Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
J Pathol Transl Med
2021 Mar 01;552:139-144. doi: 10.4132/jptm.2020.12.16.
Show Gene links
Show Anatomy links
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
.
???displayArticle.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.
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.
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.
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.
Baldi,
Concomitant EGFR mutation and ALK rearrangement in lung adenocarcinoma is more frequent than expected: report of a case and review of the literature with demonstration of genes alteration into the same tumor cells.
2014, Pubmed
Baldi,
Concomitant EGFR mutation and ALK rearrangement in lung adenocarcinoma is more frequent than expected: report of a case and review of the literature with demonstration of genes alteration into the same tumor cells.
2014,
Pubmed
Fan,
Concomitant EGFR Mutation and EML4-ALK Rearrangement in Lung Adenocarcinoma Is More Frequent in Multifocal Lesions.
2019,
Pubmed
Gainor,
ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer.
2013,
Pubmed
Hata,
Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer.
2010,
Pubmed
Lee,
Differential sensitivities to tyrosine kinase inhibitors in NSCLC harboring EGFR mutation and ALK translocation.
2012,
Pubmed
Lee,
Non-small Cell Lung Cancer with Concomitant EGFR, KRAS, and ALK Mutation: Clinicopathologic Features of 12 Cases.
2016,
Pubmed
Lindeman,
Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
2018,
Pubmed
Schmid,
Clinical Outcome of ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs).
2017,
Pubmed
Won,
Concomitant ALK translocation and EGFR mutation in lung cancer: a comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor.
2015,
Pubmed
Yang,
Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation.
2014,
Pubmed
Zheng,
Classification and Pathology of Lung Cancer.
2016,
Pubmed
