Case Report

Cystic Brain Metastases Occurring in Anaplastic Lymphoma Kinase Gene Rearranged NoneSmall-Cell Lung Cancer Patients Receiving Crizotinib Vignesh Narayanan,1 M. Justin Honce,2 Sanjana Mehrotra,3 D. Ross Camidge1 Clinical Practice Points  The central nervous system (CNS) is a common site of

 Patients with CBM were asymptomatic, and lesions

disease progression in patients with anaplastic lymphoma kinase (ALK)-rearranged nonesmall-cell lung cancer (NSCLC) treated with crizotinib.  Cystic CNS lesions have recently been identified as one possible variant noted in this disease.  Here we report 3 patients with ALK-positive NSCLC who developed cystic brain metastases (CBM) while receiving treatment with crizotinib.

progressed slowly over time even without CNSdirected therapy.  We elaborate on the unique characteristics of CBM on serial brain magnetic resonance imaging studies.  We provide a brief literature review of published case reports of CBM in NSCLC and discuss the possible mechanism of development of CBM in ALK-positive NSCLC.

Clinical Lung Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Anaplastic lymphoma kinase, Crizotinib, Cystic brain metastases, Nonesmall-cell lung cancer, Signet ring morphology

Introduction The lifetime incidence of central nervous system (CNS) disease in advanced anaplastic lymphoma kinaseerearranged (ALKþ) nonesmall-cell lung cancer (NSCLC) approaches 50%.1 Although crizotinib induces dramatic and durable responses in ALKþ NSCLC, its activity in the CNS appears less robust.2-4 The response rate in measurable, untreated CNS disease and the duration of response are less than that outside the CNS, and the CNS remains a major site of progression while receiving crizotinib, all of which may be due to relative underexposure of the CNS to the drug compared to in the rest of the body.4-6 Recently, isolated reports of cystic CNS lesions in ALKþ patients have been published.7,8 Here we report on the detailed features of cystic brain 1

Division of Medical Oncology, Department of Medicine Department of Radiology 3 Department of Pathology University of Colorado School of Medicine, Aurora, CO 2

Submitted: May 9, 2015; Revised: Jun 19, 2015; Accepted: Jul 21, 2015 Address for correspondence: Vignesh Narayanan, MD, University of Colorado Cancer Center, 12801 E 17th Ave, Aurora, CO 80045 E-mail contact: [email protected]

1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.07.003

metastases (CBM) in ALKþ NSCLC occurring during therapy with crizotinib.

Case Reports Case 1

A previously healthy 32-year-old male former light smoker was diagnosed with metastatic adenocarcinoma of the lung in November 2008. In January 2010, after 3 lines of systemic chemotherapy, fluorescent in-situ hybridization (FISH) analysis revealed an ALK gene rearrangement, prompting initiation of crizotinib in a phase 1 clinical trial, with resultant near-complete regression of active disease sites in the lungs, lymph nodes, and pericardium on serial positron emission tomographic scans. The most recent CNS imaging before commencement of crizotinib was in December 2008 and was normal. In April 2011, surveillance magnetic resonance imaging (MRI) of the brain performed in the absence of CNS symptoms revealed numerous subcentimeter-size cystic lesions, which were homogenously T2 hyperintense and T1 hypointense, and lacked adjacent vasogenic edema or enhancement (Figure 1A-F). Most lesions were centrally bright on fluid-attenuated inversion recovery (FLAIR) sequences. Lesions along the lateral left temporal lobe and left parietal lobe also exhibited some nodular enhancement. An excisional biopsy of a cystic

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NSCLC Patients Receiving Crizotinib Figure 1 Imaging Results for Case 1. Brain Magnetic Resonance Imaging. (A-F) April 2011. Axial T2 (A-C) and FLAIR (D-F) Weighted Imaging Demonstrating Numerous Cystic Appearing Lesions Scattered Throughout Brain (Arrows), With Some FLAIR Hyperintensity But No Surrounding Vasogenic Edema. (G-I) July 2012. Axial T2 Imaging Showing Slow Progression in Size of Lesions (Arrows) Over Prior 15 Months While Receiving Crizotinib. Lesions Are Devoid of Vasogenic Edema Despite Substantial Increases in Size. No Enhancement Developed Despite Increase in Size. (J-L) August 2013. Axial T2 Imaging Showing Marked Decrease in Size or Disappearance of Numerous Cystic Lesions After Transition of Therapy to AP26113 (Arrows). (M-O) September 2014. Axial T2 Imaging Showing Stable Size of Most of Scattered Lesions in Brain on AP26113 (Arrows)

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Abbreviation: FLAIR ¼ fluid-attenuated inversion recovery.

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Vignesh Narayanan et al brain lesion was performed; analysis revealed abundant mucinous material on histopathology, but no malignant cells were identified despite an extensive search by immunohistochemistry. The patient declined whole-brain radiotherapy (WBRT), but crizotinib was continued as a result of excellent systemic disease control. Between April 2011 and July 2012, follow-up brain MRI demonstrated a gradual increase in size of several lesions (Figure 1G-I). Additionally, faint regions of enhancement were noted in the lesions in the left temporal and left parietal lobes but without vasogenic edema. In July 2012, the development of new chest wall metastases prompted a change in therapy to a newer-generation ALK inhibitor, AP26113. Follow-up brain MRI in August 2013 while the patient was receiving AP26113 demonstrated radiographic response, with substantial decrease in size of many of the CNS lesions (Figure 1J-L). Over numerous follow-up studies, as of September 2014, no CNS progression has occurred, and nodular contrast enhancement associated with the lesions in the left temporal, parietal, and frontal lobes has nearly resolved (Figure 1M-O).

Case 2 A 56-year-old previously healthy male never smoker was diagnosed with metastatic NSCLC (mucinous adenocarcinoma with bronchoalveolar features) in February 2008. By October 2009, he had progressive disease after 3 lines of chemotherapy, and ALK positivity was confirmed by FISH. Crizotinib was initiated in November 2009 in a clinical trial, with a partial response by the Response Evaluation Criteria in Solid Tumors. The most recent CNS imaging performed before commencement of crizotinib was in December 2007 and was normal. In June 2011, in the absence of CNS symptoms, the patient underwent a surveillance brain MRI that revealed numerous homogenously T2-hyperintense and T1-hypointense cystic-appearing lesions scattered throughout the brain (Figure 2A-E). On FLAIR imaging, the lesions were heterogeneous, with varying signal intensities ranging from isointense to hyperintense. Postcontrast imaging revealed regions of irregular nodular heterogeneous enhancement at the margins of several of the larger lesions. Excisional biopsy of one of these lesions was performed, and analysis confirmed a thin strip of adenocarcinoma cells around mucinous pools, compatible with metastatic NSCLC. The patient underwent WBRT, and crizotinib was continued for systemic benefit. Between June 2011 and October 2012, the CNS lesions slowly decreased in size with reduced contrast enhancement (Figure 2F-H). In December 2012, a few lesions in the left parietooccipital lobe began to increase in size and enhancement and were treated by stereotactic radiosurgery (SRS). By July 2013, several other brain lesions had slowly increased in size (Figure 2I-K), and therapy was switched to AP26113. Repeat imaging on AP26113 demonstrated a decrease in size of a few of the lesions, while most others remained stable. Follow-up MRI as of September 2014 continued to demonstrate stability of brain lesions. (Figure 2L-N).

Case 3 A previously healthy 62-year-old male former smoker was diagnosed with metastatic NSCLC in June 2012. An ALK rearrangement was identified, and first-line treatment with crizotinib was initiated in September 2012, with a complete response on radiographic studies. The most recent CNS imaging before the

commencement of crizotinib was in June 2012 and was normal. Surveillance MRI of the brain in August 2013 in the absence of CNS symptoms revealed several T2-hyperintense, FLAIR, and T1-hypointense cystic lesions scattered in the brain (Figure 3A-E). The lesions had a faint peripheral rim of T2 hypointensity, which was slightly bright on FLAIR but which did not demonstrate enhancement or surrounding vasogenic edema. A follow-up brain MRI in December 2013 revealed a moderate increase in size of the lesion in the left parietal lobe with minor enlargement of the lesions in the left frontal lobe and left cerebellum (Figure 3F-I). There was new, faint linear peripheral enhancement at the margins of these lesions, but cerebral edema had not developed despite the increase in size. These changes necessitated treatment with SRS. A follow-up brain MRI in October 2014 demonstrated stable brain lesions.

Discussion Brain metastases in NSCLC typically tend to be either solid and/ or heterogeneous ring-enhancing lesions at the grayewhite junction associated with cerebral edema and resultant signs and symptoms.9 However, in 3 of our patients with ALKþ NSCLC, brain metastases were notably cystic appearing (T1 hypointense, T2 hyperintense), with variable signal on FLAIR. Most lesions were not associated with vasogenic edema or contrast enhancement, although mild linear peripheral or nodular enhancement was infrequently noted, typically in the larger lesions. Histopathology revealed that these cysts contained abundant mucinous material and a thin rim of malignant cells. The variable appearance on FLAIR imaging may relate to changing compositions of these mucinous secretions. In all 3 patients, CBM were discovered on surveillance brain MRI rather than triggered by CNS symptoms at 28, 40, and 11 months after diagnosis of lung cancer, and all were first documented while receiving crizotinib treatment. We did not identify any cases of cystic CNS disease in ALKþ patients before crizotinib treatment. Additionally, beyond the lack of vasogenic edema and symptoms, CBM tended to progress slowly over time, even without CNSdirected therapy, despite systemic progression while receiving crizotinib, as in the case of the first patient, raising questions about the optimal treatment for this condition. The second and third patients received WBRT and SRS, respectively, with little lesion shrinkage, although further CNS progression was halted for a prolonged period. Two of the 3 cases were then challenged with AP26113, a next-generation ALK inhibitor with promising CNS activity,10 and although both cases demonstrated CNS benefit, shrinkage was relatively slow, consistent with the bulk of the lesions representing mucus rather than malignant cells. Other reports of CBM in NSCLC include those occurring in patients with unknown driver oncogene status, and in patients harboring either epidermal growth factor receptor (EGFR) mutations or ALK gene rearrangements.11-13 Our finding of CBM in an ALKþ patient with signet ring morphology is similar to the report by Hayashi and colleagues.7 This indicates a possible link between the histologic subtype of the NSCLC and a predilection for formation of cystic metastases, possibly akin to that of signet ring gastric cancers and development of cystic ovarian metastases.7 Certainly signet ring morphology has previously been prominently associated with ALKþ NSCLC.14,15 Furthermore, resected brain

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NSCLC Patients Receiving Crizotinib Figure 2 Imaging Results for Case 2. Brain Magnetic Resonance Imaging. (A-E) June 2011. Axial T2 (A, D, E), FLAIR (B), and Postcontrast T1 (C) Weighted Imaging Demonstrates Numerous T2-Hyperintense Lesions Scattered in Brain and Cerebellum. There Is Enhancing Nodularity At Margins of Some Lesions But No Surrounding Vasogenic Edema. (F-H) July 2012. Axial T2-Weighted Imaging After Whole-Brain Radiotherapy Demonstrating Decreased Size of Most Lesions. Enhancing Nodularity Is Resolving (Not Shown). Again, There is No Definite Vasogenic Edema Around Lesions Despite Their Size. (I-K) July 2013. Axial T2-Weighted Imaging Demonstrates New T2 Signal Adjacent to SRS-treated Left Parietal Lobe Lesion (Arrow). Several Other Lesions Are Larger, But Despite Change in Size, No Vasogenic Edema has Developed. Enhancing Nodularity Seen on Baseline Imaging is Resolved (Not Shown). (L-N) February 2014. Axial T2-Weighted Imaging Demonstrates Decreased Size but Increased Treatment-Related T2 Signal in Left Parietal Lobe attributable to AP26113. Other Lesions are Stable. No Vasogenic Edema has Developed Around These lesions

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Abbreviations: FLAIR ¼ fluid-attenuated inversion recovery; SRS ¼ stereotactic radiosurgery.

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Figure 3 Imaging Results for Case 3. Brain Magnetic Resonance Imaging. (A-E) August 2013. Axial FLAIR (A, C), T2 (B, D), and Postcontrast T1 (E) Weighted Imaging Demonstrate Multiple T2-Hyperintense, Cystic-Appearing Lesions in Left Frontal Lobe and Bilateral Parietal Lobes as Well as Left Cerebellum (B, D, Arrows). All Lesions Are Devoid of Vasogenic Edema or Enhancement. Cerebellar Lesion Has Subtle Smooth Peripheral Low T2 Signal and Corresponding FLAIR Hyperintensity. (F-I) December 2013. Axial FLAIR (F, H) and T2 (G, I) Weighted Imaging Demonstrate Interval Enlargement of Lesions in Left Frontal, Parietal Lobes, and Left Cerebellum (Arrows), and Stable Size of Small Right Parietal Lesion With Crizotinib Therapy. There Is New Faint Enhancement at Margin of Left Frontal and Parietal Lesions. No Vasogenic Edema Has Developed Despite Increases in size

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Abbreviation: FLAIR ¼ fluid-attenuated inversion recovery.

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NSCLC Patients Receiving Crizotinib lesions contained abundant mucinous material in our patients whose primary tumors were also mucinous, perhaps suggesting that the behavior of metastatic deposits in terms of mucus production is related to the histology of the primary malignancy. However, not all such cases have had signet ring histology noted.8 No large-scale follow-up series have been reported in ALKþ NSCLC looking at whether either the incidence or the type of brain metastasis that occurs varies by the underlying histology. Although sufficient crizotinib penetration to prevent the development of CNS metastases was not occurring, conceivably the levels of crizotinib present in the CNS may still have been affecting local disease behavior—for example, by creating a more differentiated state in the brain metastases (eg, one capable of significant mucus production), particularly among patients whose disease had the appropriate underlying histology. Consistent with this hypothesis— that the crizotinib rather than just the ALKþ state is responsible for the CBM in ALKþ NSCLC—is that all CBM described in ALKþ NSCLC to date, including the 3 cases described here, have been noted while receiving crizotinib therapy rather than before the commencement of the therapy.7,8

Conclusion ALK-positive NSCLC patients receiving while receiving crizotinib can develop multiple cystic CNS metastatic lesions with unique clinical, radiologic, and pathologic characteristics.

Disclosure The authors have stated that they have no conflict of interest.

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References 1. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced nonesmall-cell lung cancer harboring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011; 12: 1004-12. 2. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive nonesmall-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012; 13:1011-9. 3. Chun SG, Choe KS, Iyengar P, et al. Isolated central nervous system progression on crizotinib: an Achilles heel of nonesmall cell lung cancer with EMLe4-ALK translocation? Cancer Biol Ther 2012; 13:1376-83. 4. Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged nonesmall cell lung cancer and brain metastases. J Clin Oncol 2015; 33:1881-8. 5. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 2011; 29:e443-5. 6. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted nonesmall-cell lung cancer. J Thorac Oncol 2012; 7: 1807-14. 7. Hayashi H, Okamoto I, Tanizaki J, et al. Cystic brain metastasis in nonesmall-cell lung cancer with ALK rearrangement. J Clin Oncol 2014; 32:e122-4. 8. Saraceni C, Li PM, Gainor JF, et al. Cystic brain metastases in NSCLC harboring the EML4-ALK translocation after treatment with crizotinib. J Thorac Oncol 2015; 10:1116-7. 9. Sharma V, Prabhash K, Noronha V, et al. A systematic approach to the diagnosis of cystic brain lesions. South Asian J Cancer 2013; 2:98-101. 10. Gettinger SN, Bazhenova L, Salgia R, et al. Updated efficacy and safety of the ALK inhibitor AP26113 in patients with advanced malignancies, including ALKþ nonesmall cell lung cancer [abstract]. J Clin Oncol 2014; 32(5(suppl)): 8047. 11. Costa R, Costa RB, Bacchi C, et al. Adenocarcinoma of the lung presenting with atypical cystic brain lesions. BMJ Case Rep 2014; 2014:1-3. 12. Zee YK, Chin TM, Wong AS. Fatal cystic change of brain metastasis after response to gefitinib in nonesmall-cell lung cancer. J Clin Oncol 2009; 27:e145-6. 13. Kaneda H, Okamoto I, Nakagawa K, et al. Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangementepositive nonesmall cell lung cancer. J Thorac Oncol 2013; 8:e32-3. 14. Yoshida A, Tsuta K, Nakamura H, et al. Comprehensive histologic analysis of ALK-rearranged lung carcinomas. Am J Surg Pathol 2011; 35:1226-34. 15. Nishino M, Klepeis VE, Yeap BY, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol 2012; 25:1462-72.

Cystic Brain Metastases Occurring in Anaplastic Lymphoma Kinase Gene Rearranged Non-Small-Cell Lung Cancer Patients Receiving Crizotinib.

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