J Pathol Transl Med.  2021 Mar;55(2):139-144. 10.4132/jptm.2020.12.16.

A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma

• Lee KC
• Koh J
• Chung DH
• Jeon YK

• KMID: 2513900
• DOI: http://doi.org/10.4132/jptm.2020.12.16

Abstract

Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

Keyword

Lung adenocarcinoma; Epidermal growth factor receptor; Anaplastic lymphoma kinase; Concomitant alteration; Targeted gene sequencing

Figure

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  Fig. 1 Radiologic findings of the ground-glass nodule (GGN). (A, B) Coronal and axial computed tomography scan reveals a 1.7-cm GGN (arrows) with an inner solid portion measuring 0.5 cm in the right lower lobe of the lung. (C) The GGN (arrow) shows mild uptake on the positron emission tomography–computed tomography fusion scan, and no other hypermetabolic lesions are found.

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  Fig. 2 Pathologic features of the tumor. Microscopic evaluation of the tumor section shows lung adenocarcinoma with a predominantly acinar pattern (green circle) but also a lepidic portion (blue circle). Anaplastic lymphoma kinase (ALK) immunohistochemistry (IHC) reveals the focal expression of ALK within the part of the tumor showing lepidic growth. On ALK fluorescence in-situ hybridization (FISH), split signals (yellow circles) are seen within the ALK IHC-positive area whereas the ALK IHC-negative area is conformed as negative. H&E, hematoxylin and eosin.

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  Fig. 3 Results of targeted sequencing of the anaplastic lymphoma kinase (ALK) immunohistochemistry (IHC)/fluorescence in-situ hybridization (FISH)–positive and -negative portions of the tumor. (A) Next-generation sequencing identified epidermal growth factor receptor (EGFR) L858R and L833V point mutations in both the ALK IHC/FISH-positive and -negative portions of the tumor, albeit with different variant allele frequencies. Tissues for targeted sequencing were obtained from separate slides to avoid potential contamination. Since both EGFR mutations were found in the same read, it is likely that they occurred in the same allele. (B) Soft clipped reads of ALK (left) and EML4 (echinoderm microtubule-associated protein-like 4) (right) with breakpoints at intron 18 of EML4 and intron 19 of ALK were found in the ALK IHC/FISH-positive portion of the tumor and suggested the fusion of the two genes.

Reference

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