A 65-year-old woman, never-smoker, was referred for a second opinion in January 2014 because of an abnormal computed tomography (CT) of the chest with a mass in the right lower lobe. Extensive evaluation in the referring hospital had not revealed a diagnosis. A clear overview of the medical disease history is demonstrated in a timeline (Figure 1). Her medical history consisted of a right-sided mastectomy for breast cancer in 2006, with no adjuvant treatment indicated. On the staging 18-fluordeoxyglucose positron emission tomography-computed tomography (18FDG-PET-CT) for the breast cancer in 2006 an asymptomatic, 30-mm diameter, lobulated 18FDG-negative solitary mass was seen in the right lower lobe. Bronchoscopic sampling for cytology and microbiological cultures showed neither proof of malignancy nor infection, and follow-up was chosen. Serial follow-up chest CTs up to December 2011 (total follow-up of 5 years) showed no change and follow-up was ended.
In August 2013, she was seen in the referring hospital because of a productive cough, dyspnea on exertion, tiredness, and weight loss since the last 3 months. There was no fever nor night sweats. 18FDG-PET-CT revealed an intense 18FDG-avid mass in the right lower lobe, just next to the old pulmonary lesion, with intense hilar lymphadenopathy (Figure 2). Differential diagnosis consisted of malignancy (metastatic breast cancer or primary lung cancer) or infection. Bronchoscopic sampling, CT-guided biopsy, and endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) revealed no malignancy and cultures were negative (Table 1). Transthoracic biopsy of the mass showed fibrosis and a chronic inflammation with histiocytic reaction. A video-assisted thoracoscopy with partial wedge resection of the pulmonary nodule was performed to obtain a definitive diagnosis and to rule out or confirm malignancy. Pathologic analysis of the resection specimen showed fibrosis with bronchiectasis, focal inflammation, and bronchiolisation of the alveoli, but no malignancy or microorganisms (Table 1). With a diagnosis suggestive of cryptogenic organizing pneumonia, prednisone 0.5 mg/kg/day was initiated, although, due to steroid side-effects, limited in dose and duration (prednisone 0.5 mg/kg/day for 3 weeks followed by gradual tapering of the dose, total duration of prednisone treatment was 2 months). Despite the steroids, her complaints worsened and the patient was referred to our tertiary center in January 2014. A new 18FDG-PET-CT showed progression of the 18FDG-avid lesion with extension into the mediastinum and lymph node station 4R, with also mass effect on the right pulmonary artery and invasion of the left superior pulmonary vein (Figure 2). There was no evidence of extrathoracic lesions. Because of the invasive growth, malignancy was again in the differential diagnosis. In our hospital, renewed analysis was performed with bronchoscopy and mediastinoscopy, both without evidence of malignancy or infection (Table 1). Cytology of the bronchial aspirate showed sporadic hyphae (most probable Aspergillus), but without growth on culture and these were considered contamination or colonization. In March 2014, a multidisciplinary decision was made for a treatment with a higher dose of prednisone 1 mg/kg/day in combination with macrolide antibiotic treatment for 3 months (with slow tapering of the steroids) under suspicion of cryptogenic organizing pneumonia, but without clinical or radiologic response. Additional diagnostics were considered for the growing part of the lesion, but a CT-guided biopsy and surgical sampling were both not possible because of the risk of a massive bleeding. A follow-up 18FDG-PET-CT was scheduled to evaluate whether in the follow-up lesions would become better accessible for further diagnostic work-up. During the pulmonary work-up, in March 2014, the patient developed new complaints of progressive muscle weakness and sensibility loss of the right upper arm. She was hospitalized in the referring hospital. Additional brain imaging with magnetic resonance imaging (MRI) revealed multiple brain lesions in the cortex and watershed region, in the left corpus callosum, the left thalamus and partially in the right semioval center, which were considered brain metastases by the referring hospital (Figure 3). The MRI was revised by an experienced neuro-radiologist in our hospital who withheld a differential diagnosis of ischemia and metastasis. The brain lesions were not accessible for a biopsy because of the location and small size. Because of a poor clinical condition combined with a differential diagnosis of ischemia, no brain radiation was initiated. Patient was discharged after 11/2-week hospitalization in the referring hospital. The neuro-oncology multidisciplinary team advised follow-up MRI 3 months later. On this MRI (May 2014), two lesions had enlarged significantly with marked perilesional edema but other lesions showed shrinkage (Figure 4). The radiologic appearance with restrictive diffusion of these lesions on diffusion-weighted images was suggestive for (atypical) cerebral abscesses rather than metastases. The 18FDG-PET-CT showed further growth of the mass in the right lower lobe but without distant lesions. At the same time, the patient developed multiple ill-defined skin lesions. Because of her worse clinical condition, she was hospitalized in our tertiary hospital and cerebral and skin biopsies were performed: both showed marked inflammation and fungal hyphae with dichotomous branching, suggestive for Aspergillus, there was no evidence for malignancy (Table 1; Figures 5 and 6). Cultures of the wound fluid after skin biopsy also revealed Aspergillus (Table 1). The definitive diagnosis of proven invasive aspergillosis with pulmonary, mediastinal, cerebral, and skin involvement was made. Treatment with voriconazole was initiated with monitoring of serum and cerebral spinal fluid (CSF) voriconazole levels. Because of progressive somnolence caused by hydrocephalus, repeated CSF drainage was necessary. Eventually, five neurosurgical procedures were needed for effective control of the infection and adequate drainage of the CSF, with in the end placement of an internal ventriculo-peritoneal drain. During treatment with voriconazole, there was a slow clinical recovery. Additional immunological analysis did not reveal an immunity disorder; there were normal titers of total IgG, IgM, IgG, and IgA, there were no complement abnormalities, screening for antinuclear antibodies and antineutrophil cytoplasmic antibodies was negative. Only the use of prednisone could be identified as immunosuppressant factor which aided the further dissemination of this opportunistic infection. MRI of the brain performed after 6 months of treatment showed marked improvement without evidence of hydrocephalus, the chest CT also improved. Patient was discharged in December 2014, 7 months after admission. She rehabilitated and made a near complete recovery.
Timeline. Abbreviations: 18FDG, 18-fluordeoxyglucose; CT, computed tomography; VATS, video assisted thoracic surgery; 18FDG-PET-CT, 18-fluordeoxyglucose positron emission tomography-computed tomography; EBUS-TBNA, endobronchial ultrasound with transbronchial needle aspiration; MRI, magnetic resonance imaging.