Unique Clinicopathologic Features Characterize ALK-Rearranged Lung Adenocarcinoma in the Western Population

Purpose: The anaplastic large cell kinase gene (ALK) is rearranged in ∼5% of lung adenocarcinomas within the Asian population. We evaluated the incidence and the characteristics of ALK-rearranged lung adenocarcinomas within the western population and the optimal diagnostic modality to detect ALK rearrangements in routine clinical practice. Experimental Design: We tested 358 lung adenocarcinomas from three institutions for ALK rearrangements by fluorescent in situ hybridization (FISH) and immunohistochemistry with and without tyramide amplification. The clinicopathologic characteristics of tumors with and without ALK rearrangements were compared. Results: We identified 20 (5.6%) lung adenocarcinomas with ALK rearrangements within our cohort of western patients. ALK rearrangement was associated with younger age (P = 0.0002), never smoking (P < 0.0001), advanced clinical stage (P = 0.0001), and a solid histology with signet-ring cells (P < 0.0001). ALK rearrangement was identified by FISH in 95% of cases and immunohistochemistry with and without tyramide amplification in 80% and 40% of cases, respectively, but neither FISH nor immunohistochemistry alone detected all cases with ALK rearrangement on initial screening. None of the ALK-rearranged tumors harbored coexisting EGFR mutations. Conclusions: Lung adenocarcinomas with ALK rearrangements are uncommon in the western population and represent a distinct entity of carcinomas with unique characteristics. For suspected cases, dual diagnostic testing, with FISH and immunohistochemistry, should be considered to accurately identify lung adenocarcinomas with ALK rearrangement. (Clin Cancer Res 2009;15(16):5216–23)

[1]  S. Digumarthy,et al.  Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Mark A. Rubin,et al.  Clinical significance of TTF‐1 protein expression and TTF‐1 gene amplification in lung adenocarcinoma , 2009, Journal of cellular and molecular medicine.

[3]  A. Sihoe,et al.  The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS , 2009, Cancer.

[4]  M. Gerstein,et al.  Distinct genomic aberrations associated with ERG rearranged prostate cancer , 2009, Genes, chromosomes & cancer.

[5]  Y. Ishikawa,et al.  EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset , 2009, Modern Pathology.

[6]  Y. Ishikawa,et al.  A mouse model for EML4-ALK-positive lung cancer , 2008, Proceedings of the National Academy of Sciences.

[7]  S. Ogawa,et al.  Oncogenic mutations of ALK kinase in neuroblastoma , 2008, Nature.

[8]  D. Gary Gilliland,et al.  Activating mutations in ALK provide a therapeutic target in neuroblastoma , 2008, Nature.

[9]  H. Sugimura,et al.  EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. , 2008, Lung cancer.

[10]  Derek Y. Chiang,et al.  EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer , 2008, Clinical Cancer Research.

[11]  W. Gerald,et al.  Lung Adenocarcinoma: Modification of the 2004 WHO Mixed Subtype to Include the Major Histologic Subtype Suggests Correlations Between Papillary and Micropapillary Adenocarcinoma Subtypes, EGFR Mutations and Gene Expression Analysis , 2008, The American journal of surgical pathology.

[12]  Rongshi Li,et al.  Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy , 2008, Medicinal research reviews.

[13]  Francesca Demichelis,et al.  EML4-ALK fusion lung cancer: a rare acquired event. , 2008, Neoplasia.

[14]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[15]  G. Sommer,et al.  Reference , 2008 .

[16]  Yuki Togashi,et al.  EML4-ALK Fusion Is Linked to Histological Characteristics in a Subset of Lung Cancers , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[17]  Laura A. Sullivan,et al.  Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer , 2007, Cell.

[18]  Anthony J Alberg,et al.  Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). , 2007, Chest.

[19]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[20]  F. Detterbeck.  Lumping, splitting, and sorting. , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[21]  A. Iafrate,et al.  Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. , 2007, The Journal of molecular diagnostics : JMD.

[22]  O. Miettinen,et al.  Survival of patients with stage I lung cancer detected on CT screening. , 2006, The New England journal of medicine.

[23]  J. Tchinda,et al.  TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. , 2006, Cancer research.

[24]  Quynh-Thu Le,et al.  Non-small cell lung cancer: Clinical practice guidelines in oncology , 2006 .

[25]  Kenji Suzuki,et al.  Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma , 2006, International journal of cancer.

[26]  H. Sasaki,et al.  Epidermal growth factor receptor gene mutation defines distinct subsets among small adenocarcinomas of the lung. , 2006, Lung cancer.

[27]  S. Lester,et al.  Manual of Surgical Pathology , 2005 .

[28]  C. Tzen,et al.  Female sex and bronchioloalveolar pathologic subtype predict EGFR mutations in non-small cell lung cancer. , 2005, Chest.

[29]  P. Jänne,et al.  Bronchioloalveolar carcinoma: A Review of the Epidemiology, Pathology, and Treatment , 2005, Seminars in respiratory and critical care medicine.

[30]  Elisabeth Brambilla,et al.  Pathology and genetics of tumours of the lung , pleura, thymus and heart , 2004 .

[31]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[32]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[33]  William Pao,et al.  Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  R. Gascoyne,et al.  ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. , 2003, Blood.

[35]  L. Sobin,et al.  The TNM system: Our language for cancer care , 2002, Journal of surgical oncology.

[36]  P. Tamboli,et al.  Primary Signet-Ring Cell Carcinoma of Lung: Immunohistochemical Study and Comparison With Non-Pulmonary Signet-Ring Cell Carcinomas , 2001, The American journal of surgical pathology.

[37]  S. Suster,et al.  Primary signet ring cell adenocarcinomas of the lung: a clinicopathological study of 15 cases , 2001, Histopathology.

[38]  P. D. Dal Cin,et al.  TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. , 2000, The American journal of pathology.

[39]  K. Pulford,et al.  Expression of the ALK tyrosine kinase gene in neuroblastoma. , 2000, The American journal of pathology.

[40]  C. Griffin,et al.  Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. , 1999, Cancer research.

[41]  Takaaki Ito,et al.  Primary signet-ring cell carcinoma of the lung: histochemical and immunohistochemical characterization. , 1999, Human pathology.

[42]  S. Pileri,et al.  The EnVision++ system: a new immunohistochemical method for diagnostics and research. Critical comparison with the APAAP, ChemMate, CSA, LABC, and SABC techniques. , 1998, Journal of clinical pathology.

[43]  É. Mezey,et al.  Immunohistochemical signal amplification by catalyzed reporter deposition and its application in double immunostaining. , 1996, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[44]  S. Hirohashi,et al.  Small adenocarcinoma of the lung. Histologic characteristics and prognosis , 1995, Cancer.

[45]  D N Shapiro,et al.  Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. , 1994, Science.

[46]  D. Sarma,et al.  Primary signet-ring cell carcinoma of the lung. , 1990, Human pathology.

[47]  Y. Sakao,et al.  Prognostic significance of a histologic subtype in small adenocarcinoma of the lung: the impact of nonbronchioloalveolar carcinoma components. , 2007, The Annals of thoracic surgery.

[48]  A. Bernheim,et al.  High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. , 1996, Blood.

[49]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.