Dig Dis Sci DOI 10.1007/s10620-014-3129-z
REVIEW
Appendiceal Skip Inflammation and Ulcerative Colitis Sang Hyoung Park • Edward V. Loftus Jr. Suk-Kyun Yang
•
Received: 23 January 2014 / Accepted: 20 March 2014 Ó Springer Science+Business Media New York 2014
Abstract In recent decades, the appearance of inflammation near the appendix in patients with distal ulcerative colitis (UC) has been highlighted. Many epidemiological studies have confirmed the link between appendectomy and decreased incidence of UC. However, the clinical significance of appendiceal orifice inflammation (AOI) or periappendiceal red patch (PARP) as a ‘‘skip lesion’’ in UC has not been well elucidated. In this review, we summarized the literature regarding AOI/PARP and the role of this lesion in relation to UC. Since the appendiceal ‘‘skip area’’ in UC was first described in 1958, several reports using histologic examination of colectomy specimens and colonoscopy have been published. AOI/PARP has been more frequently associated with distal, mild UC than extensive, severe disease. Although it is still controversial, AOI/PARP seems to have little prognostic implication in the disease course of UC, including remission, relapse and proximal disease extension. However, some case reports have raised the possibility of a relationship between AOI/ PARP and appendiceal neoplasms such as appendiceal cystadenoma and appendiceal adenocarcinoma. In addition, some investigators have treated UC patients who were resistant to conventional medical therapy with appendectomy and have reported inconsistent therapeutic effect.
S. H. Park S.-K. Yang (&) Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea e-mail: [email protected] E. V. Loftus Jr. (&) Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street. S.W., Rochester, MN 55905, USA e-mail: [email protected]
Further research may lead to the discovery of etiologic and pathogenic roles of appendiceal inflammation in UC. Keywords Ulcerative colitis Appendiceal orifice inflammation Peri-appendiceal red patch Skip lesion
Introduction Traditionally, ulcerative colitis (UC) is considered a subtype of inflammatory bowel disease (IBD) that is characterized by continuous mucosal inflammation extending proximally from the rectum without any skipped areas. However, previous studies have reported a peri-appendiceal patch of inflammation in the cecum in patients with UC (Fig. 1). Although the clinical significance of appendiceal orifice inflammation [AOI; it is also called ‘‘peri-appendiceal red patch’’ (PARP) or ‘‘cecal patch’’] is still debatable, AOI/PARP has been considered to be a distinct ‘‘skip lesion’’ of UC. Moreover, many investigators have suggested that the appendix per se, previously considered a vestigial organ, may play an important role in mucosal immune function in the pathogenesis of UC, because of the inverse relationship between prior appendectomy and the risk of UC development in humans [1–3] and genetically engineered animals [4, 5]. The existing literature on AOI/PARP in UC as a skip lesion is sparse, and the findings are inconsistent. In addition, there is no published systematic review of AOI/ PARP in UC to date. Therefore, to review and analyze the existing data in the literature, we identified all the studies concerning AOI/PARP published up to May 2012, using the PUBMED databases. Reference lists from published articles, reviews and abstracts from major gastrointestinal meetings were also reviewed. We excluded editorials,
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Fig. 1 Endoscopy of appendiceal orifice inflammation (AOI)/periappendiceal red patch (PARP)
letters, comments and foreign language articles without an abstract in English. Based on these data, the historical, epidemiological, diagnostic and therapeutic aspects of AOI/PARP are summarized here. We also reviewed studies of appendiceal neoplasms in relation to appendiceal inflammation in UC and therapeutic appendectomy in UC patients who are refractory to medical treatment.
Appendiceal Inflammation in UC: Histologic Reports Using Surgical Specimens Skip inflammation of the peri-appendiceal region in UC was first described in 1958 by Lumb and Protheroe [6]. They examined 152 surgical specimens (including 53 total colectomies, comprising terminal ileum, entire colon, rectum and anal canal; 76 primary colectomies, comprising terminal ileum and colon but excluding rectum and anal canal; 12 partial colectomies, comprising left side of colon varying in length from 30 to 60 cm; and 11 rectal stumps, rectum and anal canal) from UC patients. In eight cases, typical ulceration was found as islands within normal mucosa, with a tendency to occur in the cecum opposite the ileocecal valve. In one case, typical UC inflammation occurred around the appendiceal orifice. These lesions were designated as ‘‘skip areas.’’ In 1974, Cohen et al. [7] described a case of appendiceal involvement of UC as a skip lesion. They reported a 39-year-old female patient with long-standing left-sided colitis who underwent total colectomy showing typical UC changes in the appendix as a skip lesion (the cecum and ascending colon were not involved), and first termed the condition ‘‘ulcerative appendicitis.’’
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The frequency of appendiceal lesions (including periappendiceal area) based on review of colectomy specimens is summarized in Table 1. In 1976, Jahadi and Shaw [8] found that 14 of 30 UC patients (47 %) had appendiceal involvement, and all of these cases had chronic UC involving the right colon or the cecum. In 1992, Goldblum and Appelman [9] described that all of the 66 cases with colitis changes in the appendix had adjacent cecal involvement, concluding that the appendix is not involved as a skip lesion in cases of extensive UC. Other studies [10, 11] showed that between 71 and 88 % of children with extensive UC had active inflammation in the appendix. However, they were unable to either support or refute the possibility of appendiceal involvement in distal UC, because all patients included in these studies underwent colectomy for colitis involving the right colon or pancolitis. In 1990, Davison and Dixon [12] described appendiceal ‘‘skip lesions’’ in 13 of 62 cases of UC (21 %) coming to surgical resection. In 7 of 13 patients, the disease extent of UC was proctitis or left-sided colitis. In 1994, Groisman et al. [13] reported that ulcerative appendicitis was present in 18 of the 21 cases of non-extensive UC (86 %), regardless of how limited the extent of colonic involvement. In the same year, Kroft et al. [14] detected appendiceal involvement as a skip lesion in 6 of 39 proctocolectomy specimens (15 %) containing appendices removed for UC. In 1998, Scott et al. [15] compared the prevalence of appendiceal inflammation in UC and Crohn’s disease, using colonic carcinoma and acute appendicitis specimens as controls. The prevalence of appendiceal ‘‘skip lesion’’ in UC (48 %) was higher than in colonic carcinoma (8 %) but was similar to that in Crohn’s disease (52 %). They concluded that appendiceal inflammation commonly occurs as a ‘‘skip lesion’’ in UC and histologically resembles the colonic disease rather than acute appendicitis. In 1999, Perry et al. [16] found discontinuous appendiceal involvement in 7 of 57 patients (12.3 %) undergoing proctocolectomy for UC. Taken together, appendiceal skip inflammation in UC was apparently observed in surgical specimens of UC with various frequencies. Although some investigators have had inconsistent findings, this discrepancy may be accounted for by the diverse criteria used to define ‘‘histological abnormality.’’ Also, studies using colectomy specimens had a significant limitation in that colectomy is usually performed in severe and refractory cases after a period of medical therapy and it is unclear whether this is a continuous or skip lesion in case of extensive colitis involving right colon; therefore, the frequency of appendiceal skip involvement in patients with mild to moderate disease activity could not be evaluated. In addition, medical therapy frequently produces the patchiness of mucosal inflammation [17] that may lead to the false conclusion of appendiceal involvement as a true skip lesion in UC.
Dig Dis Sci Table 1 Histologic reports of appendiceal or peri-appendiceal inflammation using surgical specimens in ulcerative colitis
References
Study type
Number of UC patients
Lumb and Protheroe [6]
Retrospective
152
Number of UAa
Disease extent of UC
8
Total colon: 96
(5.3 %)
Partial involvement: 45 Rectal stumps: 11
Cohen et al. [7]
Case report
Jahadi and Shaw [8]
Retrospective
30
1
1 14 (46.7 %)
Transverse colon: 1 Right colon: 30
Shalygina et al. [11]
Retrospective
16
14 (88.0 %)
Total colitis: 16
Davison and Dixon [12]
Retrospective
62
13 (21.0 %)
Ascending: 4 Transverse: 2 Descending: 2 Sigmoid: 4
Goldblum et al. [9]
Retrospective
87
66 (75.9 %)
Rectum: 1 Pancolitis: 87
Kahn et al. [10]
Retrospective
17
12 (71 %)
Universal UC: 17
Groisman et al. [13]
Retrospective
21
18 (85.7 %)
Ascending: 7 Transverse: 9 Descending: 3 Rectum: 2
U;A ulcerative appendicitis, UC; ulcerative colitis a
Kroft et al. [14]
Retrospective
39
6 (15.4 %)
Scott et al. [15]
Retrospective
50
24 (48.0 %)
Quiescent to distal: 92 % Pancolitis: 26 Subtotal colitis: 24
Perry et al. [16]
Retrospective
Including peri-appendiceal lesion
Appendiceal Inflammation in UC: Endoscopic Reports Until the 1990s, the incidence of AOI/PARP identified by colonoscopy had not been known, mainly because endoscopic examinations for typical UC were often discontinued once the upper limit of inflammation had been reached. In addition, total colonoscopy is often not performed in patients with severe UC, because of the perceived risk of colonic perforation. With increased awareness of AOI/ PARP among endoscopists, improvement of bowel preparation methods, and the advancement of endoscopic technology, reports of AOI/PARP detected by endoscopy have increased rapidly. The reports of AOI/PARP using colonoscopy are summarized in Table 2. In these endoscopic reports, AOI/PARP was generally defined as a macroscopic inflammation around the appendiceal orifice and/or surrounding cecum such as mucosal erythema, granularity, erosion/ulceration and friability. AOI/PARP in UC was first identified endoscopically in 1993 by Saitoh et al. [18]. They reported a 50-year old male with left-sided colitis and peri-appendiceal inflammation with typical UC changes at appendectomy performed to rule out appendiceal malignancy. After this case report, several reports of AOI/PARP using
57
7 (12.3 %)
Ascending: 4 Distal to hepatic flexure: 3
colonoscopy were published from multiple facilities. In 1997, Takizawa et al. [19] reviewed colonoscopic findings of 41 cases of UC, and reported that 5 patients (12 %) had AOI/PARP. They recommended that endoscopists meticulously examine the peri-appendiceal area during colonoscopy in patients with UC. In the same year, D’Haens et al. [20] prospectively observed 20 cases with left-sided UC and reported that 15 patients (75 %) had peri-appendiceal inflammation with or without cecal inflammation, separated from the distal colitis by macroscopically and microscopically uninvolved mucosa. This study reported the highest proportion of endoscopic peri-appendiceal inflammation in distal UC so far. In 1998, Okawa et al. [21] reported that 10 of 56 untreated UC patients (18 %) who underwent total colonoscopy had UC at the mouth of the appendix. They suggested that determination of the clinical significance of peri-appendiceal skip lesions would contribute to elucidation of the pathogenesis of UC. In 1999, Horie et al. [22] reviewed 16 patients with distal UC who underwent total colonoscopy and found that 4 patients had peri-appendiceal inflammation (25 %). The authors concluded that periappendiceal inflammation was thought to develop in the early stage of the disease course of UC. In the same year, Yang et al. [23] found that 24 of 96 patients with active
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Dig Dis Sci Table 2 Endoscopic reports of appendiceal inflammation in ulcerative colitis
References
Study type
Number of UC patients
Saitoh et al. [18]
Case report
1
Takizawa et al. [19]
Prospective
41
Number of UA 1 5 (12.2 %)
Disease extent of UC Left-sided colitis: 1 Proctitis: 2 Left-sided colitis: 1 Extensive colitis: 1 Segmental: 1
D’Haens et al. [20]
Prospective
20
15 (75.0 %)
Left-sided colitis: 20
Okawa et al. [21]
Prospective
56
10 (17.9 %)
Proctitis: 6 Left-sided colitis: 4 Extensive colitis: 0
Horie et al. [22] Yang et al. [23]
Prospective Prospective
16 94
4 (25.0 %)
Proctitis: 4
24 (25.5 %)
Left-sided colitis: 0 Proctitis: 18 Left-sided colitis: 6 Extensive colitis: 0
Yamagashi et al. [24]
Prospective
279
54 (19.4 %)
Proctitis: 8 Left-sided colitis: 25 Extensive colitis: 21
Matsumoto et al. [25]
Prospective
40
23 (57.5 %)
Proctitis: 9 Left-sided colitis: 14 Extensive colitis: 0
Mutinga et al. [26]
Retrospective
127
12 (9.4 %)
Proctitis: 1 Left-sided colitis: 11
Ladefoged et al. [27]
Prospective
73
20 (27.4 %)
Proctitis: 15 Left-sided colitis: 23 Extensive colitis: 12 Others: 25
Byeon et al. [28]
Prospective
Rubin et al. [29]
Retrospective
94
48 (51.1 %)
Proctitis: 38 Left-sided colitis: 10
367
29 (7.9 %)
Proctitis : 4 Left-sided colitis: 18 Extensive colitis: 5 Unknown: 2
n/a; not applicable, UA; ulcerative appendicitis, UC; ulcerative colitis
Naves et al. [30]
Retrospective
subtotal UC (26 %) had AOI and concluded that this finding is not a result of patchy improvement secondary to medical therapy and that AOI is more frequently observed in patients with less extensive disease (37 % in proctitis, 17 % in left-sided colitis and 0 % in extensive colitis). In 2002, Yamagishi et al. [24] reported 54 patients (19.4 %) had AOI/PARP among 279 patients with UC who underwent total colonoscopy. In 28 of 35 patients (80 %) who were followed up endoscopically, the activity in the AOI correlated well with that in the distal lesion. In the same year, Matsumoto et al. [25] found that 23 of 40 patients with active distal UC (57.5 %) had endoscopic evidence of AOI. In 2004, Mutinga et al. [26] reported that 12 of 127 patients
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n/a
14
Proctitis: 11 Left-sided colitis: 3
with left-sided UC (9.4 %) had active inflammation in the cecum and/or ascending colon. However, among these 12 patients, nine had just microscopic, but not endoscopic, lesions in the right colon. In 2005, Ladefoged et al. [27] identified that 20 of 73 UC patients (27 %) had discontinuous AOI, also concluding that this lesion is common in patients with IBD. However, they stated that patients with an otherwise normal colon may also show congestion of this area with or without minimal microscopic inflammation. In the same year, in a subsequent study after the study of Yang et al. [23], Byeon et al. [28] found AOI endoscopically in 48 of 94 patients with newly diagnosed distal UC (51 %). In 2010, Rubin et al. [29] reported that 29 of 367 patients with
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distal UC (7.9 %) had endoscopic evidence of PARP. In 20 of 43 colonoscopic exams (46.5 %) that were performed on 29 patients with PARP, the histologic activity in the PARP paralleled the activity confirmed in the distal colon. Only including 30 exams that obtained biopsies, 67 % (20/30) showed parallel histologic activity to the distal lesions. They reported that 23 of 29 patients with PARP (79 %) were male. Naves et al. [30] also found that 11 of 14 patients with AOI (78 %) were men. Although they suggested that PARP/AOI seems to have a male predominance in UC, this finding was not consistent with other studies [19, 21–23, 26, 28] which showed either no gender predominance or a female predominance. In summary, AOI/PARP occurs as a skip lesion mainly in distal UC rather than extensive disease (not pancolitis), and the endoscopic and histologic disease activity of this lesion seems to parallel that of the distal colitis. Except the first case report [18] and the study of Byeon et al. [28] only including newly diagnosed UC, the remaining studies included both newly diagnosed UC and treated UC patients.
Pathophysiologic and Diagnostic Implication of the Appendiceal Skip Lesion In 2005, Matsushita et al. [31] investigated the CD4/CD8 ratio in the inflamed and uninflamed colonic mucosa, especially in the appendiceal mucosa, of UC patients, in order to clarify the role of the appendix in the development of UC. They observed an increased CD4/CD8 ratio and predominant infiltration of CD4 ? CD69? T cells in the appendix, suggesting that the appendix may be a priming site in the development of UC. In the same year, the preferential migration of CD62L ? CD? cells into the appendix [32] and the increased proliferation of immature plasma cells in the appendix of UC patients [33] were reported. These studies suggested that the appendix may play a primary role in the pathogenesis of UC. In 2012, Park et al. [34] reported follow-up results of 20 patients with AOI without concomitant typical UC. In 20 patients with AOI alone, typical UC developed in five patients over a mean follow-up of 18.4 months, concluding that AOI may precede development of UC, at least in some cases. Taken together, AOI seems to play a role in the development of UC, and AOI might be an important diagnostic clue for the diagnosis of UC on some occasions [35].
Clinical Course of UC with the Appendiceal Skip Lesion Beyond the real prevalence of this phenotypic form of UC, it is not well established if UC patients with AOI/PARP have a different prognosis regarding disease severity, risk
of proximal extension or development of colorectal dysplasia/carcinoma. In fact, there are no particular therapeutic or monitoring recommendations for patients with AOI/ PARP. Therefore, it is important to evaluate the clinical course of UC patients with AOI/PARP for therapeutic and monitoring plan. D’Haens et al. [20] observed that one of 15 patients with AOI needed a colectomy, while another also had a clear extension of his disease to more proximal segments, concluding that UC patients with AOI at initial examination also suffered from a more aggressive disease course with more frequent relapses. In follow-up, 1 of 15 patients (6.7 %) with AOI on initial examination and 4 of 5 patients (80.0 %) without AOI on initial examination had not experienced any disease relapses. One recent pathological study of colectomy specimens suggested that patients with appendiceal ulceration were more likely to develop pouchitis [the appendiceal ulceration was present in 13 of 32 pouchitis patients (41 %) and in none of the 26 controls (0 %) (p = 0.002)] [35], but this finding needs to be confirmed at other centers. In contrast, Matsumoto et al. [25] reported that the histologic grade of inflammation in the ascending colon was higher in patients with AOI than in patients without AOI, and yet the endoscopic remission rate at 12 months was higher in patients with AOI than in patients without AOI. They concluded that AOI in distal UC may be indicative not only of histologically active disease, but also a predictive factor for subsequent shortterm response to therapy. However, other investigators have stated that AOI may have no prognostic implication. Perry et al. [16] reported that 7 patients with discontinuous AOI were clinically indistinguishable from 50 patients without AOI in terms of age at surgery, pretreatment medications, type of surgery, interval from diagnosis to definitive procedure, complications, functional results (including number of bowel movements per day) and clinical course. Byeon et al. [28] reported that AOI may have no prognostic implications in terms of remission, relapse and proximal disease extension in UC because patients with AOI showed no difference in prognosis compared with patients without AOI. In 2011, Naves et al. [30] performed a 1:2 case–control study matched by disease extent, smoking habit, and date and age at diagnosis of UC. In the comparison between 14 patients with AOI and 25 patients without AOI, no differences in clinical outcomes or therapeutic requirements were found. They concluded that UC with AOI represented a phenotypic presentation of UC with similar clinical outcomes as classic distal UC in terms of a probability to develop proximal extension of disease or to require immunosuppressive therapy or colectomy. Although it remains controversial as to the clinical significance of AOI/PARP in UC patients, this lesion seems to have no prognostic implication in distal UC patients. However, we still do not
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know the effect of this lesion and therapy on long-term outcomes, including appendiceal cancer risk.
Therapeutic Appendectomy Several studies have suggested a therapeutic effect of appendectomy for UC (Table 3). In 2000, Okazaki et al. [36] reported a 21-year old male who underwent appendectomy for the treatment of ulcerative proctitis, whose symptoms (bloody stools) resolved within 1 month of surgery and who sustained remission even after 3 years. In 2003, another study from Japan [37] also showed the therapeutic effect of appendectomy in distal UC patients. In 2009, Bolin et al. [38] reported a prospective case series of patients with ulcerative proctitis, who underwent therapeutic appendectomy in the absence of history suggestive of previous appendicitis. Among the 30 patients with UC, endoscopic AOI was observed in 3 patients (10 %) before surgery. After appendectomy, 90 % of patients improved their clinical activity index and 40 % experienced a clinical remission by 12 months. In 3 patients with endoscopic AOI before appendectomy, one patient achieved clinical remission by 10 months and the remaining two patients did not achieve clinical remission after appendectomy. In 2011, Bageacu et al. [39] reported a case series of eight patients with ulcerative proctitis who underwent elective appendectomy for the treatment of UC. All patients had mucosal healing of proctitis with a mean follow-up of 3.6 years. The authors suggested the need for controlled trials to properly evaluate the role of appendectomy in the Table 3 The results of therapeutic appendectomy for ulcerative colitis References
Study type
Okazaki et al. [36]
Case report
Jarnerot et al. [41]
Number of UC patients
Resolution of symptoms after appendectomy
Follow-up after appendectomy
1
1 (100.0 %)
3 years
Case series
6
1 (16.7 %)
2–4 years
Selby et al. [40]
Case series
8
7 (87.5 %)
n/a
Jo et al. [37]
Case series
9
5 (55.6 %)
4 weeks
Bolin et al. [38]
Case series
30
12 (40.0 %)
1 year
Bageacu et al. [39]
Case series
8
8 (100.0 %)
3.6 years
The Appendiceal Inflammation and the Appendiceal Neoplasm A few case reports have suggested a possible association between UC and appendiceal adenocarcinoma, and some have recommended careful follow-up of long-standing UC patients with AOI due to the possible development of appendiceal adenocarcinoma and cystadenoma [42–47]. The authors suspected the same mechanisms as in colorectal cancer and UC [46]. Takeda et al. [47] suggested that the AOI in patients with UC may block excretion from the cavity, resulting in the occurrence of appendiceal mucocele and adenocarcinoma. In 2009, Orta et al. [48] reported a retrospective case–control study of primary appendiceal neoplasm in IBD patients. Although there was no significant difference in prevalence of appendiceal cystadenomas between IBD patients and non-IBD controls, appendiceal cystadenomas were 15-fold more prevalent among IBD patients with synchronous colorectal neoplasia compared with controls. In this regard, it has been suggested that distal UC patients with AOI be treated with systemic agents because topical agents cannot reach this region.
Conclusion
n/a; not applicable, UC; ulcerative colitis
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treatment of UC. On the other hand, in 2002, Selby et al. [40] reported an Australian series of eight patients who underwent appendectomy after the onset of UC, one of whom (12.5 %) required ongoing immunosuppressive therapy after appendectomy, considered as a marker of resistant disease. This proportion was not significantly different from the crude frequency of immunosuppressive therapy (18 %, 43/239) found in patients without appendectomy. In 2001, a Swedish case series of six patients with UC refractory to standard pharmacological treatments who underwent appendectomy included one patient whose disease seemed to follow a milder clinical course after surgery and another whose UC was apparently not influenced [41]. However, this trial was stopped by the authors because of the difficulties in interpreting findings in the remaining four patients due to confounding factors, including changes in smoking habits pre- and post-appendectomy, and the effect of ongoing treatment with various pharmacological agents. They stated that their general impression was that appendectomy did not influence the course of UC. Future controlled studies are needed to resolve this controversy of therapeutic appendectomy.
There is increasing evidence that AOI is a ‘‘skip lesion’’ in patients with UC. AOI is mainly accompanied by distal UC, and the disease course of UC patients with AOI seems
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to be similar to UC patients without AOI. In addition, the activity of AOI seems to correlate with that of distal UC lesion. However, we cannot draw any consistent conclusion that AOI/PARP has a prognostic implication regarding remission, relapse, proximal disease extension and development of colonic or appendiceal malignancy because of the variability in studies and insufficient data. Welldesigned clinical trials are needed to identify the pathogenesis and the real entity of AOI in UC and to diagnose and treat this phenotype efficiently. Conflict of interest
None.
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19. Takizawa H, Koike M, Hirose S, Asakura H. Appendiceal involvement in patients with ulcerative colitis. Dig Endosc. 1997;9:217–221. 20. D’Haens G, Geboes K, Peeters M, Baert F, Ectors N, Rutgeerts P. Patchy cecal inflammation associated with distal ulcerative colitis: a prospective endoscopic study. Am J Gastroenterol. 1997;92:1275–1279. 21. Okawa K, Aoki T, Sano K, Harihara S, Kitano A, Kuroki T. Ulcerative colitis with skip lesions at the mouth of the appendix: a clinical study. Am J Gastroenterol. 1998;93:2405–2410. 22. Horie H, Konishi F, Togashi K, Kashiwagi H, Kanazawa K. Significance of periappendiceal inflammation in the patients with distal ulcerative colitis. Dig Endosc. 1999;11:119–124. 23. Yang SK, Jung HY, Kang GH, et al. Appendiceal orifice inflammation as a skip lesion in ulcerative colitis: an analysis in relation to medical therapy and disease extent. Gastrointest Endosc. 1999;49:743–747. 24. Yamagishi N, Iizuka B, Nakamura T, Suzuki S, Hayashi N. Clinical and colonoscopic investigation of skipped periappendiceal lesions in ulcerative colitis. Scand J Gastroenterol. 2002;37:177–182. 25. Matsumoto T, Nakamura S, Shimizu M, Iida M. Significance of appendiceal involvement in patients with ulcerative colitis. Gastrointest Endosc. 2002;55:180–185. 26. Mutinga ML, Odze RD, Wang HH, Hornick JL, Farraye FA. The clinical significance of right-sided colonic inflammation in patients with left-sided chronic ulcerative colitis. Inflamm Bowel Dis. 2004;10:215–219. 27. Ladefoged K, Munck LK, Jorgensen F, Engel P. Skip inflammation of the appendiceal orifice: a prospective endoscopic study. Scand J Gastroenterol. 2005;40:1192–1196. 28. Byeon JS, Yang SK, Myung SJ, et al. Clinical course of distal ulcerative colitis in relation to appendiceal orifice inflammation status. Inflamm Bowel Dis. 2005;11:366–371. 29. Rubin DT, Rothe JA. The peri-appendiceal red patch in ulcerative colitis: review of the University of Chicago experience. Dig Dis Sci. 2010;55:3495–3501. 30. Naves JE, Lorenzo-Zuniga V, Marin L, et al. Long-term outcome of patients with distal ulcerative colitis and inflammation of the appendiceal orifice. J Gastrointest Liver Dis. 2011;20:355–358. 31. Matsushita M, Takakuwa H, Matsubayashi Y, Nishio A, Ikehara S, Okazaki K. Appendix is a priming site in the development of ulcerative colitis. World J Gastroenterol. 2005;11:4869–4874. 32. Farkas SA, Hornung M, Sattler C, et al. Preferential migration of CD62L cells into the appendix in mice with experimental chronic colitis. Eur Surg Res. 2005;37:115–122. 33. Kawachiya T, Oshitani N, Jinno Y, et al. Significance of increased proliferation of immature plasma cells in the appendix of patients with ulcerative colitis. Int J Mol Med. 2005;15:417–423. 34. Park SH, Yang SK, Kim MJ, et al. Long term follow-up of appendiceal and distal right-sided colonic inflammation. Endoscopy. 2012;44:95–98. 35. Yantiss RK, Sapp HL, Farraye FA, et al. Histologic predictors of pouchitis in patients with chronic ulcerative colitis. Am J Surg Pathol. 2004;28:999–1006. 36. Okazaki K, Onodera H, Watanabe N, et al. A patient with improvement of ulcerative colitis after appendectomy. Gastroenterology. 2000;119:502–506. 37. Jo Y, Matsumoto T, Yada S, et al. Histological and immunological features of appendix in patients with ulcerative colitis. Dig Dis Sci. 2003;48:99–108. 38. Bolin TD, Wong S, Crouch R, Engelman JL, Riordan SM. Appendicectomy as a therapy for ulcerative proctitis. Am J Gastroenterol. 2009;104:2476–2482. 39. Bageacu S, Coatmeur O, Lemaitre JP, et al. Appendicectomy as a potential therapy for refractory ulcerative proctitis. Aliment Pharmacol Ther. 2011;34:257–258.
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Dig Dis Sci 40. Selby WS, Griffin S, Abraham N, Solomon MJ. Appendectomy protects against the development of ulcerative colitis but does not affect its course. Am J Gastroenterol. 2002;97:2834–2838. 41. Jarnerot G, Andersson M, Franzen L. Laparoscopic appendectomy in patients with refractory ulcerative colitis. Gastroenterology. 2001;120:1562–1563. 42. Moreira VF, Milicua JM, Garcia Sanchez A, et al. Ulcerative colitis, pericholangitis and cancer of the appendix. Rev Clin Esp. 1979;154:237–241. 43. Odze RD, Medline P, Cohen Z. Adenocarcinoma arising in an appendix involved with chronic ulcerative colitis. Am J Gastroenterol. 1994;89:1905–1907. 44. Zannoni U, Masci C, Bazzocchi R, et al. Cancer of the appendix in long-standing ulcerative colitis: a case report. Tumori. 1997; 83:958–959. 45. Lakatos PL, Gyori G, Halasz J, et al. Mucocele of the appendix: an unusual cause of lower abdominal pain in a patient with
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ulcerative colitis. A case report and review of literature. World J Gastroenterol. 2005;11:457–459. 46. Villanueva Saenz E, Perez-Aguirre J, Belmonte MC, Martinez PH, Marquez RM, Carranza RJ. Appendix adenocarcinoma associated with ulcerative colitis: a case report and literature review. Tech Coloproctol. 2006;10:54–56. 47. Takeda Y, Nakase H, Mikami S, et al. Possible link between ulcerative colitis and in situ adenocarcinoma of an appendiceal mucocele: importance of inflammation in the appendiceal orifice related to UC. Inflamm Bowel Dis. 2008;14:873–874. 48. Orta L, Trindade AJ, Luo J, Harpaz N. Appendiceal mucinous cystadenoma is a neoplastic complication of IBD: case-control study of primary appendiceal neoplasms. Inflamm Bowel Dis. 2009;15:415–421.
REVIEW
Appendiceal Skip Inflammation and Ulcerative Colitis Sang Hyoung Park • Edward V. Loftus Jr. Suk-Kyun Yang
•
Received: 23 January 2014 / Accepted: 20 March 2014 Ó Springer Science+Business Media New York 2014
Abstract In recent decades, the appearance of inflammation near the appendix in patients with distal ulcerative colitis (UC) has been highlighted. Many epidemiological studies have confirmed the link between appendectomy and decreased incidence of UC. However, the clinical significance of appendiceal orifice inflammation (AOI) or periappendiceal red patch (PARP) as a ‘‘skip lesion’’ in UC has not been well elucidated. In this review, we summarized the literature regarding AOI/PARP and the role of this lesion in relation to UC. Since the appendiceal ‘‘skip area’’ in UC was first described in 1958, several reports using histologic examination of colectomy specimens and colonoscopy have been published. AOI/PARP has been more frequently associated with distal, mild UC than extensive, severe disease. Although it is still controversial, AOI/PARP seems to have little prognostic implication in the disease course of UC, including remission, relapse and proximal disease extension. However, some case reports have raised the possibility of a relationship between AOI/ PARP and appendiceal neoplasms such as appendiceal cystadenoma and appendiceal adenocarcinoma. In addition, some investigators have treated UC patients who were resistant to conventional medical therapy with appendectomy and have reported inconsistent therapeutic effect.
S. H. Park S.-K. Yang (&) Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea e-mail: [email protected] E. V. Loftus Jr. (&) Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street. S.W., Rochester, MN 55905, USA e-mail: [email protected]
Further research may lead to the discovery of etiologic and pathogenic roles of appendiceal inflammation in UC. Keywords Ulcerative colitis Appendiceal orifice inflammation Peri-appendiceal red patch Skip lesion
Introduction Traditionally, ulcerative colitis (UC) is considered a subtype of inflammatory bowel disease (IBD) that is characterized by continuous mucosal inflammation extending proximally from the rectum without any skipped areas. However, previous studies have reported a peri-appendiceal patch of inflammation in the cecum in patients with UC (Fig. 1). Although the clinical significance of appendiceal orifice inflammation [AOI; it is also called ‘‘peri-appendiceal red patch’’ (PARP) or ‘‘cecal patch’’] is still debatable, AOI/PARP has been considered to be a distinct ‘‘skip lesion’’ of UC. Moreover, many investigators have suggested that the appendix per se, previously considered a vestigial organ, may play an important role in mucosal immune function in the pathogenesis of UC, because of the inverse relationship between prior appendectomy and the risk of UC development in humans [1–3] and genetically engineered animals [4, 5]. The existing literature on AOI/PARP in UC as a skip lesion is sparse, and the findings are inconsistent. In addition, there is no published systematic review of AOI/ PARP in UC to date. Therefore, to review and analyze the existing data in the literature, we identified all the studies concerning AOI/PARP published up to May 2012, using the PUBMED databases. Reference lists from published articles, reviews and abstracts from major gastrointestinal meetings were also reviewed. We excluded editorials,
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Fig. 1 Endoscopy of appendiceal orifice inflammation (AOI)/periappendiceal red patch (PARP)
letters, comments and foreign language articles without an abstract in English. Based on these data, the historical, epidemiological, diagnostic and therapeutic aspects of AOI/PARP are summarized here. We also reviewed studies of appendiceal neoplasms in relation to appendiceal inflammation in UC and therapeutic appendectomy in UC patients who are refractory to medical treatment.
Appendiceal Inflammation in UC: Histologic Reports Using Surgical Specimens Skip inflammation of the peri-appendiceal region in UC was first described in 1958 by Lumb and Protheroe [6]. They examined 152 surgical specimens (including 53 total colectomies, comprising terminal ileum, entire colon, rectum and anal canal; 76 primary colectomies, comprising terminal ileum and colon but excluding rectum and anal canal; 12 partial colectomies, comprising left side of colon varying in length from 30 to 60 cm; and 11 rectal stumps, rectum and anal canal) from UC patients. In eight cases, typical ulceration was found as islands within normal mucosa, with a tendency to occur in the cecum opposite the ileocecal valve. In one case, typical UC inflammation occurred around the appendiceal orifice. These lesions were designated as ‘‘skip areas.’’ In 1974, Cohen et al. [7] described a case of appendiceal involvement of UC as a skip lesion. They reported a 39-year-old female patient with long-standing left-sided colitis who underwent total colectomy showing typical UC changes in the appendix as a skip lesion (the cecum and ascending colon were not involved), and first termed the condition ‘‘ulcerative appendicitis.’’
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The frequency of appendiceal lesions (including periappendiceal area) based on review of colectomy specimens is summarized in Table 1. In 1976, Jahadi and Shaw [8] found that 14 of 30 UC patients (47 %) had appendiceal involvement, and all of these cases had chronic UC involving the right colon or the cecum. In 1992, Goldblum and Appelman [9] described that all of the 66 cases with colitis changes in the appendix had adjacent cecal involvement, concluding that the appendix is not involved as a skip lesion in cases of extensive UC. Other studies [10, 11] showed that between 71 and 88 % of children with extensive UC had active inflammation in the appendix. However, they were unable to either support or refute the possibility of appendiceal involvement in distal UC, because all patients included in these studies underwent colectomy for colitis involving the right colon or pancolitis. In 1990, Davison and Dixon [12] described appendiceal ‘‘skip lesions’’ in 13 of 62 cases of UC (21 %) coming to surgical resection. In 7 of 13 patients, the disease extent of UC was proctitis or left-sided colitis. In 1994, Groisman et al. [13] reported that ulcerative appendicitis was present in 18 of the 21 cases of non-extensive UC (86 %), regardless of how limited the extent of colonic involvement. In the same year, Kroft et al. [14] detected appendiceal involvement as a skip lesion in 6 of 39 proctocolectomy specimens (15 %) containing appendices removed for UC. In 1998, Scott et al. [15] compared the prevalence of appendiceal inflammation in UC and Crohn’s disease, using colonic carcinoma and acute appendicitis specimens as controls. The prevalence of appendiceal ‘‘skip lesion’’ in UC (48 %) was higher than in colonic carcinoma (8 %) but was similar to that in Crohn’s disease (52 %). They concluded that appendiceal inflammation commonly occurs as a ‘‘skip lesion’’ in UC and histologically resembles the colonic disease rather than acute appendicitis. In 1999, Perry et al. [16] found discontinuous appendiceal involvement in 7 of 57 patients (12.3 %) undergoing proctocolectomy for UC. Taken together, appendiceal skip inflammation in UC was apparently observed in surgical specimens of UC with various frequencies. Although some investigators have had inconsistent findings, this discrepancy may be accounted for by the diverse criteria used to define ‘‘histological abnormality.’’ Also, studies using colectomy specimens had a significant limitation in that colectomy is usually performed in severe and refractory cases after a period of medical therapy and it is unclear whether this is a continuous or skip lesion in case of extensive colitis involving right colon; therefore, the frequency of appendiceal skip involvement in patients with mild to moderate disease activity could not be evaluated. In addition, medical therapy frequently produces the patchiness of mucosal inflammation [17] that may lead to the false conclusion of appendiceal involvement as a true skip lesion in UC.
Dig Dis Sci Table 1 Histologic reports of appendiceal or peri-appendiceal inflammation using surgical specimens in ulcerative colitis
References
Study type
Number of UC patients
Lumb and Protheroe [6]
Retrospective
152
Number of UAa
Disease extent of UC
8
Total colon: 96
(5.3 %)
Partial involvement: 45 Rectal stumps: 11
Cohen et al. [7]
Case report
Jahadi and Shaw [8]
Retrospective
30
1
1 14 (46.7 %)
Transverse colon: 1 Right colon: 30
Shalygina et al. [11]
Retrospective
16
14 (88.0 %)
Total colitis: 16
Davison and Dixon [12]
Retrospective
62
13 (21.0 %)
Ascending: 4 Transverse: 2 Descending: 2 Sigmoid: 4
Goldblum et al. [9]
Retrospective
87
66 (75.9 %)
Rectum: 1 Pancolitis: 87
Kahn et al. [10]
Retrospective
17
12 (71 %)
Universal UC: 17
Groisman et al. [13]
Retrospective
21
18 (85.7 %)
Ascending: 7 Transverse: 9 Descending: 3 Rectum: 2
U;A ulcerative appendicitis, UC; ulcerative colitis a
Kroft et al. [14]
Retrospective
39
6 (15.4 %)
Scott et al. [15]
Retrospective
50
24 (48.0 %)
Quiescent to distal: 92 % Pancolitis: 26 Subtotal colitis: 24
Perry et al. [16]
Retrospective
Including peri-appendiceal lesion
Appendiceal Inflammation in UC: Endoscopic Reports Until the 1990s, the incidence of AOI/PARP identified by colonoscopy had not been known, mainly because endoscopic examinations for typical UC were often discontinued once the upper limit of inflammation had been reached. In addition, total colonoscopy is often not performed in patients with severe UC, because of the perceived risk of colonic perforation. With increased awareness of AOI/ PARP among endoscopists, improvement of bowel preparation methods, and the advancement of endoscopic technology, reports of AOI/PARP detected by endoscopy have increased rapidly. The reports of AOI/PARP using colonoscopy are summarized in Table 2. In these endoscopic reports, AOI/PARP was generally defined as a macroscopic inflammation around the appendiceal orifice and/or surrounding cecum such as mucosal erythema, granularity, erosion/ulceration and friability. AOI/PARP in UC was first identified endoscopically in 1993 by Saitoh et al. [18]. They reported a 50-year old male with left-sided colitis and peri-appendiceal inflammation with typical UC changes at appendectomy performed to rule out appendiceal malignancy. After this case report, several reports of AOI/PARP using
57
7 (12.3 %)
Ascending: 4 Distal to hepatic flexure: 3
colonoscopy were published from multiple facilities. In 1997, Takizawa et al. [19] reviewed colonoscopic findings of 41 cases of UC, and reported that 5 patients (12 %) had AOI/PARP. They recommended that endoscopists meticulously examine the peri-appendiceal area during colonoscopy in patients with UC. In the same year, D’Haens et al. [20] prospectively observed 20 cases with left-sided UC and reported that 15 patients (75 %) had peri-appendiceal inflammation with or without cecal inflammation, separated from the distal colitis by macroscopically and microscopically uninvolved mucosa. This study reported the highest proportion of endoscopic peri-appendiceal inflammation in distal UC so far. In 1998, Okawa et al. [21] reported that 10 of 56 untreated UC patients (18 %) who underwent total colonoscopy had UC at the mouth of the appendix. They suggested that determination of the clinical significance of peri-appendiceal skip lesions would contribute to elucidation of the pathogenesis of UC. In 1999, Horie et al. [22] reviewed 16 patients with distal UC who underwent total colonoscopy and found that 4 patients had peri-appendiceal inflammation (25 %). The authors concluded that periappendiceal inflammation was thought to develop in the early stage of the disease course of UC. In the same year, Yang et al. [23] found that 24 of 96 patients with active
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Dig Dis Sci Table 2 Endoscopic reports of appendiceal inflammation in ulcerative colitis
References
Study type
Number of UC patients
Saitoh et al. [18]
Case report
1
Takizawa et al. [19]
Prospective
41
Number of UA 1 5 (12.2 %)
Disease extent of UC Left-sided colitis: 1 Proctitis: 2 Left-sided colitis: 1 Extensive colitis: 1 Segmental: 1
D’Haens et al. [20]
Prospective
20
15 (75.0 %)
Left-sided colitis: 20
Okawa et al. [21]
Prospective
56
10 (17.9 %)
Proctitis: 6 Left-sided colitis: 4 Extensive colitis: 0
Horie et al. [22] Yang et al. [23]
Prospective Prospective
16 94
4 (25.0 %)
Proctitis: 4
24 (25.5 %)
Left-sided colitis: 0 Proctitis: 18 Left-sided colitis: 6 Extensive colitis: 0
Yamagashi et al. [24]
Prospective
279
54 (19.4 %)
Proctitis: 8 Left-sided colitis: 25 Extensive colitis: 21
Matsumoto et al. [25]
Prospective
40
23 (57.5 %)
Proctitis: 9 Left-sided colitis: 14 Extensive colitis: 0
Mutinga et al. [26]
Retrospective
127
12 (9.4 %)
Proctitis: 1 Left-sided colitis: 11
Ladefoged et al. [27]
Prospective
73
20 (27.4 %)
Proctitis: 15 Left-sided colitis: 23 Extensive colitis: 12 Others: 25
Byeon et al. [28]
Prospective
Rubin et al. [29]
Retrospective
94
48 (51.1 %)
Proctitis: 38 Left-sided colitis: 10
367
29 (7.9 %)
Proctitis : 4 Left-sided colitis: 18 Extensive colitis: 5 Unknown: 2
n/a; not applicable, UA; ulcerative appendicitis, UC; ulcerative colitis
Naves et al. [30]
Retrospective
subtotal UC (26 %) had AOI and concluded that this finding is not a result of patchy improvement secondary to medical therapy and that AOI is more frequently observed in patients with less extensive disease (37 % in proctitis, 17 % in left-sided colitis and 0 % in extensive colitis). In 2002, Yamagishi et al. [24] reported 54 patients (19.4 %) had AOI/PARP among 279 patients with UC who underwent total colonoscopy. In 28 of 35 patients (80 %) who were followed up endoscopically, the activity in the AOI correlated well with that in the distal lesion. In the same year, Matsumoto et al. [25] found that 23 of 40 patients with active distal UC (57.5 %) had endoscopic evidence of AOI. In 2004, Mutinga et al. [26] reported that 12 of 127 patients
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n/a
14
Proctitis: 11 Left-sided colitis: 3
with left-sided UC (9.4 %) had active inflammation in the cecum and/or ascending colon. However, among these 12 patients, nine had just microscopic, but not endoscopic, lesions in the right colon. In 2005, Ladefoged et al. [27] identified that 20 of 73 UC patients (27 %) had discontinuous AOI, also concluding that this lesion is common in patients with IBD. However, they stated that patients with an otherwise normal colon may also show congestion of this area with or without minimal microscopic inflammation. In the same year, in a subsequent study after the study of Yang et al. [23], Byeon et al. [28] found AOI endoscopically in 48 of 94 patients with newly diagnosed distal UC (51 %). In 2010, Rubin et al. [29] reported that 29 of 367 patients with
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distal UC (7.9 %) had endoscopic evidence of PARP. In 20 of 43 colonoscopic exams (46.5 %) that were performed on 29 patients with PARP, the histologic activity in the PARP paralleled the activity confirmed in the distal colon. Only including 30 exams that obtained biopsies, 67 % (20/30) showed parallel histologic activity to the distal lesions. They reported that 23 of 29 patients with PARP (79 %) were male. Naves et al. [30] also found that 11 of 14 patients with AOI (78 %) were men. Although they suggested that PARP/AOI seems to have a male predominance in UC, this finding was not consistent with other studies [19, 21–23, 26, 28] which showed either no gender predominance or a female predominance. In summary, AOI/PARP occurs as a skip lesion mainly in distal UC rather than extensive disease (not pancolitis), and the endoscopic and histologic disease activity of this lesion seems to parallel that of the distal colitis. Except the first case report [18] and the study of Byeon et al. [28] only including newly diagnosed UC, the remaining studies included both newly diagnosed UC and treated UC patients.
Pathophysiologic and Diagnostic Implication of the Appendiceal Skip Lesion In 2005, Matsushita et al. [31] investigated the CD4/CD8 ratio in the inflamed and uninflamed colonic mucosa, especially in the appendiceal mucosa, of UC patients, in order to clarify the role of the appendix in the development of UC. They observed an increased CD4/CD8 ratio and predominant infiltration of CD4 ? CD69? T cells in the appendix, suggesting that the appendix may be a priming site in the development of UC. In the same year, the preferential migration of CD62L ? CD? cells into the appendix [32] and the increased proliferation of immature plasma cells in the appendix of UC patients [33] were reported. These studies suggested that the appendix may play a primary role in the pathogenesis of UC. In 2012, Park et al. [34] reported follow-up results of 20 patients with AOI without concomitant typical UC. In 20 patients with AOI alone, typical UC developed in five patients over a mean follow-up of 18.4 months, concluding that AOI may precede development of UC, at least in some cases. Taken together, AOI seems to play a role in the development of UC, and AOI might be an important diagnostic clue for the diagnosis of UC on some occasions [35].
Clinical Course of UC with the Appendiceal Skip Lesion Beyond the real prevalence of this phenotypic form of UC, it is not well established if UC patients with AOI/PARP have a different prognosis regarding disease severity, risk
of proximal extension or development of colorectal dysplasia/carcinoma. In fact, there are no particular therapeutic or monitoring recommendations for patients with AOI/ PARP. Therefore, it is important to evaluate the clinical course of UC patients with AOI/PARP for therapeutic and monitoring plan. D’Haens et al. [20] observed that one of 15 patients with AOI needed a colectomy, while another also had a clear extension of his disease to more proximal segments, concluding that UC patients with AOI at initial examination also suffered from a more aggressive disease course with more frequent relapses. In follow-up, 1 of 15 patients (6.7 %) with AOI on initial examination and 4 of 5 patients (80.0 %) without AOI on initial examination had not experienced any disease relapses. One recent pathological study of colectomy specimens suggested that patients with appendiceal ulceration were more likely to develop pouchitis [the appendiceal ulceration was present in 13 of 32 pouchitis patients (41 %) and in none of the 26 controls (0 %) (p = 0.002)] [35], but this finding needs to be confirmed at other centers. In contrast, Matsumoto et al. [25] reported that the histologic grade of inflammation in the ascending colon was higher in patients with AOI than in patients without AOI, and yet the endoscopic remission rate at 12 months was higher in patients with AOI than in patients without AOI. They concluded that AOI in distal UC may be indicative not only of histologically active disease, but also a predictive factor for subsequent shortterm response to therapy. However, other investigators have stated that AOI may have no prognostic implication. Perry et al. [16] reported that 7 patients with discontinuous AOI were clinically indistinguishable from 50 patients without AOI in terms of age at surgery, pretreatment medications, type of surgery, interval from diagnosis to definitive procedure, complications, functional results (including number of bowel movements per day) and clinical course. Byeon et al. [28] reported that AOI may have no prognostic implications in terms of remission, relapse and proximal disease extension in UC because patients with AOI showed no difference in prognosis compared with patients without AOI. In 2011, Naves et al. [30] performed a 1:2 case–control study matched by disease extent, smoking habit, and date and age at diagnosis of UC. In the comparison between 14 patients with AOI and 25 patients without AOI, no differences in clinical outcomes or therapeutic requirements were found. They concluded that UC with AOI represented a phenotypic presentation of UC with similar clinical outcomes as classic distal UC in terms of a probability to develop proximal extension of disease or to require immunosuppressive therapy or colectomy. Although it remains controversial as to the clinical significance of AOI/PARP in UC patients, this lesion seems to have no prognostic implication in distal UC patients. However, we still do not
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know the effect of this lesion and therapy on long-term outcomes, including appendiceal cancer risk.
Therapeutic Appendectomy Several studies have suggested a therapeutic effect of appendectomy for UC (Table 3). In 2000, Okazaki et al. [36] reported a 21-year old male who underwent appendectomy for the treatment of ulcerative proctitis, whose symptoms (bloody stools) resolved within 1 month of surgery and who sustained remission even after 3 years. In 2003, another study from Japan [37] also showed the therapeutic effect of appendectomy in distal UC patients. In 2009, Bolin et al. [38] reported a prospective case series of patients with ulcerative proctitis, who underwent therapeutic appendectomy in the absence of history suggestive of previous appendicitis. Among the 30 patients with UC, endoscopic AOI was observed in 3 patients (10 %) before surgery. After appendectomy, 90 % of patients improved their clinical activity index and 40 % experienced a clinical remission by 12 months. In 3 patients with endoscopic AOI before appendectomy, one patient achieved clinical remission by 10 months and the remaining two patients did not achieve clinical remission after appendectomy. In 2011, Bageacu et al. [39] reported a case series of eight patients with ulcerative proctitis who underwent elective appendectomy for the treatment of UC. All patients had mucosal healing of proctitis with a mean follow-up of 3.6 years. The authors suggested the need for controlled trials to properly evaluate the role of appendectomy in the Table 3 The results of therapeutic appendectomy for ulcerative colitis References
Study type
Okazaki et al. [36]
Case report
Jarnerot et al. [41]
Number of UC patients
Resolution of symptoms after appendectomy
Follow-up after appendectomy
1
1 (100.0 %)
3 years
Case series
6
1 (16.7 %)
2–4 years
Selby et al. [40]
Case series
8
7 (87.5 %)
n/a
Jo et al. [37]
Case series
9
5 (55.6 %)
4 weeks
Bolin et al. [38]
Case series
30
12 (40.0 %)
1 year
Bageacu et al. [39]
Case series
8
8 (100.0 %)
3.6 years
The Appendiceal Inflammation and the Appendiceal Neoplasm A few case reports have suggested a possible association between UC and appendiceal adenocarcinoma, and some have recommended careful follow-up of long-standing UC patients with AOI due to the possible development of appendiceal adenocarcinoma and cystadenoma [42–47]. The authors suspected the same mechanisms as in colorectal cancer and UC [46]. Takeda et al. [47] suggested that the AOI in patients with UC may block excretion from the cavity, resulting in the occurrence of appendiceal mucocele and adenocarcinoma. In 2009, Orta et al. [48] reported a retrospective case–control study of primary appendiceal neoplasm in IBD patients. Although there was no significant difference in prevalence of appendiceal cystadenomas between IBD patients and non-IBD controls, appendiceal cystadenomas were 15-fold more prevalent among IBD patients with synchronous colorectal neoplasia compared with controls. In this regard, it has been suggested that distal UC patients with AOI be treated with systemic agents because topical agents cannot reach this region.
Conclusion
n/a; not applicable, UC; ulcerative colitis
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treatment of UC. On the other hand, in 2002, Selby et al. [40] reported an Australian series of eight patients who underwent appendectomy after the onset of UC, one of whom (12.5 %) required ongoing immunosuppressive therapy after appendectomy, considered as a marker of resistant disease. This proportion was not significantly different from the crude frequency of immunosuppressive therapy (18 %, 43/239) found in patients without appendectomy. In 2001, a Swedish case series of six patients with UC refractory to standard pharmacological treatments who underwent appendectomy included one patient whose disease seemed to follow a milder clinical course after surgery and another whose UC was apparently not influenced [41]. However, this trial was stopped by the authors because of the difficulties in interpreting findings in the remaining four patients due to confounding factors, including changes in smoking habits pre- and post-appendectomy, and the effect of ongoing treatment with various pharmacological agents. They stated that their general impression was that appendectomy did not influence the course of UC. Future controlled studies are needed to resolve this controversy of therapeutic appendectomy.
There is increasing evidence that AOI is a ‘‘skip lesion’’ in patients with UC. AOI is mainly accompanied by distal UC, and the disease course of UC patients with AOI seems
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to be similar to UC patients without AOI. In addition, the activity of AOI seems to correlate with that of distal UC lesion. However, we cannot draw any consistent conclusion that AOI/PARP has a prognostic implication regarding remission, relapse, proximal disease extension and development of colonic or appendiceal malignancy because of the variability in studies and insufficient data. Welldesigned clinical trials are needed to identify the pathogenesis and the real entity of AOI in UC and to diagnose and treat this phenotype efficiently. Conflict of interest
None.
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