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Response to crizotinib in a squamous cell lung carcinoma patient harbouring echinoderm microtubule‐associated protein‐like 4‐anaplastic lymphoma translocation: A case report

Abstract Squamous cell lung cancer (SCC) presenting with anaplastic lymphoma kinase (ALK) translocation is rare. We present a case of ALK gene translocation‐SCC in which a remarkable tumor response to crizotinib was achieved after the failure of prior chemoradiotherapy. Considering this remarkable response, we conclude that ALK testing in female non‐smokers or in any patient unresponsive to the initial regimen of chemotherapy, is recommended for SCC patients.


Introduction
Lung cancer is the leading cause of cancer death worldwide, with morbidity and mortality rates increasing in both developed and developing countries. 1 The specific molecular changes in certain lung cancer cases have provided excellent opportunities for the development of new targeted therapies. Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement is found in 2-7% of patients with non-small cell lung cancer (NSCLC) overall. 2 But a low reported frequency range of 0-2.5% anaplastic lymphoma kinase (ALK) mutation is found in squamous cell lung cancer (SCC) patients. 3 Crizotinib, a novel ALK tyrosine kinase inhibitor, has already shown impressive single-agent activity in ALK-positive lung adenocarcinomas (ADCs). In ADCs, the objective response rate to crizotinib is about 60% and its median progressionfree survival is nearly 10 months. 4,5 Nowadays, a low percentage of SCC patients are enrolled in clinical trials; thus, the efficacy of ALK inhibitors for these patients is not wellknown. In this report, we present a case of successful crizotinib treatment of an ALK rearrangement in an SCC patient.

Case report
A 37-year old female never-smoker presented to our hospital with a one-month history of coughing. Positron emission tomography-computed tomography (PET/CT) scans revealed a 4.0*4.2 cm mass at the superior lobe of the left lung and contralateral mediastinal lymph node enlargements (T2N3M0 stageIIIB) (Fig 1a). A pathological diagnosis of SCC was obtained using needle biopsy. Hematoxylin and eosin staining showed the typical morphology of SCC cells (Fig 2a). Immunohistochemistry (IHC) analysis demonstrated positivity in cytokeratin (CK) 5/6 and P63, and negativity in CK7, Napsin A, and thyroid transcription factor-1.
Concurrent chemoradiotherapy with six cycles of doxetaxel and cisplatin (DP; docetaxel 75 mg/m2 D1; ciplatin 25 mg/m2 D1-3) chemotherapy regimens and three dimensional-conformal radiotherapy (2Gy per fraction, 1 fraction per day, total radiation dose 60Gy, 5 fractions per week, 30 fractions) was performed from July 2013 until November 2013. The curative effect achieved was a partial response. Unfortunately, during routine examination, the presence of multiple metastases in the right lung on CT scan images and the presence of right parietal lobe metastases indicated cancer progression (Fig 1b). Wild-type epidermal growth factor receptor variant tumor tissue was detected by amplification refractory mutation system (AmoyDx, Xiamen China), and ALK protein expression by Ventana ALK IHC assay (Ventana Medical Systems, Roche, Tuscon, AZ, USA) (Fig 2b). The patient received gamma knife radiosurgery (total dose 24 Gy at 50% isodose, 2 fractions, 2 days) to treat brain metastases in June 2014, then underwent crizotinib treatment (250 mg/bid, orally) in July 2014. After two months, chest CT scan images demonstrated a decrease in tumor size (Fig 1c). According to Response Evaluation Criteria in Solid Tumors guidelines (version 1.1), this patient was considered as having a partial response (PR) to crizotinib. During crizotinib treatment, abnormal hepatic and renal function were not found. There were no treatment-related adverse events, including gastrointestinal reaction, flickering vision, or cordis damage. To date, after nine months, the disease remains stable.

Disscusion
In NSCLC, ALK rearrangement is associated with distinct clinicopathological features, including a young age of onset, absent or minimal smoking history, and adenocarcinoma histology. 6 This case demonstrated ALK rearrangement in a young, female never-smoker with SCC. However, the proportion of ALK rearrangement is very low in SCC. Recent studies have reported ALK rearrangement frequencies ranging from 1-6.5% in SCC. 3 10,11 These studies illustrated that biopsies might represent an incomplete sampling of these complex tumors. In some cases, core needle biopsy may be too difficult to obtain a complete sample in order to determine lymph node metastasis. Therefore, to ensure appropriate management, oncologists need to be aware of the existence of patients harboring EML4-ALK positive SCC. Moreover, clinical features might be useful to help identify a subset of patients who require ALK testing (e.g. patients with minimal or no smoking history), regardless of the histological type of their tumors.
Crizotinib has demonstrated an excellent clinical response in patients with EML4-ALK-positive lung adenocarcinoma. However, the efficacy of crizotinib for ALK positive-SCC patients is not yet well known. Only one case has been reported in which crizotinib had an obvious effect on pure SCC. 9 Our case is the second report of the effectiveness of crizotinib for ALK-mutation SCC.

Conclusion
In summary, this case indicates that patients with SCC could harbor EML4-ALK translocation. Therefore, ALK testing in female non-smokers or in any patient unresponsive to the initial regimen of chemotherapy, is recommended for SCC patients, in order to determine the indication for crizotinib treatment.

Disclosure
No authors report any conflict of interest.