British Journal of Radiology 75 (2002),275-278 © 2002 The British Institute of Radiology
Cryptococcus infection in a patient with nasopharyngeal carcinoma: imaging findings mimicking pulmonary metastases
L-M Sun, MD
1
T-Y Chen, MD
2
W-J Chen, MD
3
M-J Hsieh, MD
4
J-W Liu, MD
5
C-C Huang, MD
3 and
C-J Wang, MD
1
Departments of 1 Radiation Oncology, 2 Radiology, 3 Pathology and 4 Division of Thoracic and Cardiovascular Surgery, Department of Cardiovascular Surgery and 5 Division of Infectious Diseases, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital Kaohsiung Center, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 833, Taiwan
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Abstract
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An asymptomatic pulmonary mass was found in a 42-year-old unmarried male with controlled nasopharyngeal carcinoma (NPC) during routine follow-up chest radiography 8 months following completion of radiotherapy. Chest CT demonstrated a 3x2 cm2 left lower lobe (LLL) mass, with further small nodules in the same lobe. A presumptive diagnosis of lung metastases was made, and the patient underwent surgical resection with left lower lobectomy and mediastinal lymph node dissection. Pathologic examination of the masses in the LLL revealed granulomatous inflammation with cryptococcus infection. The dissected lymph nodes revealed anthracosis. The patient received 6 months of antifungal treatment with fluconazole. His NPC showed no evidence of local recurrence or distant metastases. Recognition that pulmonary cryptococcus infection can mimic metastases is important in reaching the correct diagnosis and therefore determining the correct treatment.
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Introduction
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Nasopharyngeal carcinoma (NPC) is a highly prevalent malignancy in south-east China, Hong Kong and Taiwan. Radiation therapy (RT) is the main treatment modality for all locally and regionally confined stages. Bone, followed by lung and liver, are the most common sites of distant metastases [1, 2]. Infection has been recognized as a complication in patients with NPC [3]. We describe a patient with NPC treated with RT, whose follow-up chest radiograph revealed pulmonary masses. CT findings favoured lung metastases. He underwent surgical resection of the lung nodules following a presumptive diagnosis of lung metastases from NPC. However, the pathology revealed granulomatous inflammation with cryptococcus infection. He received antifungal treatment thereafter. His NPC showed no evidence of recurrence.
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Case report
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A 42-year-old male steelworker diagnosed with poorly differentiated NPC was referred for consideration of RT. Complete oncology work-up demonstrated T2bN0M0, stage IIB disease [4], and radical RT without systemic chemotherapy was prescribed. External beam irradiation was given over 2 months (dose to the nasopharyngeal area 75.6 Gy/42 fractions; dose to the bilateral neck lymphatics 61 Gy/33 fractions). The patient tolerated irradiation well, without interruption of the treatment schedule.
After treatment, regular follow-up with nasopharyngoscopy showed no local recurrence. 8 months after completion of RT, during a routine check up, an asymptomatic pulmonary mass was found on the chest radiograph (Figure 1
). Chest CT demonstrated a 3x2 cm2 left lower lobe (LLL) mass with attachment to the adjacent pleura (Figure 2). Further smaller nodules were also found, but there was no mediastinal lymphadenopathy. These features were suggestive of multiple pulmonary metastases.
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Figure 2. Axial CT demonstrating a 3x2 cm2 left lower lobe mass (arrow) with attachment to the adjacent pleura. There is another nodule affecting the posterior basal segment more centrally (white arrowhead).
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Following a presumptive diagnosis of lung metastases from NPC, the patient underwent surgical resection. Operative findings revealed a 4.5 cm tumour in the LLL, with three other separate tumours in the same lobe. Left lower lobectomy with regional (N1) and mediastinal (N2) lymph node dissection was performed. Pathological examination of the lung masses showed consolidation and granulomatous inflammation with infiltration of lymphocytes, histiocytes and multinucleated giant cells. Groups of yeast-form fungi in the alveolar spaces and fibrinoid exudates were also noted (Figure 3). A special stain with mucicarmine proved cryptococcus infection (Figure 4). The dissected lymph nodes (N1 and N2) showed deposition of anthracotic pigments. The patient's HIV antibody was negative. However, serology test for cryptococcus antigen was positive, with a 1:128 titre (CALAS kit; Meridian Diagnostics, Inc., Cincinnati, OH). The India ink stain of cerebrospinal fluid (CSF) for cryptococcus was negative. Microscopy and culture for acid fast bacilli was negative. Antifungal treatment (fluconazole) was instigated for 6 months. The patient's NPC remained locally controlled, with no evidence of distant metastases. The follow-up chest radiograph returned to normal.
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Figure 3. (a) The lung tissue reveals chronic granulomatous inflammation, with fibrosis and consolidation of the interstitium. There are dense lymphocytic and histiocytic infiltrates, with scattered multinucleated giant cells (arrowheads) noted (haematoxylin & eosin stain, x100). (b) Numerous, variable size yeast forms of fungi (arrows) are present in the giant cells or in the extracellular areas (periodic acid Schiff stain, x400).
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Figure 4. Encapsulated forms of cryptococcus (arrows) are well demonstrated by mucicarmine stain (x1000).
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Discussion
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NPC has unique characteristics with regard to its epidemiology, histological features and response to RT. The prognosis of patients with localized disease is fair, with a 5-year survival rate of 50–60% [1]. However, patients with stage IVC (distant metastases) disease have a grave outcome. For metastatic lesions, systemic chemotherapy can be offered, and surgical excision and/or RT may be given to selected patients with palliative intent. Lung metastases are not rare in NPC patients, and the median survival time is 16.3 months [2]. The diagnosis of lung metastases is based on imaging findings and should be confirmed by pathology. In the case presented here, imaging studies were strongly suggestive of pulmonary metastases but the diagnosis was changed to fungal infection after surgery and pathological examination.
Infection has been recognized as a complication in patients with malignancy [3]. An immunocompromised status caused by treatment toxicity or tumour involvement of bone marrow may contribute to this. In patients with NPC and other head and neck cancers, the occurrence of oropharyngeal candidiasis is not rare during the course of RT and it may manifest as an acute toxic effect of treatment [5]. Cryptococcus is a systemic infection caused by the encapsulated yeast-like fungus Cryptococcus neoformans. Inhalation of the organism is considered to be the usual route of infection. Two distinct varieties of Cryptococcus neoformans are recognized based on phenotypic, serological, genetic, biochemical and epidemiological criteria. Var. neoformans is found worldwide and is the type isolated from avian excreta. Healthy persons with a history of heavy exposure to pigeons have a much higher rate of positive delayed skin tests to cryptococcal antigen [6]. The patient in this study did not breed pigeons, and the possibility of direct infection from this route should be low. Var. gattii is found in tropical and subtropical climates and is associated with the eucalyptus tree. Considering the subtropical and tropical localization and plantation of eucalyptus trees in Taiwan, there is evidence to show significant prevalence of var. gattii in this area [7, 8].
Patients with immunologic defects in T-cell mediated host defense mechanisms appear to be at increased risk for cryptococcosis. Currently, AIDS is the predisposing factor in approximately 80–90% of cryptococcal infections [8]. The central nervous system (CNS) is the most frequently affected site. CNS involvement is almost always indicated by abnormalities in CSF. Smears using India ink demonstrate the organism in suspected cases. Meningitis is the most common manifestation and has an indolent presentation, which may lead to a delay in diagnosis. CNS cryptococcosis is more effectively demonstrated by MRI than by CT. CT findings are not specific and may be confused with other infectious inflammatory, vascular or neoplastic disorders. The spectrum of MRI appearances reflects the pathological mechanism of invasion by the fungus, but a normal CT does not exclude the diagnosis [9, 10]. This patient's anti-HIV antibody was negative. The India ink CSF study for cryptococcus was negative and the patient's infection seemed to be confined to the lung alone. Pulmonary cryptococcosis may be asymptomatic or may cause minor pulmonary symptoms. In non-immunosuppressed patients, pulmonary cryptococcosis may progress or regress spontaneously, or may remain stable for long periods.
Three forms of pulmonary cryptococcus disease are recognized: (1) air space collections of fungus, causing well defined masses; (2) granulomatous infection, producing poorly defined masses; and (3) airway colonization, resulting in no significant radiographic findings [11]. Pulmonary manifestations on imaging commonly result in a single, fairly well circumscribed mass that is usually at the periphery of the lung and is often pleural-based. Adjacent clusters of small nodules may accompany the larger nodule. Although an isolated cluster of small pulmonary nodules is strongly suggestive of benign disease [12], larger nodules may mimic metastatic disease. Calcification of the nodule(s) and the adjacent lymph nodes is extremely uncommon, and cavitation is relatively uncommom compared with its frequency in the other mycoses. As with blastomycosis, larger mass-like opacities with minimal infectious symptoms tend to suggest primary or metastatic disease [13].
Percutaneous fine needle aspiration biopsy of lung is a relatively simple invasive procedure with good patient acceptance, low morbidity and almost negligible mortality. It provides a diagnosis of pulmonary, hilar and mediastinal masses quickly and accurately, but should be limited to cases that are both truly indicated and technically feasible and to those in which the possible benefits outweigh the risks [14, 15]. This procedure would have spared this patient a lobectomy. However, patients with a single known primary malignancy and multiple pulmonary nodules who present for percutaneous needle biopsy will have pulmonary metastases in the vast majority of cases. Biopsy in these patients rarely changes the clinical course, as other diagnoses are rarely established [16]. Given the clinical circumstances, our patient proceeded to surgery without prior needle biopsy. Without surgical intervention to obtain a pathological diagnosis, he may have been treated presumptively and inappropriately as having metastatic disease. In patients who have no identifiable predisposing immunologic defects, fluconazole therapy is a logical choice for the treatment of pulmonary cryptococcus, although the optimal dose, duration and efficacy are not well established.
In summary, we describe a NPC patient with pulmonary cryptococcus infection. Although it is very rare, recognition that pulmonary fungal infection can mimic metastases is important in the management of patients with NPC.
Received for publication July 25, 2001.
Revision received October 18, 2001.
Accepted for publication November 15, 2001.
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Abstract
Introduction
