Complete Radiological Response of Metastatic Anaplastic Lymphoma Kinase-Positive Signet Ring Lung Adenocarcinoma to Systemic Chemotherapy

Abstract

Twenty-seven-year-old woman attended Accident and Emergency department complaining of right-sided pleuritic chest pain for the past 3 to 4 weeks. She had no significant medical or surgical history. Her chest x-ray examination showed bulky right-sided hilar mass, consolidation in the right lower lung zone with ipsilateral pleural effusion (Figures 1A, B). Her routine blood tests were normal except of mildly elevated inflammatory markers. She underwent bronchoscopy, which did not reveal intrabronchial lesions. Cytology from bronchioalveolar lavage sample showed abnormal cells with signet ring features (Figure 2A). Transbronchial biopsy of right hilar mass showed adenocarcinoma with signet ring features (Figure 2B) that was positive on immunohistochemistry for thyroid transcription factor 1 (3 ) (Figure 2C) and was consistent with primary lung adenocarcinoma. Signet ring variant of lung primary adenocarcinoma is rare and can be associated with a novel genetic translocation joining the echinoderm microtubule-associated protein-like 4 gene (EML4) and the anaplastic lymphoma kinase (ALK) gene, forming EML4-ALK fusion gene. As previously described, presence of EML4-ALK fusion gene is associated with expression of ALK protein (2 ), which was confirmed by immunohistochemistry using anti-ALK antibody (DAKO Company, Carpinteria, CA) (Figure 2D).1,2 ALK positivity was confirmed on fluorescence in situ hybridization (FISH) as described previously.3 Positron emission tomography/computed tomography scan showed extensive neck, mediastinal, and paraaortic lymphadenopathy with multiple necrotic, and metabolically active lesions in right hilum and right lung base, which was extending through diaphragm into the posterior segments of the liver (Figures 3A–D). She was commenced on systemic chemotherapy with carboplatin (area under the curve 6) and pemetrexed (500 mg/m) every 21 days for a total of six cycles. She tolerated chemotherapy very well, and restaging positron emission tomography/computed tomography scan showed remarkable radiological response with significant decrease both in size and activity within all metastatic sites (Figures 3A–J). She continued on maintenance pemetrexed chemotherapy (500 mg/m every 21 days) for six more cycles with no evidence of disease progression 10 months after diagnosis. Signet ring variant of primary lung adenocarcinoma is very rare and is associated with EML4-ALK gene fusion that comprises approximately 5% of unselected patients with non-small cell lung cancer (NSCLC).1 In selected population of patients who are younger than 40 years, never/light smokers, and have nonsquamous histology, incidence of EML4ALK gene fusion may be as high as 13%.1 EML4-ALK positivity is associated with lack of response to epidermal growth factor receptor tyrosine kinase inhibitors.1 Recently published results of phase I/II clinical trial with orally bioavailable inhibitor (PF-0341066; crizotinib) of the ALK and c-Met/Hepatocyte Growth Factor receptor (HGFR) tyrosine kinases in patients with metastatic NSCLC who harbor EML4-ALK fusion gene showed remarkable response rates with minimal toxicity.3 Currently, crizotinib is investigated in two phase III randomized trials as a second-line treatment in patients with advanced/metastatic NSCLC with EML4-ALK gene fusion. We report herein complete radiological response to systemic chemotherapy with carboplatin and pemetrexed in this rare variant of NSCLC.