Cytomorphologic features of advanced lung adenocarcinomas tested for EGFR and KRAS mutations: A retrospective review of 50 cases

Marotti, Jonathan D.; Schwab, Constantin; McNulty, Nancy J.; Rigas, James R.; DeLong, Peter; Memoli, Vincent A.; Tsongalis, Gregory J.; Padmanabhan, Vijayalakshmi

doi:10.1002/dc.21749

Cited by 15 publications

(19 citation statements)

References 46 publications

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“…In the present study, we found that 10% of the 77 analyzed adenocarcinoma samples harbored EGFR mutations, 35% of which carried KRAS mutations, while 51% of the 54 samples analyzed for KRAS mutations were negative regarding both mutation types. KRAS mutation results were moderately high for the detection of KRAS mutations with cytomorphological features of adenocarcinomas (12,13), but are in accordance with the recently reported prevalence of NSCLC patients with KRAS mutations (27%) detected using COLD-PCR (14) and 36.9% KRAS mutations detected in malignant pleural effusion of lung adenocarcinoma in a Dutch population (15). …”

Section: Discussionsupporting

confidence: 88%

Application of PCR methods to evaluate EGFR, KRAS and BRAF mutations in a small number of tumor cells in cytological material from lung cancer patients

Lewandowska¹,

Jóźwicki²,

Jochymski³

et al. 2013

Oncology Reports

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The epidermal growth factor receptor (EGFR) mutation status in the tyrosine kinase domain is known to be a predictor of the response to gefitinib or erlotinib in lung cancer; thus, a non-surgical procedure of tumor specimen collection is critical for mutation analysis. The aim of the present study was to analyze the EGFR, KRAS and BRAF status in limited cytological material. To the best of our knowledge, this is the first time that the quantitative scale of tumor cells and the percentage of tumor cells in cytological material were evaluated at the early stages of pathomorphological material qualification for EGFR, KRAS and BRAF mutation analysis. Our results revealed that even 100–1,000 tumor cells from fine needle aspiration (FNA) samples provided reliable results of mutation analysis when sensitive real-time polymerase chain reaction (PCR) methods were used. EGFR mutations were detected in 10% (7/71) and KRAS mutations were detected in 35% (19/54) of the lung adenocarcinoma cases. In addition, we reported the most common inhibiting mutation (p.T790M) found in coexistence with p.L858R in an FNA sample from a patient, for whom short-term improvement after erlotinib treatment was observed before further progression of the disease. Subsequently, mutual exclusion of EGFR and KRAS mutations was observed. Cytological samples with a small number of tumor cells obtained via FNA, endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) or brushing are suggested to be used for diagnostic purposes after careful selection by cytopathologists and analysis using a validated, sensitive real-time PCR method.

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Section: Discussionsupporting

confidence: 88%

Application of PCR methods to evaluate EGFR, KRAS and BRAF mutations in a small number of tumor cells in cytological material from lung cancer patients

Lewandowska¹,

Jóźwicki²,

Jochymski³

et al. 2013

Oncology Reports

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“…Several studies showed an association of KRAS mutations with poor differentiation 27, 33 . KRAS mutations were found to be associated with a solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma 34 , or more likely to invade visceral pleura 32 .…”

Section: Discussionmentioning

confidence: 99%

Association Between Computed Tomographic Features and Kirsten Rat Sarcoma Viral Oncogene Mutations in Patients With Stage I Lung Adenocarcinoma and Their Prognostic Value

Wang

Schabath

Liu

et al. 2016

Clinical Lung Cancer

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Background To investigate the association between computed tomographic (CT) features and KRAS mutations in patients with stage I lung adenocarcinoma and their prognostic value. Patients and Methods Seventy-nine patients with pathologic stage I lung adenocarcinoma, available KRAS mutational status, preoperative CT images, and survival data were included in the study. Seven CT features including spiculation, concavity, ground-glass opacity, bubblelike lucency, air bronchogram, pleural retraction, and pleural attachment were evaluated. The association between the clinical characteristics, CT features and mutational status was analyzed using Student's t test, Chi-square or Fisher's exact test, and logistic regression. The association between CT features, mutational status, and overall survival was analyzed using Kaplan-Meier survival curves with the log-rank test and Cox proportional hazard regression. Results The prevalence of KRAS mutations was 41.77%. Spiculation was significantly associated with KRAS mutations (OR = 2.99; 95% CI = 1.16 – 7.68). While KRAS mutational status was not significantly associated with overall survival, presence of pleural attachment was associated with an increased risk of death (HR = 2.46; 95% CI = 1.09 – 5.53). When analyzing combined KRAS mutational status and pleural attachment, patients with wild-type KRAS and no pleural attachment had significantly better survival compared to those with wild-type KRAS and with pleural attachment (p = 0.014). Conclusion These data suggest that spiculation was associated with KRAS mutations while pleural attachment was associated with overall survival in patients with stage I lung adenocarcinoma. Combining analysis of KRAS mutational status and CT features could better predict survival.

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“…First, several studies showed an association of KRAS mutations with poor differentiation. 22-24 Although there is currently no standardized grading system for lung adenocarcinomas, solid growth pattern is the central parameter in grading of adenocarcinomas system-wide, and it is likely that the presence of solid growth pattern, at least in part, explains the association of KRAS mutations and poor differentiation in those studies. Furthermore, an association of KRAS mutations with a gene expression profile correlating with solid histology was noted in a study by Motoi et al 21 Lastly, an association of KRAS mutations and “tumor islands”, which in turn were associated with solid growth pattern, was recently reported by Onozato et al 31 …”

Section: Discussionmentioning

confidence: 99%

“…17-20 However, mucinous carcinomas account for only a minority of lung adenocarcinomas with KRAS mutations in western populations, 18, 20, 21 and therefore this association is unlikely to explain the distinct clinical characteristics imparted by KRAS mutations. Several prior studies also suggested that KRAS mutations are associated with poor differentiation, 22-24 but this finding has been inconsistent across publications. Furthermore, because grading of lung carcinomas is not well-established, it is not known which morphologic features (growth pattern, cytologic features, necrosis, etc) may have imparted this association.…”

Section: Introductionmentioning

confidence: 95%

KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma

et al. 2013

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KRAS mutations define a clinically-distinct subgroup of lung adenocarcinoma patients, characterized by smoking history, resistance to EGFR-targeted therapies, and adverse prognosis. Whether KRAS- mutated lung adenocarcinomas also have distinct histopathologic features is not well established. We tested 180 resected lung adenocarcinomas for KRAS and EGFR mutations by high-sensitivity mass spectrometry-based genotyping (Sequenom) and PCR-based sizing assays. All tumors were assessed for the proportion of standard histologic patterns (lepidic, acinar, papillary, micropapillary, solid and mucinous), several other histologic and clinical parameters, and TTF-1 expression by immunohistochemistry. Among 180 carcinomas, 63 (35%) had KRAS mutations (KRAS+), 35 (19%) had EGFR mutations (EGFR+), and 82 (46%) had neither mutation (KRAS-/EGFR-). Solid growth pattern was significantly over-represented in KRAS+ carcinomas: the mean ± standard deviation for the amount of solid pattern in KRAS+ carcinomas was 27 ± 34% compared to 3 ± 10% in EGFR+ (P<0.001) and 15 ± 27% in KRAS-/EGFR- (P=0.033) tumors. Furthermore, at least focal (>20%) solid component was more common in KRAS+ (28/63; 44%) compared to EGFR+ (2/35; 6%; P<0.001) and KRAS-/EGFR- (21/82; 26%; P=0.012) carcinomas. KRAS mutations were also over-represented in mucinous carcinomas, and were significantly associated with the presence of tumor-infiltrating leukocytes and heavier smoking history. EGFR mutations were associated with non-mucinous non-solid patterns, particularly lepidic and papillary, lack of necrosis, lack of cytologic atypia, hobnail cytology, TTF-1 expression, and never/light smoking history. In conclusion, extended molecular and clinicopathologic analysis of lung adenocarcinomas reveals a novel association of KRAS mutations with solid histology and tumor-infiltrating inflammatory cells, and expands on several previously recognized morphologic and clinical associations of KRAS and EGFR mutations. Solid growth pattern was recently shown to be a strong predictor of aggressive behavior in lung adenocarcinomas, which may underlie the unfavorable prognosis associated with KRAS mutations in these tumors.

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Cytomorphologic features of advanced lung adenocarcinomas tested for EGFR and KRAS mutations: A retrospective review of 50 cases

Cited by 15 publications

References 46 publications

Application of PCR methods to evaluate EGFR, KRAS and BRAF mutations in a small number of tumor cells in cytological material from lung cancer patients

Application of PCR methods to evaluate EGFR, KRAS and BRAF mutations in a small number of tumor cells in cytological material from lung cancer patients

Association Between Computed Tomographic Features and Kirsten Rat Sarcoma Viral Oncogene Mutations in Patients With Stage I Lung Adenocarcinoma and Their Prognostic Value

KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma

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