Clinical Review & Education

JAMA Oncology Clinical Challenge

Progressive Dry Cough in a Patient With ROS1-Rearranged Lung Adenocarcinoma Undergoing Crizotinib Therapy Chang-Yao Chu, MD; Hong-Ping Er, MD; Chien-Chung Lin, MD, PhD

A New consolidation lesion vs primary tumor

B

CT-guided biopsy and CT scan

Figure. A, The comparison of the chest computed tomographic (CT) scan of the new consolidation lesion (red arrowheads) mimicking recurrence (right panel) with the primary tumor (yellow arrowhead) in the initial CT scan (left panel). B, Microscopic findings of a CT-guided biopsy (left panel) and CT scan after resuming ceritinib treatment (right panel). Granulomatous inflammation or sarcoid-like reaction with predominant T-cell infiltration (hematoxylin and eosin stain, magnification ×200) and less B cell infiltration. Inset: double immunohistochemical staining showing abundant T cells (CD3, red staining; red arrowheads) and rare B cell infiltration (CD20, brown staining; yellow arrowhead). The CT scan after resuming ceritinib treatment for 2 months showed decreased lung consolidation and the primary tumor (yellow arrowhead).

A 69-year-old man with a smoking history and complaints of back pain and cough for 2 weeks was found to have a right lung mass on chest radiography results. A chest computed tomography (CT) scan showed a right upper lobe lung mass with multiple lymphadenopathies (N3), and bone scan and brain magnetic resonance imaging results showed multiple metastatic foci. A biopsy was performed, and the pathologic report showed a poorly differentiated lung adenocarcinoma with ROS1 rearrangement identified by immunohistochemical staining (clone: D4D6; H-score: 280) and further confirmative fluorescence in situ hybridization. The patient received ceritinib, 450 mg/day, and his tumor and brain and bone metastatic lesions subsequently decreased in size. The ceritinib was then shifted to crizotinib, 500 mg/day, when the reimbursement of crizotinib as a first-line therapy was approved by Taiwan's National Health Insurance system. Three weeks after the first dose of crizotinib, the patient developed a dry cough without fever or purulent sputum. There was no significant finding on physical examination except mild crackles over the right lung field, although chest radiography results showed a new consolidation lesion over the right upper lobe. Meanwhile, the results of mycobacterial and bacteriologic surveys were unremarkable. The tumor marker carcinoembryonic antigen level decreased from an initial 14.76 to 0.71 ng/mL (reference range, 0-5.00 ng/mL [to convert to micrograms per liter, multiply by 1]). A CT scan was arranged, and developing lung cancer with lymphangitic carcinomatosis was highly suspected by the radiologist (Figure, A). A bronchoscopy with bronchial brushing and biopsy was performed, and no pathogen was identified.

WHAT IS YOUR DIAGNOSIS?

A. Treat with chemotherapy for disease recurrence because the agents available for recurrent ROS1 tumors remain limited B. Administer antibiotics with coverage for pneumonia pathogen for 7 to 10 days and a repeated CT scan in 4 weeks C. Administer steroid treatment and discontinue crizotinib and other tyrosine kinase inhibitors (TKIs) permanently because TKI-induced interstitial lung disease is highly suspected D. Perform a CT-guided biopsy for histological confirmation of recurrence or identification of other benign disease, such as granulomatous inflammation

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Clinical Review & Education JAMA Oncology Clinical Challenge

Diagnosis D. Perform a CT-guided biopsy for histological confirmation of recurrence or identification of other benign disease, such as granulomatous inflammation

Discussion The pathological findings of the patient’s CT-guided biopsy were compatible with inflammation or SLR. The main feature of this patient was the mild presenting symptom but with the rapid development of consolidated lung with interstitial pneumonia on his CT scan. The diagnosis of bacterial pneumonia was rejected because the patient had a dry cough only, and findings of bronchial washings were negative. Disease recurrence was considered, but the decreasing carcinoembryonic antigen levels seemed inconsistent. Although a similar CT finding can be found in tyrosine kinase inhibitor (TKI)– induced interstitial lung disease (ILD), the mild symptom was incompatible with this diagnosis. There was no direct evidence to support the change of treatment to chemotherapy or steroids. With this in mind, clinicians must consider rebiopsy, and the diagnosis of the SLR was compatible with clinical symptoms and CT findings. Cancer-associated SLR is characterized by epithelioid cell granulomas with T-cell infiltration in pathologic findings (Figure, B) and observed in patients with hematological malignancies or solid tumors. In contrast to sarcoidosis with systemic involvement, cancer-associated SLR is usually asymptomatic, and the incidence of SLR lymphadenopathy in lung cancer ranges from 1.3% to 11%.1 Sarcoid-like reaction with ground-glass pulmonary infiltrates or lung consolidation is rare. Although fluorodeoxyglucose positron emission tomography is useful for evaluating the recurrence of lung cancer, it has been reported to produce false-positive results in cases of SLR.2 Sarcoid-like reactions are elicited by antigenic factors released from the tumor cells and are mostly identified in the lymph nodes draining a malignant tumor. These antigenic factors may be either shed by the tumor cells or released during tumor necrosis. Therefore, such reactions can be identified at diagnosis or after chemotherapy and immunotherapy.3 In infiltrating tumors, the production of interferon gamma by local natural killer cells and T cells ARTICLE INFORMATION Author Affiliations: Division of Surgical Pathology, Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Chu); Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Er, Lin); Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Lin); Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan (Lin). Corresponding Author: Chien-Chung Lin, MD, PhD, National Cheng Kung University Hospital, 138 Sheng Li Rd, Tainan 704, Taiwan ([email protected]).

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activates the dendritic cells, which then present the antigen to naive CD4+ T cells, converting them into T helper 1 cells and contributing to the maturation of macrophages and granuloma formation. In an observational cohort study of 127 patients with lung cancer undergoing curative resection, 19 (14.9%) had coexistent granulomatous inflammation in the resected specimen.1 Some treatments for cancer may produce necrotic material or metabolic substances and induce granulomatosis, such as Bacillus Calmette-Guerin therapy for bladder cancer and interleukin-2 treatment for kidney cell carcinoma. Immune checkpoint inhibitors have changed the therapeutic landscape for lung cancer, and several reports have described the development of SLRs after the use of immune checkpoint inhibitors, especially cytotoxic T-lymphocyte–associated protein 4 inhibitors.4 Assessing the expression of programmed cell death (PD) 1 and PD ligand 1 (PD-L1) in peripheral blood mononuclear cells in patients receiving nivolumab therapy, a recent study showed that an elevated expression of PD-L1 sequential to blocking PD-1/PD-L1 interaction can be associated with SLRs.5 Although SLRs have been reported in patients receiving chemotherapy and immunotherapy, to our knowledge, this is the first report of a pulmonary consolidation pattern in a patient with ROS1 rearrangement receiving an anaplastic lymphoma kinase/ROS1 inhibitor. Sarcoid-like reactions often respond to corticosteroid treatment and do not require the discontinuation of treatment. Conversely, in TKI-induced ILDs, the destroyed endothelium of alveolar vessels or pneumocytes leads to the release of cytokines and the recruitment of more inflammatory cells that, in turn, induce more damage to the endothelial cells.6 Deaths associated with TKIinduced ILD have been reported, and permanent discontinuation of TKIs is required in severe cases. In this case, while the patient’s dry cough was not severe, he decided to halt his crizotinib use. He further refused steroid use and asked to resume the ceritinib treatment. His dry cough improved substantially, and the lung consolidation lesion subsequently decreased (Figure, B). In conclusion, in cases involving a radiological pattern of disease progression, such as a new lung consolidation lesion associated with TKI use, our article suggests that a routine rebiopsy is needed to confirm the SLR and avoid misinterpretation.

Applied Nanomedicine, National Cheng Kung University, from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project of the Ministry of Education in Taiwan, as well as grant MOST108-2314-B-006 -092 -MY2 from the Ministry of Science and Technology, Taiwan. Additional Contributions: We thank the patient for granting permission to publish this information. REFERENCES 1. Dagaonkar RS, Choong CV, Asmat AB, et al. Significance of coexistent granulomatous inflammation and lung cancer. J Clin Pathol. 2017;70 (4):337-341. doi:10.1136/jclinpath-2016-203868

Published Online: October 1, 2020. doi:10.1001/jamaoncol.2020.2809

2. Chowdhury FU, Sheerin F, Bradley KM, Gleeson FV. Sarcoid-like reaction to malignancy on whole-body integrated (18)F-FDG PET/CT: prevalence and disease pattern. Clin Radiol. 2009; 64(7):675-681. doi:10.1016/j.crad.2009.03.005

Conflict of Interest Disclosures: The authors acknowledge the financial support of the Center of

3. Tetzlaff MT, Nelson KC, Diab A, et al. Granulomatous/sarcoid-like lesions associated with

checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients. J Immunother Cancer. 2018;6(1):14. doi:10.1186/s40425-0180323-0 4. Gkiozos I, Kopitopoulou A, Kalkanis A, Vamvakaris IN, Judson MA, Syrigos KN. Sarcoidosis-like reactions induced by checkpoint inhibitors. J Thorac Oncol. 2018;13(8):1076-1082. doi:10.1016/j.jtho.2018.04.031 5. Paolini L, Poli C, Blanchard S, et al. Thoracic and cutaneous sarcoid-like reaction associated with anti-PD-1 therapy: longitudinal monitoring of PD-1 and PD-L1 expression after stopping treatment. J Immunother Cancer. 2018;6(1):52. doi:10.1186/ s40425-018-0372-4 6. Pellegrino B, Facchinetti F, Bordi P, Silva M, Gnetti L, Tiseo M. Lung toxicity in non–small-cell lung cancer patients exposed to ALK inhibitors: report of a peculiar case and systematic review of the literature. Clin Lung Cancer. 2018;19(2):e151-e161. doi:10.1016/j.cllc.2017.10.008

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