Abstract

OBJECTIVE. The purpose of this article is to describe the CT findings of ipilimumab-associated colitis.
MATERIALS AND METHODS. In this retrospective study, 16 patients diagnosed with ipilimumab-associated colitis and available CT scans obtained at the time of symptoms were found by a search through the electronic medical record database. Two radiologists reviewed the CT images in consensus for the presence of bowel wall thickening, bowel mucosal enhancement, bowel distention, pneumatosis, pericolic fat stranding, and mesenteric vessel engorgement. Medical records were reviewed to note clinical features, management, and outcome.
RESULTS. The common CT findings of ipilimumab-associated colitis were mesenteric vessel engorgement (13/16 [81.3%]) followed by bowel wall thickening (12/16 [75%]) and fluid-filled colonic distention (4/16 [25%]). None of the patients had pneumatosis or halo or target signs. Two distinct CT patterns of ipilimumab-associated colitis were observed: first, the diffuse colitis pattern (n = 12), which is characterized by mesenteric vessel engorgement with mild diffuse bowel wall thickening or fluid-filled distended colon; and, second, the segmental colitis associated with diverticulosis (SCAD) pattern (n = 4), which is characterized by segmental moderate wall thickening and associated pericolic fat stranding in a segment of preexisting diverticulosis. Clinical features and management also differed according to the CT pattern. Patients with the diffuse colitis pattern presented with watery diarrhea and were treated with steroids, whereas the patients with the SCAD pattern presented with mixed watery and bloody diarrhea and cramping pain and were treated with steroids and antibiotics.
CONCLUSION. Two different radiologic and clinical manifestations of ipilimumab-associated colitis were observed: the diffuse colitis pattern and the SCAD pattern.
Immunotherapy is an emerging paradigm in cancer treatment. Nowadays, a greater understanding of immune regulatory and antitumor response mechanisms has been achieved. Cytotoxic T lymphocyte antigen–4 (CTLA-4) has been established as a key negative regulator of immune response, and blockade of CTLA-4 potentiates T cell–mediated immune response [1]. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully humanized monoclonal antibody that blocks CTLA-4 and thereby augments the T cell immune response to cancer cells [2, 3]. The U.S. Food and Drug Administration approved ipilimumab as monotherapy for unresectable or metastatic melanoma in March 2011 [4].
Inhibition of CTLA-4 by ipilimumab can also lead to immune-related adverse events, including colitis, dermatitis, hepatitis, endocrinopathy, and pancreatitis. The frequency of immune-related adverse events and severe dose-limiting immune-related adverse events (grades 3–4) increase with dose [4]. Colitis is the most common significant adverse effect [5]. Ipilimumab can cause dysregulation of gastrointestinal mucosal immune system, causing an inflammatory cell infiltration in gastrointestinal mucosa and leading to diarrhea and colitis-associated symptoms [6, 7]. These effects can be quite severe and can necessitate cessation of treatment.
Appropriate management of immune-related toxicities requires the cooperation of a multi-disciplinary team, including the treating oncologists, gastroenterologists, pathologists, and radiologists [4]. To our knowledge, there have been only a few reports briefly describing the imaging findings of ipilimumab-associated colitis as diffuse or focal bowel wall thickening [3, 8, 9]. Therefore, the purpose of this study is to describe the CT radiologic findings and characteristic patterns of ipilimumab-associated colitis that should be recognized in a timely fashion and communicated to referring oncologists.

Materials and Methods

Patients

This study was approved by the institutional review board of Dana-Farber Cancer Institute, and the requirement for informed consent was waived. Twenty-three patients with melanoma undergoing ipilimumab treatment who visited an outpatient clinic or emergency department with a chief complaint of gastrointestinal symptoms or who required consultation for gastrointestinal symptoms were identified in the electronic medical record database. An additional search of the radiology database did not add patients. Of the 23 patients identified, six patients were excluded because they had non–immune-mediated causes of their symptoms, as follows: one patient had constipation, one patient had blood-tinged stool due to hemorrhoids, one patient had a positive Clostridium difficile stool test, one patient had extensive peritoneal metastases, one patient had right lower quadrant pain due to large pelvic metastases, and one patient had colon perforation caused by necrosis of a serosal metastasis of the colon. The last patient was excluded because the colon perforation was secondary to disease response to ipilimumab rather than an immune-mediated adverse inflamma-tory event. The remaining 17 patients were diagnosed as having ipilimumab-associated colitis on the basis of the complete workup, including clinical features and radiologic, pathologic, endoscopic, or laboratory findings. One of these 17 patients was excluded because of the lack of an available CT scan at the time of symptoms. Finally, 16 consecutive patients (mean age, 62.4 ± 11.6 years; 12 men and four women) who were diagnosed with ipilimumab-associated colitis and who underwent CT scans at the time of gastrointestinal symptoms were included in this study.
Ipilimumab was administered at a dose of 3 mg/kg every 3 weeks during the induction period (four doses) and then every 12 weeks during the maintenance phase. All patients underwent contrast-enhanced CT of the chest, abdomen, and pelvis at treatment initiation (baseline CT) and every 3–4 months during ipilimumab treatment (restaging CT scans). All patients in our series also underwent CT scans of the abdomen and pelvis at the time of symptoms.

CT Acquisition

CT scans of the abdomen and pelvis or chest were performed by using a 64-MDCT scanner (Aquilion 64, Toshiba America Medical Systems) with the following protocols: 64-MDCT scanner at 0.5-mm collimation, 120 kVp, tube current maximum of 500 mA using dose modulation with noise index of 12.5 HU, 0.5-second gantry rotation time, and a table speed of 26.5 mm per rotation. One hundred milliliters of iopromide (300 mg I/mL; Ultravist 300, Bayer HealthCare Pharmaceuticals) was injected IV with an automated injector (Stellant, Medrad) at a rate of 2–3 mL/s, with a scan delay of 60 seconds. Oral contrast agent (diatrizoate meglumine; Gastrografin, Bracco Diagnostics) was administrated before the CT scans. Axial images with 5-mm thickness and coronal images with 4-mm thickness were reconstructed using standard abdomen algorithms and were transferred to the PACS.

Image Analysis

CT scans were evaluated on a PACS retrospectively and jointly by two radiologists with 12 and 7 years of experience. Disagreement was minor and was resolved through consensus. The CT scans were analyzed for the presence of bowel wall thickening, bowel mucosal enhancement, bowel distention, pneumatosis, perforation, pericolic fat stranding, and mesenteric vessel engorgement in the colon. The bowel wall thickness was measured at two representative locations on the PACS, and the mean value was used for grading. The degree of bowel wall thickness was graded as mild (4–8 mm), moderate (8–12 mm), and severe (> 12 mm), which is modified from the criteria described by Bharucha et al. [10]. Wall thickness of 4 mm or less was considered normal because the normal colonic wall thickness can reach 3–4 mm when the lumen is collapsed [11]. The extent of colon wall thickening were recorded as focal (a few centimeters), segmental (10–30 cm), multisegmental (separate sites of segmental bowel wall thickening), and diffuse (> 30 cm) [12]. The colonic mucosal enhancement was evaluated and compared with the enhancement of other segments of the gastrointestinal tract, such as the small bowel and stomach. The presence of mural stratification, such as a “target” or “halo” appearance of bowel, was recorded. Bowel distention was defined as large-bowel diameter greater than 6 cm or small-bowel diameter greater than 2.5 cm [13, 14]. Mesenteric vessel engorgement was defined as prominence or tortuosity of the vasa recta increased over the baseline CT.
CT scans performed at the time of gastrointestinal symptoms were compared with the baseline pretreatment CT scans to identify interval change or development of the aforementioned CT findings. Any available follow-up CT studies were also assessed for resolution of the acute colitis-related findings after cessation of ipilimumab.

Clinical Correlation

Clinical data regarding ipilimumab treatment duration, symptoms, laboratory abnormalities, pathologic results of endoscopic biopsy specimens, and the treatment of the ipilimumab-associated colitis were recorded during review of the medical records. The baseline CT scan obtained before the start of ipilimumab was compared with all available follow-up CT scans. The radiologic response according to the immune-related response criteria were determined at the time of diagnosis of ipilimumab-associated colitis at the time of next CT follow-up (i.e., complete response, partial response, stable disease, and progressive disease) [3].

Statistical Analysis

Results were statistically analyzed to identify the difference between patients with two distinct imaging patterns, which are described in the Results section. The Mann-Whitney U test was used to compare mean bowel wall thickness, and the Fisher exact test or chi-square test was used to compare the categoric data, using MedCalc software (MedCalc). All p values of less than 0.05 were considered to indicate a statistically significant difference.

Results

CT Findings

The clinical features and imaging findings of all patients are described in Table 1. The common CT findings of ipilimumab-associated colitis were mesenteric vessel engorgement (13/16 [81.3%]) followed by bowel wall thickening (12/16 [75%]). Mesenteric vessel engorgement was very common in the CT scans at the time of colitis symptoms, but resolved at the immediate follow-up CT scans in all patients with this finding. In four patients, only mesenteric vessel engorgement was noted, without bowel wall thickening, which may suggest that it is an early finding of ipilimumab-associated colitis. Fluid-filled distended colon suggestive of diarrhea was noted in four (25%) patients. Increased mucosal enhancement was noted in three (18.8%) patients. Small-bowel involvement was not present except in two patients showing mild wall thickening of terminal ileum. Colon perforation was noted in one patient. None of the patients with ipilimumab-associated colitis had pneumatosis or halo or target signs suggestive of bowel wall edema or bowel obstruction.
TABLE 1: Clinical Features and Imaging Findings of 16 Patients With Ipilimumab-Associated Colitis
Patient No.Treatment CycleClinical FeaturesImaging FindingsPathology ResultsTreatment
Diarrhea or Stools (Frequency)OthersBowel WallOthersUnderlying Diverticulosis
11Watery (4–6/d)HepatitisNoneNoneNoneNASteroid (oral)
23Watery (< 4/d)Abdominal pain and skin rashNoneMesenteric vessel engorgementNoneMild active colitisSteroid (oral)
33Watery (4–6/d)Nausea and vomitingNoneFluid-filled colonic distentionNoneNormal mucosaSteroid (IV and oral)
43Watery (< 4/d)NoneNoneFluid-filled distention and mesenteric vessel engorgementNoneMild active colitisSteroid (IV and oral)
52Watery (< 4/d)HypophysitisMultisegmental mild bowel wall thickening at terminal ileum, cecum, and sigmoidMesenteric vessel engorgementDiffuseMild active colitisSteroid (oral)
64Watery and mucus (4–6/d)Abdominal pain and feverDiffuse moderate bowel wall thickening of whole colonMesenteric vessel engorgementScatteredNASteroid (IV and oral)
72Watery (4–6/d)Fever and rectal painSegmental moderate bowel wall thickening of rectumNoneScatteredMild active colitisSteroid (IV and oral)
83Watery (⁥ 7/d)NoneSegmental mild bowel wall thickening of rectosigmoid colonMesenteric vessel engorgementDiffuseModerate-tosevere active colitisSteroid (IV and oral)
92Watery (4–6/d)NoneDiffuse mild bowel wall thickening of whole colonFluid-filled colonic distention and mesenteric vessel engorgementScatteredModerate-tosevere active colitisSteroid (IV and oral) and infliximab
103Frequent loose stools (4–6/d)Skin rashDiffuse mild bowel wall thickening of sigmoid and descending colonMesenteric vessel engorgementDiffuseSevere active colitisSteroid (IV and oral)
112Watery (> 8/d)Abdominal pain and feverDiffuse moderate bowel wall thickening of whole colon with fat stranding and bowel perforationMesenteric vessel engorgement and fluid and air-filled colonic distentionDiffuseSevere active colitisSteroid (IV and oral) and total colectomy
124Watery (4–6/d)Abdominal painDiffuse mild bowel wall thickening of ascending and transverse colonMesenteric vessel engorgementNoneNASteroid (IV and oral)
134Watery and bloody (4–6/d)Abdominal pain and skin rashSegmental moderate bowel wall thickening of sigmoid colonMesenteric vessel engorgementDiffuseModerate active colitisSteroid (IV and oral) and antibiotics
144Watery and bloody (≥ 7/d)Abdominal painSegmental severe bowel wall thickening of sigmoid colon with fat strandingMesenteric vessel engorgementDiffuseModerate active colitisSteroid (oral) and antibiotics
151Watery and bloody (4–6/d)Abdominal painSegmental moderate bowel wall thickening of sigmoid colon with fat stranding and segmental bowel wall thickening in terminal ileum and cecumMesenteric vessel engorgementDiffuseNASteroid (IV and oral) and antibiotics
164Frequent loose stools (≥ 7/d)Abdominal pain and feverSegmental moderate bowel wall thickening of sigmoid colon with fat strandingMesenteric vessel engorgementDiffuseMild active colitisSteroid (oral) and antibiotics

Note—NA = not available.

Two distinct patterns of ipilimumab-associated colitis were observed, as illustrated in Figure 1 and Table 2. The first pattern is characterized by mesenteric vessel engorgement with mild diffuse bowel wall thickening or fluid-filled distended colon. These are nonspecific findings frequently seen in any kind of colitis (Fig. 2). The second pattern is characterized by segmental moderate wall thickening and associated pericolic fat stranding in a segment of preexisting diverticulosis (Fig. 3). In this study, we labeled the first pattern as diffuse colitis and the second pattern as segmental colitis associated with diverticulosis (SCAD). The distribution of the bowel wall thickening varied in the patients with the diffuse colitis pattern, as follows: pancolitis (n = 3), terminal ileum or cecum and sigmoid colon (n = 1), ascending and transverse colon (n = 1), descending and sigmoid colon (n = 1), and rectosigmoid colon (n = 2). In contrast, the SCAD pattern in all four affected patients involved the sigmoid colon, where underlying diffuse diverticulosis was present. In addition, baseline CT in those four patients showed mild (n = 3) or moderate (n = 1) bowel wall thickening preexisting in the sigmoid colon, which may suggest the presence of subclinical chronic inflammation [15]. The SCAD pattern resembles typical diverticulitis seen in other settings, with similar appearance of segmental wall thickening, pericolic fat stranding, pelvic fascial thickening, mesenteric vessel engorgement, and a few inflamed diverticula.
Fig. 1A —Illustration of two distinct patterns of ipilimumab-associated colitis.
A, Diffuse colitis pattern is characterized by three findings: mild diffuse bowel wall thickening (straight arrows), mesenteric vessel engorgement (arrowheads), and fluid-filled colonic distention (curved arrow).
Fig. 1B —Illustration of two distinct patterns of ipilimumab-associated colitis.
B, Segmental colitis associated with diverticulosis pattern is characterized by segmental and circumferential bowel wall thickening (arrows) in sigmoid colon in area of preexisting diffuse diverticulosis and mesenteric vessel engorgement (arrowheads).
Fig. 2A —72-year-old woman with watery diarrhea during ipilimumab treatment.
A, Coronal contrast-enhanced CT image shows diffuse colitis pattern with mild diffuse bowel wall thickening (straight arrows), mesenteric vessel engorgement (arrowheads), and fluid-filled colonic distention (curved arrow).
Fig. 2B —72-year-old woman with watery diarrhea during ipilimumab treatment.
B, CT performed 1 month later shows progressive colonic distention and multifocal sites of perforation (arrowheads).
Fig. 3A —63-year-old man who presented with left lower quadrant pain and bloody diarrhea during ipilimumab treatment.
A, Axial contrast-enhanced CT image obtained before starting ipilimumab treatment (baseline CT) shows moderate wall thickening (arrow) of sigmoid colon with underlying diverticulosis.
Fig. 3B —63-year-old man who presented with left lower quadrant pain and bloody diarrhea during ipilimumab treatment.
B, Axial CT image obtained at time of symptoms shows segmental colitis associated with diverticulosis pattern, with severe segmental and circumferential sigmoid colonic wall thickening (arrow) and pericolic fat stranding (arrowheads).
TABLE 2: Radiologic Findings and Clinical Features of 16 Patients With Ipilimumab-Associated Colitis, by Colitis Pattern
Findings and FeaturesDiffuse Colitis Pattern (n = 12)Segmental Colitis Associated With Diverticulosis (n = 4)Sum (n = 16)pa
Radiologic findings    
 Bowel wall thickness (mm), mean ± SD6.2 ± 3.513.8 ± 7.68.3 ± 5.80.014
 Bowel wall thickening   0.046
  None404 
  Mild505 
  Moderate336 
  Severe011 
  Extent of bowel wall thickening   0.074
  None404 
  Segmental235 
  Multisegmental112 
  Diffuse505 
 Fat stranding1340.027
 Mesenteric vessel engorgement94130.529
 Fluid-filled bowel distention4040.517
 Underlying diverticulosis   0.077
  None505 
  Scattered diverticula303 
  Diffuse diverticulosis448 
Clinical features    
 Diarrhea and stool   0.001
  Watery11011 
  Watery and bloody033 
  Frequent loose stools112 
 Abdominal pain4480.077
 Fever3141.000

Note—Except where noted otherwise, data are no. of patients.

a
Fisher exact test for data of 2 × 2 table or chi-square test for data of 2 × 3 or 3 × 4 tables.
Between the two distinct CT patterns, the bowel wall thickness was significantly greater in the SCAD pattern than that in the diffuse colitis pattern (13.8 ± 7.6 mm vs 6.2 ± 3.5 mm; p = 0.014), and pericolic fat stranding was significantly more common in the SCAD pattern than that in the diffuse colitis pattern (75% vs 8.3%; p = 0.027). The fluid-filled colonic distention was found only in the diffuse colitis pattern (Table 2).

Clinical Features

The most common clinical symptoms in our series were watery diarrhea and increased number of bowel movements. The median number of treatment cycles and the time from beginning ipilimumab therapy to CT at the time of symptoms was 3 cycles and 8 weeks, respectively (range, 1–4 cycles and 2–14 weeks, respectively). In all patients, colitis symptoms started within 1 or 2 weeks after the last ipilimumab administration.
Differences in the clinical features between patients with the diffuse colitis pattern and patients with the SCAD pattern were observed (Table 2). In the patients with the diffuse colitis pattern, profuse watery stool was predominant, whereas the mixed watery and bloody diarrhea with frequently associated cramping pain predominated in the patients with the SCAD pattern. However, systemic symptoms such as fever and chills were not frequent in either groups. Examinations for stool leukocytes, stool cultures, and a C. difficile titer were within normal limits in all patients. Immune-related adverse events outside the gastrointestinal tracts were observed in five patients (skin rash, n = 3; hepatitis, n = 1; hypophysitis, n = 1).
Among patients with the diffuse colitis pattern, three were treated with oral steroids and nine were treated initially with IV steroids followed by oral steroids. Two patients were refractory to steroid therapy. In one patient, symptoms resolved after administration of infliximab, a monoclonal antibody against tumor necrosis factor–α used to treat autoimmune disease. In the other refractory patient, pancolitis with colonic distention progressed on serial imaging, and multifocal bowel perforation developed (seven perforation sites were confirmed on the surgical specimen). In all but two patients with the diffuse colitis pattern (one underwent total colectomy and one had no available follow-up CT), the abnormal CT findings at the time of colitis completely resolved on the follow-up restaging CT scans (median, 12 weeks; range, 8–17 weeks).
The patients with the SCAD pattern were treated with steroids and antibiotics. Symptoms resolved within 2–6 weeks after treatment in all patients. One patient showed marked improvement of the bowel wall thickening at the first follow-up CT performed 11 weeks after the colitis; the other three patients showed relatively slow improvement of bowel wall thickening, which decreased to baseline at the second follow-up CT scans (median, 22 weeks; range, 16–24 weeks).
Regarding treatment response at the time of development of the gastrointestinal symptoms (median interval from the beginning of the ipilimumab, 9 weeks), 14 of 16 patients (87.5%) achieved partial response (n = 4) or stable disease (n = 10), and only two patients (12.5%) had progressive disease. However, at the time of follow-up CT scans (median, 12 weeks; range, 8–23 weeks, after cessation of ipilimumab treatment), eight patients (50%) had stable disease and six patients (37.5%) had progressive disease. For two patients, no follow-up data were available. After cessation of ipilimumab treatment, treatment response changed from stable disease or partial response to progressive disease in six patients (37.5%).

Discussion

According to prior reports of ipilimumab-associated colitis [4, 7, 1618], the diarrhea has been described as watery or loose stool with 4–8 bowel movements per day, without fever, nausea, vomiting, or weight loss, but sometimes associated with abdominal pain and bloody diarrhea [5]. It has rarely led to serious complications such as intestinal perforation, which is seen in fewer than 1% of patients [4, 19]. CT findings of ipilimumab-associated colitis have included diffuse or focal bowel wall thickening [3, 9]. These descriptions are generally concordant with our results.
In four of 16 patients in our study, we observed CT findings of the SCAD pattern that resemble the typical findings of segmental colitis or acute diverticulitis of the sigmoid colon [11] (Fig. 1). Interestingly, we found that clinical features and management also differed according to the CT pattern. Patients with diffuse colitis pattern generally presented with watery diarrhea and were treated with steroids, whereas patients with the SCAD pattern generally presented with mixed watery and bloody diarrhea and cramping pain, treated with steroids and antibiotics. The clinical features of patients with the SCAD pattern were different from those of usual infectious diverticulitis, in terms of relatively mild systemic symptoms and lack of evidence of fecal bacterial pathogen or fecal leukocyte.
To our knowledge, there has been no report regarding a potential association between underlying diverticulosis and ipilimumab-associated colitis, even though some clinical trials regard the presence of active diverticulitis (not the presence of diverticula or history of diverticulitis) as a contraindication to the use of ipilimumab. Ipilimumab is known to cause dysregulation of gastrointestinal mucosal immunity, as evidenced by inflammatory cell infiltration into gastrointestinal mucosa and altered antibody levels to enteric flora [7]. The immune system in the intestinal mucosa, which is composed of epithelium, connective tissue, and immune cells (e.g., macrophages, dendritic cells, plasma cells, and T cells), is extremely complex and continuously interacts with antigens of food and of bacteria [6]. Disruption of this delicate system causes variety of immune-related bowel disease, such as inflammatory bowel disease. In case of ipilimumab-associated immune-related adverse events, disruption is thought to result from nonspecific or cross-reactive tissue damage caused by activated T cells [5]. The diverticula can result in loss of normal anatomic structure, fecal stasis, and subsequent bacterial overgrowth, which may cause disruption of mucosal immunity. Indeed, it has been reported that the frequency of sigmoid inflammation in inflammatory bowel disease, such as ulcerative colitis or Crohn disease, is increased in patients with coexistent colonic diverticulosis [20]. Likewise, we postulate that immune-mediated inflammation associated with ipilimumab administration might be increased in the coexistent colonic diverticulosis. Further investigation is warranted.
Segmental colitis associated with diver-ticulosis syndrome recently has been appreciated as a distinctive clinical entity and is characterized by chronic localized inflammation of the sigmoid colon bearing diverticula with rectal sparing (sigmoiditis), which may mimic endoscopic and pathologic features of inflammatory bowel disease [21]. The clinical presentation of the SCAD syndrome consists of left-sided abdominal pain, bowel alterations, and rectal bleeding; however, systemic symptoms such as fever, nausea or vomiting, or weight loss are rare, and laboratory findings are usually normal. The cause of SCAD syndrome has not been determined, but a role of bacterial overgrowth promoted by fecal stasis has been postulated [22]. It may be possible that the chronic inflammation in the SCAD syndrome is aggravated by the immune dysregulation effect of ipilimumab. Further investigation is warranted to identify the relationship between ipilimumab-associated colitis and underlying diverticulosis or the SCAD syndrome.
Over the past decade, chemotherapy-associated colitis has been an important cause of colitis. Various conventional chemotherapeutic agents can cause neutropenic enterocolitis characterized by cecal wall thickening on CT, right-sided abdominal pain, and fever, which are associated with neutropenia caused by a cytotoxic drug mechanism. New oral molecular-targeted agents, such as sorafenib, erlotinib, sunitinib, and imatinib, sometimes result in enterocolitis related to the oral administration route [23]. The molecular-targeted agents can cause variety of bowel toxicities in different patterns according to their drug mechanism. Bevacizumab can cause pneumatosis, perforation, and surgical anastomotic site dehiscence, probably because of ischemia caused by its antiangiogenic drug mechanism [24]. Rituximab, which is an anti-CD20 monoclonal antibody used as a form of B cell–targeted therapy in rheumatoid arthritis or lymphoma, can cause new-onset ulcerative colitis or exacerbation of preexisting colitis [24]. Ipilimumab is an immunomodulator with a mechanism of action different from those of other cytotoxic or molecular-targeted agents in that it enhances the host's immune response to treat cancer. Hence, ipilimumab-associated colitis may manifest in a different way. Ipilimumab is the first U. S. Food and Drug Administration–approved immunomodulating drug. Several novel immunomodulators, such as tremelimumab, are undergoing clinical trials. It is, therefore, worthwhile to note the characteristics of immune-related adverse events associated with immunomodulators.
Even though the CT findings of ipilimumab-associated colitis are nonspecific, the two distinct CT patterns described and another important observations are helpful for differentiating this type of colitis from others. One noteworthy observation is that there was no pneumatosis or bowel wall edema, including no halo or target signs. It can be helpful to exclude ipilimumab-associated colitis if those findings are present on CT. Mesenteric vessel engorgement was the most common finding (81.3%), and four patients with mild symptoms showed only mesenteric vessel engorgement without bowel wall thickening, which may suggest that mesenteric vessel engorgement is an early sign of ipilimumab-associated colitis. The observed mesenteric vessel engorgement was present only on the CT scans obtained at the time of colitis, not present on the baseline CT or the follow-up CT scans. Therefore, in clinical setting of diarrhea in patients with melanoma, interval engorgement of mesenteric vessels should be evaluated by comparison of the CT at the time of symptoms and baseline CT scan. Fluid-filled distended colon also can reflect the presence of diarrhea, an active process, and it should be noted. Ipilimumab-associated colitis is a significant complication and may lead to severe colitis and cessation of ipilimumab treatment. Early recognition and management is very important. It is therefore essential for radiologists to recognize the CT patterns of ipilimumab-associated colitis as well as the clinical manifestations.
This study has several limitations, including its retrospective nature. The number of patients is relatively small. In clinical practice, CT is performed selectively for clinically evident colitis, which can raise the issue of selection bias. Indeed, all patients in our study were treated with steroids after cessation of ipilimumab treatment. The proportion of imaging findings of ipilimumab-associated colitis can vary according to its severity. However, the included patients were screened to
exclude all possible confounding factors, permitting the description of the imaging findings of ipilimumab-associated colitis.
In summary, two different radiologic and clinical manifestations of ipilimumab-associated colitis were observed: the diffuse colitis pattern and the SCAD pattern. Mesenteric vessel engorgement and fluid-filled distended colon are also worth noting in that they can reflect the active process.

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Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: W468 - W474
PubMed: 23718569

History

Submitted: August 5, 2012
Accepted: September 28, 2012
First published: April 25, 2013

Keywords

  1. colitis
  2. CT
  3. diverticulosis
  4. ipilimumab
  5. segmental colitis

Authors

Affiliations

Kyung Won Kim
Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 450 Brookline Ave, MA 02115.
Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Seoul Asan Medical Center, Seoul, Korea.
Nikhil H. Ramaiya
Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 450 Brookline Ave, MA 02115.
Katherine M. Krajewski
Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 450 Brookline Ave, MA 02115.
Atul B. Shinagare
Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 450 Brookline Ave, MA 02115.
Stephanie A. Howard
Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 450 Brookline Ave, MA 02115.
Jyothi P. Jagannathan
Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, 450 Brookline Ave, MA 02115.
Nageatte Ibrahim
Department of Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA.

Notes

Address correspondence to K. W. Kim ([email protected]).

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