This article is mentioned in:

Introduction

Gefitinib, which is one of the highly promising epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), is administered orally once daily for patients with non-small-cell lung cancer (NSCLC) (1). Among NSCLCs, adenosquamous cell lung cancer (ASCLC) is a morphologically mixed type of tumor, including two cell components, adenocarcinoma and squamous cell carcinoma, in varying proportions, each representing ≥10% of the entire tumor (2). Previous studies evaluated the possibility of monoclonality and similar biological characteristics, including the frequency of EGFR mutation, of the two components (3–12). However, the number of currently available studies on the response of EGFR-positive ASCLC to gefitinib therapy is limited (13). We herein report a case of metastatic ASCLC successfully treated with gefitinib.

Case report

A 66-year-old female, with no smoking history, presented at the Mito Medical Center (Mito, Japan) with a cough and intermittent hemoptysis over the past 6 weeks. Chest radiography and computed tomography (CT) revealed a large cavitary mass in the lower lobe of the left lung (Fig. 1). Bronchoscopy revealed a tumor occluding the left lower bronchus, with active bleeding. The patient was initially diagnosed with adenocarcinoma on the basis of histopathological examination of transbrochial biopsy specimens. Distant metastasis was not detected. The patient’s Eastern Cooperative Oncology Group performance status score was 1. In order to prevent deterioration of the respiratory condition due to hemoptysis, the patient underwent lobectomy of the left lower lung and mediastinal lymph node dissection. The resected tumor exhibited adenocarcinomatous and squamous cell carcinomatous components, with each comprising ≥10% of the tumor (Fig. 2). The final pathological diagnosis was ASCLC staged as pT2bN2M0. The two components of the surgically resected tumor were precisely separated by manual microdissection under microscopic observation, to avoid contamination of each sample from different components. An EGFR exon 19 deletion was identified in both components. Soon after the surgical resection, the patient received four courses of chemotherapy with carboplatin and pemetrexed. However, six months after the chemotherapy, small cavitary metastases (≤10 mm) were identified in the lungs bilaterally (Fig. 3). Therefore, treatment with 250 mg of gefitinib once daily was initiated. A chest CT scan on day 28 of gefitinib administration revealed a substantial regression of the metastatic cavitary tumors in both lungs, with thinning of the walls (Fig. 4). There were no severe side-effects, such as lung toxicity. Treatment with gefitinib was continued in the outpatient clinic without any signs of tumor progression 19 months after the initiation of the treatment.

Figure 1 Chest computed tomography scan revealed a large cavitary mass in the lower lobe of the left lung.

Figure 2 The resected tumor exhibited components of (A) adenocarcinoma and (B) squamous cell carcinoma, with each comprising ≥10% of the tumor.

Figure 3 Chest computed tomography scan 6 months after the initiation of chemotherapy revealed small cavitary metastases (≤10 mm) in the lungs bilaterally.

Figure 4 Chest computed tomography scan on day 28 of gefitinib administration revealed substantial regression of the metastatic cavitary tumors in the lungs bilaterally, with thinning of the walls.

Discussion

Lung cancer is the leading cause of cancer-related mortality worldwide (14). NSCLCs are the most frequent type of lung tumors, with two major histological subtypes: adenocarcinomas and squamous cell carcinomas. A less frequent subtype of NSCLCs, ASCLC, is a morphologically mixed type of tumor, including two cell components, adenocarcinoma and squamous cell carcinoma, in varying proportions, each representing ≥10% of the entire tumor (2). Previous studies have suggested that ASCLC represents 0.3–5% of NSCLCs (15,16). In certain ASCLC patients, cavitary formation was observed (17,18). Kazerooni et al (18) reported that four of 30 cases exhibited cavitary formation. Cavities may be formed as a result of a unidirectional check-valve mechanism (17). Another mechanism of cavity formation may depend on the ischemic or colliquative tumor necrosis associated with neutrophil infiltration into the central portion of lesion. Cavitary formation due to tumor necrosis is common in squamous cell carcinomas, particularly in those developing peripherally in the lung (19). In our patient, the primary lesion exhibited cavitary formation and its wall was composed of the squamous cell carcinomatous component, which was pathologically confirmed. Certain metastatic lesions ≤10 mm also exhibited cavitation. Notably, the wall of the cavities, which were composed of the squamous cell carcinomatous component, were thinned with gefitinib therapy, although the cavities themselves did not change in size in the majority of the pulmonary lesions. The frequency of EGFR mutation-positive ASCLC patients was previously reported (3–12). However, the number of studies on the response of the lesions, either shrinkage or disappearance of pulmonary metastases with cavitary formation, specifically to gefitinib therapy is limited (13). Furthermore, there has been no report on long-term survivors who were successfully treated with gefitinib. Recently, Shukuya et al (13) reviewed the efficacy of gefitinib for non-adenocarcinoma NSCLC patients, including two ASCLC patients, and reported a response rate of 50%, a disease control rate 100% and a median progression-free survival of 5.3 months (13).

Although ASCLC is included in NSCLCs, the frequency of EGFR abnormalities has not been completely evaluated, due to the rarity of ASCLC (3–12). Two previous studies (4,5), reported EGFR abnormalities in ASCLC tumors identical to those previously described in primary lung adenocarcinoma: Ohtsuka et al (4) identified EGFR TK-domain gene mutations in 2 (50%) of 4 patients with ASCLC, whereas Kang et al (5) identified EGFR mutations in 11 (44%) of 25 ASCLC patients. However, Sasaki et al (11) reported that only four (15.4%) of 26 patients with ASCLC were positive for EGFR mutation.

The possibility of monoclonality and similar biological characteristics regarding genetic alterations, chromosomal abnormalities and immunohistochemical reactions in the two components of ASCLCs were evaluated in previous studies (3–12). With regard to EGFR mutations, Kang et al (5) demonstrated identical changes in the two components of ASCLC tumors, with of the nine mutations in 11 ASCLC patients being located in exon 19 (5). Furthermore, Toyooka et al (8) reported that three (27%) of the 11 ASCLC patients harboured EGFR mutations (two mutations in exon 19 and one in exon 21), which were identical in the two components. In our case, an EGFR mutation (exon 19 deletion) was identified in the two components of the surgically resected tumor. Taken together, the results of previous studies and our findings indicated that TKIs may be a reasonable therapeutic option for ASCLC patients harbouring EGFR mutations. Furthermore, identical EGFR mutations in the adenocarcinomatous and squamous cell carcinomatous components suggest the possibility of monoclonality and similar biological characteristics of the two components.

The present study suggested that gefitinib is a viable therapeutic option for EGFR mutation-positive patients with ASCLC. However, further investigations into the molecular determinants of tumor monoclonality in the histogenesis of ASCLC and response to EGFR-targeted therapies in patients with ASCLC are required.

References