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Miliary Brain Metastases in a Patient with ROS1-Rearranged Lung Adenocarcinoma: A Case Report
Case Report
Miliary Brain Metastases in a Patient with ROS1-Rearranged Lung Adenocarcinoma A Case Report Katarzyna Dziadziuszko, MD,* Edyta Szurowska, MD, PhD,* Joanna Pienkowska, MD, PhD,* Jacek Jassem, MD, PhD,† and Rafal Dziadziuszko, MD, PhD†
A
38-year-old woman with a smoking history of 15 packyears was admitted to the hospital with severe dyspnea, cough, and weight loss. Computed tomography (CT) scan of the chest revealed a paravertebral mass in the right upper lobe with a massive pleural thickening surrounding the whole right lung, pleural effusion in the right pleural cavity, mediastinal adenopathy, and small metastatic lesions in the left lung (Fig. 1A). Thoracoscopy followed by drainage of pleural fluid led to a pathological diagnosis of papillary lung adenocarcinoma. Molecular profiling showed ROS1 rearrangement in fluorescence in situ hybridization assay (commercial certified laboratory service with in-house developed probes against ROS1 gene). The patient received four cycles of palliative chemotherapy consisting of pemetrexed and cisplatin, which resulted in disease stabilization. After a short treatment-free interval, she experienced clinical and radiological signs of progression and was commenced on crizotinib, an anaplastic lymphoma kinase (ALK), ROS1, and MET inhibitor, 250 mg twice daily. Subsequent chest CT showed a partial response of the thoracic lesions (Fig. 1B), accompanied by a marked symptomatic improvement. Six months after initiation of crizotinib, she presented with fatigue, dysarthria, and depression, with episodes of catatonia. Contrast-enhanced CT showed no brain lesions and continued response in the chest. Brain magnetic resonance imaging (MRI) revealed miliary dissemination in the form of small (2–7 mm) high signal nodules in T2 and proton density–weighted images, involving almost exclusively the grey matter: cerebral cortex, basal ganglia, and thalamus (Fig. 2A and B). Some of the metastases showed restricted diffusion in DWI images and ADC maps. Diagnosis of brain dissemination was confirmed by Gd-DTPA–enhanced MRI, which revealed enhancing lesions on T1-weighted images (Fig. 3A). Crizotinib was temporarily stopped, patient received whole-brain radiotherapy (WBRT) at a dose of 30 Gy in 10 *Second Department of Radiology, †Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland. Disclosure: The authors declare no conflict of interest. Address for correspondence: Katarzyna Dziadziuszko, MD, Second Department of Radiology, Medical University of Gdansk, Debinki 7, 80–210 Gdansk, Poland. E-mail: [email protected] Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0905-0e34
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FIGURE 1. Contrast-enhanced computed tomography of the chest—mediastinal window. Neoplastic pleural thickening of the right lung. A, Initial chest computed tomography examination. B, After 4 months of crizotinib treatment. C, After 13 months of crizotinib treatment. Journal of Thoracic Oncology ® • Volume 9, Number 5, May 2014
Journal of Thoracic Oncology ® • Volume 9, Number 5, May 2014
Miliary Brain Metastases
FIGURE 2. Miliary brain metastases developed after 6 months of commencement of crizotinib treatment— small high-intensity lesions in the cerebral cortex and basal ganglia. A, proton density–weighted MRI image. B, T2-weighted MRI image, transverse plane. MRI, magnetic resonance imaging.
fractions, and crizotinib was restarted. WBRT resulted in a marked symptomatic improvement, with resolution of depression and only a slight dysarthria. T1-weighted Gd-DTPA contrast-enhanced MRI performed 4 months after WBRT showed continued partial response in the brain (Fig. 3B), and CT showed continued partial response in the chest (Fig. 1C).
DISCUSSION Approximately 10% to 25% of patients with lung cancer are initially diagnosed with brain metastases and another 40% to 50% will develop brain dissemination during the course of their disease.1 Miliary dissemination presenting as multiple punctate tumor nodules with a perivascular distribution is a rare manifestation of brain metastases.2 Very few cases of miliary brain metastases have been reported, usually detected by MRI examinations; CT is less useful in such cases. This form of dissemination arises most often from lung adenocarcinoma.2 ROS1 gene rearrangement is found in 1% to 2% of lung adenocarcinomas and tumors harboring this feature are particularly sensitive to crizotinib.3 In the present case, a patient with lung adenocarcinoma harboring ROS1 rearrangement
developed miliary brain metastases involving almost exclusively grey matter while on crizotinib therapy. Brain imaging was not performed before commencement of crizotinib therapy due to lack of symptoms of CNS involvement; therefore, we cannot exclude pre-existing brain dissemination. However, neurological and psychiatric symptomatic deterioration of the patient was striking, accompanied by miliary brain metastases in the brain, whereas a continued response in the chest was observed. Taken together, clinical and radiological findings of this patient indicated exclusive progression in the CNS. To our knowledge, this is the first report of such a radiological image of an ROS1-rearranged lung cancer. Progressions in the brain with continued response in the extracranial sites have been described for ALK-rearranged adenocarcinoma patients treated with crizotinib.4 This phenomenon is likely due to a low penetration of crizotinib through the blood– brain barrier possibly resulting in insufficient inhibition of ROS1 protein. Next-generation ROS1 inhibitors with presumably better CNS penetration are currently evaluated in clinical trials (ASP3026, AP26113; clinicaltrials.gov identifiers NCT01284192 and NCT01449461, respectively).5 It is hoped
FIGURE 3. T1-weighted Gd-DTPA contrast-enhanced magnetic resonance images, sagittal plane. Miliary brain metastases developed after 6 months of commencement of crizotinib treatment (A) with partial regression after palliative brain radiotherapy and further 4 months of crizotinib treatment (B). Gd-DTPA, gadopentetate dimeglumine. Copyright © 2014 by the International Association for the Study of Lung Cancer
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Journal of Thoracic Oncology ® • Volume 9, Number 5, May 2014
Dziadziuszko et al.
that these agents will be associated with a better CNS control of ROS1-rearranged lung cancer. In summary, present description may indicate that central nervous system constitutes a sanctuary site for ROS1rearranged lung cancer, similar to ALK-driven lung cancer. REFERENCES 1. Yamanaka R. Medical management of brain metastases from lung cancer (Review). Oncol Rep 2009;22:1269–1276.
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2. Iguchi Y, Mano K, Goto Y, et al. Miliary brain metastases from adenocarcinoma of the lung: MR imaging findings with clinical and post-mortem histopathologic correlation. Neuroradiology 2007;49:35–39. 3. Rothschild SI, Gautschi O. Crizotinib in the treatment of non–small-cell lung cancer. Clin Lung Cancer 2013;14:473–480. 4. Chun SG, Choe KS, Iyengar P, Yordy JS, Timmerman RD. Isolated central nervous system progression on Crizotinib: an Achilles heel of nonsmall cell lung cancer with EML4-ALK translocation? Cancer Biol Ther 2012;13:1376–1383. 5. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013;18:865–875.
Copyright © 2014 by the International Association for the Study of Lung Cancer
Miliary Brain Metastases in a Patient with ROS1-Rearranged Lung Adenocarcinoma A Case Report Katarzyna Dziadziuszko, MD,* Edyta Szurowska, MD, PhD,* Joanna Pienkowska, MD, PhD,* Jacek Jassem, MD, PhD,† and Rafal Dziadziuszko, MD, PhD†
A
38-year-old woman with a smoking history of 15 packyears was admitted to the hospital with severe dyspnea, cough, and weight loss. Computed tomography (CT) scan of the chest revealed a paravertebral mass in the right upper lobe with a massive pleural thickening surrounding the whole right lung, pleural effusion in the right pleural cavity, mediastinal adenopathy, and small metastatic lesions in the left lung (Fig. 1A). Thoracoscopy followed by drainage of pleural fluid led to a pathological diagnosis of papillary lung adenocarcinoma. Molecular profiling showed ROS1 rearrangement in fluorescence in situ hybridization assay (commercial certified laboratory service with in-house developed probes against ROS1 gene). The patient received four cycles of palliative chemotherapy consisting of pemetrexed and cisplatin, which resulted in disease stabilization. After a short treatment-free interval, she experienced clinical and radiological signs of progression and was commenced on crizotinib, an anaplastic lymphoma kinase (ALK), ROS1, and MET inhibitor, 250 mg twice daily. Subsequent chest CT showed a partial response of the thoracic lesions (Fig. 1B), accompanied by a marked symptomatic improvement. Six months after initiation of crizotinib, she presented with fatigue, dysarthria, and depression, with episodes of catatonia. Contrast-enhanced CT showed no brain lesions and continued response in the chest. Brain magnetic resonance imaging (MRI) revealed miliary dissemination in the form of small (2–7 mm) high signal nodules in T2 and proton density–weighted images, involving almost exclusively the grey matter: cerebral cortex, basal ganglia, and thalamus (Fig. 2A and B). Some of the metastases showed restricted diffusion in DWI images and ADC maps. Diagnosis of brain dissemination was confirmed by Gd-DTPA–enhanced MRI, which revealed enhancing lesions on T1-weighted images (Fig. 3A). Crizotinib was temporarily stopped, patient received whole-brain radiotherapy (WBRT) at a dose of 30 Gy in 10 *Second Department of Radiology, †Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland. Disclosure: The authors declare no conflict of interest. Address for correspondence: Katarzyna Dziadziuszko, MD, Second Department of Radiology, Medical University of Gdansk, Debinki 7, 80–210 Gdansk, Poland. E-mail: [email protected] Copyright © 2014 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/14/0905-0e34
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FIGURE 1. Contrast-enhanced computed tomography of the chest—mediastinal window. Neoplastic pleural thickening of the right lung. A, Initial chest computed tomography examination. B, After 4 months of crizotinib treatment. C, After 13 months of crizotinib treatment. Journal of Thoracic Oncology ® • Volume 9, Number 5, May 2014
Journal of Thoracic Oncology ® • Volume 9, Number 5, May 2014
Miliary Brain Metastases
FIGURE 2. Miliary brain metastases developed after 6 months of commencement of crizotinib treatment— small high-intensity lesions in the cerebral cortex and basal ganglia. A, proton density–weighted MRI image. B, T2-weighted MRI image, transverse plane. MRI, magnetic resonance imaging.
fractions, and crizotinib was restarted. WBRT resulted in a marked symptomatic improvement, with resolution of depression and only a slight dysarthria. T1-weighted Gd-DTPA contrast-enhanced MRI performed 4 months after WBRT showed continued partial response in the brain (Fig. 3B), and CT showed continued partial response in the chest (Fig. 1C).
DISCUSSION Approximately 10% to 25% of patients with lung cancer are initially diagnosed with brain metastases and another 40% to 50% will develop brain dissemination during the course of their disease.1 Miliary dissemination presenting as multiple punctate tumor nodules with a perivascular distribution is a rare manifestation of brain metastases.2 Very few cases of miliary brain metastases have been reported, usually detected by MRI examinations; CT is less useful in such cases. This form of dissemination arises most often from lung adenocarcinoma.2 ROS1 gene rearrangement is found in 1% to 2% of lung adenocarcinomas and tumors harboring this feature are particularly sensitive to crizotinib.3 In the present case, a patient with lung adenocarcinoma harboring ROS1 rearrangement
developed miliary brain metastases involving almost exclusively grey matter while on crizotinib therapy. Brain imaging was not performed before commencement of crizotinib therapy due to lack of symptoms of CNS involvement; therefore, we cannot exclude pre-existing brain dissemination. However, neurological and psychiatric symptomatic deterioration of the patient was striking, accompanied by miliary brain metastases in the brain, whereas a continued response in the chest was observed. Taken together, clinical and radiological findings of this patient indicated exclusive progression in the CNS. To our knowledge, this is the first report of such a radiological image of an ROS1-rearranged lung cancer. Progressions in the brain with continued response in the extracranial sites have been described for ALK-rearranged adenocarcinoma patients treated with crizotinib.4 This phenomenon is likely due to a low penetration of crizotinib through the blood– brain barrier possibly resulting in insufficient inhibition of ROS1 protein. Next-generation ROS1 inhibitors with presumably better CNS penetration are currently evaluated in clinical trials (ASP3026, AP26113; clinicaltrials.gov identifiers NCT01284192 and NCT01449461, respectively).5 It is hoped
FIGURE 3. T1-weighted Gd-DTPA contrast-enhanced magnetic resonance images, sagittal plane. Miliary brain metastases developed after 6 months of commencement of crizotinib treatment (A) with partial regression after palliative brain radiotherapy and further 4 months of crizotinib treatment (B). Gd-DTPA, gadopentetate dimeglumine. Copyright © 2014 by the International Association for the Study of Lung Cancer
e35
Journal of Thoracic Oncology ® • Volume 9, Number 5, May 2014
Dziadziuszko et al.
that these agents will be associated with a better CNS control of ROS1-rearranged lung cancer. In summary, present description may indicate that central nervous system constitutes a sanctuary site for ROS1rearranged lung cancer, similar to ALK-driven lung cancer. REFERENCES 1. Yamanaka R. Medical management of brain metastases from lung cancer (Review). Oncol Rep 2009;22:1269–1276.
e36
2. Iguchi Y, Mano K, Goto Y, et al. Miliary brain metastases from adenocarcinoma of the lung: MR imaging findings with clinical and post-mortem histopathologic correlation. Neuroradiology 2007;49:35–39. 3. Rothschild SI, Gautschi O. Crizotinib in the treatment of non–small-cell lung cancer. Clin Lung Cancer 2013;14:473–480. 4. Chun SG, Choe KS, Iyengar P, Yordy JS, Timmerman RD. Isolated central nervous system progression on Crizotinib: an Achilles heel of nonsmall cell lung cancer with EML4-ALK translocation? Cancer Biol Ther 2012;13:1376–1383. 5. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 2013;18:865–875.
Copyright © 2014 by the International Association for the Study of Lung Cancer