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Medicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30075548MD-D-18-0038710.1097/MD.0000000000011646116465700Research ArticleClinical Case ReportOrganizing pneumonia resembling disease progression in a non-small-cell lung cancer patient receiving ceritinib A case reportLim Sun M. MD, PhDaAn Hee-Jung MD, PhDbPark Hyung S. MD, PhDcKwon Hyeong J. MD, PhDdY. Kim Eun MD, PHDeHur Jin MD, PhDfMoon Yong W. MD, PhDa∗NA.  a Medical Oncology, Department of Internal Medicineb Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnamc Division of Medical Oncology, Department of Internal Medicine,d Department of Pathologye Division of Pulmonology, Department of Internal Medicinef Department of Radiology, Yonsei University College of Medicine, Seoul, Korea.∗ Correspondence: Yong W. Moon, Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 463-712, Korea. (e-mail: ymoon@cha.ac.kr).8 2018 03 8 2018 97 31 e1164615 3 2018 28 6 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract
Rationale:
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), a distinct molecular entity, is highly sensitive to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib or ceritinib. Interstitial lung disease is a rare (1.2%) pulmonary toxicity that can result from ALK TKIs, however, organizing pneumonia has not been reported to date.

Patient concerns:
A 45-year-old Korean female with ALK-rearranged metastatic lung adenocarcinoma underwent ceritinib treatment and exhibited a partial response, until she developed organizing pneumonia resembling disease progression.

Diagnoses:
Multiple rebiopsies confirmed the involvement of organizing pneumonia in the pathology.

Interventions:
Ceritinib was stopped and the patient was treated with intravenous antibiotics followed by oral antibiotics for two weeks.

Outcomes:
After recovering from organizing pneumonia, ceritinib was successfully rechallenged and the patient attained a complete response.

Lessons:
When a new mass-like lesion develops in the lungs of responding patients, benign lung conditions, including organizing pneumonia should be considered in differential diagnoses.

Keywords
anaplastic lymphoma kinaseechinoderm microtubulenon-small cell lung cancerpneumoniatyrosine kinase inhibitorOPEN-ACCESSTRUE
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1 Introduction
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs), including crizotinib or ceritinib. In the first-line setting, crizotinib and ceritinib have demonstrated improved PFS compared to platinum-based doublet chemotherapy.[1,2] Although patients dramatically respond to initial ALK inhibitor therapy, they invariably develop acquired resistance exhibiting regrowth of a lung tumor. Often, biopsies of regrowing tumor lesions are performed to elucidate the mechanisms of resistance to ALK inhibitor. Recently, approximately 50% of patients who progressed on ALK TKIs harbored newly acquired ALK mutations which can be further inhibited by newer generation ALK TKIs.[3]

Interstitial lung disease, a rare (1.2%) pulmonary toxicity, can result from ALK TKIs,[1–3] but organizing pneumonia caused by ceritinib has not been reported to date. Herein, we report a case of organizing pneumonia resembling disease progression in a patient with non-small-cell lung cancer who received ceritinib. This study was approved by the Institutional Review Board of CHA Bundang Medical Center (South Korea), and the informed consent was waived due to the retrospective collection of data which secured the anonymity of the patient.

2 Case report
In September 2015, a 45-year-old Korean female with ALK-rearranged metastatic lung adenocarcinoma was administered ceritinib 750 mg, a second-generation ALK inhibitor. Her brief anticancer treatment history comprised right lower lobectomy (pT3N0M0) in February 2014, followed by adjuvant chemotherapy with vinorelbine and cisplatin. From September 2014, she received pemetrexed and cisplatin as the first-line therapy for the metastatic disease, followed by pemetrexed maintenance.

In the subsequent second-line therapy of ceritinib in October 2015, she exhibited a partial response in accordance with the response evaluation criteria in solid tumor (version 1.1)[4] with substantial tumor shrinkage of 78% (Fig. 1B) compared with that in the baseline scan (Fig. 1A). She maintained the partial response until a follow-up computed tomography (CT scan in April 2016 (Fig. 1C), which revealed newly appearing mass-like lesions in the left apex and right middle lobe (Fig. 1E). Assuming the presumptive disease progression, we performed a rebiopsy of the new lesion in the left apex to consider it for a new clinical trial; however, the transbronchial lung biopsy of the left apex mass revealed organizing pneumonia, non-infectious pneumonia defined as granulation tissue plugs within the lumens of small airways and extending into the alveolar ducts and alveoli.[5]

Figure 1 Chest CT finding at (A) the baseline showing the right middle lobe mass; (B) after one cycle showing a partial response with 78% tumor shrinkage; (C) lung mass achieving near complete response; (D) lung mass in the complete response; (E) newly developed mass-like nodules on both upper lobes and right middle lobe; and (F) disappeared organizing pneumonia in both upper lobes and right middle lobe.

She underwent a repeat CT-guided gun biopsy of the left apex mass and a transbronchial lung biopsy of the right middle lobe mass to eliminate inappropriate targeting in biopsy; however, the pathology confirmed chronic inflammation (Fig. 2A) from the biopsy of the right middle lobe mass and organizing pneumonia (Fig. 2B) from that of the left apex mass. Because her symptoms included a mild cough without fever, she was presumably diagnosed with drug-induced organizing pneumonia. Thus, ceritinib was withheld, and the patient was treated with intravenous antibiotics, followed by oral antibiotics for two weeks. A 3-week follow-up CT scan revealed improved consolidation in the right middle lobe and left apex. Because the patient exhibited no specific symptoms, ceritinib was readministered at a one-level reduced dose from May 2, 2016. A 1-month follow-up CT scan revealed resolution of the consolidations in the left apex and right upper lobe (Fig. 1F). In July 2016, she attained a complete response (Fig. 1D); at present, she is still undergoing ceritinib treatment, having received 55 cycles of the treatment.

Figure 2 A, H&E staining of biopsy from the right middle lobe mass showing chronic inflammation. Some inflammatory cells and macrophages are present. B, H&E staining of a biopsy specimen from the left apex mass showing organizing pneumonia. Arrows indicate that aggregates of loose fibroblasts are present. Lymphocytes are present to a variable degree within the interstitium.

3 Discussion
This case presents the occurrence of organizing pneumonia, which was initially confused with disease progression in a patient with lung adenocarcinoma receiving ALK inhibitor therapy. Had the patient been withdrawn from ceritinib because of presumptive disease progression, she would not have attained a complete response. After ruling out disease progression, we rechallenged the drug and the patient showed favorable response to it.

Interstitial pneumonia associated with epidermal growth factor receptor (EGFR) TKI is estimated to occur in approximately 1% of patients with cancer and is radiologically classified into the following 4 types: acute interstitial pneumonia (AIP)-like; bronchiolitis obliterans organizing pneumonia (BOOP)-like; acute eosinophilic pneumonia-like; and nonspecific ground-glass opacity (GGO).[6–8] Endo et al [5] reported that the most common type is the nonspecific GGO type (40%–50%), followed by AIP-like type (20%–30%). To the best of our knowledge, only a few cases of ALK inhibitor-caused interstitial pneumonia have been reported to date, and ours is the first BOOP-like case to be reported. The pathogenesis behind BOOP-like change is unclear at present, but the inflammatory response may be owing to ALK TKI.

In the era of targeted therapy, when encountered with the development of a new mass-like lesion in the lungs of responding patients with cancer, medical oncologists should consider benign lung conditions, including organizing pneumonia, in differential diagnoses. Furthermore, an aggressive diagnostic approach, including surgical rebiopsy, should be considered to avoid erroneous elimination of the therapeutic opportunity from responding patients.

Author contributions
Conceptualization: Sun M. Lim.

Data curation: Sun M. Lim, Hyung S. Park, Eun Y. Kim, Jin Hur.

Formal analysis: Sun M. Lim.

Methodology: Hyeong J. Kwon.

Supervision: Hee-Jung An, Yong W. Moon.

Abbreviations: BOOP = bronchiolitis obliterans organizing pneumonia, EGFR = epidermal growth factor receptor, EML4-ALK = echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, GGO = ground-glass opacity, TKI = tyrosine kinase inhibitor.

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI16C1559).

The authors declare no conflicts of interest.
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