Usul Afsar Cigdem, Sahin Berksoy, Gunaldi Meral, Kılıc Bagir Emine, Gumurdulu Derya, Burgut Refik, Erkisi Melek, Kara Ismail Oguz, Paydas Semra, Karaca Feryal, Ercolak Vehbi
Department of Medical Oncology, Istanbul Training and Research Hospital Istanbul, Turkey.
Department of Medical Oncology, Cukurova University Medical Faculty Adana, Turkey.
Int J Clin Exp Pathol. 2015 Sep 1;8(9):9760-71. eCollection 2015.
Non-small cell lung carcinoma is the leading cause of cancer related to death in the world. Squamous cell lung carcinoma (SqCLC) is the second most frequent histological subtype of lung carcinomas. Recently, growth factors, growth factor receptors, and signal transduction system-related gene amplifications and mutations are extensively under investigation to estimate the prognosis and to develop individualized therapies in SqCLC. In this study, besides the signal transduction molecule phosphatidyl inositol-3-phosphate kinase (IP3K) p110α, we explored the expressions of fibroblast growth factor 2 (FGF2) and receptor-1 (FGFR1) in tumor tissue and also their clinical and prognostic significance in patients with early/advanced SqCLC.
From 2005 to 2013, 129 patients (23 early, 106 advanced disease) with a histopathological SqCLC diagnosis were selected from the hospital files of Cukurova University Medical Faculty for this study. Two independent pathologists evaluated FGFR1, FGF2, and PI3K (p110α) expressions in both tumor and stromal tissues from 99 of the patients with sufficient tissue samples, using immunohistochemistry. Considering survival analysis separately for patients with both early and advanced stage diseases, the relationship between the clinical features of the patients and expressions were evaluated by univariate and multivariate analyses.
FGFR1 expression was found to be low in 59 (60%) patients and high in 40 (40%) patients. For FGF2; 12 (12%) patients had high, 87 (88%) patients had low expression and for IP3K; 31 (32%) patients had high and 66 (68%) patients had low expressions. In univariate analysis, overall survival (OS) was significantly associated with stage of the disease and the performance status of the patient (P<0.0001 and P<0.001). There was no significant difference in OS of the patients with either low or high expressions of FGFR1, FGF2, and IP3K. When the patients with early or advanced stage disease were separately taken into consideration, the relationship did not differ, either. Any of FGFR1, FGF2 or IP3K expressions was not found predictive for the treatment of early or advanced staged patients. On the other hand, the expressions of both FGFR1 and FGF2 were significantly different with respect to smoking, scar of tuberculosis and scar of radiotherapy (P=0.002; P=0.06 and P=0.05, respectively).
There has not been identified an effective individualized treatment for SqCLC yet. Therefore, in order to be able to develop such a treatment in the future, it is essential to identify the genetic abnormalities that are responsible for the biological behaviors and carcinogenesis of SqCLC. Although we could not show the prognostic and predictive significance of FGFR1, FGF2 and IP3K expressions in SqCLC, we determined the expression rates of FGFR1, FGF2 and IP3K as a reference for Turkish patients. In conclusion, we want to put some emphasis on the fact that, pulmonary fibrosis which is a late complication of radiotherapy at stage III disease, and the scar of tuberculosis could be associated with FGFR1 and FGF2 expressions.
非小细胞肺癌是全球癌症相关死亡的主要原因。肺鳞状细胞癌（SqCLC）是肺癌中第二常见的组织学亚型。近来，生长因子、生长因子受体以及与信号转导系统相关的基因扩增和突变受到广泛研究，以评估SqCLC的预后并制定个体化治疗方案。在本研究中，除了信号转导分子磷脂酰肌醇-3-磷酸激酶（IP3K）p110α，我们还探究了成纤维细胞生长因子2（FGF2）和受体-1（FGFR1）在肿瘤组织中的表达情况，以及它们在早期/晚期SqCLC患者中的临床和预后意义。
2005年至2013年，从库库洛瓦大学医学院医院档案中选取129例经组织病理学诊断为SqCLC的患者（23例早期患者，106例晚期患者）纳入本研究。两名独立病理学家采用免疫组织化学方法，对99例有足够组织样本的患者的肿瘤和基质组织中的FGFR1、FGF2和PI3K（p110α）表达进行评估。分别对早期和晚期疾病患者进行生存分析，通过单因素和多因素分析评估患者临床特征与表达之间的关系。
发现59例（60%）患者FGFR1表达低而40例（40%）患者FGFR1表达高。对于FGF2，12例（12%）患者表达高，87例（88%）患者表达低；对于IP3K，31例（32%）患者表达高，66例（68%）患者表达低。在单因素分析中，总生存期（OS）与疾病分期和患者体能状态显著相关（P<0.0001和P<0.001）。FGFR1、FGF2和IP3K表达低或高的患者的OS无显著差异。当分别考虑早期或晚期疾病患者时，这种关系也无差异。未发现FGFR1、FGF2或IP3K的任何一种表达可预测早期或晚期患者的治疗效果。另一方面，FGFR1和FGF2的表达在吸烟、结核瘢痕和放疗瘢痕方面有显著差异（分别为P=0.002；P=0.06和P=0.05）。
目前尚未确定SqCLC有效的个体化治疗方法。因此，为了未来能够开发出这样的治疗方法，识别导致SqCLC生物学行为和致癌作用的基因异常至关重要。尽管我们未能显示FGFR1、FGF2和IP3K表达在SqCLC中的预后和预测意义，但我们确定了FGFR1、FGF2和IP3K的表达率，作为土耳其患者的参考。总之，我们想强调的是，III期疾病放疗的晚期并发症肺纤维化以及结核瘢痕可能与FGFR1和FGF2表达有关。
