Prognostic implications of cell cycle-related proteins in primary resectable pathologic N2 nonsmall cell lung cancer.

Patients who have pathologic N2 (pN2) nonsmall cell lung cancer (pN2 NSCLC) represent a heterogeneous group with regard to prognosis and treatment. Molecular features of NSCLC seem to be of interest. For the current study, to select an appropriate therapeutic strategy for each patient, patients with N2 NSCLC were stratified into homogenous subgroups according to the expression profiles of cell cycle-related markers. The expression levels of retinoblastoma protein (pRb), cyclin D1, p16, p53, and p21 proteins and values of the Ki-67 labeling index were evaluated in 61 primary surgically resected tumor specimens from patients with pN2 NSCLC using immunohistochemistry. The prognostic impact of these markers on overall survival was analyzed in both univariate and multivariate analyses. In univariate analysis, p21, p16, and Ki-67 were correlated significantly with survival. In multivariate analysis, only p21 and p16 influenced survival. Indeed, the group of patients with pN2 NSCLC who were positive for p21 and p16 had the most favorable overall survival (P = .001) and were correlated significantly with the clinical lymph node (cN) status (cN2 disease; P = .008). Moreover, no significant difference in survival was observed between patients with cN0/cN1 disease and patients with cN2 disease within the group (P = .4333). Loss of control of cell-cycle checkpoints is a common occurrence in pN2 NSCLC. Functional cooperation between different cell-cycle regulators constitutes another level of regulation in cell growth control and tumor suppression. Preoperative patients with pN2 NSCLC, even those with cN2 disease, who have positive p21 and p16 protein expression in their primary tumors are expected to have a favorable postoperative prognosis and may be candidates for primary resection.

Mohamed S ，Yasufuku K ，Hiroshima K ，Nakajima T ，Yoshida S ，Suzuki M ，Sekine Y ，Shibuya K ，Iizasa T ，Farouk A ，Fujisawa T ... -  《CANCER》

Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance.

Inactivation of the Rb pathway in non-small cell lung carcinoma (NSCLC) occurs mostly through inactivation of the cyclin-dependent kinase inhibitor p16(INK4A) and/or up-regulation of cyclin D1. In order to assess the frequency and the prognostic value of these abnormalities in NSCLC, immunohistochemical analysis of Rb, p16(INK4), and cyclin D1 has been performed on 168 cases of NSCLC including 77 squamous cell carcinomas, 43 adenocarcinomas, and 48 basaloid carcinomas. The reduced survival rate of basaloid carcinoma (stage I-II) compared with other histological types of NSCLC was confirmed (p = 0.008). Loss of protein expression of Rb and p16(INK4A) was observed in 12 per cent and 58 per cent of NSCLC cases respectively and cyclin D1 overexpression in 43 per cent. There was an inverse correlation between Rb and p16 expression ( p < 0.0001) and a direct correlation between Rb and cyclin D1 expression ( p = 0.0007). In univariate analysis, Rb-negative adenocarcinomas at stages I-II had a significantly shorter survival than Rb-positive cases ( p = 0.04) and stages I-II p16-positive cases had a shorter survival than p16-negative cases ( p = 0.02), which was more significant in basaloid carcinoma ( p = 0.003). p16 status retained its influence on survival in multivariate analysis at stage I-II for all cases ( p = 0.01) and for basaloid carcinoma ( p = 0.005). Cyclin D1 overexpression did not influence survival. Combined Rb/p16/cyclin D1 phenotypes in univariate analysis showed a shorter survival for Rb-negative/p16-positive/cyclin D1-negative tumours ( p = 0.002). These results, linked to previous data, indicate that the Rb pathway of G1 arrest is initially disrupted in the vast majority of NSCLCs (83 per cent), but could not confirm an unfavourable role for each individual event (p16(INK4A) loss or cyclin D1 up-regulation) in prognosis.

Brambilla E ，Moro D ，Gazzeri S ，Brambilla C ... -  《JOURNAL OF PATHOLOGY》

Altered retinoblastoma protein expression in nonsmall cell lung cancer: its synergistic effects with altered ras and p53 protein status on prognosis.

Dosaka-Akita H ，Hu SX ，Fujino M ，Harada M ，Kinoshita I ，Xu HJ ，Kuzumaki N ，Kawakami Y ，Benedict WF ... -  《CANCER》

Skip metastasis in nonsmall cell lung carcinoma: predictive markers and isolated tumor cells in N1 lymph nodes.

Skip metastasis to mediastinal lymph nodes is a prognostic factor for patients with nonsmall cell lung carcinoma (NSCLC). Little is known about the biologic behavior of tumors with noncontinuous spread to the mediastinal lymph nodes. In patients with pN2 skip metastases, micrometastases to N1 lymph nodes, which only mimic skip metastases, have not been investigated. In a retrospective study, the authors analyzed the primary tumor specimens from 45 patients with pN2 NSCLC (18 patients had squamous cell carcinomas, 23 had adenocarcinomas, and 4 had large cell carcinomas). They immunohistochemically evaluated the expression of p21, p53, MUC-1, Bcl-2, c-ErbB-2, and E-cadherin. Survival rates and biomarker expression levels were compared between patients with pN2 disease and infiltration of N1 lymph nodes (without skip metastasis [n = 28]) and patients with pN2 disease without N1 infiltration (with skip metastasis [n = 17]). To evaluate micrometastasis in the pN1 lymph nodes of 17 patients with skip metastases, lymph nodes were stained using the anticytokeratin antibody, AE1/AE3. The 5-year survival rate of patients with skip metastases was 41%, compared with 14% for patients without skip metastases (P = 0.019). In a multivariate analysis, the incidence of skip metastases did not vary significantly according to gender, age, histology, pT status, or cM status. Three skip-positive patients (17.6%) had micrometastatic tumor involvement of pN1 lymph nodes. After adding these patients to the group of patients without skip metastases, there was still a significant difference in survival between the two groups. p53, MUC-1, c-ErbB-2, and E-cadherin expression levels in primary tumor specimens were not significantly different in patients with continuous metastasis and patients with skip metastases. Patients with skip metastases expressed lower levels of p21 (P = 0.026), whereas Bcl-2 expression levels were considerably higher (P = 0.019) compared with the corresponding levels in patients without skip metastases. Patients with NSCLC and pN2 skip metastases have a more favorable prognosis than do patients with pN2 disease without skip metastases. Tumor specimens from these patients exhibit elevated expression of the antiapoptosis gene BCL2 and lower expression levels of p21 relative to patients with pN2 disease without skip metastases. Micrometastases occurred in 3 of 17 (17.6%) patients with pN2 disease and skip metastases diagnosed by routine histopathology.

Prenzel KL ，Baldus SE ，Mönig SP ，Tack D ，Sinning JM ，Gutschow CA ，Grass G ，Schneider PM ，Dienes HP ，Hölscher AH ... -  《CANCER》

Prognostic significance of p27KIP1 expression in resected non-small cell lung cancers: analysis in combination with expressions of p16INK4A, pRB, and p53.

Whether a prognostic role for expression of the tumor suppressor gene (TSG) products exists in resected non-small call lung cancers (NSCLCs) remains controversial. Our study was performed to determine the value of TSGs expressions for patients survival in NSCLCs. We examined 108 resected NSCLCs for the expression of TSG products, p27(KIP1), p16(INK4A), pRB, and p53 that govern cell cycle transition by immunohistochemistry and compared them with patient clinical characteristics and prognoses. Abnormal expressions of p27(KIP1), p16(INK4A), pRB, and p53 were found in 61 (57%), 53 (49%), 42 (39%), and 48 (44%), respectively, of the 108 NSCLCs. Univariate analysis showed abnormal expression of p27(KIP1) to be a strong indicator for poor patient survival, not only in the total cohort (P = 0.0024), but also in subgroups with T1-T2 (P = 0.016), N0 (P = 0.047), and squamous cell carcinomas (P = 0.026), but not according to the expression of p16(INK4A), pRB, or p53. In the Cox regression analysis, p27(KIP1) expression was found to be an independent prognostic factor (P = 0.0148) and associated with pathological stage (P = 0.0278). Our results suggest that abnormal p27(KIP1) expression may be a useful indicator to predict postoperative prognosis, especially in patients with early stage NSCLCs, as compared to other TSG products examined.

Hirabayashi H ，Ohta M ，Tanaka H ，Sakaguchi M ，Fujii Y ，Miyoshi S ，Matsuda H ... -  《JOURNAL OF SURGICAL ONCOLOGY》