ALK-rearranged lung squamous cell carcinoma responding to alectinib: a case report and review of the literature

Numerous oncogenic driver mutations have been identified in patients with non-small cell lung cancer. Research has reported that two genes in particular (human epidermal growth factor receptor [EGFR] and anaplastic lymphoma kinase [ALK]) are associated with improvements in therapeutic efficiency in non-small cell lung cancer patients receiving targeted therapies. ALK fusion genes are typically identified in approximately 5.0% of patients with lung adenocarcinoma, although they are rare in patients with squamous cell carcinoma (SqCC) [1, 2]. Treatment of metastatic ALK-rearranged non-small cell lung cancer with ALK inhibitors leads to higher response rates and improved progression-free survival relative to conventional chemotherapy regimens [3, 4]. However, the efficacy of such treatment for ALK-rearranged lung SqCC remains unknown, as ALK-rearranged lung SqCC is very rare and ALK testing is not routinely performed in this patient population. Herein, we describe a rare case of ALK-rearranged lung SqCC responding to alectinib.

A 52-year-old Japanese-Brazilian woman without a history of smoking was referred to our hospital for evaluation of severe left back pain and a left hilar mass observed on a chest radiograph. Computed tomography of the chest revealed a solitary tumor in the left lower lobe with direct invasion to the seventh thoracic vertebra and rib. The patient also had mediastinal lymphadenopathy, left adrenal metastasis, and multiple bone metastases (Fig. 1a-b). Pathological examination of the transbronchial needle aspiration biopsy specimen revealed undifferentiated cancer with a mild tendency of cornification (hematoxylin and eosin staining, Fig. 2a). Upon immunohistochemical (IHC) analysis, the tumor cells exhibited strong positive staining for p40 and cytokeratin 5/6, but were negative for thyroid transcription factor-1 (Fig. 2b-d). Based on these findings, the patient was diagnosed with Stage IV lung SqCC and was treated with palliative radiotherapy and first-line systemic chemotherapy with cisplatin plus vinorelbine. After 2 cycles of chemotherapy, there was no evidence of a response. Second-line chemotherapy was thus indicated. Despite a diagnosis of SqCC, the patient underwent ALK testing, as she was a non-smoker diagnosed with lung cancer harboring the wild-type EGFR gene. IHC analysis indicated that the tumor cells were positive (2+ staining) for the ALK antibody (Histofine ALK iAEP Detection Kit; Nichirei Bioscience Inc., Tokyo, Japan). ALK break-apart fluorescence in situ hybridization (FISH) (Vysis ALK Break Apart FISH Probe Kit; Abbott Molecular, Inc., Des Plaines, IL, USA) confirmed the presence of an ALK gene rearrangement with a rearrangement-positive cell rate of 46.0% (Fig. 3). The patient was subsequently treated with alectinib, a selective ALK inhibitor. After 2 weeks of treatment, the symptoms gradually improved. After 3 months, a follow-up computed tomography scan revealed a remarkable response in the primary lesion and significant shrinkage of the left adrenal gland metastasis (Fig. 1c-d). At the latest follow-up, 11 months after commencing alectinib treatment, there was no evidence of progression or any remarkable toxicity.

Our diagnosis of SqCC was confirmed by p40 immunostaining, which is useful and highly specific for the diagnosis of SqCC [5, 6]. Additionally, in our case, the results of the ALK detection test were concordant between IHC staining and FISH. Yamamoto et al. [7] reported a similar case, which was diagnosed with ALK-rearranged lung SqCC. The diagnosis was confirmed by IHC staining, which was positive for p40, but negative for thyroid transcription factor-1. The pathological specimen of their case [7] was also obtained from the primary lesion by bronchoscopic biopsy and no adenocarcinoma component was detected in the biopsy specimen. The case reported by Yamamoto et al. [7] was positive on FISH with a rearrangement-positive cell rate of just 20.0%, but negative on IHC staining. Ilie et al. [8] reported that cases with discordant ALK detection test results (i.e., FISH positive, but IHC staining negative) had lower rearrangement-positive cell rates of 15.0–20.0% and exhibited a tendency towards a lower response to crizotinib. However, since the case described by Yamamoto et al. [7] was treated with radiotherapy without chemotherapy, it remains unclear whether the patient exhibited a marked response to ALK targeted therapies. As shown in Table 1, only a few cases of ALK-rearranged lung SqCC responding to crizotinib have been reported to date [9‐12]. Alectinib is a new drug that is expected to be safer and more effective than crizotinib as a first-line chemotherapy treatment for patients with ALK-rearranged lung adenocarcinoma [13]. Recently, Tamiya et al. [14] reported a case of ALK-rearranged lung SqCC that was treated with alectinib, although no response was observed. In our case, the patient with ALK-rearranged lung SqCC exhibited an antitumor response to alectinib. Further case reports are needed to confirm the efficacy of ALK targeted therapies for the treatment of ALK-rearranged lung SqCC patients.

There are some limitations to our case report. Our histological specimen was small and was obtained from a mediastinal lymph node. For this reason, there was the potential for an adenocarcinoma component to be contained in other regions or for there to be discrepancies between the primary lesion and metastatic lesions due to the heterogeneity and distribution of the tumor. In contrast, Hou et al. [15] reported a high concordance rate of ALK rearrangement between primary tumors and paired metastatic lymph nodes, which supports the findings of our case report.