Correspondence *Department of Medicine, University of Chicago, 5841 S Maryland Avenue, MC 4080, Chicago, IL 60637, USA

Email drubin@medicine.bsd.uchicago.edu

The case

A 75-year-old female presented to her gastroenterologist with a 1 month history of diarrhea. She described passing five nonbloody, liquid stools per day, associated with abdominal cramping and urgency. She denied having any nocturnal symptoms, fever or vomiting. Furthermore, she denied recent exposure to acquaintances who were unwell, food toxins or antibiotics.

Her past medical history was notable for chronic myelomonocytic leukemia (CMML), diagnosed 6 years previously and managed expectantly by monitoring monthly serial complete blood counts. The patient's medical history also included long-standing hypothyroidism, treated with a stable dose of levothyroxine, and gastroesophageal reflux disease, treated with rabeprazole for approximately 1 year. The patient's reflux was complicated by nondysplastic Barrett's esophagus, diagnosed 3 years previously. The patient's other medications included celecoxib and echinacea, initiated 6 months before the onset of her diarrhea and taken for osteoarthritis and cold prevention, respectively.

Physical examination revealed a well-nourished woman without orthostatic hypotension who was not distressed. Abdominal examination revealed normal, active bowel sounds and no organomegaly, tenderness, or palpable masses. A rectal examination revealed large, nonthrombosed, external hemorrhoids, normal rectal tone, and a rectal vault empty of stool.

Laboratory tests revealed a hemoglobin level of 9.1 g/dl, a platelet count of 103 10³ and a white blood cell (WBC) count of 24,000 (42% neutrophils, 11% band forms, 11% lymphocytes, 31% monocytes). These values were consistent with her known CMML and stable compared to a recently drawn CBC. Stool evaluation for Clostridium difficile and enteric pathogens was negative. Levels of tissue transglutaminase IgA, anti-Saccharomyces cerevisiae antibodies, and Escherichia coli outer membrane porin protein C were normal and the titer of perinuclear antineutrophil cytoplasmic antibodies was elevated. Rabeprazole, echinacea, and celecoxib were discontinued and she was empirically treated with metronidazole, stool-bulking agents, and loperamide, all without relief.

The patient's persistent symptoms prompted colonoscopic evaluation. The colonic mucosa was found to be diffusely erythematous and friable, with multiple scattered erosions present from the anal verge to the cecum. Random biopsies revealed diffuse chronic and active acute colitis without evidence of cytomegalic viral inclusions.

The initial impression from the colonoscopy and biopsy results was that the patient probably had ulcerative colitis and she was treated with mesalamine (4 g daily for 4 months), without improvement. Prednisone was added, and the dose was gradually increased to 40 mg daily; this treatment was continued for 8 weeks and resulted in partial relief of diarrhea; however, owing to mood disturbances and proximal muscle weakness, steroid therapy was discontinued. The patient's diarrhea persisted and she lost 9.07 kg (20 lb), at which time, approximately 5 months after her original presentation, she was referred to our center. Colonoscopy was repeated, which now showed rectal ulcerations and nodular lesions, pancolitis, and friability of the ileocecal valve (Figure 1); the terminal ileum could not be intubated.

Figure 1 Endoscopic image of a 75-year-old female with leukemic colitis.

The image shows rectal ulcerations and nodular lesions.

Full figure and legend (26K)Figures & Tables indexDownload Power Point slide (70K)

Biopsies of the rectum and colon demonstrated a dense mucosal infiltrate of immature monocytes and granulocytes (Figure 2), which was confirmed with immunohistochemical stains for CD4, lysozyme, and CD14. These findings were consistent with myelomonocytic leukemic infiltration of the colonic mucosa. Importantly, no evidence of acute blastic transformation was noted.

Figure 2 Histologic image of a 75-year-old female with leukemic colitis.

A dense mucosal infiltrate of immature monocytes and granulocytes can be seen, consistent with myelomonocytic leukemic infiltration of the colonic mucosa (stained with hematoxylin and eosin, original magnification 200).

Full figure and legend (96K)Figures & Tables indexDownload Power Point slide (146K)

The discovery of leukemic infiltration of the colon was interpreted as aggressive CMML and the patient was treated with systemic hydroxyurea (500 mg daily) and mesalamine rectal suppositories (1 g nightly). This resulted in a decreased WBC count and relief of her diarrhea. She remained stable on this therapy for 3 years, until she developed a recurrence of her diarrhea. Flexible sigmoidoscopy found ulcerations of the rectal mucosa; biopsies again demonstrated leukemic infiltration. The patient went on to develop a rising WBC count and neurologic deterioration consistent with acute disseminated encephalomyelitis. The patient died after a prolonged period in the neurological intensive care unit.

Discussion of diagnosis

Extramedullary involvement of the gastrointestinal tract with leukemia is relatively rare, as patients are much more likely to present with involvement of the lymphoreticular organs and sanctuary sites such as the brain, testes and ovaries.¹ The reported autopsy incidence of gastrointestinal involvement by leukemia ranges from 5.7% to 13% and is as high as 20% in cases of acute lymphocytic leukemia.^{1, 2, 3, 4} When it does occur, leukemic involvement of the gastrointestinal tract has been described in locations from the mouth to the anus, in both solid and hollow organs. In one of the largest autopsy series, Cornes and colleagues⁵ evaluated almost 15,000 consecutive autopsies and identified 264 cases of leukemia. They cited the stomach, ileum, and proximal colon as the most commonly involved sites, whereas the duodenum and distal colon were less commonly affected.

On the basis of autopsy data, microscopic involvement of the gastrointestinal tract is more common than gross leukemic infiltration (55% vs 25%).² Macroscopically, gastrointestinal tract involvement can assume a variety of forms, including necrosis, hemorrhage, ulceration, or polypoid lesions.⁵

Leukemic involvement of the gastrointestinal tract must be confirmed histologically, as it was in the case described here. Radiographic studies might produce results that raise suspicion of leukemic involvement, but they can also result in erroneous diagnoses that delay appropriate therapy. For example, Limberakis and colleagues⁶ described a case of leukemic infiltration of the colon that was manifest on plain films of the abdomen as thickening of the bowel wall in the transverse colon. In the same patient, a water-soluble contrast enema revealed severe ulceration that extended from the right colon to the rectum and mimicked severe ulcerative colitis.⁵ One study of 84 CT scans in leukemic patients found that CT could not, by itself, distinguish between old hematomas, foci of infection, and leukemic infiltration.⁷ As radiographic technology improves, however, characteristic findings of leukemic infiltration might be better visualized and identified correctly.

Diffrential diagnosis

In this case, diarrhea was the clinical manifestation of leukemic gastrointestinal infiltration. There are, however, many other possible clinically important presentations. Patients with mild, nonspecific abdominal pain, indigestion, or nausea⁸ have been described, as have patients with malabsorption due to protein-losing enteropathy.⁹ Acute presentations include intussusception, appendicitis, necrotizing enteritis, perforation, and sepsis.⁹ Multiple authors have reported anorectal manifestations including perianal ulcers, abscesses, mucosal sloughing, and severe prolapsing hemorrhoids thought to be infiltrated with leukemic cells.¹⁰

Inflammatory bowel disease

IBD comprises two major disorders: ulcerative colitis and Crohn's disease. Ulcerative colitis is characterized by inflammation of the mucosal layer of the colon, which typically begins in the rectum and potentially extends proximally. Crohn's disease is characterized by transmural inflammation that can affect any portion of the gastrointestinal tract, often in a discontinuous pattern. Diarrhea, abdominal pain, and gastrointestinal bleeding can be seen in patients with either disorder, depending on the location and extent of disease. The diagnosis is typically made based on a characteristic clinical history and typical endoscopic and pathologic findings. An association between the development of IBD and a pre-existing hematologic malignancy has been reported, however, the pathogenic relationship has not been elucidated.¹¹ Given her age, concomitant CMML, the absence of crypt architectural distortion on pathology specimens and the predominantly monocytic infiltrate, IBD was thought to be a less likely diagnosis in this patient.

Ischemic colitis

Ischemic colitis is a form of mesenteric ischemia. In most cases, the vascular insult is nonocclusive in nature and most commonly affects the 'watershed' areas of the colon such as the splenic flexure and rectosigmoid junction. Ischemic colitis is characterized by mild abdominal pain, diarrhea and rectal bleeding, severe cases of ischemic colitis can progress to peritonitis and shock. The diagnosis can be made based on a patient's clinical history, abdominal imaging and endoscopy, which frequently demonstrates a segmental distribution of mucosal injury and rectal sparing. Mild to moderately severe ischemic colitis requires supportive treatment, which includes intravenous fluids, bowel rest, and antibiotics. Severe cases can require surgical exploration and colonic resection. Although ischemic colitis has been reported in the setting of hematologic malignancy, this condition has most often been described in the setting of chemotherapy or in the presence of a hypercoagulable state.¹² In this patient, diffuse mucosal injury and rectal involvement argued against ischemia as the diagnosis.

Drug-induced diarrhea

Iatrogenesis should always be suspected in cases of acute and chronic diarrhea, especially when the initiation of a medication is temporally related to the onset of symptoms. Depending on the medication, drug-related diarrhea can be osmotic, secretory or inflammatory in nature. Levothyroxine, rabeprazole, celecoxib, and echinacea all have reported gastrointestinal toxicity with diarrhea;¹³ however, only celecoxib has been linked to the development of inflammatory diarrhea in the setting of microscopic colitis.¹ In this patient, chronic use of all of the above medications argued against a drug effect as the cause of new onset diarrhea.

Infectious diarrhea

Viral, bacterial and protozoal agents are well-known causes of acute and chronic diarrhea. Specific infectious etiologies are suspected on the basis of clinical history, travel, exposure to particular foods, recent exposure to antibiotics, and the patient's level of immune competence. Distinct histopathologic features mean that infectious enterocolitis is usually readily distinguished from IBD; however, there are several well-known infections that mimic IBD. These include (but are not limited to) shigellosis, amoebiasis, salmonellosis, yersiniosis, campylobacteriosis, tuberculosis and infections with C. difficile, cytomegalovirus, and herpes virus.² Stool studies and biopsy specimens in this patient revealed no evidence of acute or chronic infectious diarrhea.

Treatment and management

The course of disease experienced by this patient suggested that gastrointestinal involvement with leukemia might parallel leukemic disease activity, as acceleration of the patient's WBC doubling time coincided with a worsening of her diarrhea. As such, treatment of the underlying leukemia addressed the gastrointestinal symptoms.

Patient age, functional status, and comorbidities are all considered when the physician is deciding on a treatment plan with the patient. This often results in the exclusion of elderly patients from aggressive treatment options such as bone marrow or stem-cell transplantation, which might provide a cure. As such, many patients are left with the option of cytoreductive therapy with hydroxyurea, which is indicated in cases of rapidly rising WBC counts, constitutional symptoms, or visceral involvement.¹⁴ In this case, the age of the patient limited the options for aggressive therapy of her leukemia (and, therefore, of the associated colitis), so topical rectal mesalamine therapy was used to provide some symptomatic relief. This approach to the treatment of colonic involvement of CMML has not been previously described in the literature.

In this patient, the initially stable WBC count contributed to a delay in diagnosis; however, the elevated percentage of monocytes might have been an early indicator of CMML progression. Furthermore, there are two known types of CMML, with one form manifesting with higher WBC counts than the other. As such, the CBC may not be the best indicator of disease activity in the latter category of patients, to which this patient likely belonged.¹⁵

Conclusion

Leukemic involvement of the gastrointestinal tract must be considered in any patient with acute or chronic leukemia who presents with unusual gastrointestinal symptoms, or in any patient with symptoms of colitis if the etiology is not immediately evident. Pathologists who review gastrointestinal biopsy specimens from patients with underlying leukemia must be made aware of this clinical history, as leukemic involvement of the mucosa can be difficult to detect. Furthermore, when patients do not respond to therapy appropriate to the postulated diagnosis, prompt consideration must be given to alternative diagnoses. In this case, an initial misdiagnosis of ulcerative colitis resulted in aggressive steroid therapy. Treatment failure prompted further investigation, rather than more aggressive therapy for IBD. Finally, recurrent gastrointestinal symptoms in a patient with known leukemic involvement of the gastrointestinal tract should raise suspicion for leukemic relapse or progression.

References

1. Calvo N et al. (2006) Intestinal side effects of COX-2 inhibitors. Ugeskr Laeger 168: 1343–1344 | PubMed |
2. Shepherd NA (1991) Pathological mimics of chronic inflammatory bowel disease. J Clin Pathol 44: 726–733 | PubMed | ChemPort |
3. Barcos M et al. (1987) An autopsy study of 1,206 acute and chronic leukemias (1958 to 1982). Cancer 60: 827–837 | Article | PubMed | ISI | ChemPort |
4. Prolla JC and Kirsner JB (1964) The gastrointestinal lesions and complications of the leukemias. Ann Intern Med 61: 1084–1103 | PubMed |
5. Cornes JS et al. (1961) Gastroduodenal ulceration and massive hemorrhage in patients with leukemia, multiple myeloma, and malignant tumors of lymphoid tissue. Gastroenterology 41: 337–344 | PubMed | ChemPort |
6. Limberakis AJ et al. (1978) Leukemic infiltration of the colon. Am J Roentgenol 131: 725–728 | ChemPort |
7. Horowitch S and Wasserman LR (1959) Diseases of the anus and rectum associated with hematologic disorders. In Diseases of the Colon and Anorectum, 1159–1167 (Ed. Turell R) Philadelphia: Saunders
8. Sullivan MP and Hrgovcic M (1973) Extramedullary leukemia. In Clinical Pediatric Oncology, xii, 602 (Eds Sutow WW et al.) Saint Louis: Mosby
9. Cornes JS and Jones TG (1962) Leukaemic lesions of the gastrointestinal tract. J Clin Pathol 15: 305–313 | PubMed | ChemPort |
10. [No authors listed] (1975) Editorial: leukaemia and the bowel. Med J Aust 1: 89–90
11. Makarem JA et al. (2005) Crohn's disease in leukemia: report of a case, with a review of the literature. Dig Dis Sci 50: 1950
12. Dosik GM et al. (1979) Necrotizing colitis in patients with cancer. Am J Med 67: 646–656 | Article | PubMed | ChemPort |
13. Micromedex^® Healthcare Series [http://www.thomsonhc.com/]
14. Bowen DT (2005) Chronic myelomonocytic leukemia: lost in classification? Hematol Oncol 23: 26–33 | Article | PubMed |
15. Bennett JM et al. (1994) The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87: 746–754 | PubMed | ISI | ChemPort |

Contact the journal about this article

Subject areas under which this article appears: Inflammatory bowel disease | Large intestine