- Email: [email protected]
Cancer and pediatric inflammatory bowel disease
Seminars in Pediatric Surgery (2007) 16, 205-213
Cancer and pediatric inflammatory bowel disease Mark L. Kayton, MD From the Division of Pediatric Surgery, Department of Surgery, The Memorial Sloan–Kettering Cancer Center, New York, New York. KEYWORDS Cancer; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Pediatric; Lymphoma; Transplant
Cancer in children may be mistakenly diagnosed as inflammatory bowel disease (IBD), and specific cancers may develop in patients who truly have IBD. Ulcerative colitis patients historically carry an increased risk of colorectal adenocarcinoma, but current practices of surveillance and early surgery may have an impact on this. Crohn’s disease patients require surveillance for colon cancer, but are also likely to be at increased risk for small bowel tumors and lymphoma. Some malignancies affecting IBD patients are sequelae of immunomanipulation, performed in the interest of IBD therapy itself. Knowing the cancer risks associated with IBD and those associated with agents used for IBD treatment, and practicing long-term surveillance for these tumors, are central components of caring for patients with IBD. Lessons learned from the fields of oncology and bone marrow transplantation may provide future directions and potential cures in IBD. © 2007 Elsevier Inc. All rights reserved.
For patients with inflammatory bowel disease (IBD), the threat of cancer comes as a double-edged sword. On one hand, a diagnosis of IBD may reflect a predisposition toward the future development of cancer. On the other hand, some of the very medications used to treat IBD have recently been implicated in cancer formation. Despite these findings, a surprising hope may be emerging for IBD patients—ironically, distilled from the field of oncology itself—that hematopoietic stem cell transplantation may be useful in the treatment of IBD. The data behind these observations will be explored in this chapter.
Relevance of the problem for pediatric surgeons IBD is most commonly diagnosed during adolescence and young adulthood,1 and several studies indicate that the incidence, particularly that of Crohn’s disease, has increased durAddress reprint requests and correspondence: Mark L. Kayton, MD, Memorial Sloan-Kettering Cancer Center, Department of Surgery, Division of Pediatric Surgery, 1275 York Avenue, New York, NY 10021. E-mail: [email protected].
1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.04.010
ing the late 20th century.2,3 Although we classically think of colorectal cancer as being the major long-term concern in refractory IBD [especially in ulcerative colitis (UC) and Crohn’s colitis], pediatric surgeons must recognize that surveillance for cancer in IBD does not end at the ileocecal valve. Some of the cancers discussed in this chapter are not colorectal, and some are not even adenocarcinoma. Knowledge of these risks should assist pediatric surgeons in their ability to consult with, counsel, operate on, and follow IBD patients. There are two principal areas in which pediatric surgeons may have pivotal insight with respect to cancer and IBD. The first is in the recognition of cases of cancer when they masquerade as purported IBD diagnoses. The second area is in understanding the particular cancer risks, for adenocarcinoma as well as for other kinds of cancers, that patients with IBD will experience over their lifetimes, and using this knowledge to guide surgical decision making.
Cancer masquerading as IBD Pediatric surgeons who consult on patients with complex abdominal or perianal problems may be better equipped
206 Table 1
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007 Cancer-specific mortality for colorectal and other groups of cancers
Author (year)
Analysis type 14
Nordenholz (1995)
Ekbom (1992)15 Persson (1996)16
Jess (2006)17
No. patients Mortality from colorectal ca
130 Community-based review of death certificates in Rochester, New York Population-based 4776 cohort in central Sweden Population-based 2798 cohort in Stockholm
Population-based cohort in Olmsted County, Minnesota
692
Mortality from other cancers
UC: 8 of 59 patients (14%) Crohn’s: 3 of 71 patients (4%)
UC: 10 of 59 patients (17%) Crohn’s: 10 of 71 (14%)
UC: SMR 4.4 (3.2–5.9)ⴱ Crohn’s: SMR 1.7 (0.5–3.9)
UC: SMR 1.0 (0.7–1.5) Crohn’s: SMR 0.9 (0.8 –1.3)
UC: SMR 2.85 (1.59 – 4.69) Crohn’s: SMR 0.30 (0.01–1.66)
UC: SMR 1.21 (0.91–1.57) Crohn’s: SMR 1.11 (0.76 –1.56)
Mortality from all GI malignancies (adenocarcinoma, leiomyosarcoma, lymphoma) UC: SMR from GI malignancies, 2.2 (0.7–5.2) Crohn’s: SMR from GI malignancies, 4.7 (1.7–10)
*SMR, Standardized Mortality Ratio; parentheses, 95% confidence interval.
than many other subspecialists to recognize and diagnose cases of childhood cancer. Literature reports in which cases of perianal and intraperitoneal malignancies have been mistakenly labeled as IBD are instructive in this regard. When a child is referred to a pediatric surgeon because of a persistant, painful, perianal mass suggestive of an abscess— often part of the symptom complex in IBD—suspicion of a malignancy should arise when appropriate response to treatment fails to occur. Perianal Hodgkin’s lymphoma has been reported in an older patient treated for years for known rectosigmoid and perianal Crohn’s disease.4 Among children, 11 patients presenting with a perirectal or gluteal mass are described by Hill and colleagues. Each of these 11 masses was diagnosed as an abscess, but only 1 underwent biopsy as part of the initial management. Protracted courses of antibiotics and incision and drainage were employed in most cases, so delay in diagnosis averaged 2.1 months from the time of presentation. All proved to be rhabdomyosarcoma of clinical group III or IV by the time of diagnosis. Only 2 patients were alive and diseasefree at over 3 years of follow up.5 Abdominal malignancies can be mistakenly diagnosed and treated as if they were IBD, as well. Physicians at Johns Hopkins Hospital reported the case of a 14-year-old girl with malignant peritoneal mesothelioma who was treated for presumed IBD for a prolonged period of time. The authors acknowledged the subtlety to this diagnosis. They suggested that the omental inflammation observed early in her course, disproportionate to observed intestinal inflammation, was one of the only clues to the diagnosis.6 Diagnostic complexity is even higher when pronounced mural thickening and ulceration of the intestine are encountered. Primary intestinal lymphomas have been misdiagnosed as IBD in children and young adults.7-9 McCullough and coworkers point out the utility of immunohistochemistry in distinguishing colonic involvement by mantle zone
lymphoma rather than IBD, as their patient had biopsy findings that included crypt abscesses, regenerative changes, and atypical lymphoid infiltrates in the lamina propria of the colon.9 Lastly, it is possible for cancer to develop in the context of proven IBD, yet be anatomically obscured by it. This may result in a delay in diagnosis. A case report describes a 19-year-old male who presented with clinical manifestations of IBD-related colitis, and was found at colonoscopy to have a cecal ulcer harboring a diffuse large-cell lymphoma.10 Multiple case reports describe Hodgkin’s disease involving the colon, realized only postoperatively in young adults with longstanding IBD.11-13 The remainder of this chapter will revolve around the types and consequences of cancer, both common and uncommon, that may develop in the setting of IBD.
Cancer mortality in IBD Do IBD patients have an overall increased risk of dying of cancer? UC patients, but probably not Crohn’s patients, have a higher risk of dying from colorectal cancer than the general population does. Nordenholz (Table 1) moreover found that colorectal cancer deaths occurred 3 times more commonly among UC patients than among Crohn’s patients.14 The data from two large population-based studies support a statistically significantly higher mortality for colorectal cancer among UC patients, on the order of 2.8 to 4.4 times higher than the general population.15,16 These figures are expressed as Standardized Mortality Ratios (SMR)—the ratio of observed versus expected deaths—and are included in Table 1. Crohn’s disease patients have an increased risk of dying of GI malignancies in general. Inclusion of nonadenocarci-
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noma in the last study in Table 1, by Jess and coworkers,17 helps to illustrate this. The authors presented standardized mortality ratios for all GI malignancies grouped together, including patients who developed small bowel lymphoma and small bowel leiomyosarcoma in the setting of Crohn’s disease. This inclusion of nonadenocarcinoma helps boost the statistically significant standardized mortality rate for GI malignancies in Crohn’s disease, and it is an important reflection of increasing awareness that noncolorectal cancers must be scrutinized as contributing to the mortality risk of IBD.
Cancer incidence in IBD Mortality figures do not necessarily convey, however, the rate of occurrence of cancer; for that, we must look to incidence data. When we do, interesting findings emerge on the association of noncolorectal malignancies with Crohn’s disease as well as with UC. Two recent population-based cohort studies serve to illustrate this. The two studies disagree on estimates of the colorectal carcinoma rates but converge remarkably in their identification of the risk of noncolorectal cancers among IBD patients. Jess and coworkers18 provided cancer incidence data from their population-based cohort study of 692 IBD patients from the Rochester, Minnesota region. Median follow up was 14 years. There was no significant increase in the standardized colorectal carcinoma incidence rates over that of the general population, for either ulcerative colitis patients or for Crohn’s patients. However, the 3 small bowel tumors (an adenocarcinoma, a leiomyosarcoma, and a local lymphoma) seen among the 314 Crohn’s patients reflected a greater than 40-fold increase in the standardized incidence rate for small bowel tumors, over that of the general population (95% CI 8.5-120). The results of a second population-based, matched cohort study involving 5529 IBD subjects in Manitoba by Bernstein and coworkers19 did find an increase in the incidence rate ratios (IRR) for colon cancer (that is, the incidence rates among IBD patients standardized for age and gender, compared with the incidence in a matched population cohort). The increased incidence rate ratios for colon carcinoma were seen among both Crohn’s patients (IRR 2.64; 95% CI 1.69-4.12) and UC patients (IRR 2.75; 95% CI 1.91-3.97). But Crohn’s patients also had a significantly increased incidence rate ratio of cancer of all sites (IRR 1.29; 95% CI 1.07-1.54) and of lymphoma in particular (IRR 2.40; 95% CI 1.17-4.97). In the following section, particular cancers associated with IBD will be examined, starting with colorectal adenocarcinoma. Other cancers purportedly associated with IBD will also be discussed. Some of these supposed associations, such as gastrointestinal stromal tumors (GIST), are likely pure coincidence. Others, like small bowel adenocarcinomas, are more data-driven. Still others, as is the emerging
207 case with lymphomas, are so striking that they are presently altering the way we treat IBD. A common thread that will tie many of these malignancies together—particularly melanoma, squamous cell carcinoma, Kaposi’s sarcoma, and the lymphoproliferative disorders—is that the cancers most intimately tied to immune surveillance are those that should be of special concern to IBD patients.
Colorectal adenocarcinoma in IBD Colorectal carcinoma represents the best-known instance of an association between IBD and cancer. Although colorectal carcinoma rarely may be diagnosed during childhood or adolescence—in the setting of either Crohn’s colitis20 or UC21—a more common concern on the minds of most families is the child’s lifetime risk. Population-based studies, mentioned in the preceding section, have had conflicting results with respect to whether “all comers” among IBD patients have a generally increased risk above that of the population. Potential reasons for this include increasing safety and patient acceptance of colectomy and increasing use of colonoscopic screening. The data from studies looking solely at childhood-incidence IBD, on the other hand, suggest that there is a very meaningful risk of future colorectal cancer when IBD has its onset during the pediatric years. In a meta-analysis looking at studies reporting subsequent long-term colorectal cancer incidence among patients developing UC in childhood, Eaden and coworkers concluded that the cumulative probabilities of developing colorectal carcinoma were 5.5% at 10 years following onset of UC symptoms, 10.8% at 20 years, and 15.7% at 30 years. These rates for adenocarcinoma after childhood-onset UC appeared slightly higher than the cumulative probabilities found among those with adult-onset UC.22 Results for UC are echoed among Crohn’s colitis patients. Gillen and coworkers found among 113 patients with age of onset for Crohn’s colitis between 15 and 25 years old, that the relative risk of developing colorectal cancer was 13.3 (95% CI 3.6-34.1).23 Factors contributing to an increased risk of developing colorectal cancer in patients with all forms of IBD have been found to include a family history of colorectal cancer in a first degree relative (associated with a doubling of the relative risk),24 greater extent of colonic involvement,23,25 and younger age at diagnosis.25,26 This last risk factor, younger age at diagnosis, should be particularly striking to practitioners who treat children: in Ekbom’s study, in univariate analysis, the standardized incidence ratio for colorectal cancer among patients diagnosed with UC between age 0 and 14 was 118.3 times that of the control population (95% CI 63.0-202.3). A smaller, although still significantly elevated, incidence ratio persisted after adjusting for such factors as extent of disease at diagnosis and length of follow up.25 Lastly, the presence of colonic strictures in either UC27 or Crohn’s28 should prompt suspicion of malignancy.
208 Table 2
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007 Current colorectal cancer screening guidelines
Eaden and Mayberry, 200239
Itzkowitz and Present, 200596
Collins et al., 200638
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
Screening colonoscopy 8–10 years after onset of symptoms Colonoscopy every 3 years in the second decade Colonoscopy every 2 years in the third decade Colonoscopy yearly by the fourth decade For left-sided disease, begin regular surveillance 15–20 years from onset of symptoms With sclerosing cholangitis, colonoscopy should be done annually Screening colonoscopy 8–10 years after onset of symptoms For proctosigmoiditis alone, risk is not felt to be increased over the population at large and standard population surveillance recommendations may apply For extensive or left-sided colitis, colonoscopy every 1–2 years following screening colonoscopy After 2 negative surveillance exams, may go to every 1–3 years until 20 years After 20 years, colonoscopy should be yearly If biopsies are “indefinite” for dysplasia, follow-up surveillance should occur within 3–6 months With sclerosing cholangitis, colonoscopy should be done annually For extensive colitis or Crohn’s colitis, colonoscopy 8 years after onset of symptoms For less extensive disease, colonoscopy 15 years after onset of symptoms Continue surveillance every 3 years for 10 years, every 2 years for 10 years, then every year If no histologic inflammation seen, intervals can be extended back to every 3 years With sclerosing cholangitis, colonoscopy should be offered promptly and then yearly thereafter
Other risk factors are particular to the type of IBD. In the case of UC, additional features associated with an increased risk of developing colorectal cancer include the presence of backwash ileitis29 and the coexistant diagnosis of sclerosing cholangitis.30-32 The risk imparted by sclerosing cholangitis is not abrogated among adult patients following orthotopic liver transplantation.33-35 With respect to Crohn’s disease, an increased risk of colorectal cancer is present in those with any colonic involvement by Crohn’s, but this is not the case for those with disease confined to the terminal ileum at diagnosis.26 Crohn’s patients undergoing colonoscopy for changes in symptoms were found to have higher odds of being diagnosed with colon cancer than matched controls having colonoscopy for screening or surveillance.36
Use of surveillance colonoscopy It has been surprisingly difficult to prove that colonoscopic surveillance reduces mortality from colorectal cancer in UC. Choi and colleagues found those undergoing surveillance were diagnosed at a significantly earlier Dukes’ stage than those not under surveillance in a nonrandomized study. There was a resultant 5-year survival of 77.2% among surveillance patients compared with 36% among nonsurveillance patients.37 Studies of the benefit of colonoscopy suffer from being nonrandomized (randomized trials of colonoscopy versus none would carry obvious ethical obstacles) and for lead time bias (that is, the perceived increase in survival simply because the cancer was detected long before it would have otherwise become clinically evident). Direct reduction in mortality as a result of colonoscopic surveillance has been difficult to prove in most studies. A recent Cochrane review states, “There is no clear evidence that surveillance colonoscopy
prolongs survival in patients with extensive colitis. There is evidence that cancers tend to be detected at an earlier stage in patients who are undergoing surveillance . . . .”38 Nonetheless, surveillance colonoscopy remains widely practiced, as it probably should be, and there are an abundance of published recommendations for its implementation and frequency. Current guidelines from a variety of sources are listed in Table 2. Eaden39 advocates that the same program should be followed for patients with Crohn’s colitis as for those with UC. At colonoscopy, the finding of high-grade dysplasia in any IBD patient should prompt a plan for colectomy, and the finding of low-grade dysplasia should also prompt serious consideration of colectomy, as many of these patients will progress to high-grade dysplasia or cancer in a short period of time.40,41 It is hoped that molecular markers will be validated that may even be amplified from stool DNA, to someday supplant colonoscopy as the preferred means of surveillance.38 Colectomy impacts on the colorectal cancer risk because most or all of the potentially cancer-bearing end organ is removed, but some mention should be made as to the risk of dysplasia in the ileal pouch and, if left behind, in the anal transition zone. Sarigol and colleagues at The Cleveland Clinic tracked 76 pediatric patients by means of mucosal biopsies of ileal pouches. Of the 76 patients, 64 patients had undergone stapled ileoanal anastomosis with preservation of the anal transition zone, whereas 12 had undergone rectal mucosectomy with hand-sewn anastomosis. With a mean interval of 5 years between surgery and last biopsy, dysplasia was not identified in any of the patients. The authors nonetheless recommend continued endoscopic surveillance of the pouch.42 This is probably wise, as a study of 178 adult patients from the same institution, each having undergone stapled ileal pouch– anal anastomosis with a minimum of 10 years of follow
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Cancer and Pediatric IBD
up apiece, identified dysplasia in the anal transition zone in 8 of the 178 (4.5%).43
Risk-modifying drugs in colorectal adenocarcinoma Ursodiol Altered excretion of bile acids, with an increased proportion of secondary bile acids contacting the colonic epithelium, has been postulated to be at the heart of the elevated risk of colorectal cancer found among IBD patients. This may be particularly relevant for those who develop both IBD and sclerosing cholangitis. Ejderhamn and colleagues in 1990 studied fecal bile acid excretion in 18 children with IBD in comparison to excretion from 5 controls who were healthy children of medical staff. In support of the concept of altered bile acid excretion, the investigators found that fecal excretion (in milligrams per day) as well as concentration (in milligrams per gram of feces) of conjugated and unconjugated bile acids were increased in the IBD patients compared with control children.44 Ursodiol supplementation, by changing the colonic concentration of secondary bile acids such as deoxycholic acid, has been studied with encouraging results as a cancerprotective agent in IBD. A cross-sectional study examining ursodiol use among 59 patients with UC and primary sclerosing cholangitis found that, even after adjustment for multiple variables including duration of disease and sulfasalazine use, ursodiol use was significantly associated with decreased prevalence of colonic dysplasia.45 In a randomized, placebo-controlled trial assessing ursodiol’s effect in 52 patients with sclerosing cholangitis, a subset of patients with both UC and primary sclerosing cholangitis demonstrated a relative risk of 0.26 for the development of colorectal dysplasia or cancer (95% CI 0.07-0.99).46 And in a prospective, double-blinded, randomized, placebo-controlled treatment study of 19 patients with UC who had already manifested colonic dysplasia, 2 placebo-treated patients progressed to require colectomy, whereas none of the ursodiol-patients patients developed progression of dysplasia, although overall aneuploidy and dysplasia scores were not found to be statistically different between the two groups.47 Particularly in the setting of UC without primary sclerosing cholangitis, ursodiol will require more study.
209 case-control study by Eaden and coworkers, which showed a dramatic 75% reduction (P ⬍ 0.00001 on univariate analysis) in cancer risk among UC patients taking 5-ASA. The results were partially confounded by increased contact with physicians and more frequent colonoscopy among the same patients, but the benefit persisted, albeit less dramatically (P ⬍ 0.05), on statistical analysis adjusting for these confounding variables, and was seen particularly in the group taking ⱖ1.2 g per day of mesalazine.49 A large epidemiologic study50 has bolstered these findings, but several other studies have failed to find a benefit.51,52 It may be that the observed benefit is present but either the magnitude of the effect is small, or that 5-ASA must be taken for many years to appreciate a benefit.
Folate Folate supplementation is thought by some practitioners to diminish colorectal cancer risk. Evidence for this is fair but not perfect. For example, a case-control study on folate intake by Freudenheim and coworkers compared 428 colon and 372 rectal cancer patients with matched neighborhood controls. The study identified a significant reduction in the risk of rectal cancer, but not colon cancer, among men (odds ratio 0.31, 95% CI 0.16-0.59) and a borderline reduction for women (odds ratio 0.50, 95% CI 0.24-1.03) for the use of folate.53 As the side effect profile is negligible, many have adopted its use.
Small bowel adenocarcinoma The occurrence of small bowel adenocarcinoma is mainly of concern among Crohn’s patients. In a population-based cohort of 1251 Crohn’s patients published by Persson and coworkers, a more than 15-fold increase in the rate of observed versus expected small bowel cancers was reported, which was highly statistically significant.54 A regional cohort of 373 patients studied by Munkholm and coworkers found a 50-fold increase in the relative risk for small bowel cancer among Crohn’s patients, also highly significant.55 Both of these studies used organ-specific statistics (eg, “small intestine”), so although it is likely that most of these small bowel cancers were adenocarcinomas, it cannot be definitively ascertained. Risk factors thought to predispose Crohn’s patients to small bowel cancer include jejunal Crohn’s disease, occupations involving hazardous material exposure, and use of 6-mercaptopurine.56
5-Aminosalicylates The anticancer effects of 5-aminosalicylate (5-ASA) compounds, including mesalazine and sulfasalazine, are controversial. There is underlying basic science showing that mesalazine reversibly inhibits proliferation and induces apoptosis in colon cancer cells.48 Human studies have shown conflicting results. The most famous report is a
Non-adenocarcinomas in IBD Neurofibromatosis and IBD There are three patients reported in the literature who had the coexistence of neurofibromas, cafe-au-lait spots, and
210 Crohn’s disease.57,58 Unless more data become available, this presently falls under the category of coincidence.
Gastrointestinal stromal tumors (GIST) and IBD In 1999, a Viennese group reported the resection of a 8 ⫻ 5 ⫻ 6 cm, terminal ileal, c-kit positive GIST in an area of Crohn’s ileitis.59 Another patient was found to have a c-kit positive GIST within a Meckel’s diverticulum discovered at laparotomy for initial flareup of terminal ileal Crohn’s.60 There have been three other reports of GIST coexisting with IBD,28,61,62 although two were termed leiomyosarcomas and c-kit staining was not mentioned. With five case reports, this entity appears coincidental as well.
Neuroendocrine tumors and IBD In 1994, an apparent curiosity was reported by Listinsky at the University of Alabama: a high-grade neuroendocrine carcinoma arising at a former ileostomy site, in an adult treated for ulcerative colitis since the age of 15.63 The neuroendocrine tumor was metastatic at presentation and the patient died under treatment for metastatic disease. Other case reports demonstrate carcinoids found incidentally in association with diseased bowel resected from IBD patients; for instance, Le Marc’hadour and coworkers present two cases of carcinoids found in appendices, where neighboring histologic abnormalities including hyperplasia of enteroendocrine cells were observed.64 This hints that a underlying drive to hyperplasia may exist, and that these are perhaps not merely incidental carcinoids. If that is true, one might expect that more cases and larger series exist. Indeed, Greenstein and colleagues have presented 6 carcinoids found in Crohn’s patients and 5 among UC patients, all discovered incidentally. Nine of the 11 were appendiceal and the remaining 2 were in the small bowel. But after presenting 11 such cases from the Mount Sinai Hospital, the authors point out that since Mount Sinai’s case records include over 3000 patients with IBD, there is no evidence that these 11 cases represent an elevated incidence of carcinoids among IBD patients.65 Finally, a larger series of 14 incidentally discovered neuroendocrine neoplasms was reported among IBD patients at the Cleveland Clinic. This series included 8 patients with Crohn’s and six with UC. Six of these 14 neuroendocrine neoplasms were found in the rectum, 4 in the appendix, 2 in the sigmoid, and 2 in the small bowel. Histology of 11 of the neuroendocrine tumors showed well-differentiated carcinoid, and the remaining 3 were poorly differentiated, mixed adenocarcinoma and small cell carcinoma.66 Surgeons and pathologists should be aware of the potential coexistence of IBD and carcinoids, but it remains unestablished as to whether there is a common etiologic mechanism. To date, it not been shown that incidence of carcinoids in IBD exceeds that of the normal population.
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007
Soft-tissue tumors and IBD A 1986 paper by Israel and Nissenblatt reported two soft tissue tumors, an extraosseous osteosarcoma of the hip and a thoracic desmoid tumor, in patients who also developed IBD.67 Although a potential association with osteosarcoma has not been supported by a single case report since, the mention of desmoid tumor is noteworthy. Desmoid tumors have been reported in the mesentery among patients with Crohn’s, in the absence of Gardner’s syndrome.68 Prior surgery has been postulated as a risk factor for mesenteric desmoids in other cases.69
Melanoma and IBD The question of whether IBD patients have an underlying predisposition to the development of malignancy, on the basis of immune system dysregulation, was raised by Greenstein and associates in a 1992 study of 11 cases of melanoma among IBD patients. The authors posed the question as to whether some immunosuppressive aspect of the patients’ treatment could have been responsible for the later development of melanoma. Potential factors including use of steroids and azulfidine and exposure to radiation were considered, although on the basis of this series, none could be specifically implicated.70 However, other cancers with clear bases in immunodysregulation have been reported in the context of IBD, such as squamous cell carcinoma and Kaposi’s sarcoma.
Squamous cell carcinoma and IBD Case reports and small series describe anorectal squamous cell carcinomas arising in IBD patients.71-73 Greenstein and coworkers suggest that the frequency of these lesions among IBD patients observed by the Mount Sinai group is 30 times higher than that expected.74 Squamous cell cancers of the skin had a significantly increased standardized incidence ratio (2.2, 95% CI 1.1-3.9) in the Swedish populationbased cohort study of 4776 IBD patients compiled by Ekbom and coworkers This increased incidence was chiefly found among Crohn’s patients. Surveillance bias is discussed by the authors as a possible confounding factor.75 Little information has been compiled about the particular immunosuppressive treatments used before a diagnosis of squamous cell carcinoma.
Kaposi’s sarcoma and IBD Seven English-language case reports discuss the discovery of Kaposi’s sarcoma among patients with clear-cut IBD in the absence of human immunodeficiency virus (HIV).76-82 An additional two reports date from 1970 and earlier, so are unlikely to be related to HIV as well.83,84 In each case, patients had been treated with varieties of immunosuppression for their IBD (Table 3). Six cases had visceral involve-
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211
Table 3 Kaposi’s sarcoma reported in association with IBD among HIV(⫺) patients Author (year)
Patient IBD type and age duration Immunosuppression
Gordon (1966)84 65 Adlersberg 63 (1970)83 Meltzer (1987)53 83 Koop (1987)78 29 Thompson (1989)76 Puy-Montbrun (1991)77 Tedesco (1999)79 Cohen (2001)80
22 36 68 67
Bursics (2005)81 49
Unclear, 4 Steroids months UC, 9 months Steroids UC, 6 months Crohn’s, 4 years UC, 14 months Crohn’s, 16 years UC, 8 years
Steroids Steroids
Crohn’s, 25 years UC, 5 years
Steroids
Steroids Steroids, azathioprine Steroids
Steroids
ment by Kaposi’s sarcoma, and three were both visceral and cutaneous. All cases arose in the setting of immunosuppression. These cases are a harbinger of a much larger debate—that is, the role of immunosuppression in causing “secondary” malignancies among IBD patients. In this regard, no subject has stirred greater controversy than the topic of lymphoma.
Lymphoma and IBD The debate over whether there is an increased risk of lymphoma, as a result of IBD or its treatment, has recently become eclipsed by a 2007 report describing the occurrence of eight cases of hepatosplenic T-cell lymphoma among young patients (ages 12-31) with IBD. All eight had been treated with infliximab, a tumor necrosis factor-␣ blocking agent that is FDA-approved for the treatment of refractory IBD. Six of the eight cases were fatal within a year.85 A direct causality related to infliximab therapy is difficult to firmly establish, as the patients all received multiple prior or simultaneous immunosuppressive therapies. But the stark rarity of hepatosplenic T-cell lymphoma, with only about a hundred published cases,85 coupled with prior assertions that infliximab may be related to other cases of lymphoma,86,87 should give pause to any clinician who doubts that lymphoma can arise as a consequence of IBD therapy. Before this, a link between IBD and lymphoma was murky. Claims of an association were supported by numerous case reports, but among population-based or cohort studies, this association was either present,74 absent,54,75,88,89 or equivocal.90 A metaanalysis exclusively admitting cohort studies of azathioprine or 6-mercaptopurine use among IBD patients showed a significant relative risk of 4.18 for the development of lymphoma, lending further credence to the concept that this is related to immunosuppression. Even if this im-
parted risk is true, the authors note, the incidence is rare; several hundred to several thousand person-years of follow-up would be required to result in each additional case of lymphoma; and use of these immunosuppressants should probably not be contraindicated.91
Therapeutic possibilities from oncology The vigorous debate about immunosuppression highlights the fact that symptomatic control of IBD hinges on the ability to control the immune system, long before most patients are ever considered for intestinal surgery. Adoptive transfer of Crohn’s disease susceptibility is believed to have occurred from donor to recipient of a nonmyeloablative stem cell transplant, with subsequent clinical manifestation of the disease in the recipient.92 This is consistent with reports of other autoimmune diseases, such as autoimmune thyroiditis,93 that have appeared to result from adoptive transfer following transplant. If IBD can be transferred by immune system replacement, it follows that in reciprocal fashion it may also be cured by stem cell transplantation. Such ideas now have a foundation in clinical data. Ten of 11 patients with IBD who underwent allogeneic stem cell transplant for leukemia or myelodysplastic syndrome remained free of IBD symptoms at a median of 34 months follow up in a retrospective study.94 Immune system ablation followed by autologous T cell-depleted hematopoietic stem cell transplantation has been evaluated in a phase I trial for Crohn’s disease by Oyama and coworkers. Eleven of 12 patients, aged 15 to 38, were in sustained remission from refractory Crohn’s, at a median follow up of 18.5 months, and off all immunosuppressive therapies.95 Thus, from an unexpected corner of medicine, a therapy developed largely to surmount cancer itself may become a future component of IBD therapy.
References 1. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004;126:1504-17. 2. Farrokhyar F, Swarbrick ET, Irvine EJ. A critical review of epidemiological studies in inflammatory bowel disease. Scand J Gastroenterol 2001;36(1):2-15. 3. Barton JR, Gillon S, Ferguson A. Incidence of inflammatory bowel disease in Scottish children between 1968 and 1983; marginal fall in ulcerative colitis, three-fold rise in Crohn’s disease. Gut 1989; 30:618-22. 4. Sivarajasingham N, Adams SA, Smith MEF, et al. Perianal Hodgkin’s lymphoma complicating Crohn’s disease. Int J Colorectal Dis 2003; 18(2):174-6. 5. Hill DA, Dehner LP, Gow KW, et al. Perianal rhabdomyosarcoma presenting as a perirectal abscess: a report of 11 cases. J Pediatr Surg 2002;37(4):576-81. 6. Oberto C, Schwarz KB, Zambidis E, et al. Malignant peritoneal mesothelioma in a pediatric patient mimicking inflammatory bowel disease. Dig Dis Sci 2004;49(3):434-7.
212 7. Merino MJ, Livolsi VA. Small cell malignant tumors of childhood: clinically presenting as inflammatory bowel disease. Conn Med 1979; 43(10):621-4. 8. Maaravi Y, Wengrower D, Leibowitz G. A unique presentation of lymphoma of the colon. J Clin Gastroenterol 1993;17(1):49-51. 9. McCullough JE, Kim CH, Banks PM. Mantle zone lymphoma of the colon simulating diffuse inflammatory bowel disease. Dig Dis Sci 1992;37(6):934-8. 10. Kapoor G, Albrecht RJ, Craver R, et al. Diffuse large cell lymphoma presenting as inflammatory bowel disease in an adolescent with ataxia telangiectasia. Leuk Res 1996;20(11-12):997-8. 11. Codling BW, Keighley MRB, Slaney G. Hodgkin’s disease complicating Crohn’s colitis. Surgery 1977;82(5):625-8. 12. Vanbockrijck M, Cabooter M, Casselman J, et al. Primary Hodgkin disease of the ileum complicating Crohn disease. Cancer 1993;72: 1784-9. 13. Vincenzi B, Finolezzi E, Fossati C, et al. Unusual presentation of Hodgkin’s disease mimicking inflammatory bowel disease. Leuk Lymphoma 2001;42(3):521-6. 14. Nordenholtz KE, Stowe SP, Stormont JM, et al. The cause of death in inflammatory bowel disease: a comparison of death certificates and hospital charts in Rochester, New York. Am J Gastroenterol 1995; 90(6):927-32. 15. Ekbom A, Helmick CG, Zack M, et al. Survival and causes of death in patients with inflammatory bowel disease: a population-based study. Gastroenterol 1992;103:954-60. 16. Persson P-G, Bernell O, Leijonmarck C-E, et al. Survival and causespecific mortality in inflammatory bowel disease: a population-based study. Gastroenterol 1996;110:1339-45. 17. Jess T, Loftus EV Jr, Harmsen WS, et al. Survival and cause specific mortality in patients with inflammatory bowel disease: a long term outcome study in Olmsted County, Minnesota, 1940-2004. Gut 2006;55: 1248-54. 18. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Gastroenterology 2006;130:1039-46. 19. Bernstein CN, Blanchard JF, Kliewer E, et al. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91:854-62. 20. Tiszlavicz L, Kapin M, Várkonyi A, et al. Adenocarcinoma of the colon developing on the basis of Crohn’s disease in childhood. Eur J Pediatr 2000;160:168-72. 21. Michener WM, Gage RP, Sauer WG, et al. The prognosis of chronic ulcerative colitis in children. N Engl J Med 1961;265:1075-9. 22. Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48:526-35. 23. Gillen CD, Andrews HA, Prior P, et al. Crohn’s disease and colorectal cancer. Gut 1994;35:651-5. 24. Askling J, Dickman PW, Karlén P, et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001;120:1356-62. 25. Ekbom A, Helmick C, Zack M, et al. Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 1990;323:1228-33. 26. Ekbom A, Helmick C, Zack M, et al. Increased risk of large-bowel cancer in Crohn’s disease with colonic involvement. Lancet 1990;336: 357-9. 27. Gumaste V, Sachar DB, Greenstein AJ. Benign and malignant colorectal strictures in ulcerative colitis. Gut 1992;33(7):938-41. 28. Stahl TJ, Schoetz DJ Jr, Roberts PL, et al. Crohn’s disease and carcinoma: increasing justification for surveillance? Dis Colon Rectum 1992;35:850-6. 29. Heuschen UA, Hinz U, Allemeyer EH, et al. Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001;120:841-7. 30. Broomé U, Löfberg R, Veress B, et al. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology 1995;22(5):1404-8.
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007 31. Marchesa P, Lashner BA, Lavery IC, et al. The risk of cancer and dysplasia among ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1997;92(8):1285-8. 32. Shetty K, Rybicki L, Brzezinski A, et al. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1999;94(6):1643-9. 33. Knechtle SJ, D’Alessandro AM, Harms BA, et al. Relationships between sclerosing cholangitis, inflammatory bowel disease, and cancer in patients undergoing liver transplantation. Surgery 1995;118(4): 615-20. 34. Loftus EV Jr, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998; 27(3):685-90. 35. Vera A, Gunson BK, Ussatoff V, et al. Colorectal cancer in patients with inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis. Transplantation 2003;75(12):1983-8. 36. Siegel CA, Sands BE. Risk factors for colorectal cancer in Crohn’s colitis: a case-control study. Inflamm Bowel Dis 2006;12(6):491-6. 37. Choi PM, Nugent FW, Schoetz DJ Jr, et al. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 1993;105:418-24. 38. Collins PD, Mpofu C, Watson AJ, et al. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database Syst Rev 2006;2:CD000279. 39. Eaden JA, Mayberry JF. Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease. Gut 2002;51:v10-2 (suppl V). 40. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994;343:71-4. 41. Itzkowitz SH. Cancer prevention in patients with inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:1133-44. 42. Sarigol S, Wyllie R, Gramlich T, et al. Incidence of dysplasia in pelvic pouches in pediatric patients after ileal pouch-anal anastomosis for ulcerative colitis. J Pediatr Gastroenterol Nutr 1999;28(4):429-34. 43. Remzi FH, Fazio VW, Delaney CP, et al. Dysplasia of the anal transition zone after ileal pouch-anal anastomosis. Dis Colon Rectum 2003;46:6-13. 44. Ejderhamn J, Rafter JJ, Strandvik B. Faecal bile acid excretion in children with inflammatory bowel diseaes. Gut 1991;32:1346-51. 45. Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001;134: 89-95. 46. Pardi DS, Loftus EV Jr, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124:889-93. 47. Sjöqvist U, Tribukait B, Öst Á, et al. Ursodeoxycholic acid treatment in IBD-patients with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind, randomized controlled pilot study. Anticancer Res 2004;24:3121-8. 48. Reinacher-Schick A, Schoeneck A, Graeven U, et al. Mesalazine causes a mitotic arrest and induces caspase-dependent apoptosis in colon carcinoma cells. Carcinogenesis 2003;24(3):443-51. 49. Eaden J, Abrams K, Ekbom A, et al. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000; 14:145-53. 50. van Staa TP, Card T, Logan RF, et al. 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut 2005;54:1573-8. 51. Bernstein CN, Blanchard JF, Metge C, et al. Does the use of 5-aminosalicylates in inflammatory bowel disease prevent the development of colorectal cancer? Am J Gastroenterol 2003;98:2784-8. 52. Terdiman JP, Steinbuch M, Blumenthals WA, et al. 5-Aminosalicylic acid therapy and the risk of colrectal cancer among patients with inflammatory bowel disease. Inflamm Bowel Dis 2007;13:1-5.
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53. Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991;20(2): 368-74. 54. Persson P-G, Karlén P, Bernell O, et al. Crohn’s disease and cancer: a population-based cohort study. Gastroenterol 1994;107:1675-9. 55. Munkhold P, Langholz E, Davidsen M, et al. Intestinal cancer risk and mortality in patients with Crohn’s disease. Gastroenterology 1993;105: 1716-23. 56. Lashner BA. Risk factors for small bowel cancer in Crohn’s disease. Dig Dis Sci 1992;37(8):1179-84. 57. Henderson RG, Long PJ, Al-Nafussi AI, et al. Paget’s disease with benign osteopetrosis and Crohn’s disease. J R Soc Med 1985;78(9): 766-8. 58. Cameron EM, Raeburn A, Ford MJ. Neurofibromatosis and inflammatory bowel disease. Scott Med J 1989;34(4):500-1. 59. Pfeffel F, Stiglbauer W, Depisch D, et al. Coincidence of Crohn’s disease and a high-risk gastrointestinal stromal tumor of the terminal ileum. Digestion 1999;60:363-6. 60. Mijandrušic Sinèic B, Kovac D, Jašic M, et al. Crohn’s disease and a gastrointestinal stromal tumor in an 81-year-old man: a rare coincidence. Zentralbl Chir 2005;130:597-9. 61. Laukhuf F, Tischer KH, Strobel K, et al. Crohn’s disease and stromal sarcoma of the small bowel: a rare coincidence. Z Gastroenterol 2002;40(3):193-6. 62. Papadopoulos N, Goritsas C, Rontogianni D, et al. Coexistence of inflammatory bowel disease and gastrointestinal stromal tumor: a case report. Int J Intern Med 2003;4:7-9. 63. Listinsky CM, Halpern NB, Workman RB, et al. Ultrastructural and immunocytochemical features of a case of neuroendocrine carcinoma developing in a prior ileostomy site. Ultrastruct Pathol 1994;18(5): 503-9. 64. Le Marc’hadour F, Bost F, Peoc’h M, et al. Carcinoid tumour complicating inflammatory bowel disease. Pathol Res Pract 1994;190: 1185-92. 65. Greenstein AJ, Balasubramanian S, Harpaz N, et al. Carcinoid tumor and inflammatory bowel disease: a study of eleven cases and review of the literature. Am J Gastroenterol 1997;92(4):682-5. 66. Sigel JE, Goldblum JR. Neuroendocrine neoplasms arising in inflammatory bowel disease: a report of 14 cases. Mod Pathol 1998;11(6): 537-42. 67. Israel KJ, Nissenblatt MJ. Association of inflammatory bowel disease (IBD) with indolent soft-tissue sarcomas: report of two cases and review of literature. J Surg Oncol 1986;32(2):125-30. 68. DiGiacomo JC, Lazenby AJ, Salloum LJ. Mesenteric fibromatosis associated with Crohn’s disease. Am J Gastroenterol 1994;89(7):1103-5. 69. Slater G, Greenstein AJ. Mesenteric fibromatosis in Crohn’s disease. J Clin Gastroenterol 1996;22(2):147-9. 70. Greenstein AJ, Sachar DB, Shafir M, et al. Malignant melanoma in inflammatory bowel disease. Am J Gastroenterol 1992;87(3):317-20. 71. Slater G, Greenstein A, Aufses AH Jr. Anal carcinoma in patients with Crohn’s disease. Ann Surg 1984;199(3):348-50. 72. Kulaylat MN, Doerr R, Butler B, et al. Squamous cell carcinoma complicating idiopathic inflammatory bowel disease. J Surg Oncol 1995; 59(1):48-55. 73. Frisch M, Johansen C. Anal carcinoma in inflammatory bowel disease. Br J Cancer 2000;83(1):89-90. 74. Greenstein AJ, Gennuso R, Sachar DB, et al. Extraintestinal cancers in inflammatory bowel disease. Cancer 1985;56:2914-21. 75. Ekbom A, Helmick C, Zack M, et al. Extracolonic malignancies in inflammatory bowel disease. Cancer 1991;67:2015-9.
213 76. Thompson GB, Pemberton JH, Morris S, et al. Kaposi’s sarcoma of the colon in a young HIV-negative man with chronic ulcerative colitis. Dis Colon Rectum 1989;32(1):73-6. 77. Puy-Montbrun T, Pigot F, Vuong PN, et al. Kaposi’s sarcoma of the colon in a young HIV-negative woman with Crohn’s disease. Dig Dis Sci 1991;36(4):528-31. 78. Koop HO, Holodniy M, List AF. Fulminant Kaposi’s sarcoma complicating long-term corticosteroid therapy. Am J Med 1987;83(4): 787-9. 79. Tedesco M, Benevolo M, Frezza F, et al. Colorectal Kaposi’s sarcoma in an HIV-negative male in association with ulcerative rectocolitis: a case report. Anticanc Res 1999;19:3045-8. 80. Cohen RL, Tepper RE, Urmacher C, et al. Kaposi’s sarcoma and cytomegaloviral ileocolitis complicating long-standing Crohn’s disease in an HIV-negative patient. Am J Gastroenterol 2001;96:3028-31. 81. Bursics A, Morvay K, Ábrahám K, et al. HHV-8 positive, HIV negative disseminated Kaposi’s sarcoma complicating steroid dependent ulcerative colitis: a successfully treated case. Gut 2005;54(7):1049-50. 82. Meltzer SJ, Rotterdam HZ, Korelitz BI. Kaposi’s sarcoma occurring in association with ulcerative colitis. Am J Gastroenterol 1987;82(4): 378-81. 83. Adlersberg R. Kaposi’s sarcoma complicating ulcerative colitis: report of a case. Am J Clin Pathol 1970;54(1):143-6. 84. Gordon HW, Rywlin AM. Kaposi’s sarcoma of the large intestine associated with ulcerative colitis. Gastroenterology 1966;50(2): 248-53. 85. Mackey AC, Green L, Liang L-C, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44: 265-7. 86. Ljung T, Karlén P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004;53:849-53. 87. Sandborn WJ, Loftus EV. Balancing the risks and benefits of infliximab in the treatment of inflammatory bowel disease. Gut 2004;53: 780-2. 88. Lewis JD, Bilker WB, Brensinger C, et al. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001;121:1080-7. 89. Loftus EV Jr, Tremaine WJ, Habermann TM, et al. Risk of lymphoma in inflammatory bowel disease. Am J Gastroenterol 2000;95:2308-12. 90. Askling J, Brandt L, Lapidus A, et al. Risk of haematopoietic cancer in patients with inflammatory bowel disease. Gut 2005;54:617-22. 91. Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54:1121-5. 92. Sonwalkar SA, James RM, Ahmad T, et al. Fulminant Crohn’s colitis after allogeneic stem cell transplantation. Gut 2003;52:1518-21. 93. Sklar C, Boulad F, Small T, et al. Endocrine complications of pediatric stem cell transplantation. Front Biosci 2001;6:g17-22. 94. Ditschkowski M, Einsele H, Schwerdtfeger R, et al. Improvement of inflammatory bowel disease after allogeneic stem-cell transplantation. Transplantation 2003;75(10):1745-7. 95. Oyama Y, Craig RM, Traynor AE, et al. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn’s disease. Gastroenterology 2005;128:552-63. 96. Itzkowitz SH, Present DH. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005;11(3):314-21.
Cancer and pediatric inflammatory bowel disease Mark L. Kayton, MD From the Division of Pediatric Surgery, Department of Surgery, The Memorial Sloan–Kettering Cancer Center, New York, New York. KEYWORDS Cancer; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Pediatric; Lymphoma; Transplant
Cancer in children may be mistakenly diagnosed as inflammatory bowel disease (IBD), and specific cancers may develop in patients who truly have IBD. Ulcerative colitis patients historically carry an increased risk of colorectal adenocarcinoma, but current practices of surveillance and early surgery may have an impact on this. Crohn’s disease patients require surveillance for colon cancer, but are also likely to be at increased risk for small bowel tumors and lymphoma. Some malignancies affecting IBD patients are sequelae of immunomanipulation, performed in the interest of IBD therapy itself. Knowing the cancer risks associated with IBD and those associated with agents used for IBD treatment, and practicing long-term surveillance for these tumors, are central components of caring for patients with IBD. Lessons learned from the fields of oncology and bone marrow transplantation may provide future directions and potential cures in IBD. © 2007 Elsevier Inc. All rights reserved.
For patients with inflammatory bowel disease (IBD), the threat of cancer comes as a double-edged sword. On one hand, a diagnosis of IBD may reflect a predisposition toward the future development of cancer. On the other hand, some of the very medications used to treat IBD have recently been implicated in cancer formation. Despite these findings, a surprising hope may be emerging for IBD patients—ironically, distilled from the field of oncology itself—that hematopoietic stem cell transplantation may be useful in the treatment of IBD. The data behind these observations will be explored in this chapter.
Relevance of the problem for pediatric surgeons IBD is most commonly diagnosed during adolescence and young adulthood,1 and several studies indicate that the incidence, particularly that of Crohn’s disease, has increased durAddress reprint requests and correspondence: Mark L. Kayton, MD, Memorial Sloan-Kettering Cancer Center, Department of Surgery, Division of Pediatric Surgery, 1275 York Avenue, New York, NY 10021. E-mail: [email protected].
1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.04.010
ing the late 20th century.2,3 Although we classically think of colorectal cancer as being the major long-term concern in refractory IBD [especially in ulcerative colitis (UC) and Crohn’s colitis], pediatric surgeons must recognize that surveillance for cancer in IBD does not end at the ileocecal valve. Some of the cancers discussed in this chapter are not colorectal, and some are not even adenocarcinoma. Knowledge of these risks should assist pediatric surgeons in their ability to consult with, counsel, operate on, and follow IBD patients. There are two principal areas in which pediatric surgeons may have pivotal insight with respect to cancer and IBD. The first is in the recognition of cases of cancer when they masquerade as purported IBD diagnoses. The second area is in understanding the particular cancer risks, for adenocarcinoma as well as for other kinds of cancers, that patients with IBD will experience over their lifetimes, and using this knowledge to guide surgical decision making.
Cancer masquerading as IBD Pediatric surgeons who consult on patients with complex abdominal or perianal problems may be better equipped
206 Table 1
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007 Cancer-specific mortality for colorectal and other groups of cancers
Author (year)
Analysis type 14
Nordenholz (1995)
Ekbom (1992)15 Persson (1996)16
Jess (2006)17
No. patients Mortality from colorectal ca
130 Community-based review of death certificates in Rochester, New York Population-based 4776 cohort in central Sweden Population-based 2798 cohort in Stockholm
Population-based cohort in Olmsted County, Minnesota
692
Mortality from other cancers
UC: 8 of 59 patients (14%) Crohn’s: 3 of 71 patients (4%)
UC: 10 of 59 patients (17%) Crohn’s: 10 of 71 (14%)
UC: SMR 4.4 (3.2–5.9)ⴱ Crohn’s: SMR 1.7 (0.5–3.9)
UC: SMR 1.0 (0.7–1.5) Crohn’s: SMR 0.9 (0.8 –1.3)
UC: SMR 2.85 (1.59 – 4.69) Crohn’s: SMR 0.30 (0.01–1.66)
UC: SMR 1.21 (0.91–1.57) Crohn’s: SMR 1.11 (0.76 –1.56)
Mortality from all GI malignancies (adenocarcinoma, leiomyosarcoma, lymphoma) UC: SMR from GI malignancies, 2.2 (0.7–5.2) Crohn’s: SMR from GI malignancies, 4.7 (1.7–10)
*SMR, Standardized Mortality Ratio; parentheses, 95% confidence interval.
than many other subspecialists to recognize and diagnose cases of childhood cancer. Literature reports in which cases of perianal and intraperitoneal malignancies have been mistakenly labeled as IBD are instructive in this regard. When a child is referred to a pediatric surgeon because of a persistant, painful, perianal mass suggestive of an abscess— often part of the symptom complex in IBD—suspicion of a malignancy should arise when appropriate response to treatment fails to occur. Perianal Hodgkin’s lymphoma has been reported in an older patient treated for years for known rectosigmoid and perianal Crohn’s disease.4 Among children, 11 patients presenting with a perirectal or gluteal mass are described by Hill and colleagues. Each of these 11 masses was diagnosed as an abscess, but only 1 underwent biopsy as part of the initial management. Protracted courses of antibiotics and incision and drainage were employed in most cases, so delay in diagnosis averaged 2.1 months from the time of presentation. All proved to be rhabdomyosarcoma of clinical group III or IV by the time of diagnosis. Only 2 patients were alive and diseasefree at over 3 years of follow up.5 Abdominal malignancies can be mistakenly diagnosed and treated as if they were IBD, as well. Physicians at Johns Hopkins Hospital reported the case of a 14-year-old girl with malignant peritoneal mesothelioma who was treated for presumed IBD for a prolonged period of time. The authors acknowledged the subtlety to this diagnosis. They suggested that the omental inflammation observed early in her course, disproportionate to observed intestinal inflammation, was one of the only clues to the diagnosis.6 Diagnostic complexity is even higher when pronounced mural thickening and ulceration of the intestine are encountered. Primary intestinal lymphomas have been misdiagnosed as IBD in children and young adults.7-9 McCullough and coworkers point out the utility of immunohistochemistry in distinguishing colonic involvement by mantle zone
lymphoma rather than IBD, as their patient had biopsy findings that included crypt abscesses, regenerative changes, and atypical lymphoid infiltrates in the lamina propria of the colon.9 Lastly, it is possible for cancer to develop in the context of proven IBD, yet be anatomically obscured by it. This may result in a delay in diagnosis. A case report describes a 19-year-old male who presented with clinical manifestations of IBD-related colitis, and was found at colonoscopy to have a cecal ulcer harboring a diffuse large-cell lymphoma.10 Multiple case reports describe Hodgkin’s disease involving the colon, realized only postoperatively in young adults with longstanding IBD.11-13 The remainder of this chapter will revolve around the types and consequences of cancer, both common and uncommon, that may develop in the setting of IBD.
Cancer mortality in IBD Do IBD patients have an overall increased risk of dying of cancer? UC patients, but probably not Crohn’s patients, have a higher risk of dying from colorectal cancer than the general population does. Nordenholz (Table 1) moreover found that colorectal cancer deaths occurred 3 times more commonly among UC patients than among Crohn’s patients.14 The data from two large population-based studies support a statistically significantly higher mortality for colorectal cancer among UC patients, on the order of 2.8 to 4.4 times higher than the general population.15,16 These figures are expressed as Standardized Mortality Ratios (SMR)—the ratio of observed versus expected deaths—and are included in Table 1. Crohn’s disease patients have an increased risk of dying of GI malignancies in general. Inclusion of nonadenocarci-
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Cancer and Pediatric IBD
noma in the last study in Table 1, by Jess and coworkers,17 helps to illustrate this. The authors presented standardized mortality ratios for all GI malignancies grouped together, including patients who developed small bowel lymphoma and small bowel leiomyosarcoma in the setting of Crohn’s disease. This inclusion of nonadenocarcinoma helps boost the statistically significant standardized mortality rate for GI malignancies in Crohn’s disease, and it is an important reflection of increasing awareness that noncolorectal cancers must be scrutinized as contributing to the mortality risk of IBD.
Cancer incidence in IBD Mortality figures do not necessarily convey, however, the rate of occurrence of cancer; for that, we must look to incidence data. When we do, interesting findings emerge on the association of noncolorectal malignancies with Crohn’s disease as well as with UC. Two recent population-based cohort studies serve to illustrate this. The two studies disagree on estimates of the colorectal carcinoma rates but converge remarkably in their identification of the risk of noncolorectal cancers among IBD patients. Jess and coworkers18 provided cancer incidence data from their population-based cohort study of 692 IBD patients from the Rochester, Minnesota region. Median follow up was 14 years. There was no significant increase in the standardized colorectal carcinoma incidence rates over that of the general population, for either ulcerative colitis patients or for Crohn’s patients. However, the 3 small bowel tumors (an adenocarcinoma, a leiomyosarcoma, and a local lymphoma) seen among the 314 Crohn’s patients reflected a greater than 40-fold increase in the standardized incidence rate for small bowel tumors, over that of the general population (95% CI 8.5-120). The results of a second population-based, matched cohort study involving 5529 IBD subjects in Manitoba by Bernstein and coworkers19 did find an increase in the incidence rate ratios (IRR) for colon cancer (that is, the incidence rates among IBD patients standardized for age and gender, compared with the incidence in a matched population cohort). The increased incidence rate ratios for colon carcinoma were seen among both Crohn’s patients (IRR 2.64; 95% CI 1.69-4.12) and UC patients (IRR 2.75; 95% CI 1.91-3.97). But Crohn’s patients also had a significantly increased incidence rate ratio of cancer of all sites (IRR 1.29; 95% CI 1.07-1.54) and of lymphoma in particular (IRR 2.40; 95% CI 1.17-4.97). In the following section, particular cancers associated with IBD will be examined, starting with colorectal adenocarcinoma. Other cancers purportedly associated with IBD will also be discussed. Some of these supposed associations, such as gastrointestinal stromal tumors (GIST), are likely pure coincidence. Others, like small bowel adenocarcinomas, are more data-driven. Still others, as is the emerging
207 case with lymphomas, are so striking that they are presently altering the way we treat IBD. A common thread that will tie many of these malignancies together—particularly melanoma, squamous cell carcinoma, Kaposi’s sarcoma, and the lymphoproliferative disorders—is that the cancers most intimately tied to immune surveillance are those that should be of special concern to IBD patients.
Colorectal adenocarcinoma in IBD Colorectal carcinoma represents the best-known instance of an association between IBD and cancer. Although colorectal carcinoma rarely may be diagnosed during childhood or adolescence—in the setting of either Crohn’s colitis20 or UC21—a more common concern on the minds of most families is the child’s lifetime risk. Population-based studies, mentioned in the preceding section, have had conflicting results with respect to whether “all comers” among IBD patients have a generally increased risk above that of the population. Potential reasons for this include increasing safety and patient acceptance of colectomy and increasing use of colonoscopic screening. The data from studies looking solely at childhood-incidence IBD, on the other hand, suggest that there is a very meaningful risk of future colorectal cancer when IBD has its onset during the pediatric years. In a meta-analysis looking at studies reporting subsequent long-term colorectal cancer incidence among patients developing UC in childhood, Eaden and coworkers concluded that the cumulative probabilities of developing colorectal carcinoma were 5.5% at 10 years following onset of UC symptoms, 10.8% at 20 years, and 15.7% at 30 years. These rates for adenocarcinoma after childhood-onset UC appeared slightly higher than the cumulative probabilities found among those with adult-onset UC.22 Results for UC are echoed among Crohn’s colitis patients. Gillen and coworkers found among 113 patients with age of onset for Crohn’s colitis between 15 and 25 years old, that the relative risk of developing colorectal cancer was 13.3 (95% CI 3.6-34.1).23 Factors contributing to an increased risk of developing colorectal cancer in patients with all forms of IBD have been found to include a family history of colorectal cancer in a first degree relative (associated with a doubling of the relative risk),24 greater extent of colonic involvement,23,25 and younger age at diagnosis.25,26 This last risk factor, younger age at diagnosis, should be particularly striking to practitioners who treat children: in Ekbom’s study, in univariate analysis, the standardized incidence ratio for colorectal cancer among patients diagnosed with UC between age 0 and 14 was 118.3 times that of the control population (95% CI 63.0-202.3). A smaller, although still significantly elevated, incidence ratio persisted after adjusting for such factors as extent of disease at diagnosis and length of follow up.25 Lastly, the presence of colonic strictures in either UC27 or Crohn’s28 should prompt suspicion of malignancy.
208 Table 2
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007 Current colorectal cancer screening guidelines
Eaden and Mayberry, 200239
Itzkowitz and Present, 200596
Collins et al., 200638
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Screening colonoscopy 8–10 years after onset of symptoms Colonoscopy every 3 years in the second decade Colonoscopy every 2 years in the third decade Colonoscopy yearly by the fourth decade For left-sided disease, begin regular surveillance 15–20 years from onset of symptoms With sclerosing cholangitis, colonoscopy should be done annually Screening colonoscopy 8–10 years after onset of symptoms For proctosigmoiditis alone, risk is not felt to be increased over the population at large and standard population surveillance recommendations may apply For extensive or left-sided colitis, colonoscopy every 1–2 years following screening colonoscopy After 2 negative surveillance exams, may go to every 1–3 years until 20 years After 20 years, colonoscopy should be yearly If biopsies are “indefinite” for dysplasia, follow-up surveillance should occur within 3–6 months With sclerosing cholangitis, colonoscopy should be done annually For extensive colitis or Crohn’s colitis, colonoscopy 8 years after onset of symptoms For less extensive disease, colonoscopy 15 years after onset of symptoms Continue surveillance every 3 years for 10 years, every 2 years for 10 years, then every year If no histologic inflammation seen, intervals can be extended back to every 3 years With sclerosing cholangitis, colonoscopy should be offered promptly and then yearly thereafter
Other risk factors are particular to the type of IBD. In the case of UC, additional features associated with an increased risk of developing colorectal cancer include the presence of backwash ileitis29 and the coexistant diagnosis of sclerosing cholangitis.30-32 The risk imparted by sclerosing cholangitis is not abrogated among adult patients following orthotopic liver transplantation.33-35 With respect to Crohn’s disease, an increased risk of colorectal cancer is present in those with any colonic involvement by Crohn’s, but this is not the case for those with disease confined to the terminal ileum at diagnosis.26 Crohn’s patients undergoing colonoscopy for changes in symptoms were found to have higher odds of being diagnosed with colon cancer than matched controls having colonoscopy for screening or surveillance.36
Use of surveillance colonoscopy It has been surprisingly difficult to prove that colonoscopic surveillance reduces mortality from colorectal cancer in UC. Choi and colleagues found those undergoing surveillance were diagnosed at a significantly earlier Dukes’ stage than those not under surveillance in a nonrandomized study. There was a resultant 5-year survival of 77.2% among surveillance patients compared with 36% among nonsurveillance patients.37 Studies of the benefit of colonoscopy suffer from being nonrandomized (randomized trials of colonoscopy versus none would carry obvious ethical obstacles) and for lead time bias (that is, the perceived increase in survival simply because the cancer was detected long before it would have otherwise become clinically evident). Direct reduction in mortality as a result of colonoscopic surveillance has been difficult to prove in most studies. A recent Cochrane review states, “There is no clear evidence that surveillance colonoscopy
prolongs survival in patients with extensive colitis. There is evidence that cancers tend to be detected at an earlier stage in patients who are undergoing surveillance . . . .”38 Nonetheless, surveillance colonoscopy remains widely practiced, as it probably should be, and there are an abundance of published recommendations for its implementation and frequency. Current guidelines from a variety of sources are listed in Table 2. Eaden39 advocates that the same program should be followed for patients with Crohn’s colitis as for those with UC. At colonoscopy, the finding of high-grade dysplasia in any IBD patient should prompt a plan for colectomy, and the finding of low-grade dysplasia should also prompt serious consideration of colectomy, as many of these patients will progress to high-grade dysplasia or cancer in a short period of time.40,41 It is hoped that molecular markers will be validated that may even be amplified from stool DNA, to someday supplant colonoscopy as the preferred means of surveillance.38 Colectomy impacts on the colorectal cancer risk because most or all of the potentially cancer-bearing end organ is removed, but some mention should be made as to the risk of dysplasia in the ileal pouch and, if left behind, in the anal transition zone. Sarigol and colleagues at The Cleveland Clinic tracked 76 pediatric patients by means of mucosal biopsies of ileal pouches. Of the 76 patients, 64 patients had undergone stapled ileoanal anastomosis with preservation of the anal transition zone, whereas 12 had undergone rectal mucosectomy with hand-sewn anastomosis. With a mean interval of 5 years between surgery and last biopsy, dysplasia was not identified in any of the patients. The authors nonetheless recommend continued endoscopic surveillance of the pouch.42 This is probably wise, as a study of 178 adult patients from the same institution, each having undergone stapled ileal pouch– anal anastomosis with a minimum of 10 years of follow
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up apiece, identified dysplasia in the anal transition zone in 8 of the 178 (4.5%).43
Risk-modifying drugs in colorectal adenocarcinoma Ursodiol Altered excretion of bile acids, with an increased proportion of secondary bile acids contacting the colonic epithelium, has been postulated to be at the heart of the elevated risk of colorectal cancer found among IBD patients. This may be particularly relevant for those who develop both IBD and sclerosing cholangitis. Ejderhamn and colleagues in 1990 studied fecal bile acid excretion in 18 children with IBD in comparison to excretion from 5 controls who were healthy children of medical staff. In support of the concept of altered bile acid excretion, the investigators found that fecal excretion (in milligrams per day) as well as concentration (in milligrams per gram of feces) of conjugated and unconjugated bile acids were increased in the IBD patients compared with control children.44 Ursodiol supplementation, by changing the colonic concentration of secondary bile acids such as deoxycholic acid, has been studied with encouraging results as a cancerprotective agent in IBD. A cross-sectional study examining ursodiol use among 59 patients with UC and primary sclerosing cholangitis found that, even after adjustment for multiple variables including duration of disease and sulfasalazine use, ursodiol use was significantly associated with decreased prevalence of colonic dysplasia.45 In a randomized, placebo-controlled trial assessing ursodiol’s effect in 52 patients with sclerosing cholangitis, a subset of patients with both UC and primary sclerosing cholangitis demonstrated a relative risk of 0.26 for the development of colorectal dysplasia or cancer (95% CI 0.07-0.99).46 And in a prospective, double-blinded, randomized, placebo-controlled treatment study of 19 patients with UC who had already manifested colonic dysplasia, 2 placebo-treated patients progressed to require colectomy, whereas none of the ursodiol-patients patients developed progression of dysplasia, although overall aneuploidy and dysplasia scores were not found to be statistically different between the two groups.47 Particularly in the setting of UC without primary sclerosing cholangitis, ursodiol will require more study.
209 case-control study by Eaden and coworkers, which showed a dramatic 75% reduction (P ⬍ 0.00001 on univariate analysis) in cancer risk among UC patients taking 5-ASA. The results were partially confounded by increased contact with physicians and more frequent colonoscopy among the same patients, but the benefit persisted, albeit less dramatically (P ⬍ 0.05), on statistical analysis adjusting for these confounding variables, and was seen particularly in the group taking ⱖ1.2 g per day of mesalazine.49 A large epidemiologic study50 has bolstered these findings, but several other studies have failed to find a benefit.51,52 It may be that the observed benefit is present but either the magnitude of the effect is small, or that 5-ASA must be taken for many years to appreciate a benefit.
Folate Folate supplementation is thought by some practitioners to diminish colorectal cancer risk. Evidence for this is fair but not perfect. For example, a case-control study on folate intake by Freudenheim and coworkers compared 428 colon and 372 rectal cancer patients with matched neighborhood controls. The study identified a significant reduction in the risk of rectal cancer, but not colon cancer, among men (odds ratio 0.31, 95% CI 0.16-0.59) and a borderline reduction for women (odds ratio 0.50, 95% CI 0.24-1.03) for the use of folate.53 As the side effect profile is negligible, many have adopted its use.
Small bowel adenocarcinoma The occurrence of small bowel adenocarcinoma is mainly of concern among Crohn’s patients. In a population-based cohort of 1251 Crohn’s patients published by Persson and coworkers, a more than 15-fold increase in the rate of observed versus expected small bowel cancers was reported, which was highly statistically significant.54 A regional cohort of 373 patients studied by Munkholm and coworkers found a 50-fold increase in the relative risk for small bowel cancer among Crohn’s patients, also highly significant.55 Both of these studies used organ-specific statistics (eg, “small intestine”), so although it is likely that most of these small bowel cancers were adenocarcinomas, it cannot be definitively ascertained. Risk factors thought to predispose Crohn’s patients to small bowel cancer include jejunal Crohn’s disease, occupations involving hazardous material exposure, and use of 6-mercaptopurine.56
5-Aminosalicylates The anticancer effects of 5-aminosalicylate (5-ASA) compounds, including mesalazine and sulfasalazine, are controversial. There is underlying basic science showing that mesalazine reversibly inhibits proliferation and induces apoptosis in colon cancer cells.48 Human studies have shown conflicting results. The most famous report is a
Non-adenocarcinomas in IBD Neurofibromatosis and IBD There are three patients reported in the literature who had the coexistence of neurofibromas, cafe-au-lait spots, and
210 Crohn’s disease.57,58 Unless more data become available, this presently falls under the category of coincidence.
Gastrointestinal stromal tumors (GIST) and IBD In 1999, a Viennese group reported the resection of a 8 ⫻ 5 ⫻ 6 cm, terminal ileal, c-kit positive GIST in an area of Crohn’s ileitis.59 Another patient was found to have a c-kit positive GIST within a Meckel’s diverticulum discovered at laparotomy for initial flareup of terminal ileal Crohn’s.60 There have been three other reports of GIST coexisting with IBD,28,61,62 although two were termed leiomyosarcomas and c-kit staining was not mentioned. With five case reports, this entity appears coincidental as well.
Neuroendocrine tumors and IBD In 1994, an apparent curiosity was reported by Listinsky at the University of Alabama: a high-grade neuroendocrine carcinoma arising at a former ileostomy site, in an adult treated for ulcerative colitis since the age of 15.63 The neuroendocrine tumor was metastatic at presentation and the patient died under treatment for metastatic disease. Other case reports demonstrate carcinoids found incidentally in association with diseased bowel resected from IBD patients; for instance, Le Marc’hadour and coworkers present two cases of carcinoids found in appendices, where neighboring histologic abnormalities including hyperplasia of enteroendocrine cells were observed.64 This hints that a underlying drive to hyperplasia may exist, and that these are perhaps not merely incidental carcinoids. If that is true, one might expect that more cases and larger series exist. Indeed, Greenstein and colleagues have presented 6 carcinoids found in Crohn’s patients and 5 among UC patients, all discovered incidentally. Nine of the 11 were appendiceal and the remaining 2 were in the small bowel. But after presenting 11 such cases from the Mount Sinai Hospital, the authors point out that since Mount Sinai’s case records include over 3000 patients with IBD, there is no evidence that these 11 cases represent an elevated incidence of carcinoids among IBD patients.65 Finally, a larger series of 14 incidentally discovered neuroendocrine neoplasms was reported among IBD patients at the Cleveland Clinic. This series included 8 patients with Crohn’s and six with UC. Six of these 14 neuroendocrine neoplasms were found in the rectum, 4 in the appendix, 2 in the sigmoid, and 2 in the small bowel. Histology of 11 of the neuroendocrine tumors showed well-differentiated carcinoid, and the remaining 3 were poorly differentiated, mixed adenocarcinoma and small cell carcinoma.66 Surgeons and pathologists should be aware of the potential coexistence of IBD and carcinoids, but it remains unestablished as to whether there is a common etiologic mechanism. To date, it not been shown that incidence of carcinoids in IBD exceeds that of the normal population.
Seminars in Pediatric Surgery, Vol 16, No 3, August 2007
Soft-tissue tumors and IBD A 1986 paper by Israel and Nissenblatt reported two soft tissue tumors, an extraosseous osteosarcoma of the hip and a thoracic desmoid tumor, in patients who also developed IBD.67 Although a potential association with osteosarcoma has not been supported by a single case report since, the mention of desmoid tumor is noteworthy. Desmoid tumors have been reported in the mesentery among patients with Crohn’s, in the absence of Gardner’s syndrome.68 Prior surgery has been postulated as a risk factor for mesenteric desmoids in other cases.69
Melanoma and IBD The question of whether IBD patients have an underlying predisposition to the development of malignancy, on the basis of immune system dysregulation, was raised by Greenstein and associates in a 1992 study of 11 cases of melanoma among IBD patients. The authors posed the question as to whether some immunosuppressive aspect of the patients’ treatment could have been responsible for the later development of melanoma. Potential factors including use of steroids and azulfidine and exposure to radiation were considered, although on the basis of this series, none could be specifically implicated.70 However, other cancers with clear bases in immunodysregulation have been reported in the context of IBD, such as squamous cell carcinoma and Kaposi’s sarcoma.
Squamous cell carcinoma and IBD Case reports and small series describe anorectal squamous cell carcinomas arising in IBD patients.71-73 Greenstein and coworkers suggest that the frequency of these lesions among IBD patients observed by the Mount Sinai group is 30 times higher than that expected.74 Squamous cell cancers of the skin had a significantly increased standardized incidence ratio (2.2, 95% CI 1.1-3.9) in the Swedish populationbased cohort study of 4776 IBD patients compiled by Ekbom and coworkers This increased incidence was chiefly found among Crohn’s patients. Surveillance bias is discussed by the authors as a possible confounding factor.75 Little information has been compiled about the particular immunosuppressive treatments used before a diagnosis of squamous cell carcinoma.
Kaposi’s sarcoma and IBD Seven English-language case reports discuss the discovery of Kaposi’s sarcoma among patients with clear-cut IBD in the absence of human immunodeficiency virus (HIV).76-82 An additional two reports date from 1970 and earlier, so are unlikely to be related to HIV as well.83,84 In each case, patients had been treated with varieties of immunosuppression for their IBD (Table 3). Six cases had visceral involve-
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211
Table 3 Kaposi’s sarcoma reported in association with IBD among HIV(⫺) patients Author (year)
Patient IBD type and age duration Immunosuppression
Gordon (1966)84 65 Adlersberg 63 (1970)83 Meltzer (1987)53 83 Koop (1987)78 29 Thompson (1989)76 Puy-Montbrun (1991)77 Tedesco (1999)79 Cohen (2001)80
22 36 68 67
Bursics (2005)81 49
Unclear, 4 Steroids months UC, 9 months Steroids UC, 6 months Crohn’s, 4 years UC, 14 months Crohn’s, 16 years UC, 8 years
Steroids Steroids
Crohn’s, 25 years UC, 5 years
Steroids
Steroids Steroids, azathioprine Steroids
Steroids
ment by Kaposi’s sarcoma, and three were both visceral and cutaneous. All cases arose in the setting of immunosuppression. These cases are a harbinger of a much larger debate—that is, the role of immunosuppression in causing “secondary” malignancies among IBD patients. In this regard, no subject has stirred greater controversy than the topic of lymphoma.
Lymphoma and IBD The debate over whether there is an increased risk of lymphoma, as a result of IBD or its treatment, has recently become eclipsed by a 2007 report describing the occurrence of eight cases of hepatosplenic T-cell lymphoma among young patients (ages 12-31) with IBD. All eight had been treated with infliximab, a tumor necrosis factor-␣ blocking agent that is FDA-approved for the treatment of refractory IBD. Six of the eight cases were fatal within a year.85 A direct causality related to infliximab therapy is difficult to firmly establish, as the patients all received multiple prior or simultaneous immunosuppressive therapies. But the stark rarity of hepatosplenic T-cell lymphoma, with only about a hundred published cases,85 coupled with prior assertions that infliximab may be related to other cases of lymphoma,86,87 should give pause to any clinician who doubts that lymphoma can arise as a consequence of IBD therapy. Before this, a link between IBD and lymphoma was murky. Claims of an association were supported by numerous case reports, but among population-based or cohort studies, this association was either present,74 absent,54,75,88,89 or equivocal.90 A metaanalysis exclusively admitting cohort studies of azathioprine or 6-mercaptopurine use among IBD patients showed a significant relative risk of 4.18 for the development of lymphoma, lending further credence to the concept that this is related to immunosuppression. Even if this im-
parted risk is true, the authors note, the incidence is rare; several hundred to several thousand person-years of follow-up would be required to result in each additional case of lymphoma; and use of these immunosuppressants should probably not be contraindicated.91
Therapeutic possibilities from oncology The vigorous debate about immunosuppression highlights the fact that symptomatic control of IBD hinges on the ability to control the immune system, long before most patients are ever considered for intestinal surgery. Adoptive transfer of Crohn’s disease susceptibility is believed to have occurred from donor to recipient of a nonmyeloablative stem cell transplant, with subsequent clinical manifestation of the disease in the recipient.92 This is consistent with reports of other autoimmune diseases, such as autoimmune thyroiditis,93 that have appeared to result from adoptive transfer following transplant. If IBD can be transferred by immune system replacement, it follows that in reciprocal fashion it may also be cured by stem cell transplantation. Such ideas now have a foundation in clinical data. Ten of 11 patients with IBD who underwent allogeneic stem cell transplant for leukemia or myelodysplastic syndrome remained free of IBD symptoms at a median of 34 months follow up in a retrospective study.94 Immune system ablation followed by autologous T cell-depleted hematopoietic stem cell transplantation has been evaluated in a phase I trial for Crohn’s disease by Oyama and coworkers. Eleven of 12 patients, aged 15 to 38, were in sustained remission from refractory Crohn’s, at a median follow up of 18.5 months, and off all immunosuppressive therapies.95 Thus, from an unexpected corner of medicine, a therapy developed largely to surmount cancer itself may become a future component of IBD therapy.
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