Cyclic neutropenia

An 11-year-old boy with recently diagnosed acute lymphoblastic leukemia presented to the emergency department with severe abdominal pain that began approximately 24 hours prior to presentation. The pain was localized to the right lower quadrant with radiation to the epigastrium. The patient characterized the pain as sharp and aggravated by movement. He also complained of fever up to 40.5°C. Other symptoms included nausea, vomiting, and diarrhea. he denied melena, hematochezia, or pulmonary or urinary symptoms.

He had completed his induction chemotherapy with vincristine, daunorubicin, methotrexate, and prednisone 1 week before presentation. Of note, he had been treated prophylactically with ceftazidime and oxacillin for his significant neutropenia.

On examination, the patient had a temperature of 39°C, pulse of 110 beats per minute, respirations of 26 breaths per minute, and blood pressure of 90/50 mm Hg. Physical examination revealed a diffusely tender abdomen with guarding and rebound tenderness, especially in the right lower quadrant. Bowel sounds were markedly decreased. Laboratory findings included a white blood cell count of 800/µL (reference range, 4000-10 000/µL); hematocrit, 23% (reference range, 31%-43%); and platelet count, 161 X 10^sup 3^/µL (reference range, 150-350 × 10^sup 3^µL). Abdominal radiographs showed a markedly thickened right ascending colon wall with a moderate amount of ascites, but no free air was seen. The patient was immediately taken to the operating room.

Intraoperatively, the peritoneal surfaces were diffusely covered by serofibrinous exudates. The cecum was edematous, hemorrhagic, and thickened. A right hemicolectomy with ileostomy and mucous fistula was performed, and the specimen was submitted to the surgical pathology department, where it was processed routinely.

Grossly, the serous surface of cecum showed the changes described above. The appendix was unremarkable. The cecum was opened longitudinally to reveal a hemorrhagic and edematous mucosa with multifocal ulceration and necrosis, as illustrated in Figure 1. No perforation was identified. Histologically, mucosal ulceration, intramucosal hemorrhage, and necrosis were evident, together with a mild to moderate mononuclear inflammatory infiltrate that consisted mainly of lymphocytes, plasma cells, and histiocytes. No evidence of a leukemic infiltrate was identified. Significantly, polymorphonuclear leukocytes and granulocytes were strikingly absent (Figure 2). A Gram stain revealed abundant gram-positive bacilli (Figure 3), whereas a silver stain showed fungal forms most consistent with Candida species (Figure 4).

What is your diagnosis?

Pathologie Diagnosis: Typhilitis (Neutropenic Enterocolitis)

Neutropenic enterocolitis (NE) was originally described in 1970 in an autopsy series as a terminal complication of childhood leukemia in patients who were neutropenic as the result of chemotherapy or aplastic crisis.1 Neutropenic enterocolitis is a life-threatening complication in patients treated for hematologic malignancies and has been seen more frequently in these patients in recent years because of the increasing use of intensive chemotherapy regimens.2 It has also been described in patients with solid tumors, multiple myeloma, aplastic anemia, acquired immunodeficiency syndrome, and cyclic neutropenia.3

The pathogenesis of NE is unclear but appears to be multifactorial. It is believed to involve initial mucosal damage followed by inflammation and edema, which progress to ulceration, necrosis, and perforation.4 The cecum is the most vulnerable portion of the lower gastrointestinal tract to developing NE, because it is the least vascularized and most distensible region of the colon.

The finding that most cases of NE occur in leukemic patients treated with chemotherapy has led to the hypothesis that cytotoxic chemotherapeutic medications are important in the pathogenesis. Chemotherapeutic drugs may predispose the cecum to breaks in its mucosal layer that serve as points of entry for bacteria and fungi. Numerous chemotherapeutic agents have been associated with the development of NE, including cytarabine, daunorubicin, methotrexate, vincristine, paclitaxel, doxorubicin, and steroids.5

Prolonged exposure to antibiotics results in a marked shift in the gut microflora toward toxin-producing bacteria, such as Staplylococcus aureus, Pseudomonas aeruginosa, and Clostridium septicum.6 Necrosis of the mucosal surface of the ileocecal region probably provides a favorable environment for the spores of Clostridium species to germinate and may be their portal of entry into the bloodstream.

Often, NE is difficult to diagnose on the basis of clinical findings alone. Symptoms such as abdominal pain, fever, diarrhea, and gastrointestinal bleeding are nonspecific, and routine laboratory tests are of limited value in the diagnosis. The use of steroids may further obscure the diagnosis by masking the symptoms of abdominal pain altogether. In addition, the full Symptomatologie complex of severe abdominal pain, vomiting, diarrhea, fever, melena or hematochezia, and sepsis may occur within hours or within a number of days.

The pattern of NE on plain abdominal radiographs is nonspecific. Although ultrasonography may be used, the imaging modality of choice for diagnosing NE is computed tomography. Computed tomography demonstrates diffuse thickening of the cecal wall, intramural edema or hemorrhage, inflammatory bowel changes, free air, and abscess formation. Computed tomography can also be used to differentiate NE from other disease processes, including pseudomembranous colitis, appendicitis, appendiceal abscess, or lymphomatous deposits,7 which may have a similar presentation.

Gross pathologic findings usually include diffuse bowel wall thickening with mucosal and intramural edema and necrosis, mucosal ulcerations, and intramural or intraluminal hemorrhage. Histologically, ulceration and hemorrhagic necrosis of the intestinal mucosa are generally present, as well as a mild to moderate mononuclear inflammatory infiltrate made up of lymphocytes, plasma cells, and histiocytes. Absence of granulocytes is a significant and typical feature of the lesions. The microbiologie study of the pathologic specimens always shows bacterial and/ or fungal contamination, including Candida species and Aspergillus fiimigatiis.

The management of NE has evolved as clinical experience with the disease has grown. Timely conservative treatment may interrupt progressive necrosis and permit resolution of NE8; selective surgical management of these patients with laparotomy is reserved for patients with severe presentations and is subject to traditional surgical complications, such as perforation, abscess, gastrointestinal tract bleeding, and obstruction.

References

1. Wagner ML, Rosenberg HS, Fernbach D), Singleton EB. Typhilitis: a complication of leukemia in childhood. AIR Am J Roentgcnol. 1970;109:341-350.

2. Sloas MM, Flynn PM, Kaste SC, et al. Typhilitis in children with cancer: a 30-year experience. Clin Infect Dis. 1993:17:484-490.

3. Bavaro MF. Neutropenic enterocolitis. Curr Gastroenterol Rep. 2002;4:297301.

4. Paulino AFC, Kenney R, Forman EN, et al. Typhilitis in a patient with acute lymphoblastic leukemia prior to the administration of chemotherapy. Am J Pediatr Henwtol Oncol. 1994:16:348-351.

5. Pastore D, Specchia C, Mele G, et al. Typhlitis complicating induction therapy in adult acute myeloid leukemia. Leuk Lymphoma. 2002;43:911-914.

6. Newbold KM, Lord MC, Baglin TP. Role of dostridial organisms in neutropenic enterocolitis. J Clin Pathol. 1987:40:471.

7. Kirkpatrick ID, Creenberg HM. Gastrointestinal complications in the neutropenic patient: characterization and differentiation with abdominal CT. Radiology. 2003;226:668-674.

8. Kouroussis C, Samonis G, Androulakis N, et al. Successful conservative treatment of neutropenic enterocolitis complicating taxane-based chemotherapy: a report of five cases. Am J Clin Oncol. 2000;2:309-313.

Sa Wang, MD; Oluwole Fadare, MD

Accepted for publication September 4, 2003.

From the Departments of Pathology and Laboratory Medicine, Yale New Haven Hospital, Yale University School of Medicine, New Haven, Conn.

Corresponding author: Sa Wang, MD, Department of Pathology and Laboratory Medicine, Yale New Haven Hospital, CB 407, 20 York St, New Haven, CT 06510 (e-mail: sa.wang@yale.edu).

Reprints not available from the author.

Copyright College of American Pathologists Feb 2004
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