Clinicopathologic Features of Non-Small-Cell Lung Cancer with EML4–ALK Fusion Gene

Takahashi, Tsuyoshi; Sonobe, Makoto; Kobayashi, Masashi; Yoshizawa, Akihiko; Menju, Toshi; Nakayama, Eiichiro; Mino, Nobuya; Iwakiri, Shotaro; Satô, Kiyoshi; Miyahara, Ryoji; Okubo, Kan; Manabe, Toshiaki; Date, Hiroshi

doi:10.1245/s10434-009-0808-7

Cited by 291 publications

(243 citation statements)

References 42 publications

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“…8,13,15,17 Furthermore, our analysis did not identify the cribriform pattern, extracellular mucin, or the 'mucinous cribriform' pattern to be strong predictors for ALK rearrangements in our patient cohort, in contrast to the findings described by others. 15,17 It is unclear whether the discrepancies between our study and those from Japan represent ethnic or other differences between the study populations.…”

Section: Nishino Et Alcontrasting

confidence: 99%

“…Some features previously reported to be associated with ALK rearrangements include young age of onset, reduced smoking history, advanced stage at presentation, adenocarcinoma histology, and mutual exclusivity with activating mutations in EGFR and KRAS. 4,[7][8][9][10][11][12][13][14][15][16] In spite of the common findings among the above studies, the results of detailed pathologic analyses have varied. Previously, our microscopic analysis of 20 ALK þ lung adenocarcinomas revealed a strong association with a solid-predominant architecture and the presence of signet ring cells with intracytoplasmic mucin vacuoles and peripherally displaced and flattened nuclei.…”

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confidence: 99%

“…In contrast, morphologic analysis of resected primary ALK þ lung adenocarcinomas from a predominantly Asian patient cohort identified acinar-predominant architecture and abundant mucin production as morphologic features significantly associated with ALK rearrangements. 8,13,17 It is unclear whether these conflicting results are due to differences in tumor stage (early vs advanced), specimen source (primary vs metastatic tumor), or ethnicity in the study populations. Furthermore, at least 70% of patients with lung cancer present at an advanced stage with unresectable disease.…”

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Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

et al. 2012

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Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the ALK inhibitor crizotinib. Defining distinctive features of ALK-rearranged (ALK þ ) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK þ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/ cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 ALK þ and 215 ALKÀ lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for ALK rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary ALK þ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of ALK þ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting ALK rearrangements in lung adenocarcinomas. The scoring system predicted ALK rearrangements in a new cohort of 78 lung adenocarcinomas (29 ALK þ and 49 ALKÀ) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK þ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with ALK rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of ALK þ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment.

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Section: Nishino Et Alcontrasting

confidence: 99%

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Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

et al. 2012

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“…ALK+ NSCLC is more frequently observed in younger patients and in patients with lack of EGFR mutation. ALK+ patients are also generally never or light smokers, and predominantly have adenocarcinoma with an acinar or signet-ring pattern [15][16][17][18]. Although the selection of cases using these clinicopathological features increases the prevalence of ALK+, it's not able to identify all of cases with ALK+.…”

Section: Discussionmentioning

confidence: 99%

Clinical application of immunocytochemical detection of ALK rearrangement on cytology slides for detection or screening of lung adenocarcinoma

et al. 2013

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Immunohistochemical screening of Anaplastic lymphoma kinase (ALK) rearrangement has been regarded essential and routinely carried out to select treatment for lung adenocarcinoma. However, difficulty to approach a tumor by transbronchial lung biopsy (TBLB), it often fails to obtain tumor tissues whereas tumor cells are contained in cytology specimens simultaneously obtained when the bronchoscopy is done. Therefore we evaluated the expression of ALK protein by using immunohistochemistry (IHC) on TBLB specimens and immunocytochemistry (ICC) on brushing smear cytology slides in the same cases, and compared the concordance rate of IHC and ICC results. ICC was carried out on routine Papanicolau-stained slides after cytology diagnosis and decolorization.Results: Eighteen patients with adenocarcinoma were extracted in the Hirosaki University Hospital and the Hirosaki National Hospital. IHC and ICC results showed a very high concordance rate: sensitivity of ICC in comparison with IHC was 85.7% (6/7), specificity was 100% (11/11), 3 positive predictive value was 100% (6/6), and negative predictive value was 91.6% (11/12). Detection of ALK rearrangement using ICC on routine Papanicolau cytology slides is considered to be advantageous for lung cancer treatments.

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“…Among others, exon 19 deletion and point mutations in exon 18 and 21 deliver high sensitivity to EGFR tyrosine kinase inhibitors (TKIs) erlotinib,6 gefitinib7 and afatinib 8. The EML4‐ALK fusion gene is found in 2–7% of AC patients9 and generally occurs independently of other oncogenic drivers, including EGFR, KRAS or ERBB2 mutations 10. NSCLC patients carrying ALK rearrangements have shown resistance to anti‐EGFR TKIs but sensitivity to ALK inhibitors comprising crizotinib and ceritinib 11.…”

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KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

Nagy

Pongor

Szabó

et al. 2016

Intl Journal of Cancer

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KRAS is the most frequently mutated oncogene in non‐small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer.We divided NSCLC patients with mutation and RNA‐seq data into KRAS mutated and wild type groups. Mann‐Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a “transcriptomic fingerprint” of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis.Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage.We generated a “surrogate signature” of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself.

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Clinicopathologic Features of Non-Small-Cell Lung Cancer with EML4–ALK Fusion Gene

Abstract: EML4-ALK fusion genes were observed predominantly in adenocarcinomas, in female or nonsmoking populations. Additionally, the EML4-ALK fusions were mutually exclusive with mutations in the EGFR, KRAS, and ERBB2 genes.

Cited by 291 publications

References 42 publications

Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

Clinical application of immunocytochemical detection of ALK rearrangement on cytology slides for detection or screening of lung adenocarcinoma

KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

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