The high diagnostic accuracy of combined test of thyroid transcription factor 1 and Napsin A to distinguish between lung adenocarcinoma and squamous cell carcinoma: a meta-analysis.
Li Li,Li Xiaorong,Yin Jieyun,Song Xia,Chen Xiaochen,Feng Jiane,Gao Hongyu,Liu Li,Wei Sheng
BACKGROUND:Accurate classification of non-small cell lung cancer (NSCLC) using morphological features has several limitations. However, the use of thyroid transcription factor 1 (TTF-1) and Napsin A as markers for the identification of various subtypes of NSCLC has shown promise. This meta-analysis was designed to evaluate the diagnostic value of combined TTF-1 and Napsin A test to distinguish lung adenocarcinoma from squamous cell carcinoma. METHODS:The Medline, EMBASE and Web of Science databases were searched, along with the reference lists of relevant articles (up to May 4, 2014). Ten studies containing 1,446 subjects were identified. The sensitivity, specificity, diagnostic odds ratio (DOR) and area under the summary receiver operating characteristics curve (AUC) were calculated to estimate the combined diagnostic value of TTF-1 and Napsin A. RESULTS:The pooled sensitivity and specificity were 0.76 (95% CI: 0.69-0.83) and 1.00 (95% CI: 0.92-1.00), respectively. The positive and negative likelihood ratios were 877.60 (95% CI: 8.40-91533.40) and 0.24 (95% CI: 0.18-0.32). The DOR was 3719 (95% CI: 33-414884). The AUC was 0.92 (95%CI: 0.89-0.94). The patient's location was a source of heterogeneity for sensitivity. The patient's location, the study's sample size and the threshold used to determine positive staining were consistently found to be sources of heterogeneity for specificity in subgroup analyses and meta-regression. CONCLUSIONS:The combined test of TTF-1 and Napsin A presents a promising alternative method, useful to distinguish between lung adenocarcinoma and squamous cell carcinoma.
Immunostaining for thyroid transcription factor 1, Napsin A, p40, and cytokeratin 5 aids in differential diagnosis of non-small cell lung carcinoma.
Ikeda Satoshi,Naruse Keishi,Nagata Chigusa,Kuramochi Masami,Onuki Takuya,Inagaki Masaharu,Suzuki Keiko
The present study aimed to examine the effectiveness of immunostaining of cytological specimens in discerning squamous from non-squamous cell carcinoma. Various combinations of six antibodies were examined in order to determine the optimal combination for use in differential diagnosis. Immunostaining was performed using tumor imprint smears obtained from 70 lung carcinoma cases. The results were scored based on positive area and intensity. For objective evaluation, scores for thyroid transcription factor 1 (TTF-1), napsin A, and CK CAM5.2 were expressed with positive values, while those for p40, cytokeratin (CK) 5/6 and CK5 were expressed with negative values. Histograms were produced to evaluate which combination was the most effective in differentiating squamous cell carcinoma from adenocarcinoma. The sensitivity for these molecules in adenocarcinoma was 88% for TTF-1, 85% for napsin A, and 100% for CAM5.2. In squamous cell carcinomas, sensitivity was determined to be 90% for p40, 86% for CK5, and 76% for CK5/6. The specificity for these molecules was calculated as 100%, 95%, 43%, 98%, 100% and 95%, respectively. Each combination was evaluated for scoring and the values were averaged. The most effective combination for mode and mean was TTF-1, napsin A, p40, and CK5, for which all adenocarcinomas had a score >1, and all squamous cell carcinomas scored <-2. Immunostaining scoring may therefore be useful for the differential diagnosis of these carcinomas when a limited number of tumor cells are present.
TTF-1 and EGFR expression are related to EGFR mutation in lung adenocarcinoma.
Chen Changhao,Shen Dong,Li Jie,Sun Yuejun,Wang Jiandong
International journal of clinical and experimental pathology
Thyroid transcription factor-1 (TTF-1) is routinely used in the diagnosis of lung carcinoma and the subclassification of non-small cell lung cancer (NSCLC) in combination with other markers. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are particularly effective in NSCLC patients harboring active EGFR mutations. EGFR protein is a poor prognostic factor for NSCLC patients. The relationship between TTF-1 expression and EGFR mutation and EGFR expression has not been well documented. The aim of this study was to investigate the relationship between TTF-1 and EGFR expression and mutation, and the clinical significance in lung adenocarcinoma. We analyzed TTF-1 expression, EGFR expression and mutation in 213 cases of lung adenocarcinoma. TTF-1 and EGFR expression levels were detected by immunohistochemical staining with monoclonal antibodies. EGFR mutations in exon 18, 19, 20 and 21 were assayed by the scorpion amplification refractory mutation system (ARMS) method. Forty-eight patients with EGFR mutations in exon 19 or 21 were detected from 91 patients with TTF-1 strong positive expression (3+) (52.74%), and 35 patients were detected with either exon 19 or 21 mutations from 54 patients with both TTF1 and EGFR positive expression (64.81%). Our data indicate that TTF-1 expression was positively related to EGFR mutation ( < 0.001) and EGFR expression ( < 0.001). EGFR expression level was positively related to its mutation ( = 0.003). These results indicate TTF-1 and EGFR positive lung adenocarcinomas frequently harbor EGFR mutations.
Utility of TTF-1 and Napsin-A in the work-up of malignant effusions.
El Hag Mohamed,Schmidt Lindsay,Roh Michael,Michael Claire W
BACKGROUND:Similar to TTF-1, Napsin-A is recently used increasingly to differentiate between pulmonary adenocarcinoma (P-ADC) and extra-pulmonary adenocarcinoma (EP-ADC). The aim of this study was to compare the performance of TTF-1 and Napsin-A in determining the primary origin of adenocarcinoma in malignant serous effusion. METHODS:Following IRB approval, cellblocks from 139 cases of malignant serous effusions of histologically or clinically determined origin including: 26 P-ADC, 108 EP-ADC, 2 pulmonary squamous cell carcinoma (P-SQC), and 3 pulmonary small cell carcinoma (P-SCC) were retrieved. Each case was stained with Napsin-A and TTF-1 and evaluated for positivity and intensity of staining. RESULTS:Napsin-A and TTF-1 stained positive in 17/26 (65%) and 14/26 (54%) of P-ADC and in 2/108 (1.8%) and 0/108 (0%) of EP-ADC with a PPV of 89 and 100%, respectively. In combination, they positively stained 18/26 (70%) of P-ADC with a PPV of 90%. Out of 9 poorly differentiated P-ADC, 7 (78%) stained positive for Napsin-A, while 4 (45%) were reactive for TTF-1. Both Napsin-A and TTF-1 were negative in P-SQC, while P-SCC reacted positively for TTF-1 in 2/3 (66%) of cases and none for Napsin-A. CONCLUSION:Napsin-A and TTF-1 are both useful markers in distinguishing P-ADC from EP-ADC. However, Napsin-A performed better in poorly differentiated P-ADC and its mimickers. The nuclear staining of TTF-1 is crispier and much easier to interpret than Napsin-A cytoplasmic stain. An antibody panel including TTF-1 and Napsin-A or a dual stain will be very helpful in determining the origin of metastatic adenocarcinoma in serous effusion.
The expression of TTF-1 and Napsin A in early-stage lung adenocarcinoma correlates with the results of surgical treatment.
Ma Yunfan,Fan Mengying,Dai Liang,Kang Xiaozheng,Liu Yiqiang,Sun Yu,Yan Wanpu,Liang Zhen,Xiong Hongchao,Chen Keneng
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
Non-small cell lung cancer (NSCLC) accounts for 80 % of lung cancers, and lung adenocarcinoma (ADC) is one of the main types of NSCLC. Although there are several studies on the relationship between lung ADC immunohistochemical diagnostic markers (thyroid transcription factor 1 (TTF-1) and Napsin A) and survival, some aspects of those studies could be improved. We examined the significance of the commonly used lung ADC diagnostic markers, including TTF-1, Napsin A, and CK7, in the prognosis of early-stage lung ADC. One hundred and nineteen cases of early-stage lung ADC (N0) were selected from the prospective database of lung cancer (Jan 2000 to Dec 2009). The expression levels of TTF-1, Napsin A, and CK7 in inventoried specimens were analyzed using tissue microarray (TMA) and immunohistochemical (IHC) analysis, and the effect of the expression level of each marker on patients' survival was examined. The diagnostic sensitivity and specificity of each marker for lung ADC were as follows: TTF-1, 87.0 and 90.1 %; Napsin A, 72.2 and 90.4 %; and CK7, 94.6 and 76.0 %, respectively. Patients with high expression levels of TTF-1 and Napsin A, and high co-expression levels of TTF-1/Napsin A had better survival rates than those with low levels of expression (P < 0.05). The expression levels of CK7 were not related to patients' survival. Multivariate analysis showed that the expression levels of Napsin A and TTF-1/Napsin A are independent prognostic factors for survival. The IHC detection of TTF-1 and Napsin A in specimens should be routinely performed in postoperative early-stage lung ADC patients. Its significance lies not only in the differential diagnosis, but also in determining the prognosis.
Associations between TS, TTF-1, FR-α, FPGS, and overall survival in patients with advanced non-small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy.
Grønberg Bjørn H,Lund-Iversen Marius,Strøm Erik H,Brustugun Odd Terje,Scott Helge
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
INTRODUCTION:Pemetrexed is effective in the treatment of non-small-cell lung cancer, mainly in nonsquamous cell carcinomas. Inhibition of thymidylate synthase (TS) is considered the key mechanism of action. Folate receptor-α facilitates uptake of pemetrexed. Polyglutamation by folylpolyglutamate synthetase enhances activity and prolongs cellular retention of pemetrexed. Thyroid transcription factor-1 (TTF-1) is mainly positive in nonsquamous cell carcinoma and has been proposed as a marker for sensitivity to pemetrexed. The aim was to investigate associations between these biomarkers and survival in patients who participated in a phase III trial comparing pemetrexed plus carboplatin with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer (n = 436). In this study, there was no difference in overall survival between the two regimens. METHODS:Formalin-fixed, paraffin-embedded biopsies were collected. Percentages of tumor cells positive and highly positive for the biomarkers were assessed using immunohistochemistry (IHC) and an IHC score was calculated (range, 0-200). RESULTS:Two hundred thirty-six biopsies were analyzed (pemetrexed plus carboplatin: n = 114, gemcitabine plus carboplatin: n = 122). There was a significant difference in overall survival between those with TTF-1-positive and -negative tumors (10.4 versus 6.0 months; p < 0.001) and those with a low and a high TS IHC score (9.7 versus 6.2 months; p < 0.001). Folate receptor-α and folylpolyglutamate synthetase were not significant prognostic factors. In multivariate analyses adjusting for established prognostic characteristics, TS (p = 0.002) and TTF-1 (p = 0.003) remained significant. There were no differences in survival between the treatment arms depending on biomarker scores. CONCLUSIONS:TTF-1 positivity and low TS level were associated with prolonged survival. The associations between the biomarkers and overall survival were similar for both chemotherapy regimens.
Thyroid transcription factor 1 represses the expression of Ki-67 and induces apoptosis in non-small cell lung cancer.
Zu Yun-Fen,Wang Xi-Cai,Chen Yan,Wang Ji-Ying,Liu Xin,Li Xin,Li Cheng-Wen,Xie Yu-Cheng,Luo Yan,Shang Xie-Qin,Guo Jing
The thyroid transcription factor 1 (TTF-1) gene is associated with the differentiation of lung epithelial cells and has been reported to be an independent prognostic factor for lung adenocarcinoma patients. The aim of the present study was to detect the expression of TTF-1 in human lung cancer cell lines and to evaluate the association of overexpressed TTF-1 with Ki-67 and apoptosis in the A549 cell line. We also investigated the expression of TTF-1 and Ki-67 in Xuanwei lung adenocarcinoma. TTF-1 mRNA expression was evaluated in 10 non-small cell lung cancer (NSCLC) cell lines by quantitative real-time RT-PCR (qRT-PCR). Overexpression of TTF-1 in A549 cells was achieved by transient transfection. The TTF-1 and Ki-67 proteins were detected by immunohistochemistry and apoptosis was detected by flow cytometry. We also investigated immunohistochemically the expression of TTF-1 and Ki-67 in 62 resected cases of Xuanwei lung adenocarcinoma. Overall the expression of TTF-1 mRNA in the 10 cell lines was low. Overexpression of TTF-1 mRNA was found only in 3 (30%) of 10 NSCLC cell lines, including 1 (25%) of 4 adenocarcinoma cell lines. A549 cells overexpressing TTF-1 were found to have repressed expression of Ki-67 (P=0.012) and increased apoptosis (P=0.000). Immunohistochemical analysis of resected cases of Xuanwei lung adenocarcinoma (n=62) showed the expression of TTF-1 in 58 (93%) of 62 and Ki-67 in 22 (35%) of 62. Patients with strong immunohistochemical expression TTF-1 were statistically associated with well-differentiated phenotype (P=0.006) and inverse correlation with Ki-67 expression (P=0.016). These data suggest that TTF-1 may serve as a tumor suppressor gene based on its inverse correlation with Ki-67 proliferative activity and increase of cellular apoptosis.
Predictive factors for EGFR-tyrosine kinase inhibitor retreatment in patients with EGFR-mutated non-small-cell lung cancer - A multicenter retrospective SEQUENCE study.
Chang Gee-Chen,Tseng Chien-Hua,Hsu Kuo-Hsuan,Yu Chong-Jen,Yang Cheng-Ta,Chen Kun-Chieh,Yang Tsung-Ying,Tseng Jeng-Sen,Liu Chien-Ying,Liao Wei-Yu,Hsia Te-Chun,Tu Chih-Yen,Lin Meng-Chih,Tsai Ying-Huang,Hsieh Meng-Jer,Wu Wen-Shuo,Chen Yuh-Min
Lung cancer (Amsterdam, Netherlands)
BACKGROUND:Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations experiencing a response to EGFR-tyrosine kinase inhibitor (TKI) initially. We investigated EGFR-TKI retreatment in patients who had previously received EGFR-TKI followed by chemotherapy. MATERIALS AND METHODS:This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR-TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment. RESULTS:In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4-92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR-TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR-TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR-TKI was 8.0 months (95% CI 7.3-8.2), and retreatment EGFR-TKI was 4.1 months (95% CI 2.7-4.6). The median OS since the start of the first-line EGFR-TKI therapy was 35.9 months (95% CI 28.8-50.9), and since the start of EGFR-TKI retreatment was 12.6 months (95% CI 10.4-20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR-TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR=0.62, 95% CI 0.44-0.86; HR=0.6, 95% CI 0.43-0.86), both p<0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR=0.51, 95% CI 0.30-0.86; HR=0.52 (0.31-0.88), both p<0.05). CONCLUSIONS:EGFR-TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR-mutated NSCLC patients after failure of first-line EGFR-TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR-TKI and in females with the exon 21 mutation.
TTF-1 mRNA-positive circulating tumor cells in the peripheral blood predict poor prognosis in surgically resected non-small cell lung cancer patients.
Yoon Sun Och,Kim Young Tae,Jung Kyeong Cheon,Jeon Yoon Kyung,Kim Baek-Hui,Kim Chul-Woo
Lung cancer (Amsterdam, Netherlands)
Circulating tumor cells (CTCs) have been identified in peripheral blood of cancer patients, and reproducible detection of CTCs has demonstrated the potential as useful diagnostic and prognostic tools in several cancers. Present study aimed to determine the clinical relevance of CTCs in surgically resected non-small cell lung cancer (NSCLC) patients. CTC status in presurgery and postsurgery peripheral blood samples from 79 surgically resected NSCLC patients was investigated using thyroid transcription factor-1 (TTF-1) and cytokeratin19 (CK19) mRNA markers by nested real-time RT (reverse transcription)-PCR assay. Detection of TTF-1((+))CTCs was found to be specific to NSCLC patients. TTF-1((+))CTCs were detected in 36.1% (22/61) of patients before surgery and in 37.5% (18/48) after surgery. For CK19 mRNA-expressing CTCs (CK19((+))CTCs), the detection rate was 42.6% (26/61) before surgery, and 25.0% (12/48) after surgery. Cases with postsurgery TTF-1((+)) and/or CK19((+))TCs was more associated with disease progression (P=0.004) and shorter disease progression-free survival (P=0.006) as compared to those without postsurgery CTCs. As an individual marker, postsurgery TTF-1((+))CTCs-positive status was more associated with disease progression (P=0.004) and shorter disease progression-free survival (P=0.004) as compared to postsurgery TTF-1((+))CTCs-negative status. Particularly, patients with postsurgery TTF-1((+))CTCs, but not presurgery (Pre((-))Post((+)) cases) showed marked shorter disease progression-free survival than other patients (P<0.001). On the other hand, a CK19((+))CTC status individually did not show significant clinical relevance, and presurgery CK19((+))CTC status did not either. Present study suggests that TTF-1 mRNA-expressing CTCs might be a useful surrogate predictor of disease progression before clinical manifestations are apparent, and that monitoring of TTF-1((+))CTCs status after surgery may be useful for identifying high-risk patients among surgically resected NSCLC cases.
Non-Small-cell Lung Cancer Patients With Adenocarcinoma Morphology Have a Better Outcome Compared With Patients Diagnosed With Non-Small-cell Lung Cancer Favor Adenocarcinoma.
Shiran Iris,Heller Eyal,Jessel Shlomit,Kamer Iris,Daniel-Meshulam Inbal,Navon Rossie,Urban Damien,Onn Amir,Bar Jair
Clinical lung cancer
BACKGROUND:Non-small-cell lung cancer (NSCLC) includes 2 major histologic subtypes: squamous cell carcinoma and non-squamous carcinoma, mainly adenocarcinoma, a distinction that carries significant clinical and therapeutic implications. NSCLC is diagnosed as adenocarcinoma or as squamous cell carcinoma on the basis of histologic parameters. However, when morphology is inconclusive, tumors with immunohistochemistry (IHC) findings characteristic of adenocarcinoma are referred to as "NSCLC favor adenocarcinoma" (NFA). Our aim was to evaluate whether pulmonary adenocarcinoma diagnosis on the basis of morphology had a similar prognosis compared with NFA. PATIENTS AND METHODS:Patients with advanced NSCLC non-squamous carcinoma who were treated with a platinum-pemetrexed doublet as first-line combination chemotherapy were identified. Demographic, clinical, laboratory, and pathological data including the method of pathological diagnosis (morphology or IHC) was extracted from the clinical charts. The correlation between the various parameters and overall survival was evaluated. RESULTS:Lack of adenocarcinoma morphology, male sex, smoking history, and negative thyroid transcription factor 1 IHC were associated with worse prognosis and shorter overall survival in multivariate analysis. High white blood cell count, absolute neutrophil count, neutrophil to lymphocyte ratio, and low albumin levels were associated with shorter overall survival only in univariate analysis. CONCLUSION:Pulmonary adenocarcinoma has a better prognosis than NFA, regarding advanced NSCLC treated with platinum-pemetrexed combination chemotherapy. This distinction should be a stratification factor in clinical trials and a prognostic factor to consider in analysis of previous trials.
An Analysis of EGFR Mutations among 1506 Cases of Non-Small Cell Lung Cancer Patients in Guangxi, China.
Wei Wen-E,Mao Nai-Quan,Ning Shu-Fang,Li Ji-Lin,Liu Hai-Zhou,Xie Tong,Zhong Jian-Hong,Feng Yan,Wei Chang-Hong,Zhang Li-Tu
An association between epidermal growth factor receptor (EGFR) and clinical characteristics of non-small cell lung cancer (NSCLC) was reported ten years ago. In addition, a different type of relationship was seen in different ethic races. However, the relationship between these factors is not well understood in the Guangxi province. Up to now, there are only very limited data on the association of TTF1/EGFR protein positivity and EGFR mutation status in NSCLC. This study aims to investigate the role of EGFR gene mutation status on the clinical characteristics and the relationship with TTF-1/EGFR protein positivity of patients with NSCLC in Guangxi, China. 1506 samples from different patients with NSCLC were detected by amplification refractory mutation system for 29 hotspot mutations. Analysis of the relationship between clinical characteristics and EGFR mutation status was performed by using the crosstabs Chi-square and SPSS 21.0 software. Of 1506 samples, 537 (35.7%) revealed tyrosine kinase inhibitor (TKI) sensitive EGFR mutations with 27 (1.8%) cases harboring TKI resistant EGFR mutations or union co-existing EGFR-TKIs sensitive mutations. EGFR-TKIs sensitive mutations were not significantly associated with age and TNM-M stage (P = 0.863; P = 0.572, respectively). However, they were significantly associated with p-stage, TNM-T stage and TNM-N stage (P = 0.011, P < 0.001, P = 0.036, respectively). Immunohistochemical studies revealed that TTF-1 and EGFR protein expression level were all associated with EGFR mutation status (P < 0.001, P = 0.002, respectively). Of the 537 EGFR-TKIs sensitive mutation cases, the rates of exon 19-del, 18 G719X point, exon 21 L858R and L861Q points were 54.6, 0.9, 42.3 and 0.9%, respectively. EGFR TKI-sensitive mutations commonly occur in female, non-smoking and adenocarcinoma patients. The p-stage, TNM-T stage, TNM-N stage, EGFR and TTF-1 protein expression levels have close relationships with EGFR mutation status.
Correlation of Thyroid Transcription Factor-1 Expression with Mutations in Non-Small-Cell Lung Cancer: A Meta-Analysis.
Kim Hyeong Su,Kim Jung Han,Han Boram,Choi Dae Ro
Medicina (Kaunas, Lithuania)
OBJECTIVES:This meta-analysis investigated the relationship between thyroid transcription factor-1 (TTF-1) expression and epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) to clarify whether TTF-1 can be a potential surrogate marker for EGFR mutation status in advanced NSLCL. METHODS:A systematic searching of databases, including PubMed, EMBASE, Cochrane Library, and Google Scholar, was performed to identify studies assessing the correlation of TTF-1 expression with EGFR mutations. From 17 studies, 9764 patients were included in the combined analysis of odds ratio (OR) for the correlation between TTF-1 expression and mutations. RESULTS:Compared with NSCLCs showing negative TTF-1 expression, tumors harboring TTF-1 overexpression showed a significantly higher rate of EGFR mutations (OR = 5.19, 95% confidence interval: 3.60⁻7.47, p < 0.00001). This correlation was observed in both subgroups of East Asian (OR = 4.33, 95% CI: 3.46⁻5.41, p < 0.00001) and European patients (OR = 4.64, 95% CI: 1.41⁻15.28, p < 0.01). In addition, TTF-1 expression was significantly associated with EGFR mutations in exon 19 (OR = 4.63, 95% CI: 2.89⁻7.41, p < 0.00001) as well as exon 21 (OR = 3.16, 95% CI: 1.04⁻9.60, p = 0.04). CONCLUSIONS:This meta-analysis demonstrates a significant correlation between TTF-1 expression and EGFR mutations in patients with NSCLC. The status of TTF-1 expression may be a biomarker to guide anticancer treatment in patients with NSCLC and unknown EGFR mutation status.
Metastatic NSCLC: Clinical, molecular, and therapeutic factors associated with long-term survival.
Asselain B,Barrière J-R,Clarot C,Vabre J-P,Gentil Le Pecq B,Duval Y,Thomas P,Herman D,Grivaux M,Debieuvre D
Respiratory medicine and research
BACKGROUND:Patients with metastatic non-small-cell lung cancer (NSCLC) who survive more than 2 years are considered long-term survivors (LTSs). The present study examined factors associated with long-term survival and collected information for future comparison. METHODS:Clinical, molecular, and therapeutic data were collected from patients followed for primary stage IV (7th TNM classification) NSCLC within 2 years from diagnosis in the respiratory medicine departments of 53 French non-teaching hospitals. LTS and non-LTS records were compared. Factors associated with long-term survival were examined by univariate and multivariate analyses using logistic regression models. RESULTS:Vital status at least 2 years after diagnosis was known for 1977 stage IV NSCLC patients; 220 (11.1%) were LTSs. On multivariate analysis, independent positive factors comprised: TTF-1(+) immunochemistry, EGFR-mutation, surgery, rescue radiotherapy, and targeted therapy. Independent negative factors comprised: prediagnosis weight loss>5kg, ECOG performance status>1, and primary radiotherapy. CONCLUSIONS:Molecular biology and targeted therapy were decisive for long-term survival. With their development and their widespread implementation in clinical practice, the percentage of LTSs is expected to grow. Factors determining long-term survival found in this study should be taken into account when considering treatment options for patients with stage IV NSCLC.
Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer.
Hokari Satoshi,Tamura Yusuke,Kaneda Atsushi,Katsura Akihiro,Morikawa Masato,Murai Fumihiko,Ehata Shogo,Tsutsumi Shuichi,Ishikawa Yuichi,Aburatani Hiroyuki,Kikuchi Toshiaki,Miyazono Kohei,Koinuma Daizo
Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1.
Molecular genetic alterations in thyroid transcription factor 1-negative lung adenocarcinoma in cytology specimens: A subset with aggressive behavior and a poor prognosis.
Rodriguez Erika F,VandenBussche Christopher J,Chowsilpa Sayanan,Maleki Zahra
BACKGROUND:Patients with thyroid transcription factor 1 (TTF1)-negative pulmonary adenocarcinoma (ADC) have been reported to have a worse prognosis and to lack epidermal growth factor receptor (EGFR) mutations. This study describes a series of cytology specimens from patients with clinically confirmed pulmonary carcinoma negative for TTF1. METHODS:A search for TTF1-negative ADC from 2010 to 2017 was performed. Each patient's clinical history, pathology specimens, and molecular results were noted. Two hundred ten patients with TTF1-positive pulmonary ADC formed the control group. RESULTS:Fifty specimens were identified from 50 patients (26 females and 24 males). The median age was 58.5 years. The smoking history was as follows: 38 smokers/former smokers (76%), 10 nonsmokers (20%), and 2 patients with an unknown status (4%). Thirty-nine patients (78%) had no previous history of malignancy. The clinical stages were as follows: stage I or II (n = 2 [4%]), stage III (n = 9 [18%]), stage IV (n = 37 [74%]), and unknown (n = 2 [4%]). Patients' mean survival was 10.3 months. Molecular results were available in 43 cases. Twenty-seven cases (63%) had no mutation identified; when they were compared with the control group, TTF1-negative patients had overall shorter survival (P = .0047), even though no statistically significant difference was seen on the clinical stage. Known mutations were less frequent (P = .0095) in TTF-negative tumors (KRAS mutations, n = 11 [25%]; anaplastic lymphoma kinase [ALK], n = 3 [7%]; and EGFR, n = 2 [5%]). This was particularly true for EGFR mutations (P = .047). However, ALK rearrangements were present at an increased frequency in the TTF1-negative group (P = .018). CONCLUSIONS:Patients with TTF1-negative lung ADC have worse overall survival, a lower frequency of known mutations, and a higher frequency of ALK alterations.
Complementary value of electron microscopy and immunohistochemistry in the diagnosis of non-small cell lung cancer: A potential role for electron microscopy in the era of targeted therapy.
Albero-González Raquel,Munné-Collado Jessica,Pijuan Lara,Simón Mercedes,Gimeno-Beltrán Javier,Mojal Sergi,Salido Marta,Clavé Sergi,Juanpere Nuria,Dalmases Alba,Comerma Laura,Vázquez Ivonne,Sánchez-Font Albert,Taus Álvaro,Hernández Silvia,Lloveras Belén,Lloreta Trull Josep
With the identification of therapeutic targets for lung adenocarcinoma, it has become mandatory to distinguish it from other entities. Some cases remain classified as non-small cell lung carcinoma, not otherwise specified (NSCLC-NOS) with immunohistochemistry. Electron microscopy (EM) can be useful, allowing the identification of glandular differentiation. The aim of this study was to determine the complementary value of immunohistochemistry and EM.Forty-eight NSCLC-NOS cases were selected (PSMAR-Biobank, Barcelona, Spain). Immunohistochemistry (TTF-1, p40) was performed. Tissue was retrieved from paraffin blocks. Results were compared to the final diagnosis, derived from combination of light microscopy, immunohistochemistry, EM, molecular studies and resection specimen.Immunohistochemistry concurred with final diagnosis in 36 cases (75%, Kappa = 0.517). EM agreed with final diagnosis in 35 (72.9%, Kappa = 0.471). Immunohistochemistry had a sensitivity = 73%, specificity = 100%, positive predictive value (PPV) = 100% and negative predictive value (NPV) = 52.4% for adenocarcinoma. All adenocarcinoma cases not solved by immunohistochemistry (n = 10) were classified by EM, and vice versa. Data from EM were identical to those of immunohistochemistry: sensitivity = 73%, specificity = 100%, PPV = 100% and NPV = 52.4%. Combining both techniques, 47 cases were coincident with final diagnosis (97.9%, Kappa = 0.943).EM can provide valuable information in subtyping NSCLC-NOS, being particularly useful when immunohistochemistry is inconclusive. EM could be considered as a complementary tool for decision-making in NSCLC-NOS.
The Value of Cytokeratin 5/6, p63 and Thyroid Transcription Factor-1 in Adenocarcinoma, Squamous Cell Carcinoma and Non-Small-Cell Lung Cancer of the Lung.
Argon Asuman,Nart Deniz,Veral Ali
Turk patoloji dergisi
OBJECTIVE:It is now important to distinguish between adenocarcinoma and squamous cell carcinoma of the lung because of target-specific treatments. Our study aimed to study the efficiency of Thyroid Transcription Factor-1 (TTF-1), cytokeratin 5/6 (CK5/6) and p63 in distinguishing between adenocarcinoma and squamous cell carcinoma and to study the contribution of these markers to the diagnosis in non-small cell lung cancer. MATERIAL AND METHOD:Immunohistochemically, TTF-1, CK 5/6 and p63 were used in 72 cases of squamous cell carcinoma, 19 cases of adenocarcinoma, and 29 cases of non-small cell lung cancer whose final diagnosis was decided with the subsequent resection material. The specificity, sensitivity, and positive and negative predictive value were calculated for each marker. RESULTS:TTF-1 positivity was seen in none of the 72 squamous cell carcinomas but in all of 19 adenocarcinoma cases. CK5/6 negativity was seen in all cases of adenocarcinoma and in two cases of squamous cell carcinoma. p63 was positive in all squamous cell carcinomas and in 4 adenocarcinomas. Cytokeratin 5/6, p63 positivity and TTF-1 negativity were observed in 17 non-small cell lung cancers whose final diagnosis was squamous cell carcinoma. None of the 12 non-small cell lung cancers whose final diagnosis was adenocarcinoma exhibited positive staining for CK5/6. However, p63 staining was not seen in the biopsy but was focal in the surgical specimen in one case. All the 12 non-small cell lung cancers whose certain diagnosis was adenocarcinoma were positive for TTF-1. TTF-1, CK 5/6 and p63 seem to be useful for differentiating adenocarcinoma from squamous cell carcinoma with 100% specificity, 100% sensitivity and 100% specificity, 97% sensitivity and 87% specificity, and 100% sensitivity, respectively. CONCLUSION:We concluded that TTF-1 is a reliable marker for subtyping lung cancer. Different staining patterns can be seen with CK5/6 and p63; however, if they are used together with TTF-1 and interpreted correctly, they can be of help for the final diagnosis even in cases in which the morphology is unclear.
Prognostic value of TTF-1 expression in patients with non-small cell lung cancer: A meta-analysis.
Qian Hai-hua,Xu Tian-shu,Cai Xiao-qin,Ji Tian-li,Guo Hai-xia
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:Observational studies on the prognostic role of thyroid transcription factor 1 (TTF-1) in non-small-cell lung cancer (NSCLC) are controversial. METHODS:To clarify the impact of TTF-1 in NSCLC survival, we performed this meta-analysis that included eligible studies. The combined hazard ratios and their corresponding 95% confidence intervals were calculated in terms of overall survival. RESULTS:A total of 17 studies with 2235 patients were evaluable for this meta-analysis. The studies were categorized by histology, disease stage and patient race. Our results suggested that TTF-1 overexpression had a favorable impact on survival of patients with NSCLC, the HR (95% CI) was 0.49 (0.42 to 0.55) overall, 0.46 (0.38-0.54) in Asian patients, 0.52 (0.42-0.63) in non-Asian patients, 0.45 (0.38-0.52) in adenocarcinoma, 0.63 (0.39-0.86) in stage I NSCLC, and 0.43 (0.33-0.53) in stage IIIb-IV NSCLC. The data collected were not sufficient to determine the prognostic value of VEGF in patients with squamous cell lung carcinomas. But there was a high heterogeneity between the studies. CONCLUSION:TTF-1 overexpression indicates a favorable prognosis for patients with NSCLC, this effect appears also significant when the analysis is restricted in lung AC patients, stage I and stage IIIb-IV NSCLC.
TTF-1 Expression Predicts the Merit of Additional Antiangiogenic Treatment in Non-squamous Non-small Cell Lung Cancer.
Takeuchi Akira,Oguri Tetsuya,Yamashita Yoriko,Sone Kazuki,Fukuda Satoshi,Takakuwa Osamu,Uemura Takehiro,Maeno Ken,Fukumitsu Kensuke,Kanemitsu Yoshihiro,Ohkubo Hirotsugu,Takemura Masaya,Ito Yutaka,Niimi Akio
BACKGROUND/AIM:To investigate whether TTF-1 expression predicts a beneficial response of non-squamous non-small-cell lung cancer (NS-NSCLC) patients to bevacizumab. PATIENTS AND METHODS:We retrospectively screened 118 advanced NS-NSCLC patients who were treated with pemetrexed plus platinum derivatives alone (Bev(-)) or with bevacizumab (Bev(+)), and investigated the relationship between expression of TTF-1 and treatment outcomes. RESULTS:Among the 92 TTF-1-positive patients, clinical outcomes in the Bev(+) group were significantly better than those in the Bev(-) group (response rate, 51.4% vs. 27.3%, p=0.027; median progression-free survival, 216 days vs. 137 days, p=0.012). Overall survival in the Bev(+) group tended to be longer than that in the Bev(-) group. However, the addition of bevacizumab to the standard treatment of 26 TTF-1-negative patients offered no clinical benefit. CONCLUSION:TTF-1 expression may serve as a predictive marker to identify patients who may benefit from the addition of bevacizumab to platinum doublet therapy.
Expression of p63, TTF-1 and Maspin in Non-Small Cell Lung Carcinoma and Their Effect on the Prognosis and Differential Diagnosis.
Yaman Banu,Nart Deniz,Ekren Pervin Korkmaz,Çok Gürsel,Veral Ali
Turk patoloji dergisi
OBJECTIVE:Lung cancer is still the leading cause of cancer mortality. Antiapoptotic genes and protease inhibitors play an important role in the development of lung cancer. MATERIAL AND METHOD:p63, TTF-1 and maspin expression and their role in the differential diagnosis, overall survival, progression-free survival and other clinicopathological characteristics of the patients were investigated in 80 surgically-resected non-small cell lung carcinomas. RESULTS:The maximal tumor diameter range was 1.5-11 cm (mean: 4.06±1.8 cm). Forty-five (56.3%) tumors were adenocarcinoma, 23 (28.8%) squamous cell carcinoma, four (5%) large cell carcinoma, six (7.5%) large cell neuroendocrine carcinoma, one (1.2%) sarcomatoid carcinoma while one was (1.2%) both adenocarcinoma and squamous cell carcinoma. The patients with advanced TNM stage and a tumor diameter more than 3 cm had markedly poor survival. Immunohistochemically, p63 staining was present in 87.5% of squamous cell carcinomas, 4.3% of adenocarcinomas, 25% of large cell carcinomas, and 16.7% of large cell neuroendocrine carcinomas. Similarly, maspin was positive in 66.7% of squamous cell carcinomas and 17.4% of adenocarcinomas. The TTF-1 staining rate was higher in adenocarcinomas (84.8%). There was no immunoreactivity in squamous cell carcinomas (p < 0.001). We found that p63 and TTF-1 had no significant effect on survival in either tumor group (p > 0.05) while maspin has a negative prognostic effect in adenocarcinoma (p=0.048). CONCLUSION:This study suggests that p63 and TTF-1 are reliable markers in non-small cell lung carcinoma and can be used in differential diagnosis. Maspin has been identified as a prognostic marker in adenocarcinoma. However, more studies are required to elucidate the significance of maspin.