Clinical Neurology and Neurosurgery 135 (2015) 93–95
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case Report
Cryptococcosis mimicking lung cancer with brain metastasis Akiyuki Hiraga a,∗ , Mari Yatomi b , Daisuke Ozaki c , Ikuo Kamitsukasa a , Satoshi Kuwabara d a
Department of Neurology, Chiba Rosai Hospital, Chiba, Japan Department of Internal Medicine, Chiba Rosai Hospital, Chiba, Japan c Department of Pathology, Chiba Rosai Hospital, Chiba, Japan d Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan b
a r t i c l e
i n f o
Article history: Received 10 October 2014 Received in revised form 4 March 2015 Accepted 17 May 2015 Available online 22 May 2015 Keywords: Cryptococcosis Brain tumour Lung cancer
1. Introduction Cryptococcus neoformans is a ubiquitous organism that primarily infects the lungs and subsequently spreads to the central nervous system (CNS) through the haematogenous route [1]. Although several imaging patterns are well described in both CNS and pulmonary cryptococcosis, the diagnosis of Cryptococcus infection can be confusing if there are atypical image findings. We report the case of a patient with CNS and pulmonary cryptococcosis who presented with unusual imaging findings that mimicked lung cancer with brain metastasis. 2. Case report A 71-year-old immunocompetent woman, a full-time housewife, with a 6-month history of hypertension and a 5-year history of well-controlled hyperthyroidism, presented to a local hospital with a 3-day history of right lower limb monoparesis. Brain magnetic resonance imaging (MRI) showed a left cortical lesion (Fig. 1). She gave history of headache and appetite loss for 18 days, which was followed by diplopia. A large lung mass in the left lower lobe was observed on chest computed tomography (CT) (Fig. 2). Her symptoms worsened and she was referred to our hospital and admitted
∗ Corresponding author at: Department of Neurology, Chiba Rosai Hospital, 216 Tatsumidai-Higashi, Ichihara-shi, Chiba 290-0003, Japan. Tel.: +81 436 74 1111; fax: +81 436 74 1151. E-mail address: [email protected] (A. Hiraga). http://dx.doi.org/10.1016/j.clineuro.2015.05.014 0303-8467/© 2015 Elsevier B.V. All rights reserved.
to the department of internal medicine 35 days after neurological onset. Five days before admission, she had received oral prednisolone (20 mg/day); however, her symptoms had not improved. She had no history of contact with chicken or pigeons and had no respiratory symptoms. In addition, there were no features of immunosuppression. On admission, her body temperature was 37.6 ◦ C. She was drowsy and had neck stiffness. Her pupils were anisocoric and there were limitations of lateral gaze in the left eye along with dysarthria. Proximal muscle weakness was detected in all four limbs. Her white blood cell count was 10,500/L. Blood sugar, glycohaemoglobin, and C-reactive protein were 147 mg/dL, 6.0%, and 1.2 mg/dL, respectively. An enzyme-linked immunosorbent assay was negative for human immunodeficiency virus. Brain MRI showed a small ring-enhanced lesion with surrounding oedema in the left frontal lobe (Fig. 1). On the basis of these findings, the patient was suspected to have lung cancer with brain metastasis and carcinomatous meningitis. Non-invasive positive pressure ventilation was initiated at night because she had nocturnal dyspnoea. Lumbar puncture was performed and revealed an opening pressure of 480 mm H2 O. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 8/mm3 (21% neutrophils and 79% lymphocytes), a glucose level of 56 mg/dL, CSF/serum glucose ratio of 0.29, and a protein level of 44 mg/dL, with many yeast forms of C. neoformans (Fig. 2). Cytological examination of CSF showed no malignant cells. Cryptococcal antigen was positive in both serum and CSF. Blood cultures were positive for C. neoformans. CNS cryptococcosis was diagnosed and treatment was initiated, which included
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A. Hiraga et al. / Clinical Neurology and Neurosurgery 135 (2015) 93–95
Fig. 1. Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) (A) and T2-weighted images (T2WI) (B) 3 days after onset of symptoms show a hyperintensity in the left cerebral cortex. (C–F) MRI done 36 days after onset of symptoms, after oral corticosteroid treatment. (C) Diffusion-weighted image shows a mild hyperintense lesion of the left frontal lobe. (D) T2WI shows a small hyperintense lesion with surrounding oedema. (E) Contrast-enhanced (CE) T1-weighted images (T1WI) shower a ring-enhanced small lesion. (F) Enlarged view of CE T1WI and T2WI of the lesion.
liposomal amphotericin B administered intravenously and flucytosine administered through a nasogastric tube. A bronchoscopic lung biopsy performed the day after initiating anti-fungal treatments also showed yeast forms (Fig. 2). Despite treatment with anti-fungal drugs, her condition deteriorated. Her respiratory condition worsened probably due to brainstem dysfunction, and she
was put on a ventilator 3 days after admission. Intravenous cathecolamine was administered for treating hypotension. She eventually developed disseminated intravascular coagulation and was treated with recombinant human soluble thrombomodulin. She died 20 days after admission. The family did not provide consent for a postmortem examination.
Fig. 2. (A) Chest radiograph showing a mass in the left lower lobe of the lung. (B) Axial chest computed tomography demonstrating a 4.5 × 3.8-cm mass in the left lower lobe. (C) The lung tissue obtained by transbronchial lung biopsy reveals encapsulated forms of Cryptococcus neoformans (haematoxylin–eosin stain, 40×). (D) Yeast forms of Cryptococcus neoformans in cerebrospinal fluid (Periodic acid–Schiff staining, 40×).
A. Hiraga et al. / Clinical Neurology and Neurosurgery 135 (2015) 93–95
3. Discussion Our patient was finally diagnosed as suffering pulmonary and CNS cryptococcosis, but image findings were very atypical; chest CT showed a large mass and brain MRI showed a very small ring-enhanced lesion suggesting cryptococcoma with surrounding oedema, which was decreased by oral prednisolone treatments. Brain and lung images mimicked lung cancer with brain metastases. Depending on the immune status of patients, clinical manifestations and/or disease progression of pulmonary cryptococcosis can vary [2]. Immunocompetent patients tend to have single or multiple pulmonary nodules, which are usually 3 cm) lesions, which are rarely seen in pulmonary cryptococcosis, making it difficult to distinguish cryptococcosis from lung cancer [3]. Similar to pulmonary cryptococcosis, the imaging manifestations of CNS cryptococcosis in immunocompetent patients can also be different from the typical manifestations seen in immunocompromised patients [1,4]. On MRI, gyriform leptomeningeal enhancement, vasculitis or clusters of contrast-enhanced small cysts or nodules in Virchow–Robin spaces are the typical manifestations in immunocompetent patients; however, patients may also show a solitary, contrast-enhanced arachnoid cyst and a solitary ring-enhancing solid lesion [1]. T2 hypointensity in the lesion is also considered a characteristic feature of cerebral cryptococcoma. On the other hand, others report that cerebral cryptococcoma may rarely exhibit a ring-like contrast enhancement and solitary cryptococcomas are very rare lesions [1]. In our patient, a small solitary cryptococcoma with ring-like enhancement surrounded by obvious oedema was the primary feature of brain MRI. The size of T2-hyperintese area was decreased by prednisolone, which suggests that these areas represented oedema. On MRI, the ring enhancement probably represents the patient’s ability to mount an immune response [1]. C. neoformans has a polysaccharide capsule, which may protect it from the host inflammatory response even in immunocompetent patients [5]. This may account for a lower
95
incidence of surrounding oedema in CNS cryptococcosis. Some case reports of CNS cryptococcosis showed cerebral cryptococcomas with obvious oedema [4]; however, previous cases showed large cryptococcomas. On the other hand, our case showed a very small cerebral cryptococcoma with obvious oedema. In addition, the lesion did not show T2 hypointensity, leading to its misdiagnosis as a metastatic brain tumour. C. neoformans infection in immunocompetent patients is a diagnostic challenge to neurologists. Pulmonary cryptococcosis presenting with a pulmonary mass and associated ring-enhanced brain tumours with obvious oedema may mimic lung cancer with metastatic brain tumour. In these cases, misdiagnosis is very likely. We emphasize that the importance of obtaining rapid diagnostic confirmation of the lung and/or brain lesions (histopathology or cultures) instead of observing for several weeks or instituting empiric treatment. Awareness of this atypical form of cryptococcosis would facilitate the early recognition and treatment of such cases. Aggressive systemic antifungal treatment and in some cases surgical resection are necessary for cure. Conflict of interest statement The authors declare that there are no conflicts of interest. References [1] Chen S, Chen X, Zhang Z, Quan L, Kuang S, Luo X. MRI findings of cerebral cryptococcosis in immunocompetent patients. J Med Imaging Radiat Oncol 2011;55:52–7. [2] Choe YH, Moon H, Park SJ, Kim SR, Han HJ, Lee KS, et al. Pulmonary cryptococcosis in asymptomatic immunocompetent hosts. Scand J Infect Dis 2009;41:602–7. [3] Chang WC, Tzao C, Hsu HH, Lee SC, Huang KL, Tung HJ, et al. Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients. Chest 2006;129:333–40. [4] Saigal G, Post MJ, Lolayekar S, Murtaza A. Unusual presentation of central nervous system cryptococcal infection in an immunocompetent patient. Am J Neuroradiol 2005;26:2522–6. [5] Miszkiel KA, Hall-Craggs MA, Miller RF, Kendall BE, Wilkinson ID, Paley MN, et al. The spectrum of MRI findings in CNS cryptococcosis in AIDS. Clin Radiol 1996;51:842–50.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case Report
Cryptococcosis mimicking lung cancer with brain metastasis Akiyuki Hiraga a,∗ , Mari Yatomi b , Daisuke Ozaki c , Ikuo Kamitsukasa a , Satoshi Kuwabara d a
Department of Neurology, Chiba Rosai Hospital, Chiba, Japan Department of Internal Medicine, Chiba Rosai Hospital, Chiba, Japan c Department of Pathology, Chiba Rosai Hospital, Chiba, Japan d Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan b
a r t i c l e
i n f o
Article history: Received 10 October 2014 Received in revised form 4 March 2015 Accepted 17 May 2015 Available online 22 May 2015 Keywords: Cryptococcosis Brain tumour Lung cancer
1. Introduction Cryptococcus neoformans is a ubiquitous organism that primarily infects the lungs and subsequently spreads to the central nervous system (CNS) through the haematogenous route [1]. Although several imaging patterns are well described in both CNS and pulmonary cryptococcosis, the diagnosis of Cryptococcus infection can be confusing if there are atypical image findings. We report the case of a patient with CNS and pulmonary cryptococcosis who presented with unusual imaging findings that mimicked lung cancer with brain metastasis. 2. Case report A 71-year-old immunocompetent woman, a full-time housewife, with a 6-month history of hypertension and a 5-year history of well-controlled hyperthyroidism, presented to a local hospital with a 3-day history of right lower limb monoparesis. Brain magnetic resonance imaging (MRI) showed a left cortical lesion (Fig. 1). She gave history of headache and appetite loss for 18 days, which was followed by diplopia. A large lung mass in the left lower lobe was observed on chest computed tomography (CT) (Fig. 2). Her symptoms worsened and she was referred to our hospital and admitted
∗ Corresponding author at: Department of Neurology, Chiba Rosai Hospital, 216 Tatsumidai-Higashi, Ichihara-shi, Chiba 290-0003, Japan. Tel.: +81 436 74 1111; fax: +81 436 74 1151. E-mail address: [email protected] (A. Hiraga). http://dx.doi.org/10.1016/j.clineuro.2015.05.014 0303-8467/© 2015 Elsevier B.V. All rights reserved.
to the department of internal medicine 35 days after neurological onset. Five days before admission, she had received oral prednisolone (20 mg/day); however, her symptoms had not improved. She had no history of contact with chicken or pigeons and had no respiratory symptoms. In addition, there were no features of immunosuppression. On admission, her body temperature was 37.6 ◦ C. She was drowsy and had neck stiffness. Her pupils were anisocoric and there were limitations of lateral gaze in the left eye along with dysarthria. Proximal muscle weakness was detected in all four limbs. Her white blood cell count was 10,500/L. Blood sugar, glycohaemoglobin, and C-reactive protein were 147 mg/dL, 6.0%, and 1.2 mg/dL, respectively. An enzyme-linked immunosorbent assay was negative for human immunodeficiency virus. Brain MRI showed a small ring-enhanced lesion with surrounding oedema in the left frontal lobe (Fig. 1). On the basis of these findings, the patient was suspected to have lung cancer with brain metastasis and carcinomatous meningitis. Non-invasive positive pressure ventilation was initiated at night because she had nocturnal dyspnoea. Lumbar puncture was performed and revealed an opening pressure of 480 mm H2 O. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 8/mm3 (21% neutrophils and 79% lymphocytes), a glucose level of 56 mg/dL, CSF/serum glucose ratio of 0.29, and a protein level of 44 mg/dL, with many yeast forms of C. neoformans (Fig. 2). Cytological examination of CSF showed no malignant cells. Cryptococcal antigen was positive in both serum and CSF. Blood cultures were positive for C. neoformans. CNS cryptococcosis was diagnosed and treatment was initiated, which included
94
A. Hiraga et al. / Clinical Neurology and Neurosurgery 135 (2015) 93–95
Fig. 1. Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) (A) and T2-weighted images (T2WI) (B) 3 days after onset of symptoms show a hyperintensity in the left cerebral cortex. (C–F) MRI done 36 days after onset of symptoms, after oral corticosteroid treatment. (C) Diffusion-weighted image shows a mild hyperintense lesion of the left frontal lobe. (D) T2WI shows a small hyperintense lesion with surrounding oedema. (E) Contrast-enhanced (CE) T1-weighted images (T1WI) shower a ring-enhanced small lesion. (F) Enlarged view of CE T1WI and T2WI of the lesion.
liposomal amphotericin B administered intravenously and flucytosine administered through a nasogastric tube. A bronchoscopic lung biopsy performed the day after initiating anti-fungal treatments also showed yeast forms (Fig. 2). Despite treatment with anti-fungal drugs, her condition deteriorated. Her respiratory condition worsened probably due to brainstem dysfunction, and she
was put on a ventilator 3 days after admission. Intravenous cathecolamine was administered for treating hypotension. She eventually developed disseminated intravascular coagulation and was treated with recombinant human soluble thrombomodulin. She died 20 days after admission. The family did not provide consent for a postmortem examination.
Fig. 2. (A) Chest radiograph showing a mass in the left lower lobe of the lung. (B) Axial chest computed tomography demonstrating a 4.5 × 3.8-cm mass in the left lower lobe. (C) The lung tissue obtained by transbronchial lung biopsy reveals encapsulated forms of Cryptococcus neoformans (haematoxylin–eosin stain, 40×). (D) Yeast forms of Cryptococcus neoformans in cerebrospinal fluid (Periodic acid–Schiff staining, 40×).
A. Hiraga et al. / Clinical Neurology and Neurosurgery 135 (2015) 93–95
3. Discussion Our patient was finally diagnosed as suffering pulmonary and CNS cryptococcosis, but image findings were very atypical; chest CT showed a large mass and brain MRI showed a very small ring-enhanced lesion suggesting cryptococcoma with surrounding oedema, which was decreased by oral prednisolone treatments. Brain and lung images mimicked lung cancer with brain metastases. Depending on the immune status of patients, clinical manifestations and/or disease progression of pulmonary cryptococcosis can vary [2]. Immunocompetent patients tend to have single or multiple pulmonary nodules, which are usually 3 cm) lesions, which are rarely seen in pulmonary cryptococcosis, making it difficult to distinguish cryptococcosis from lung cancer [3]. Similar to pulmonary cryptococcosis, the imaging manifestations of CNS cryptococcosis in immunocompetent patients can also be different from the typical manifestations seen in immunocompromised patients [1,4]. On MRI, gyriform leptomeningeal enhancement, vasculitis or clusters of contrast-enhanced small cysts or nodules in Virchow–Robin spaces are the typical manifestations in immunocompetent patients; however, patients may also show a solitary, contrast-enhanced arachnoid cyst and a solitary ring-enhancing solid lesion [1]. T2 hypointensity in the lesion is also considered a characteristic feature of cerebral cryptococcoma. On the other hand, others report that cerebral cryptococcoma may rarely exhibit a ring-like contrast enhancement and solitary cryptococcomas are very rare lesions [1]. In our patient, a small solitary cryptococcoma with ring-like enhancement surrounded by obvious oedema was the primary feature of brain MRI. The size of T2-hyperintese area was decreased by prednisolone, which suggests that these areas represented oedema. On MRI, the ring enhancement probably represents the patient’s ability to mount an immune response [1]. C. neoformans has a polysaccharide capsule, which may protect it from the host inflammatory response even in immunocompetent patients [5]. This may account for a lower
95
incidence of surrounding oedema in CNS cryptococcosis. Some case reports of CNS cryptococcosis showed cerebral cryptococcomas with obvious oedema [4]; however, previous cases showed large cryptococcomas. On the other hand, our case showed a very small cerebral cryptococcoma with obvious oedema. In addition, the lesion did not show T2 hypointensity, leading to its misdiagnosis as a metastatic brain tumour. C. neoformans infection in immunocompetent patients is a diagnostic challenge to neurologists. Pulmonary cryptococcosis presenting with a pulmonary mass and associated ring-enhanced brain tumours with obvious oedema may mimic lung cancer with metastatic brain tumour. In these cases, misdiagnosis is very likely. We emphasize that the importance of obtaining rapid diagnostic confirmation of the lung and/or brain lesions (histopathology or cultures) instead of observing for several weeks or instituting empiric treatment. Awareness of this atypical form of cryptococcosis would facilitate the early recognition and treatment of such cases. Aggressive systemic antifungal treatment and in some cases surgical resection are necessary for cure. Conflict of interest statement The authors declare that there are no conflicts of interest. References [1] Chen S, Chen X, Zhang Z, Quan L, Kuang S, Luo X. MRI findings of cerebral cryptococcosis in immunocompetent patients. J Med Imaging Radiat Oncol 2011;55:52–7. [2] Choe YH, Moon H, Park SJ, Kim SR, Han HJ, Lee KS, et al. Pulmonary cryptococcosis in asymptomatic immunocompetent hosts. Scand J Infect Dis 2009;41:602–7. [3] Chang WC, Tzao C, Hsu HH, Lee SC, Huang KL, Tung HJ, et al. Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients. Chest 2006;129:333–40. [4] Saigal G, Post MJ, Lolayekar S, Murtaza A. Unusual presentation of central nervous system cryptococcal infection in an immunocompetent patient. Am J Neuroradiol 2005;26:2522–6. [5] Miszkiel KA, Hall-Craggs MA, Miller RF, Kendall BE, Wilkinson ID, Paley MN, et al. The spectrum of MRI findings in CNS cryptococcosis in AIDS. Clin Radiol 1996;51:842–50.
