Colon Cancer After Infliximab Therapy for Crohn’sDiseaseFrederico Ferreira, Susana Lopes and Guilherme Macedo

Gastroenterology Department, Hospital de Sao Joao, Porto. Portugal

Abstract Infliximab is an effective agent in the treatment of patients with Crohn’s disease. Therapy with infliximab

is generally well tolerated but there are concerns about its effects on the incidence of cancer. This case report

refers to a 47-year-old patient with long-standing Crohn’s disease, without a family history of colorectal

cancer, who had a previous diagnosis of low-grade dysplasia that was not confirmed in subsequent studies,

and was diagnosed with adenocarcinoma of the colon with peritoneal invasion after the fourth infusion of

infliximab.

1. Introduction

Infliximab, a monoclonal antibody against tumor necrosis

factor alpha (TNFa), is a well-documented treatment for pa-

tients with Crohn’s disease and is generally well tolerated. There

are, however, concerns regarding the impact of TNFa blockadeon the incidence of infections, autoimmune disorders and ma-

lignancy. It is unclear whether these therapies contribute to

malignancy or the patients’ disease itself leads to it.

2. Case Report

A 47-year-old Caucasian man, a non-smoker with a history

of episodic diarrhoea and abdominal pain was referred to our

department. He had a previous history of bloody diarrhoea at

the age of 6 years, lasting for a few months when living in

Angola. At that time a sigmoidoscopy was performed revealing

extensive ulcerations in the descending and sigmoid colon, and

he was treated with a short course of corticosteroids with

clinical improvement. Thereafter he maintained episodic diar-

rhoea and abdominal pain for which he did not seek health care.

In August 2004, because of an acute exacerbation of these

symptoms, a colonoscopy was performed showing oedema,

friable mucosa and erosions in the ileum and right colon; bi-

opsies revealed polymorphic inflammatory infiltration and an

area of low-grade dysplasia in the caecum. The small bowel

follow-through showed rigidity and diminished calibre of the

ileum and caecum.

The diagnosis of ileocolonic Crohn’s disease was established

and therapy with budesonide and mesalazine was given, the later

stopped because of the patient’s gastrointestinal intolerance.

In the next year, two colonoscopies with multiple biopsies of

the caecum and ascending colon were performed, and they were

reviewed by two independent pathologists, with no signs of dys-

plasia. During this time, he had two exacerbations of the dis-

ease, needing corticosteroid therapy with prednisolone.

One year later he was admitted to the emergency department

with obstructive symptoms, and an abdominal computed to-

mography scan revealed a peri-apendicular abscess; the patient

improved with antibacterial therapy and began imunossupres-

sionwith azathioprine, which later had to be stopped because of

hepatotoxicity. Three months later he had another exacerbation

of the disease and started induction treatment with infliximab.

In February 2006, after the third infusion of infliximab he

had an acute appendicitis requiring surgery. Three weeks later

he was again admitted to hospital because of abdominal pain.

A colonoscopy with progression to the hepatic angle showed

oedema, friability and erosions in the descending and sigmoid

colon interposed with areas of spared mucosa. Histology showed

inflammatory changes and ulceration with no signs of dysplasia.

The abdominal computed tomography scan revealed thickened

ascending colon and terminal ileum stenosis. Infliximab was

re-started.

Five weeks after the fourth infusion of infliximab, the patient

was admitted to the emergency department with an episode

of bowel occlusion. The patient was submitted to exploratory

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laparotomy during which a tumor of the ascending colon

(figure 1) with peritoneal implants was found. A right hemi-

colectomy was performed. Histological examination showed a

moderately differentiated mucinous adenocarcinoma (figure 2),

with peritoneal invasion (figure 3) pT4N2M1. The classifica-

tion referred is the standard international classification used for

staging for colorectal carcinoma: American Joint Committee

on Cancer Classification. The inicial ‘‘p’’ means that the pre-

sented classification is based on the post-operatory pathology

examination. In the mucosa downstream to the neoplasia there

were several flat adenomas with variable grade dysplasia, in-

cluding areas of high-grade dysplasia.

The patient started chemotherapy, but his general condition

deteriorated progressively and he died 4 months later.

3. Discussion

As in other cases of malignancy reported in patients treated

with infliximab, the causal relationship between colon cancer

and therapy in the present patient is difficult to prove. In this

case, 2 years before, the patient had low-grade dysplasia in the

setting of active ileocolonic Crohn’s disease, but afterwards

seven colonoscopies with biopsies, reviewed by several path-

ologists, did not reveal any evidence of dysplasia. He was then

treated with infliximab and 5months later developedmetastatic

adenocarcinoma of the colon. Colon cancer in this patient was

therefore observed after several years of Crohn’s disease and

after therapy with azathioprine and prednisolone, but the tu-

mor was detected and rapidly progressed in temporal associ-

ation with infliximab therapy. Could the use of anti-TNFaantibodies have enhanced the transition to malignancy?

Although there is no definitive proof of a causal association

between infliximab therapy and cancer, theoretically the use of

infliximab could inhibit the natural immune surveillance

mechanism allowing premalignant cells to transform into ma-

lignant cells and further enhance their ability to metastasize.[1,2]

There are only a few reports of tumors in patients treated with

infliximab. Colombel et al.[1] reported nine cases of cancer in an

institution-based cohort of 500 patients with Crohn’s disease

treated with infliximab, three of these (two cases of lung cancer

and one case of non-Hodgkin’s lymphoma) were possibly re-

lated to infliximab therapy. There are also four published

case reports[2-4] that describe the observation of an aggressive

colon cancermanifesting shortly after infliximab therapy, two of

which after only two infusions of infliximab,[2,4] reinforcing the

possibility that TNFa blockademay lead to accelerated growth,

probably by neutralizing antitumor activity of the host im-

mune system. Also, Brown et al.[5] described eight cases of

lymphoma in patients treated with infliximab. Interestingly,

tumor regression was observed in one patient after infliximab

withdrawal in the absence of any other antitumor therapy.

Data reported from prospective studies, however, do not in-

dicate an increased incidence of cancer in patients treated with

infliximab, although the follow-up is short and the sample size

relatively small.[1]

On the other hand, colorectal carcinoma can occur in

patients with Crohn’s disease, being a rare complication thatFig. 1. Macroscopic view of colon adenocarcinoma.

Fig. 2. Mucinous adenocarcinoma infiltrating the colonic wall (haematoxylin

and eosin; ·100).

Colon Cancer After Infliximab Therapy 19

ª 2010 Adis Data Information BV. All rights reserved. Biodrugs 2010; 24 Suppl. 1

could only be demonstrated in large cohorts of patients. The

literature[6] shows a certain group of patients with Crohn’s

disease being at high risk of developing colorectal carcinoma:

early onset of inflammatory bowel disease, unresected extensive

colitis, age greater than 45 years, family history of colorectal

cancer, duration of more than 8 years, strictures, fistulae, pri-

mary sclerosing cholangitis and surgically excluded segments of

colon. This patient had at least three of these risk factors,

namely age at onset, current age above 45 years and duration of

the disease. The pathogenesis of carcinoma in patients with

Crohn’s disease is also still a matter of discussion, with some

studies documenting the development of dysplasia and genetic

alterations in p53 and K-ras genes.[6]

In this case the patient had a previous diagnosis of low-grade

dysplasia in a single biopsy. The predictive value of dysplasia is

well studied in ulcerative colitis and there is general agreement

that the finding of high-grade dysplasia warrants prompt co-

lectomy because of the high rate of synchronous colorectal

cancer; more controversial is the proper course of action in

patients found to have low-grade dysplasia, because although

dysplasia is a marker for future or concurrent malignancy, it

can also regress or remain stable for long periods and there is

currently no reliable way to predict which of these outcomes

is most likely.[7] Regarding dysplasia in Crohn’s disease, Siegel

et al.[8] reviewed their experience during a 20-year period of

30 patients with intestinal carcinoma of 2883 cases of resected

Crohn’s disease, concluding that most cases of Crohn’s-related

colorectal adenocarcinomas have dysplasia found in adjacent

mucosa, but only 41% had distant dysplasia. This lower rate

in patients with Crohn’s disease compared with ulcerative col-

itis may make cancer surveillance in Crohn’s disease less

effective. To complicate matters further, the diagnosis of dys-

plasia is not straightforward, even when using specific criteria

for diagnosis; interpretation of biopsy samples may be con-

founded by interobserver variation in the recognition and

grading of dysplasia.[9] As a result, establishing a productive

screening programme for epithelial dysplasia or focal cancers in

Crohn’s disease can be expected to prove difficult, even with

dye staining or the intriguing potential of newly evolving tech-

nologies, such as confocal microendoscopy.[9,10] Other tools to

predict later cancer development in Crohn’s disease, using

molecular or genetically based markers, are still needed and

should be pursued aggressively.[10]

Taking into consideration the increased risk of colorectal

cancer in patients with Crohn’s colitis, these patients should

probably undergo surveillance as is the custom in ulcerative

colitis. The precise guidelines for surveillance inCrohn’s disease

are, however, not yet well established.

In conclusion, this case report refers to a patient with

Crohn’s disease, who had a previous diagnosis of low-grade

dysplasia that was not confirmed in subsequent studies, and

developed adenocarcinoma of the colon 5 months after begin-

ning therapy with infliximab. In this case infliximab might be

related to cancer either as a causal association or by enhancing

it in a previously susceptible patient. While this association is

not clearly studied, increased surveillance is warranted in

patients treated with infliximab or other TNFa-blocking agentswith regard to secondary neoplasms, especially in patients with

a higher risk of cancer, such as patients with longstanding and

not well treated Crohn’s disease. This studymay also encourage

the reporting of other similar cases.

Acknowledgments

Dr Ferreira received honoraria for the submission of the case report,

which was funded by Schering-Plough/MSD Portugal. The other authors

declare no potential conflicts of interest relevant to this case report.

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Fig. 3. Neoplastic cells infiltrating the visceral peritoneum (haematoxylin

and eosin; ·100).

20 Ferreira et al.

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Correspondence: Frederico Ferreira, Gastroenterology department Hospital

de Sao Joao, Alameda Professor Hernani Monteiro, 4200-319 Porto.

E-mail: fredericoferreira2@hotmail.com

Colon Cancer After Infliximab Therapy 21

ª 2010 Adis Data Information BV. All rights reserved. Biodrugs 2010; 24 Suppl. 1