As with ulcerative colitis, there are several descriptions of individuals throughout history that have been considered to possibly have Crohn’s disease when reviewed retrospectively. One of the first possible cases may have involved English Royalty: King Alfred the Great, who was the King of Wessex from 871 to 899 [62]. Alfred was known to have suffered from abdominal pain, particularly with eating, throughout his life. King Louis XIII of France was also thought to have Crohn’s disease; he was described as having had years of diarrhea, intermittent fevers, and peri-rectal abscesses [3, 63]. When he passed away at age 42, his autopsy demonstrated fistulae, abscesses, and ulcers involving the small bowel and colon, though there is some debate as to whether this could represent enteric tuberculosis. Another potential pathologic description came from Morgagni, a famed pathologist of the 1700s, where he described a 20-year old male with terminal ileal narrowing, inflammation, and perforation, with mesenteric lymphadenopathy [64].

Several similar case reports were published in the 1800s in England and Ireland. Combe and Saunders published a case of a patient with diarrhea, abdominal pain, and ileal ulceration and shortening in 1813 [65]. Similarly, in 1828, Abercrombie described a 13-year old patient with similar complaints. Fielding and Colles reported on a patient in Dublin in 1830 with diarrhea, as well as profound fistulizing disease of the perineum [66–68]. Fielding published one of the first case series on the subject, summarizing more than 30 patients from the second half to the eighteenth century with symptoms consistent with Crohn’s disease [66]. Multiple additional reports were subsequently published preceding the turn of the century, with descriptions including toxic dilation of the bowel, mesenteric lymphadenopathy, liver involvement, and enterovesicular fistulization [3, 62].

As with ulcerative colitis, recognition of Crohn’s disease, referred to at the time (and to this day) as “regional enteritis,” continued to increase in the early 1900s. With this increasing recognition also came more detailed reports of the underlying pathology of this disorder. Lartigau published a review in 1901 of the literature to date from Europe, as well as a detailed description of an individual with weight loss, abdominal pain, and diarrhea alternating with constipation. On autopsy, he was appreciated to have thickening of the distal small bowel and cecum, with a rigid ileocecal valve. Histologically, Lartigau described multiple lymphoid aggregates without central necrosis; i.e., non-caseating granulomas. This clearly distinguished this case from intestinal tuberculosis [69]. Similar granuloma were also described by Moschowitz and Wilensky in 1923 in a case series of four patients [70]. In 1913, Sir T. Kennedy Dalziel described 13 cases with similar clinical and pathologic findings, also describing inflammatory involvement of the mucosa, submucosa, and muscularis mucosa, consistent with transmural disease that distinguishes Crohn’s from ulcerative colitis [3, 62, 71].

In 1932, Burrill Crohn, Leon Ginzburg, and Gordon Oppenheimer published a landmark paper in the Journal of the American Medical Association entitled “Regional Ileitis: A Pathologic and Clinical Entity.”[72] In this seminal work, the authors described 14 patients with “cicatrizing” inflammation involving the small intestine, and in particular, the terminal ileum. They also highlighted key characteristics of the disorder, such as ulceration, peritoneal irritation, resultant chronic intestinal obstruction, and penetrating phenomenon, all of which are still considered hallmarks of the disorder today. In the published pathologic description, obtained after surgical resection of the involved ileal segment, acute and chronic inflammation was noted, as was giant cell infiltration. This work was followed by the presentation and publication of a cohort of 52 individuals with similar findings by Oppenheimer and Ginzburg in the same year [73].

The subsequent appearance of the term “Crohn’s disease” first occurred in 1933 in a case report by Harris [74], and subsequently the following year in a report by Cushway [75]. The application of this eponym was not universally well-received, however. Several other variants existed initially, including “Saunders-Abercrombie-Crohn’s Ileitis,” and “Crohn-Dalziel” disease [3, 76, 77]. Contention also may have existed between the authors of the 1932 paper from Mount Sinai, with Dr. Ginzburg submitting a potentially incendiary letter to Gastroenterology in 1986 questioning the equivalent contribution of the three authors of this original descriptive paper [78]. Despite this protestation and initial confusion, the name Crohn’s disease has become the most widely accepted name for this disorder.

Over the next several decades the clinical entity that was to come to be known as Crohn’s disease was further described and categorized as clinicians began to recognize the full extent of the disease process. Inflammatory masses were characterized by Fischer and Lurmann [79]. Brown, Bargen, and Weber described a case of more extensive small bowel involvement in 1934 [80]. Gastric involvement was later described in 1949 at the Lahey clinic by J. R. Ross, and esophageal disease was described the following year by Franklin and Taylor in London [81, 82]. Crohn’s colitis was first described in 1952 as “segmental colitis” by Wells, and this was subsequently followed up by a case series of 11 patients who initially presented with small bowel disease but subsequently developed colitis [83, 84]. Isolated Crohn’s colitis was further accepted after publications by Brooke, Morson and Lockart, and Cornes and Stecher in 1959 and 1961 [85–87].

With improved diagnostic classification of Crohn’s disease came increased understanding of the epidemiology and course of the disease. One pivotal observation appreciated in the mid-twentieth century was that the incidence of Crohn’s disease was possibly increasing. Kyle and colleagues postulated this in their work published in 1963, examining possible cases of regional enteritis in Scotland [88]. Similar increases in prevalence were appreciated in Norway in 1966 [89]. While there is reasonable concern for detection bias in these early studies due to increasing awareness of the disorder, there have subsequently been multiple studies confirming both increasing prevalence and incidence over the course of the twentieth century, including a large systematic review by Molodecky and colleagues examining 260 publications from North America, Europe and Asia published from 1920 to 2008, clearly documenting these trends [90].

As with ulcerative colitis, several clinical indices have been developed over the past several decades to better characterize disease severity in Crohn’s disease [91]. Many of these instruments were developed in the context of clinical trials. One such instrument was the Crohn’s Disease Activity Index (CDAI), which remains a mainstay of disease activity assessment in trials today [92]. This validated scoring system was designed using multivariate logistic regression from a pool of 18 disease-related symptoms. The significant predictors of disease severity were determined to be abdominal pain, general well-being, the frequency of diarrhea, the use of loperamide or diphenoxylate, the presence of extraintestinal or systemic manifestations of disease, the presence of abdominal masses, hematocrit, and weight (Table 1.3). These items are then assigned specific multipliers, yielding a sum from 0 to 600, with <150 being considered in remission, 150–219 having mildly active disease, and 219–450 having moderately active disease. While validated in a separate cohort, there remain some concerns with the inclusion of potentially subjective measures such as general well being and severity of abdominal pain in this system. In addition, while useful from a research perspective, the complicated scoring system and requirement for 7-day logs of diarrhea and pain-related symptoms have limited its application in routine patient care; as such, the CDAI has not been applied routinely in clinical practice [91]. Despite these limitations, this system has been used in numerous clinical trials of agents such as mesalamine, budesonide, 6-mercaptopurine, cyclosporine, and infliximab in both induction and maintenance of remission [93–98]. It is important to note that future drug approval may be less dependent on scoring systems such as the CDAI and more dependent on efficacy in patient-reported outcomes [99–101].

A simpler alternative to the CDAI is the Harvey Bradshaw index, which applies point-based scores for general well being, abdominal pain, number of liquid stools per day, the presence of an abdominal mass, and extraintestinal manifestations [102]. This score also has the advantage of eliminating longer recall and not requiring laboratory-based measures. In their original publication on this scoring system, Harvey and Bradshaw demonstrated that this score correlated well with the CDAI in a group of 112 patients. Despite this strong correlation and its relative ease of use, the Harvey Bradshaw index has not gained considerable traction in clinical research, though it was used in a trial assessing the ability of 6-mercaptopurine to induce steroid-free remission in children [103]. Several additional “simplified” scoring systems have been developed, including the Cape Town index and the Organisation Mondiale de Gastronterologie (OMGE), and while these validated scoring systems have been shown to correlate with each other, they also have not gained widespread use [104, 105].

Highlighting the prevalence and severity of fistulizing disease, several scoring systems have been developed specifically to assess response of this complication to specific therapies, as it was felt that this was not adequately captured by the CDAI [91, 106, 107]. The Perianal Disease Activity Index (PDAI) assesses discharge, pain, restriction of sexual activity, type of perianal disease, and degree of induration to generate a score from 0 to 20. This tool has also been used in a number of clinical trials involving peri-anal disease. An alternative scale assessing percentage change in fistula drainage has also been developed and utilized in a number of clinical trials, with a cut-off of >50 % decrease in drainage considered to be a clinically meaningful improvement in symptoms [106].

One potential alternative scoring system that focuses on quality of life of individuals with IBD was subsequently developed in 1989 by Guyatt, Mitchell, and colleagues. This questionnaire, known as the IBDQ, removed the physician assessment from the scoring system, further simplifying administration of the device [108]. The IBDQ consists of a 32-item questionnaire that assesses various aspects of social functional status, emotional well-being, systemic symptoms, and bowel-related symptoms. Both this questionnaire and a shortened version have been validated, and both can be self-administered [109, 110]. Since its development, the IBDQ has become the standard device used to assess quality of life in clinical trials. It was also utilized to develop utilities for various disease states; these estimates have subsequently been used in multiple modeling studies in therapies for inflammatory bowel disease [111].

Scoring systems to assess endoscopic activity in Crohn’s disease have also been developed. The first validated instrument of endoscopic activity was the Crohn’s Disease Endoscopic Index of Severity (CDEIS), developed by the GETAID group in France in the late 1980s [112, 113]. The CDEIS contains a total of six variables, including number of colonic segments with deep ulceration, superficial ulceration, segmental surfaces containing pseudopolyps, healing ulceration, swelling, erythema, ulceration or stenosis, and the presence of ulcerated and non-ulcerated stenosis in any segment. This scoring system generates a score from 0 to 44, with higher numbers indicating more severe disease involvement. A similar scale has been developed for assessment of the ileocolonic anastomosis in individuals who have required segmental resection; this scoring system is known as the Rutgeerts score, and uses the degree of ulceration and ileitis in the neoterminal ileum to determine a score of 0–4 to predict the likelihood of disease recurrence [114, 115]. As with the aforementioned clinically derived scores, these systems have not routinely been employed in patient care, though the common descriptors used in the scoring system are routinely employed to evaluate disease severity more generally.

Colonoscopy is a key component in the modern evaluation of patients with inflammatory bowel disease. However, for much of the twentieth century, this technology was profoundly limited both in its technology and applicability.

The majority of colonic mucosal examinations early in the history of IBD were performed at the time of autopsy. Technology in the first half of the twentieth century likely contributed to this lack of exploration. Early rigid sigmoidoscopy consisted of a simple tube, with the operator utilizing a headlamp for better visualization, and the addition of a distal light to the rigid scope did not occur until 1903 [131, 132]. These devices were soon used in the evaluation of ulcerative colitis, despite their limitations. The first endoscopic descriptions in inflammatory bowel disease involved rigid sigmoidoscopy in patients with ulcerative colitis. The first of these reports was described by John Percy Lockhart-Mummery at the same seminal meeting where many physicians used to describe the first large case series of ulcerative colitis in 1909 in the London [9]. In this seminal report, Mummery described rigid sigmoidoscopy as a potentially safe procedure if performed with minimal insufflation. In addition, he provided some of the first endoscopic descriptions of the UC, describing various degrees of ulceration “extending over a large area, the mucous membrane being excoriated and red”[9].

There were few case reports devoted to sigmoidoscopic diagnosis of Crohn’s disease early after its initial description, likely given the extent and location of the disease along with the previously described delay in recognizing colon-specific forms of the disease. In fact, Crohn himself stated in his seminal paper in 1932 that an abnormal sigmoidoscopy was not consistent with regional enteritis, and that “the diagnosis is purely roentgenographic, the clinical differentiation being impossible” [72]. With growing recognition of Crohn’s colitis, collated descriptions of the endoscopic appearance began to appear. Selzer and McCarthy published two cases in 1958 where regional enteritis was diagnosed via sigmoidoscopy [133]. In one case, sigmoidoscopy to 8 inches demonstrated a polypoid ulcerating, bleeding mass, partially obstructing the lumen and inflammatory in nature on repeat biopsy. Fistulae were subsequently discovered radiographically. In a second case, multiple pedunculated bleeding polyps were appreciated at 5 inches, which were again determined to be inflammatory. An ileosigmoid fistula was appreciated on barium enema. Lockhart-Mummery and Morson further documented sigmoidoscopic findings in patients with Crohn’s in a cases series of Crohn’s of the large intestine published in 1960. The authors carefully documented the location of disease in these 25 patients, and described normal sigmoidoscopic appearances in those with normal rectums and sigmoid colons. However, for several patients, they were able to describe strictures (“reddened, narrow, and rigid”) with active ulceration, and granularity and friability, as well as edema, and purulent discharge [134].

With the advent of “colonfiberoscopy,” or the flexible fiberoptic colonoscope, and the publication of several studies describing its application came further endoscopic characterization of Crohn’s disease and ulcerative colitis [135, 136]. A large series of 255 patients using these new techniques was published by Teague, Salmon, and Read in 1973 in Gut, in which 55 were referred for having inflammatory bowel disease [137]. The authors noted that this new technology allowed for greater characterization of both diseases, with mucosal findings not always coinciding with what was appreciated on barium study.

As the endoscopic evaluation of disease has progressed from a technical standpoint, the role of colonoscopy has grown in IBD. As previously discussed, numerous means of grading severity of disease endoscopically have been developed, looking for such key characteristics as degree of friability via application of swab or touching the mucosa, ulceration, loss of haustral folds, erythema, and granularity [43, 91]. Colorectal cancer screening is now a key component of inflammatory bowel disease care as well [138]. Lastly, surveying for mucosal healing and response to therapies is progressively being incorporated into trial design and clinical care in both ulcerative colitis and Crohn’s disease [139].

As the clinical knowledge of inflammatory bowel disease’s enteric and extraintestinal manifestations expanded, so did attempts to better characterize the pathophysiology of these diseases over the last century. There were numerous hypotheses that were postulated in the early through mid-1900s regarding the possible etiology of this disorder. Here, we will discuss several of the preeminent theories in the early twentieth century.

One of the predominant hypotheses early in the history of IBD was that the condition was caused, at least in part, by an underlying infectious organism [3, 140]. Multiple possible infectious agents were considered, from oral bacterial infectious agents to mycobacterial species, though no specific organism has been successfully cultured and proven to comply with Koch’s postulate to date. Oral bacterial agents were one of the first postulated infections thought to be involved in IBD, triggered by observing an association with dental extractions, abscesses, and the development of ulcerative colitis in several patients [3]. Bargen subsequently published a study in 1924 where he was able to induce bloody diarrhea in rabbits with bacterial fecal cultures from patients with IBD [141]. Cook and Rosenow induced colitis in another animal model via injection of rabbits with fluid derived from oral abscesses as well [142]. Numerous other bacteria were implicated in the etiology of ulcerative colitis: Pseudomonas species, Clostridium species, E. coli, Bacillus, Proteus, fungal histoplasmosis, and viral species have all been evaluated over the ensuing decades [3, 140]. While microbial culture techniques have advanced over the past several decades, no causative organism has been isolated that could routinely induce chronic enteritis and colitis in models and was discovered in individuals with the disease.

Some infectious agents have been implicated in worsening the clinical picture of ulcerative colitis, however, including Clostridium difficile and viral infections such as cytomegalovirus. More recently, attention has turned to the composition of the bacterial flora of the gut, or microbiome, and the role of dysbiosis in IBD [143]. This remains an active area of research as we attempt to discern the interactions between the colonic microenvironment and the host immune system [144, 145].

Another leading theorem that has gained growing supportive evidence over the years is that of the role of the immune dysfunction in the pathophysiology of ulcerative colitis. The hypothesis of various immune mechanisms playing a significant role in the pathophysiology of ulcerative colitis first began to formalize in the 1920s, 1930s, and 1940s [146]. Numerous potential food allergies have been implicated over the years, including food-derived and plant-based allergens. Initial research focused on hypersensitivity reactions within the colon [3, 147, 148]. This hypothesis was felt to be supported by the presence of mucosa edema and hyperemia, as well as elevated histamine levels in the mucosa and stool in a series of 17 patients with ulcerative colitis [149]. Binder and colleagues also appreciated that patients with ulcerative colitis were more likely to have other diseases postulated to be allergic in etiology at the time, including asthma, urticarial illnesses, and rhinitis [150].

It was soon appreciated, however, that inflammatory bowel disease may represent a more robust immune dysfunction than an allergic response to an environmental antigen for most patients. In the 1940s, it was appreciated that ulcerative colitis was associated with other diseases with presumed autoimmune etiologies, such as autoimmune thyroiditis, systemic lupus erythematosis, and autoimmune hemolytic anemias [151–153]. Several research groups demonstrated that specific antigens in the diet stimulated the immune system, with formation of antibodies likely secondary to increased intestinal permeability, and that avoidance of these agents improved the course of disease for some [154–156]. Kirsner and Goldgraber were two of the first researchers to appreciate the relationship of antigen exposure and the development of experimental colitis in an animal model looking at immune complex deposition using egg proteins [157]. These complexes were directly associated with areas of the colon involved with colitis. These findings were later reproduced by Callahan, Goldman, and Vial, and become a key component of experimental animal models of colitis [3, 158]. In 1960, Kirsner and Bregman described hemagglutinating and precipitating anti-colon antibodies in patients with ulcerative colitis, and these antibodies were later confirmed by several other research groups as well [3, 159, 160]. Similar immune complexes in human ulcerative colitis were later appreciated in 1978 by two additional research groups, and IgG molecules directed against basement membrane with subsequent complement activation and dense neutrophilic infiltrate in a cohort of over 60 patients with active disease were also appreciated [161, 162]. It was recognized early on, however, that these antibodies did not appear to be directly involved in the pathophysiology of the disease, and were instead considered to represent a marker of active disease and colonic inflammation.

Antibodies that were directed against bacterial components, including an antigen present in E. Coli O14 and certain species of Enterobacter were also determined to interact with proteins present in human colonic epithelium [163]. Similar antibodies were later appreciated in some family members of patients with ulcerative colitis as well [164]. It is important to note, however, that several other research groups appreciated differing results, with some antigens for specific bacterial species generating an autoantibody response to colonic epithelium while others did not [165, 166].

There was also a growing body of literature describing cellular dysfunction in hosts with IBD as well. In 1972, the Shorter hypothesis was conceived, which postulated that for some individuals, likely those with an innate predisposition, non-specific bacterial antigens generated a hypersensitivity state by crossing the mucosa of the GI tract during infancy before non-permeability was established, thereby eliciting a non-specific T cell response, with subsequent mucosal damage due to a robust inflammatory response [167]. Brandtzaeg later demonstrated that some individuals possessed an increased concentration of plasma cells, possibly explaining the increased immunoglobulins previously appreciated [3, 168]. Several early studies in the 1960s and 1970s appreciated variable levels of lymphocyte activity in patients with ulcerative colitis and Crohn’s disease, with some research groups appreciating normal activity to specific antigens and mitogens, while others demonstrated reduced global lymphocyte reactivity [169, 170]. In 1967, Bendixen and colleagues appreciated that cell mediated immunity was altered in patients with ulcerative colitis but normal in patients with Crohn’s disease [171]. It was subsequently suggested that reduced lymphocytic activity may actually be attributed to nutritional status as opposed to active inflammatory bowel disease [169].

Research has continued to unravel the functions of specific immune cell types and how they interact in inflammatory bowel disease over the past 30 years. Early initial research focused on the activity of NK cells and cytotoxic T-lymphocytes in Crohn’s disease and ulcerative colitis [3, 172–175]. Researches in 1979 and 1980 appreciated a marked increase in B-cell function, with increased immunoglobulin secretion, with different subtypes in CD and UC [176, 177]. Significant research has also delved into the role of the cell-mediated immune system, assessing how T-cell function, and in particular Th1 and Th2 cell regulation may contribute to an intrinsic defect in immune tolerance of the host microbiome [178, 179]. This work continues, however, as researchers continue to attempt to clarify this inherently complex system. Based on work conducted by Fuss and colleagues in 1996, it was initially thought that due to differences in cytokine secretion by CD4+ Th cells in the lamina propria of patients with Crohn’s disease compared to those with ulcerative colitis, that Crohn’s was primarily driven by an aberrant Th1 response and ulcerative colitis was driven by Th2 cells [180]. It has recently come to light, however, that both of these subtypes are likely involved in both diseases, and it is dysfunction of a regulatory subtype of T cell, Th17 cells, that is intrinsic to inflammatory bowel disease [181].

As medical science continued to unravel the complex interactions that comprise the immune system, further attention has been paid to particular cytokines and chemokines in the pathophysiology of inflammatory bowel disease. Cytokines are small molecules used by many types of cells to communicate with other cells, both nearby and via the vascular and lymphatic systems. When these molecules bind to their specific receptors on target cells, they can induce a wide range of cellular responses dependent on the signal and the receiving cell, ranging from marked activation and proliferation to senescence and apoptosis.

Researchers subsequently began to identify some specific cytokines as pro-inflammatory and others as immunomodulatory. It was recognized in the early 1990s that the cytokine-based milieu in patients with active ulcerative colitis and Crohn’s disease differed from normal individuals; the evidence of the pivotal role of cytokines in this process was later confirmed via the creation of knock-out murine models for cytokines thought to be involved in regulation of inflammation [182]. This led to further attempts to generate antibodies directed against inflammatory cytokines that could control inflammation in experimental mouse models [183]. Several studies attempted to target cytokines such as IL-10 and IL-11, but while efficacious in murine models, these agents did not yield significant benefit to patients [184, 185]. This pioneering work did lead to the development of anti-TNF agents, however, which have become one of the mainstays of therapy in inflammatory bowel disease. As we continue to understand how these cellular signaling proteins interact with cells, this will potentially continue to lead to further drug discovery and therapeutic options.

The explosion of genetic research in the past 20 years has also markedly impacted the understanding of the pathophysiology of ulcerative colitis. Case reports first described familial clusters of inflammatory bowel disease as early as the London 1909 Symposium, though this was not largely explored until several decades later [10, 146]. As several large case series by Kirsner and Palmer, Paulson, and Houghton and Naish, among others, began to appear in the 1950s, it became clear that there was an increased risk for family members of those with ulcerative colitis [3, 186–188] Similar observations were being made in Crohn’s disease at this time as well, with Crohn and Yarnis identifying 12 instances of multiple family members with regional enteritis [189]. In 1958, Schlesinger and Platt appreciated an increased risk among those with Ashkenazi Jewish heritage [190]. As this link became more defined, reports of disease subtype concordance were also published, with strong concordance among family members with Crohn’s disease and moderate concordance with ulcerative colitis, particularly in monozygotic twins [3]. Despite this mounting evidence, it was clear early on that inheritance patterns of inflammatory bowel disease were certainly non-Mendelian, hampering discovery of candidate genes that conveyed a strong enough risk for detection given the limited techniques available at the time. It would not be until 1996 when a true candidate gene, NOD2/CARD15 would be discovered on chromosome 16 by Hugot and colleagues [191, 192]. The function of this particular gene, which is involved in regulating the immune response to bacterial cell wall components within enteric crypts, has provided significant insight into the pathophysiology of inflammatory bowel disease, and Crohn’s disease in particular. This gene remains the strongest genetic risk factor for inflammatory bowel disease, though recent advances in genetic mapping and genome-wide association studies have subsequently yielded more than160 potential gene candidates in both ulcerative colitis and Crohn’s disease in pathways ranging from cytokine systems and MHC complex formation to intracellular signaling and apoptosis. The difficult task of determining the function and confirming the attributed risk due to each of these loci still remains [193]. However, this growing body of research has highlighted key pathways for targeting new therapies.

Surgical therapies comprised the initial predominant therapeutic options in both ulcerative colitis and Crohn’s disease. Early surgical approaches were quite different than the more uniform recommendations of colectomy for ulcerative colitis in the early 1900s, with varied approaches including appendicostomy, cecostomy, and colostomy [3, 194, 195]. There were some early proponents of ileostomy, however, including Strauss and colleagues, who advocated for this option in 1923 [196]. However, adequate surgical technique for the routine development of an ileostomy hampered the surgery until further improvement by Brooke and Turnbull in the 1950s [197–199]. At the same time, two separate surgeons, Cattell and Miller, described multi-stage surgical approaches of: (1) ileostomy, subtotal colectomy, and abdominoperineal resection, or (2) ileostomy and proctocolectomy, respectively [3]. Subsequent pouch-based procedures would later be developed by Kock, Ravitch and Parks [200–202].

Initial surgical evaluation for Crohn’s disease often consisted of open surgical exploration for concern of abdominal mass or perforated appendicitis [62]. The futility of surgical intervention was readily recognized early in the history of Crohn’s disease due to its high risk of recurrence [3]. For the first several decades after recognition of this disorder, surgical approaches typically involved either ileostomy or surgical resection of diseased segments with subsequent re-anastomosis. The latter typically lead to recurrence and further resection.