DOI: 10.1148/rg.235025162
(Radiographics. 2003;23:1287-1290.)
© RSNA, 2003
Systemic Candidiasis1
Nicholas J. E. Moore, MD,
Johnsey L. Leef, III, MD and
Yijun Pang, MD, PhD
1 From the Departments of Radiology and Pathology, University of Vermont School of Medicine, 111 Colchester Ave, Burlington, VT 05401. Received November 13, 2002; revision requested January 15, 2003 and received February 28; accepted March 5. Address correspondence to N.J.E.M. (e-mail: Nicholas.J.Moore@vtmednet.org).
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History
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A 71-year-old woman with acute myelogenous leukemia developed leukocytopenia and experienced multiple episodes of microbial infections 1 month after undergoing bone marrow transplantation and chemotherapy. Early on, the patient had a leukocyte count of less than 1,000 per high-power field and a neutrophil count of 0. Complications during hospitalization, including infection of a central venous catheter, led to treatment with multiple antibiotics and fluconazole. The patient developed new abdominal pain and fever during rebound leukocytosis, prompting evaluation with computed tomography (CT). At that time, the patient had a total leukocyte count of 62,000 and a neutrophil contribution of 72%. Despite aggressive therapy, including treatment for candidiasis with amphotericin B, the patient died of multiorgan failure 9 days after CT diagnosis of systemic candidiasis. An autopsy was performed.
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Imaging Findings
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Contrast material–enhanced CT of the abdomen and pelvis demonstrated innumerable hypoattenuating areas throughout the liver, spleen, and right kidney (Fig 1). The underlying hepatic, splenic, and renal parenchyma showed normal attenuation. There was no evidence of portal hypertension, biliary duct dilatation, or gastrointestinal inflammation. Small, bilateral pleural effusions and a pericardial effusion were present. Given the patient’s history and laboratory data, these findings strongly suggested systemic candidiasis.
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Figure 1a. Systemic candidiasis. (a) Axial contrast-enhanced CT scan shows bilateral pleural effusions (arrows) and a pericardial effusion (arrowhead), nonspecific findings that are consistent with Candida involvement in the chest. (b) CT scan shows countless 1-mm hypoattenuating areas throughout the liver and spleen in a predominantly peripheral distribution (arrows), a finding that is consistent with Candida microabscesses. (c) CT scan demonstrates multiple similar hypoattenuating areas in the right kidney (arrows) that also proved to be Candida abscesses.
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Figure 1b. Systemic candidiasis. (a) Axial contrast-enhanced CT scan shows bilateral pleural effusions (arrows) and a pericardial effusion (arrowhead), nonspecific findings that are consistent with Candida involvement in the chest. (b) CT scan shows countless 1-mm hypoattenuating areas throughout the liver and spleen in a predominantly peripheral distribution (arrows), a finding that is consistent with Candida microabscesses. (c) CT scan demonstrates multiple similar hypoattenuating areas in the right kidney (arrows) that also proved to be Candida abscesses.
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Figure 1c. Systemic candidiasis. (a) Axial contrast-enhanced CT scan shows bilateral pleural effusions (arrows) and a pericardial effusion (arrowhead), nonspecific findings that are consistent with Candida involvement in the chest. (b) CT scan shows countless 1-mm hypoattenuating areas throughout the liver and spleen in a predominantly peripheral distribution (arrows), a finding that is consistent with Candida microabscesses. (c) CT scan demonstrates multiple similar hypoattenuating areas in the right kidney (arrows) that also proved to be Candida abscesses.
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Pathologic Evaluation
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Gross examination of the liver showed innumerable subcapsular tan-white nodules that measured 1–3 mm in diameter and contained purulent material (Fig 2a, 2b). At the time of autopsy, it was estimated that these nodules replaced more than 20% of the liver parenchyma. Microscopic examination showed the nodules to be microabscesses filled with yeast forms, neutrophils, histiocytes, lymphocytes, and necrotic debris (Fig 2c). Similar gross and microscopic findings were seen in the spleen, including identification of yeast forms (Fig 3). Both the hepatic and splenic microabscesses were demarcated by discrete zones of fibrosis, indicating that they had probably developed over a period of weeks (Figs 2c, 3b).
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Figure 2a. Hepatic candidiasis. (a, b) Photographs of the sectioned liver (a) and the liver capsule (b) demonstrate 1-3-mm Candida microabscesses beneath the serosal surface and throughout the parenchyma. (c) On a photomicrograph (original magnification, x100; hematoxylin-eosin [H-E] stain) of the liver, each hepatic microabscess is filled with a mixture of inflammatory cells and necrotic debris. At higher-power photomicrography, yeast forms and pseudohyphae were also seen within the hepatic microabscesses. The fibrous capsule surrounding the microabscesses suggests that these lesions developed over several weeks.
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Figure 2b. Hepatic candidiasis. (a, b) Photographs of the sectioned liver (a) and the liver capsule (b) demonstrate 1-3-mm Candida microabscesses beneath the serosal surface and throughout the parenchyma. (c) On a photomicrograph (original magnification, x100; hematoxylin-eosin [H-E] stain) of the liver, each hepatic microabscess is filled with a mixture of inflammatory cells and necrotic debris. At higher-power photomicrography, yeast forms and pseudohyphae were also seen within the hepatic microabscesses. The fibrous capsule surrounding the microabscesses suggests that these lesions developed over several weeks.
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Figure 2c. Hepatic candidiasis. (a, b) Photographs of the sectioned liver (a) and the liver capsule (b) demonstrate 1-3-mm Candida microabscesses beneath the serosal surface and throughout the parenchyma. (c) On a photomicrograph (original magnification, x100; hematoxylin-eosin [H-E] stain) of the liver, each hepatic microabscess is filled with a mixture of inflammatory cells and necrotic debris. At higher-power photomicrography, yeast forms and pseudohyphae were also seen within the hepatic microabscesses. The fibrous capsule surrounding the microabscesses suggests that these lesions developed over several weeks.
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Figure 3a. Splenic candidiasis. (a) Photograph of the sectioned spleen shows Candida microabscess formation. (b) Photomicrograph (original magnification, x100; H-E stain) of the spleen demonstrates normal red and white pulp with an adjacent microabscess. Like the hepatic lesions, the abscesses contain inflammatory cells and necrotic debris. The yeast forms are consistent with Candida species.
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Figure 3b. Splenic candidiasis. (a) Photograph of the sectioned spleen shows Candida microabscess formation. (b) Photomicrograph (original magnification, x100; H-E stain) of the spleen demonstrates normal red and white pulp with an adjacent microabscess. Like the hepatic lesions, the abscesses contain inflammatory cells and necrotic debris. The yeast forms are consistent with Candida species.
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More disseminated infection was also confirmed by identification of microabscesses in the visceral pleura of the right lung, within the lung parenchyma itself, within the right renal cortex (Fig 4), and over the serosal surfaces of the gastrointestinal tract. Silver staining demonstrated both yeast forms and pseudohyphae within the pericardial and pleural fluid (Fig 5), a finding that is likely to account for the effusion seen at CT.
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Figure 4. Photomicrograph (original magnification, x200; H-E stain) of the kidney shows normal glomerular apparatuses adjacent to a microabscess. Again, note the fibrous pseudocapsule, which suggests that the abscess formed over several weeks.
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Figure 5. Photomicrograph (original magnification, x600; silver stain) of pericardial fluid sediment clearly depicts pseudohyphae and yeast forms, which were also seen in the pleural fluid. These findings correspond to the pericardial and pleural effusions seen at CT.
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Blastic cells were seen incidentally within the bone marrow, indicating relapse of acute myelogenous leukemia.
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Discussion
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Invasive systemic candidiasis is a significant cause of morbidity and mortality in patients with hematologic malignancies. It is a well-recognized complication of myelosuppressive therapy that classically manifests as nonspecific gastrointestinal complaints, hepatomegaly, and fever that increases with recovering neutrophil counts (1). Although the prevalence of hepatosplenic candidiasis appeared to be increasing during the 1980s (2,3), the more recent adoption of prophylactic antifungal therapy in at-risk patients has reduced its prevalence (4).
The typical patient is undergoing chemotherapy for a hematologic malignancy and has recovering neutrophil counts after a period of suppression. With immunosuppression, the risk of invasive Candida infection increases with the number of colonized sites (5). During periods of profound neutropenia, Candida species can invade intestinal mucosa and infect the liver via the portal circulation, which is believed to be a common route of systemic Candida spread.
After an assumed acute infection with Candida species that is often occult, neutropenic patients typically follow one of three courses: (a) they remain neutropenic and die of overwhelming infection despite therapy, (b) the neutropenia resolves and they respond favorably to therapy, or (c) the neutropenia reverses after candidiasis has become widespread and the resultant response to infection causes organ failure and death (6). In fact, the inflammatory response itself produces the classical clinical picture of systemic candidiasis. Furthermore, the inflammatory response is pivotal in defining the radiologic features of organ involvement. Imaging studies performed during the neutropenic phase are often normal.
Once clinical suspicion of hepatosplenic candidiasis is raised, other diagnoses such as hepatic veno-occlusive disease and graft-versus-host disease need to be considered. Laboratory tests are of limited value, however. Rebound leukocytosis (such as that seen in this patient) and elevated serum alkaline phosphatase levels have been described in hepatosplenic candidiasis but are also seen in graft-versus-host disease and veno-occlusive disease. Blood cultures are usually negative, and even positive stool cultures may merely represent colonization. Histopathologic findings can beconclusive but are dependent on analysis of representative tissue samples. Because percutaneous biopsies are more prone to sampling error, tissue samples obtained with laparoscopy or laparotomy are often necessary to make the diagnosis conclusively.
Both CT and ultrasonography (US) have proved useful in confirming hepatosplenic candidiasis, and magnetic resonance (MR) imaging is also emerging as a powerful tool. CT and MR imaging can demonstrate lesions in approximately 90% of patients, whereas US reveals lesions in 70%–75% of patients. Some reports suggest that MR imaging is more sensitive than CT in detecting visceral candidiasis (7), especially when a short inversion time inversion-recovery sequence is used (8). Investigators have also shown that MR imaging may be reliable in distinguishing the stage of disease: acute, subacute treated, or chronic healed (9). In addition, MR imaging can also serve to monitor response to antifungal therapy (10).
As in this case, CT findings in hepatosplenic candidiasis classically include multiple small, round, low-attenuation lesions distributed throughout the liver and spleen. Similar findings are sometimes seen in the kidney. Other than the liver and spleen, the kidney is the most frequently involved organ in systemic candidiasis. Occasionally, tiny areas of attenuation are seen central to the low-attenuation fluid collection, presumably representing pseudohyphae. Some of the microabscesses in the liver and spleen in this example contained such central areas of attenuation. Although not well seen in this case, peripheral enhancement has also been described in some cases. Despite the normal CT appearance of the bowel, widespread involvement was seen at postmortem examination. It is unclear whether this disease spread was radiologically occult or developed in the 9-day interim between CT and autopsy.
Although recent changes in prophylactic antimicrobial therapy in myelosuppressed patients may reduce the likelihood of systemic candidiasis in at-risk patients, the advances in more aggressive chemotherapy are likely to increase the vulnerable population. The need for accurate recognition of the radiologic features of systemic candidiasis is unlikely to change in the foreseeable future.
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References
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- Anttila VJ, Elonen E, Nordling S, Sivonen A, Ruutu T, Ruutu P. Hepatosplenic candidiasis in patients with acute leukemia: incidence and prognostic implications. Clin Infect Dis 1997; 24:375-380.[Medline]
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- van Burik JH, Leisenring W, Myerson D, et al. The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis: an autopsy study of 355 patients. Medicine (Baltimore) 1998; 77:246-254.[CrossRef][Medline]
- Schwartz RS, Mackintosh FR, Schrier SL, et al. Multivariate analysis of factors associated with invasive fungal disease during remission induction therapy for acute myelogenous leukemia. Cancer 1984; 53:411-419.[CrossRef][Medline]
- Kontoyiannis DP, Luna MA, Samuels BI, Bodey GP. Hepatosplenic candidiasis: a manifestation of chronic disseminated candidiasis. Infect Dis Clin North Am 2000; 14:721-739.[CrossRef][Medline]
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- Lamminen AE, Anttila VJ, Bondestam S, Ruutu T, Ruutu PJ. Infectious liver foci in leukemia: comparison of short-inversion-time inversion-recovery, T1-weighted spin-echo, and dynamic gadolinium-enhanced MR imaging. Radiology 1994; 191:539-543.[Abstract/Free Full Text]
- Semelka RC, Kelekis NL, Sallah S, Worawattanakul S, Ascher SM. Hepatosplenic fungal disease: diagnostic accuracy and spectrum of appearances on MR imaging. AJR Am J Roentgenol 1997; 169:1311-1316.[Abstract/Free Full Text]
- Sallah S, Semelka R, Kelekis N, Worawattanakul S, Sallah W. Diagnosis and monitoring response to treatment of hepatosplenic candidiasis in patients with acute leukemia using magnetic resonance imaging. Acta Haematol 1998; 100:77-81.[CrossRef][Medline]
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Imaging Findings
