisting of edema and fibrosis leading to splaying of the muscularis mucosae and distortion of the muscularis propria is present in Crohn disease (see the following image). Lymphangiectasia in the submucosa and subserosa is frequently observed as well.
Microscopic skipping of lesions is the cornerstone of Crohn disease diagnosis, especially in the absence of granulomas. Even in areas with extensive inflammation, there is usually adjacent, uninvolved bowel tissue, and recognition of this feature can assist with the diagnosis. Early lesions often demonstrate focal mucosal inflammation superficial to lymphoid aggregates or Peyer patches, only later developing into the characteristic aphthoid ulcers (see the following image). 
Although not specific to Crohn disease, pseudopyloric metaplasia (ulcer-associated cell lineage [UACL]) and villous architectural distortion are often seen in the small intestine. The UACL is thought to signify previous or concurrent ulceration as the pseudopyloric cells may secrete growth factors such as epidermal growth factor (EGF) that aid in mucosal healing. [55, 56]
Muscularization of the fibrotic submucosa and crypt architectural disorganization are features of chronic and so-called "burned out" Crohn disease and may be the only remaining evidence of disease in certain cases. See the image below.
The presence of intraepithelial neoplasia must be noted, and it should be categorized as low grade or high grade. If there is cytologic atypia in association with neutrophilic inflammation, the findings may represent repair or regeneration, and the case may be better categorized as "indefinite for dysplasia." 
Immunohistochemistry has a minimal role, at most, in the diagnosis of Crohn disease (CD). Immunohistochemical stains for cytomegalovirus may be useful when a patient experiences a flare of disease while on immunosuppressive therapy—to exclude reactivation of latent viral infection or new viral infection as a cause of the inflammation. It is useful for the clinician to provide the pathologist with information regarding this concern, when applicable, to prompt consideration of special staining.
Several conditions should be considered when evaluating a patient for Crohn disease. These are discussed below, as follows:
Crohn disease versus ulcerative colitis
Conditions with small bowel fissuring ulcers
Crohn disease versus ulcerative colitis
The main differential diagnosis is between Crohn disease (CD) and ulcerative colitis (UC). The distinction between these 2 conditions is important, as both increase the risk of developing adenocarcinoma, and the response to surgical treatment vary dramatically between them. [58, 59]
Although Crohn disease and ulcerative colitis each carry an increased risk of neoplastic transformation, the risk is higher and surgical intervention is better tolerated in ulcerative colitis. In Crohn disease, as noted earlier, there is a higher risk of recurrence and ulceration, fissure, and fistula formation at sites of reanastomosis or stoma formation. [60, 61]
The main features of Crohn disease that separate it from ulcerative colitis include the presence of skip lesions, granulomas, transmural inflammation, fissures, and/or involvement of any part of the gastrointestinal tract. Ulcerative colitis is generally limited to the colon, apart from minimal distal "back-wash" ileitis; however, this condition may also manifest cecal or appendiceal patches of involvement that can simulate the "skip" lesions of Crohn disease. More typically, ulcerative colitis in its untreated state is a continuous process, worse distally, with increased span of involvement distal to proximal, as the disease progresses. Moreover, ulcerative colitis usually involves only the mucosal layer of the bowel, and, in some cases, superficial submucosa, unless there is fulminant colitis (toxic megacolon).
Nonetheless, the distinction between the 2 processes can be challenging, as Crohn disease can occasionally affect only the distal colon, granulomas may be present in ulcerative colitis (although typically adjacent to ruptured crypts, whereas Crohn disease granulomas have no necessary spatial relationship to injured crypts), and the regional involvement/skip lesions of Crohn disease may not be apparent endoscopically or in small mucosal biopsies. 
In addition, treatment can markedly alter the apparent pattern of involvement by location. For example, steroid enema treatment of ulcerative colitis may eradicate endoscopic and histologic evidence of rectal injury and inflammation, leaving more severe inflammation in the proximal colon. Without complete clinical information regarding the endoscopic appearance and the history of treatment, the pathologist may misconstrue the biopsy findings and render an incorrect diagnosis.
When the distinction between Crohn disease and ulcerative colitis is impossible, some pathologists choose to render a diagnosis of "indeterminate colitis." [49, 62, 63, 64] In time, most cases will declare themselves as Crohn disease or ulcerative colitis, but approximately 30% may remain indeterminate. [49, 62]
It is critical for the pathologist and the managing physician to recognize that "indeterminate colitis" is not a third category of disease, but that it is a diagnosis of idiopathic inflammatory bowel disease (IIBD), not otherwise specified, pending additional information. Features that assist in defining Crohn disease in this setting are the presence of granulomas, transmural lymphoid aggregates, and creeping fat; however, these findings may be noted only in resection specimens.  Classification of the type of IIBD may be possible with additional clinical history, with biopsies of small intestine or stomach, or with disease recurrence and progression.
Infectious etiologies, especially yersiniosis and tuberculosis, can lead to a similar clinical and histopathologic picture as Crohn disease and must be considered. [36, 66, 54, 59] This is particularly important, given the risk for systemic infection if the patient is placed on immunosuppressive treatment for presumed Crohn disease. Therefore, it is strongly recommended that the endoscopic and managing physicians consider special studies, including special histologic stains for microorganisms, and even including polymerase chain reaction (PCR), to exclude infection, if there is any significant travel or exposure history, even remote.
Conversely, early or treated Crohn disease may manifest regionally as microscopic disease (focal active colitis) in a pattern otherwise typical of infectious or so-called "acute self-limited colitis."
Drug-induced colitis—particularly nonsteroidal anti-inflammatory drug (NSAID) toxicity, methyldopa, gold, and penicillins—can produce mucosal changes that lead to full-thickness ulcers and resultant chronic crypt architectural remodeling that can mimic Crohn disease. Drugs may also cause a granulomatous reaction. [54, 67]
Conditions with small bowel fissuring ulcers
Fissuring ulcers in the small intestine may also be seen in Behçet disease, malignant lymphoma, and "ulcerative jejunitis." The latter represents early lymphomatous transformation in celiac sprue. [26, 54]
Diverticular disease may be associated with active crypt injury in peridiverticular mucosa in a pattern that is indistinguishable from active Crohn disease. Concomitant active or active chronic injury in nearby mucosa unassociated with diverticular ostia favors a diagnosis of Crohn disease.
Crohnlike changes, including erosions, fistulae, granulomas, crypt architectural distortion, and intraepithelial neutrophilic inflammation, may be seen in the vicinity of diverticulitis. Caution should be used in making a diagnosis of Crohn disease in the sigmoid colon or in the vicinity of diverticular disease, unless there is evidence of Crohnlike histologic changes in parts of the bowel uninvolved by diverticula. 
Ischemia may result in histologic changes that mimic Crohn disease, including full-thickness mucosal ulcerations and injury, with crypt architectural remodeling and pseudopyloric metaplasia, also known as "ulcer-associated changes" or "ulcer-associated cell lineage" (UACL).