Journal of Thoracic Oncology:
CD24, a Novel Cancer Biomarker, Predicting Disease-Free Survival of Non-small Cell Lung Carcinomas: A Retrospective Study of Prognostic Factor Analysis from the Viewpoint of Forthcoming (Seventh) New TNM Classification
Lee, Hyun Ju MD*; Choe, Gheeyoung MD, PhD*; Jheon, Sanghoon MD, PhD†‡; Sung, Sook-Whan MD, PhD†‡; Lee, Choon-Taek MD, PhD§‡; Chung, Jin-Haeng MD, PhD*‡∥
Departments of *Pathology and †Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do; ‡Respiratory Center, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do; §Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do; and ∥Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Jin-Haeng Chung, MD, PhD, Department of Pathology, Seoul National University College of Medicine, Bundang Hospital and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, 300 Gumidong, Bundang-gu, Seongnam city, Gyeonggi-do 463-707, Republic of Korea. E-mail: firstname.lastname@example.org
Introduction: Metastasis-associated protein CD24 has been identified as a new prognostic factor and stem cell marker in the human neoplasm. However, the importance of the CD24 in non-small cell lung carcinomas (NSCLCs) has not been elucidated well.
Methods: We evaluated CD24 expression in 267 consecutive cases of NSCLC by immunohistochemistry using a tissue microarray technique and correlated with clinicopathologic parameters including forthcoming (seventh) new tumor node metastasis classification.
Results: CD24-high expression was demonstrated in 87 of 267 (33%) and was associated with adenocarcinoma (ADC) histology than in squamous cell carcinoma histology (64 of 165 [39%] vs. 20 of 88 [23%]; p = 0.023). Patients with CD24-high tumors tended to have a higher risk of disease progression (p < 0.001) and cancer-related death (p = 0.002). Multivariate analysis proved CD24-high expression as independent prognostic factors of disease progression and cancer-related death (p = 0.002, hazard ratio = 1.78, 95% confidence interval = 1.23–2.58 and p = 0.017, hazard ratio = 1.93, 95% confidence interval =1.13–3.31). CD24-high expression had a tendency to correlate with new pathologic stage (p-stage) (p = 0.089) rather than old p-stage (p = 0.253). Performance status and new p-stage, regardless of the tumor histology, were identified as consistent independent prognostic factors of disease progression and cancer-related death. However, age was related to a significantly shorter cancer-specific survival in ADC only.
Conclusions: CD24 expression in NSCLC is associated with ADC histology and disease progression and cancer-related death, indicative of aggressive tumor behavior. Performance status and new p-stage, to a lesser extent, age correlated with progression-free survival and cancer-specific survival, regardless of tumor histology.
Non-small cell lung carcinoma (NSCLC) is one of the most common cancers and the major cause of cancer-related death in the world, with 1.3 million deaths worldwide annually.1 The overall 5-year survival rate for lung cancer is <14%.2 Therefore, understanding the mechanism underlying lung carcinogenesis is essential for better management of lung cancer patients.
Currently, the most important conventional prognostic factors for patient survival are tumor stage at the time of diagnosis, including tumor size, pleura invasion, involvement of regional lymph nodes, and metastatic spread to distant organs. With the current tumor node metastasis (TNM) system,3 however, patients within the same stage group may have different prognoses, and especially, stage I lung cancers and stage III lung cancers are biologically heterogeneous. In this context, the last updated classification of the TNM staging system for lung cancer, published in 1997,3 is undergoing revision. A new proposals for revision of the TNM descriptors and stage groupings for lung cancer in the forthcoming (seventh) edition of the International Union Against Cancer and American Joint Committee on Cancer (AJCC) TNM Classification of Malignant Tumors from the International Association for the Study of Lung Cancer (IASLC) has just been proposed.4–9 According to the Prognostic Factors Subcommittee of the International Staging Committee, age, gender, and performance status (PS), in addition to stage, were all found to be prognostic factors for survival.10,11
In addition to these clinicopathologic variables, increased attention has focused on new molecular markers: biologic substaging in a risk stratification strategy has been proposed.12 Biomarkers that are overexpressed during cancer progression are of special interest because they may not only be used to predict patient outcome but also serve as potential targets in cancer therapy like epidermal growth factor receptor (EGFR) gene, which provides new therapeutic options with drugs specifically targeting epidermal growth factor receptor.13–15
Metastasis-associated protein CD24 is a small, heavily glycosylated cell surface protein that is attached to the cell membrane by a glycosyl-phosphatidylinositol anchor.16–19 CD24 is expressed not only in developing20–22 or regenerating23 tissue but also in granulocytes, pre-B cells,24 keratinocytes,25 and renal tubules.26 Ral GTPases signaling are important mediators of transformation, tumorigenesis, and cancer progression. CD24 is functionally relevant Ral-regulated target27 and is involved in cell adhesion and metastatic tumor spread. Interestingly, CD24 is expressed in many human carcinomas including ovarian cancer,28,29 breast carcinoma,30,31 small cell lung carcinoma,24 bladder carcinoma,27 prostate cancer,32 urothelial carcinoma,33 and renal cell carcinom.34 Moreover, high level of CD24 expression detected by immunohistochemistry (IHC) has been found in association with poor prognosis in human neoplasm.27–34 Recently, CD24 has gained new interest as cancer stem cells,35 often coupled with migration and/or adhesion molecules such as CD44,36 CD29,37 and CD31 (platelet-derived/endothelial cell adhesion molecule).38–40
Although increased CD24 has been detected in several human cancers, there is only one report of its prognostic significance in NSCLC.41 In addition, the number of cases in the previous study was limited, and their prognostic meaning of patient survival was only evaluated according to old TNM staging system.3 Therefore, it is important to validate the CD24 expression using large scale samples according to the forthcoming (seventh) new TNM stage classification.4
The purpose of this study was to clarify CD24 expression patterns in NSCLC by IHC and to correlate our findings to clinicopathologic variables such as PS, age, and gender including prognostic significance. In addition, we correlated CD24 expression with forthcoming (seventh) new TNM stage.
PATIENTS AND METHODS
Patients and Tissues
We retrospectively searched formalin-fixed and paraffin-embedded tissues of 267 consecutively resected primary NSCLC obtained from the Seoul National University Bundang Hospital from May 2003 to July 2006. Causes of death other than lung carcinoma and recurrent cases were excluded from this study. None of the patients had received neoadjuvant chemotherapy or irradiation preoperatively. The patients with NSCLC consisted of 190 men and 77 women. The mean age was 62.6 years (standard deviation, 10.6; range, 21–84 years), and the mean tumor size was 3.5 cm (standard deviation, 2.0; range, 0.4–16 cm).
The hematoxylin and eosin-stained slides were reviewed in each case to confirm the original diagnosis by two pathologists (H.J.L. and J.H.C.) independently, which was based on the World Health Organization criteria.42 Tumor specimens were histopathologically diagnosed as adenocarcinoma (ADC; n = 165), squamous cell carcinoma (SCC; n = 88), adenosquamous cell carcinoma (n = 7), large cell neuroendocrine carcinoma (n = 2), carcinoid tumor (n = 2), sarcomatoid carcinoma (n = 2), and large cell carcinoma (n = 1). Lung ADCs showed marked heterogeneity, so all tumor slides were reviewed, and the most representative sections were selected from each specimen.
The pathologic stage (p-stage) was determined by current TNM international staging system (adapted from the AJCC TNM Cancer Staging Manual).3,43 They represented 61 stage Ia, 61 stage Ib, 15 stage IIa, 44 stage IIb, 49 stage IIIa, 20 stage IIIb, and 17 stage IV tumors according to the guidelines of the AJCC. Conversely, they represented 61 stage Ia, 51 stage Ib, 48 stage IIa, 26 stage IIb, 62 stage IIIa, 5 stage IIIb, and 14 stage IV tumors according to the guidelines of the forthcoming (seventh) edition of the TNM Classification (Table 1).4 The medical records were collected including age, gender, PS using the Zubrod scale,44 and smoking history. Further data including progression of disease, patients’ survival status, and cause of death were obtained from the patients’ medical records and/or interview with the family of the patients. The median follow-up period for all patients was 47.0 months, with a range of 1 to 74 months.
Construction of Tissue Microarray
For uniform and simultaneous protein expression analysis of multiple tissue samples, we prepared tissue microarrays (TMAs). Representative core tissue sections (2 mm in diameter) were taken from the paraffin blocks and arranged in new TMA blocks using a trephine apparatus (Superbiochips Laboratories, Seoul, Korea). In cases with variable histologic features, the most representative area was selected for TMA construction. Six cores were sampled and included in the TMA block from each patient.
Immunohistochemistry for CD24 Protein
CD24 expression was analyzed by IHC. Details of the materials and methods used in this study were reported previously34 and will be briefly described. From the TMA blocks, 4-μm thick sections were deparaffinized in xylene and rehydrated in graded alcohol. Antigen retrieval was achieved by pressure cooking in 0.01 mol/liter citrate buffer for 5 minutes. The primary CD24 antibody (Ab-2, clone SN3b, Neomarkers, Fremont, CA) was diluted 1:100 and incubated at room temperature for 1 hour. The immunohistochemical reaction was visualized using the EnVision+ kit (Dako, Carpinteria, CA) according to the manufacturer’s protocol. Positive controls, consisting of cases with known reactivity for antibody, and negative controls, obtained omitting the primary antibody, were included. We also analyzed 25 nonneoplastic pulmonary parenchymal whole mount paraffin sections adjacent to the NSCLC.
CD24 expression was detected at the apical membrane of normal bronchial epithelial cells and circumferential membranous patterns of pneumocytes in the normal alveolar walls. Tumor cells were judged as positive if cytoplasmic and circumferential membranous staining was present. Immunohistochemical staining was separately and independently evaluated by two investigators (H.J.L. and J.H.C.). In the rare instance of a discrepancy in judgement, agreement was obtained by discussion at a multihead microscope. At the time of review, neither of these investigators were aware of the clinicopathologic data of the NSCLCs, because all of the slides had been coded. The staining intensity of CD24 was semiquantitatively scored into four categories: 0, no positive cell; 1+, 1 to 10% positive cells; 2+, 11 to 50% positive cells; and 3+, more than 50% positive cells.
Statistical significance of the data obtained was inferred using Statistical Package, SPSS version 15.0 for Windows (SPSS Inc, Chicago, IL). Associations between the CD24 expression and the clinicopathologic characteristics were analyzed using the Pearson χ2 or Fisher’s exact test according to test condition. Kaplan–Meier analysis was performed for survival curves, and statistical significance was assessed using the log-rank test. Progression-free survival was defined as the time from the date of surgery to the last follow-up visit or evidence of recurrence or metastasis of NSCLC. Cancer-specific survival was defined as the time from the date of surgery to the last follow-up visit or cancer-related death. Univariate analysis of progression-free survival or cancer-specific survival was performed using the Kaplan-Meier method. Multivariate Cox proportional hazard regression analysis was used to assess the prognostic significance of the CD24 expression and the other clinicopathologic characteristics on survival. Overall, 95% confidence intervals (CIs) were used throughout the analysis. Statistical significance was defined as p < 0.05.
In the nonneoplastic pulmonary parenchyma, all 25 sections expressed CD24 in the apical membrane of bronchial epithelial cells and circumferential membrane of pneumocytes in alveolar walls (Fig. 1A, B). The CD24 protein expression in NSCLC appeared mainly in the cytoplasm and circumferential membrane (Fig. 1C–F). The cytoplasmic CD24 expression in the NSCLC tissue was significantly greater than that in the nonneoplastic pulmonary parenchyma (p < 0.001). After evaluation of the 267 immunostained NSCLC specimens, 78 (29%) showed no positivity, 102 (38%) 1+ positivity, 41 (15%) 2+ positivity, and 46 (17%) 3+ positivity. For the statistical analysis, the cases were subdivided into a CD24-low expression group (0 and 1+, n =180 [67%]) and a CD24-high expression group (2+ and 3+, n =87 [33%]).
Correlations between CD24 Expression and Clinicopathologic Parameters
CD24-high positivity correlated with ADC histology better than in SCC histology (64 of 165 [39%] vs. 20 of 88 [23%]; p = 0.023). Weak correlations between CD24-high expression level and newly proposed advanced p-stage (p = 0.089), younger age (p = 0.067), and pleura invasion (p = 0.081) were also found without reaching formal statistical significance. Other clinicopathologic variables, including sex (p = 1.000), tumor size (p = 0.149), smoking (p = 0.786), PS (p = 0.609), venous invasion (p = 0.441), lymphatic invasion (p = 0.150), perineural invasion (p = 0.476), old tumor status (p = 0.242), old p-stage (p = 0.253), new tumor status (p = 0.159), and new M category (p = 0.394) did not correlate with CD24 expression (Table 2). CD24-high expression had a tendency to correlate with new p-stage (p = 0.089) rather than old p-stage (p = 0.253).
At the time of analysis, the number of cancer-specific deaths and patients with disease progression was 58 and 119, respectively. On univariate survival analysis, the conventional prognostic parameters, including tumor size, PS, pleura invasion, venous invasion, lymphatic invasion, old TNM, old p-stage, new TNM, and new p-stage reached significance for progression-free and cancer-specific survival (Table 3 and Fig. 2A, B). CD24-high expression group had a significantly shorter progression-free and cancer-specific survival than did the CD24-low expression group (p < 0.001 and p = 0.002, respectively; Fig. 3A, B). Older age also had a significantly shorter cancer-specific survival (p = 0.002). To evaluate whether CD24 positivity in NSCLC is an independent predictor of progression-free and cancer-specific survival, a multivariate analysis using the Cox proportional hazard model was performed and included venous invasion, lymphatic invasion, PS, age, new p-stage, and CD24 expression. All variables with a p < 0.05 in univariate analysis were included in a multivariate Cox model. Four variables, new p-stage (p < 0.001 and p < 0.001; progression-free and cancer-specific survival, respectively), PS (p < 0.001 and p < 0.001; progression-free and cancer-specific survival, respectively), age (p = 0.012; only in cancer-specific survival), and CD24 expression (p = 0.002 and p = 0.017; progression-free and cancer-specific survival, respectively) were significant prognostic factors for NSCLC patients. Multivariate analysis proved CD24-high expression as independent prognostic factors of disease progression and cancer-related death (p = 0.002, hazard ratio = 1.78, 95% CI = 1.23–2.58 and p = 0.017, hazard ratio = 1.93, 95% CI = 1.13–3.31, respectively; Table 4).
PS and new p-stage, regardless of the tumor histology, were identified as consistent independent prognostic factors of disease progression and cancer-related death (Tables 5 and 6). However, age was related to a significantly shorter cancer-specific survival in ADC only. CD24-high expression group reached prognostic significance for progression-free and cancer-specific survival, especially in SCC.
In this study, we examined the association of CD24 expression of NSCLC with clinicopathologic parameters including survival significance in comparison with forthcoming (seventh) new TNM stage. Kristiansen et al.41 have reported that CD24-high expression was 45% of 89 samples (ADC 49 cases and SCC 40) with cytoplasmic and membraneous staining pattern in NSCLC. In their study, normal lung parenchyma showed a strong membraneous staining pattern of pneumocytes, whereas bronchial epithelium was mostly negative. They revealed the correlation between CD24 activation and preferentially ADC histology (p = 0.001). They also found CD24 expression to be an independent predictor of shortened patient survival as evidenced by univariate and multivariate analyses in NSCLC. In this study, we expanded the number of cases (total 276 cases; ADC 165, SCC 88, and others 14) and included a survival analysis in the forthcoming (seventh) new TNM classification. We found that all 25 nonneoplastic pulmonary parenchymal sections expressed CD24 in the apical membrane of bronchial epithelial cells and circumferential membrane of pneumocytes in alveolar walls. The different expression patterns of normal bronchial epithelium between two studies might be due to use of not TMA but whole mount section. We used whole mount section, which was more accurate for IHC interpretation. In agreement with the previous study,41 the CD24 protein expression in NSCLC appeared mainly in the cytoplasm and circumferential membrane. The CD24-high expression showed 87 of 267 (33%) cases and significantly higher in ADC histology (p = 0.023). Multivariate analysis results of CD24-high expression as independent prognostic factors of disease progression and cancer-related death are concordant with the results of a previous study. CD24-high expression has been known to be involved in the tumor progression and worse biologic activity. Therefore, CD24 expression might be a novel prognostic marker for tumor recurrence or metastasis in NSCLC.
Progression of NSCLC might be associated with the strengthening of activation of CD24, especially cytoplasmic expression. The question then becomes how the strengthening of CD24 activation is related to the advancement of NSCLC. One possible mechanism is the function of the CD24, as a ligand to P-selectin, an adhesion receptor expressed on activated endothelial cells and platelets, and could thus enhance the metastatic potential of CD24-expressing tumor cells.19,45–48 Therefore, Kristiansen et al.41 hypothesized that the decreased survival of NSCLC patients with strongly CD24-positive tumors is related to an enhanced propensity of hematogenous metastasis formation, which might be P-selectin mediated.49,50
Recently, there have been many refinements to the techniques available for clinical staging, principally the routine use of high-resolution computed tomography resulted in frequent detection of early small lung cancer, which overall 5-year survival rate was surprisingly high.51,52 Moreover, stage III NSCLC patients separated into IIIa and IIIb by the 1997 international staging system3 is heterogeneous, including surgically resectable tumors and unresectable diseases treated by chemotherapy and radiotherapy. Increasingly reports were challenging some of the descriptors and suggesting revised stage groupings. Therefore, in the IASLC Lung Cancer Staging Project, there were proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumors.4 According to the IASLC staging committee, PS, age, gender, and stage were confirmed as important prognostic factors in surgically resected NSCLC and tumor histology was less important.10,11 We found that CD24-high expression tended to be correlated with new p-stage (p = 0.089) rather than old p-stage (p = 0.253) without reaching formal statistical significance. The question then becomes why new p-stage is more related to CD24-high expression rather than old p-stage. One possible explanation is that forthcoming (seventh) edition TNM classification provides more precise criteria to specimen processing, specifically looking at tumor size and how to deal with multiple tumors.53 On multivariate analyses, CD24-high expression, PS, and new p-stage, to a lesser extent, age correlated with progression-free survival and cancer-specific survival, regardless of tumor histology.
There are some limitations to generalize these results. First, we cannot exclude selection bias because all the enrolled patients were surgically resectable. Second, PS is nearly either PS 0 or 1, or 2. Third, this is a retrospective study. Despite these limitations, this is the first study to examine CD24 expression in a large number of NSCLC patients and to confirm the role of prognostic factors such as PS, age, and stage according to forthcoming (seventh) new TNM classification.
CD24 has gained new interest as cancer-stem cells35 and a potentially important prognostic marker. As a consequence, presence of CD24 antigen could be an important key to study the biology of NSCLC and can represent an important and useful tool to facilitate the development of new diagnostic and future therapeutic approaches to eliminate CD24 function in cancer cells.
This study objectively demonstrated the prognostic significance of CD24 expression using large number cases of NSCLC and evaluated CD24 expression using current TNM classification and forthcoming new TNM stage classification, respectively. Our results showed significantly greater cytoplasmic and/or circumferential membranous expression of CD24 in NSCLC than in nonneoplastic pulmonary parenchyma. A high expression of CD24 was a negative independent prognostic factor for progression-free and cancer-specific survival in NSCLC. PS and new p-stage, to a lesser extent, age correlated with progression-free survival and cancer-specific survival, regardless of tumor histology.
Supported by the Korean Science & Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine and partly supported by a grant of the Korea Healthcare technology R&D project, Ministry of Health & Welfare, Republic of Korea (A084578).
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