Abstract
Molecular classification of lung cancer correlates well with histomorphological features. However, specific histomorphological features that differentiate anaplastic lymphoma kinase (ALK)-rearranged tumors from ALK-negative tumors have not been fully evaluated. Eighty ALK-rearranged and 213 ALK-negative (91 epidermal growth factor receptor-mutated; 29 K-ras-mutated; 93 triple-negative) resected lung adenocarcinomas were analyzed for several histomorphological parameters and histological subtype. ALK-rearranged tumors were associated with younger age at presentation, frequent nodal metastasis, and higher stage of disease at diagnosis. ALK-rearranged tumors were more likely to show a solid predominant pattern than ALK-negative tumors (43.8%; 35/80; p<0.001). Unlike ALK-negative tumors, a lepidic predominant pattern was not observed in ALK-rearranged tumors (p<0.001). In multivariate analysis, the most significant morphological features that distinguished ALK-rearranged tumors from ALK-negative tumors were cribriform formation (odds ratio [OR], 3.253; p = 0.028), presence of mucin-containing cells (OR, 4.899; p = 0.008), close relationship to adjacent bronchioles (OR, 5.361; p = 0.001), presence of psammoma bodies (OR, 4.026; p = 0.002), and a solid predominant pattern (OR, 13.685; p = 0.023). ALK-rearranged tumors exhibited invasive histomorphological features, aggressive behavior and frequent expression of epithelial-mesenchymal transition markers (loss of E-cadherin and expression of vimentin) compared with other genotype (p = 0.015). Spatial proximity between bronchus and ALK-rearranged tumors and frequent solid histologic subtype with p63 expression may cause diagnostic difficulties to differentiate squamous cell carcinoma in the small biopsy, whereas p40 was rarely expressed in ALK-rearranged adenocarcinoma. Knowledge of these features may improve the diagnostic accuracy and lead to a better understanding of the characteristic behavior of ALK-rearranged tumors.
Highlights
Adenocarcinoma of the lung is the most common histological type of primary lung cancer [1] and is a heterogeneous tumor with diverse molecular, clinical, and pathological characteristics
Several studies have investigated the predictive value of pathological and morphological features in detecting anaplastic lymphoma kinase (ALK)-rearranged tumors; the results of these studies have been inconsistent because of the limited number of ALK-rearranged tumors. [12,13,14,15,16] Solid signet-ring cell subtypes and cribriform pattern have been associated with ALK rearrangement in lung adenocarcinoma. [12,15] A few studies have reported a positive histological correlation with ALK rearrangement in lung adenocarcinoma using the new International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) classification that was published in 2011. [16,17] the comparative analysis of these histomorphological features and subtypes of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations has not been clearly established in lung adenocarcinoma
We performed a detailed comprehensive analysis of the histomorphological features associated with ALK-rearranged lung adenocarcinoma based on comparisons with well-known driver oncogene mutations
Summary
Adenocarcinoma of the lung is the most common histological type of primary lung cancer [1] and is a heterogeneous tumor with diverse molecular, clinical, and pathological characteristics. [2,3] Many studies have shown correlations between morphological features and molecular alterations in lung adenocarcinoma. Several studies have investigated the predictive value of pathological and morphological features in detecting ALK-rearranged tumors; the results of these studies have been inconsistent because of the limited number of ALK-rearranged tumors. [12,15] A few studies have reported a positive histological correlation with ALK rearrangement in lung adenocarcinoma using the new International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) classification that was published in 2011. Several studies have investigated the predictive value of pathological and morphological features in detecting ALK-rearranged tumors; the results of these studies have been inconsistent because of the limited number of ALK-rearranged tumors. [12,13,14,15,16] Solid signet-ring cell subtypes and cribriform pattern have been associated with ALK rearrangement in lung adenocarcinoma. [12,15] A few studies have reported a positive histological correlation with ALK rearrangement in lung adenocarcinoma using the new International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) classification that was published in 2011. [16,17] the comparative analysis of these histomorphological features and subtypes of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations has not been clearly established in lung adenocarcinoma
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