Eur Arch Otorhinolaryngol DOI 10.1007/s00405-014-3426-3
REVIEW ARTICLE
The prognostic value of cyclin D1 expression in head and neck squamous cell carcinoma Federico M. Gioacchini • Matteo Alicandri-Ciufelli Shaniko Kaleci • Giuseppe Magliulo • Livio Presutti • Massimo Re
•
Received: 9 October 2014 / Accepted: 1 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The correlation between cyclin D1 overexpression and the clinical outcome of head and neck cancer is not defined. The aim of this meta-analysis was to evaluate the prognostic value of cyclin D1 in patients with head and neck cancer. A search thorough Ovid MEDLINE was performed to enroll all eligible articles. Twenty-two studies comprising a total of 1,929 patients with different head and neck cancers were included. Cyclin D1 overexpression was significantly associated with lymph node metastasis [OR 2.25; 95 % confidence interval (CI) 1.76–2.87] and worse disease-free survival (OR 3.06; 95 % CI 2.42–3.87]. Subgroup analysis revealed that cyclin D1 overexpression correlated significantly with nodal metastasis for laryngeal cancer (OR 2.26; 95 % CI 1.61–3.16) and was a significant poor predictor for nasopharyngeal cancer (OR 4.44; 95 % CI 1.89–10.42). Our meta-analysis suggests that cyclin D1 overexpression could represent an important prognostic indicator for patients with head and neck cancer.
F. M. Gioacchini (&) M. Alicandri-Ciufelli L. Presutti Otolaryngology Department, University Hospital of Modena, Via del Pozzo 71, 41100 Modena, Italy e-mail: [email protected] S. Kaleci Department of Diagnostic Medicine, Clinical and Public Health University Hospital of Modena, Modena, Italy G. Magliulo Department of Otorhinolaryngology ‘‘G. Ferreri’’, ‘‘La Sapienza’’ University, Rome, Italy M. Re Otorhinolaryngology Department, Marche Polytechnic University, Ancona, Italy
Keywords Cyclin D1 Head and neck cancer Biomarkers Survival Prognosis
Introduction Head and neck cancers are the tenth most common type of human cancer and comprise a heterogeneous group of tumors with different clinical and biological behavior, causing an annual mortality of more than 17,960 cases in the world [1]. Despite a rapid development in diagnosis and treatment modalities, the survival rate of patients affected by some of these cancers is still not significantly improved [2]. Traditional prognostic factors, such as tumor stage, histological grade, perineural invasion, and positive surgical margins, are currently used to predict the outcome of head and neck cancer. However, they are inadequate to determine individual patient’s prognosis after systemic treatment. So, the raising question concerning the patients prognosis is whether there is a correlation between the tumor’s behavior and any biological parameter that may help the clinician to make therapeutical decisions [3]. During the recent decades there has been increasing of interest in assessing cancer progression and predicting its course using different molecular markers [4, 5]. However, until recently, studies have not successfully identified clinically useful biomarkers of prognosis. This has been mainly due to the use of small sample sizes from single institutions, with tumors from heterogeneous head and neck subsites that have received a variety of treatments. The most critical point in cell cycle regulation is the G1 checkpoint which determines whether the cell will exit the cell cycle and go into a quiescent state (G0) or enter into the S phase and proceed with cell division [6].
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Regulation of G1-S transition of the cell cycle is tightly controlled by phosphorylation of the retinoblastoma protein (pRb) resulting in the release of essential transcription factors such as E2F-1 [7]. Moreover, the phosphorylation of pRb is regulated by a large number of regulatory proteins such as cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors [8]. Among the cyclins involved in G1 phase, Cyclin D1 appears to be most strongly implicated in human carcinogenesis. The cyclin D1 gene (CCND1) located on chromosome 11q13 is a positive regulator of the cell cycle. It encodes a nuclear protein that forms complexes with cyclin-dependent kinases 4 and 6, which phosphorylate and inactivate the retinoblastoma protein (pRb). Inactivation of pRb allows cell cycle progression from G1 to S phase [9]. The interest about cyclin D1 is greatly increased after the findings of Akervall et al. [10, 11] who observed the association between 11q13 amplification and poor prognosis in patients with squamous cell carcinoma of head and neck regions. An increased level of cyclin D1 expression has been reported in a number of malignancies including esophageal, ovarian, breast, uterine, colon, lung, prostate, lymphoma, as well as head and neck cancers [12]. Moreover, in vitro and in vivo experiments have shown that cyclin D1 overexpression is correlated with tumor growth, lymphangiogenesis, and distant metastasis [13, 14]. Therefore, cyclin D1 might be a potential prognostic factor to predict worse survival in patients’ cancer. There is some evidence suggesting that cyclin D1 overexpression is a potential predictor for poor overall survival (OS) and disease-free survival (DFS) in patients with head and neck cancer, [9, 15, 16] whereas other studies reported the contrary results [17] or any significant associations [18, 19]. The aim of our study was to perform a systematic review and meta-analysis to evaluate the prognostic value of cyclin D1 for patients with head and neck cancer.
Materials and methods Search methods for identification of studies In March 2014, a computerized MEDLINE search was performed from the start of the database until the end of February 2014 using the PubMed service of the US National Library of Medicine and the following search string was run: ‘‘Cyclin D1’’[Mesh] AND (‘‘Head and Neck Neoplasms’’[Mesh] OR ‘‘Laryngeal Neoplasms’’[Mesh] OR ‘‘Salivary Gland Neoplasms’’[Mesh] OR ‘‘Lip Neoplasms’’[Mesh] OR ‘‘Mouth Neoplasms’’[Mesh] OR ‘‘Tongue Neoplasms’’[Mesh] OR ‘‘Nasopharyngeal
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Neoplasms’’[Mesh] OR ‘‘Pharyngeal Neoplasms’’[Mesh]) Reference lists from relevant articles were hand searched for further studies. Inclusion/exclusion criteria Abstracts identified by the search were reviewed independently by two reviewers (F.M.G., M.R.), after appropriate training and piloting. Training in critical appraisal was carried out by the senior author (G.M.) to ensure that selected articles were reviewed to an appropriate standard. Articles were selected for full review in accord with the following a priori eligibility criteria: (a) studies that recruited patients with a proven diagnosis of head and neck cancer were included (b) studies that correlated cyclin D1 expression with patient survival were included, (c) only English-language studies were included, and (d) articles were included if histological samples were used to detect cyclin D1 status (excluding serum cyclin D1 and continuous variable). The full texts of selected articles were retrieved for detailed scrutiny. Studies were excluded based on the following criteria: (a) survival data not specifically reported, (b) tumors originating from thyroid gland cancer, lymphoma, and occult primary cancer, (c) in vitro studies, (d) cross-sectional studies and case–control studies, (e) studies with fewer than ten patients, (f) included patients with distant metastases or recurrent disease, (g) inadequate survival data for calculation of relative risk (RR), or data duplicated elsewhere. Data extraction and management Two authors (FMG and MR) independently reviewed articles for quality assessment and extracted data. The following data were collected from each study: first author’s last name, publication date, country of origin, characteristics of pathology, number of patients, cyclin D1 assays (cut-off level, methods of determination), and observation endpoints (OS, DFS, and lymph node metastasis). Each reviewer also scored the studies for methodological quality in accord with criteria formulated using the guidelines published by Hayden and the REMARK (REporting recommendations for tumor MARKer) guidelines for prognostic studies [20, 21]. The factors assessed included study participation and attrition; prognostic factor under study; outcome and confounding factor measurement; and the quality of the analysis. In accordance with the methodology described by Hayden and colleagues, each of the 17 quality criterion has up to 6 characteristics that define it.
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Studies were allocated a score depending on whether they did not meet (0 points), partly met (1 point), or completely met (2 points) the characteristics of each criterion. The reader is directed to Hayden et al. for further details of the descriptors for each quality criterion. Quality assessment generated a score out of 12, with low-scoring papers likely to contain greater possibility of bias. Differences of opinion were resolved by discussion, then adjudication to the senior author.
Quality assessment, risk of bias, and heterogeneity in included studies
Statistical analysis
Meta-analysis
We performed meta-analysis using a random-effects model and the heterogeneity between study was assessed by the v2 based Cochran’s Q statistic test and I2 metric. Heterogeneity was considered significant at p \ 0.01 for the Q statistic (to assess whether observed variance exceeds expected variance). And for the I2 metric (I2 = 100 % 9 (Q - df)/Q), the following cut-off points were used: I2 = 0–25 %, no heterogeneity; I2 = 25–50 %, moderate heterogeneity; I2 = 50–75 %, large heterogeneity; I2 = 75–100 %, extreme heterogeneity. Pooled effect size was considered to be significantly different if its 95 % CI did not include 1. By convention, effect size [1 implied a worse prognosis for the cycline D1 overexpression group. For OS and DFS, odds ratio (OR) and its 95 % confidence interval (95 % CI) were combined to give the effect measure. We used Peto method for pooling time-to-event data reported by the book of ‘‘systematic Reviews in health care’’ by Egger et al. [22] to extract them. Our primary objective was to evaluate the prognostic role of cyclin D1 overexpression for OS and DFS in patients with head and neck cancer. The secondary objective was to investigate whether high cyclin D1 expression was related to lymph node metastasis. The p values were two-sided, and significant difference was defined as p value less than 0.05. All statistical analyses were performed using STATA version 13 (StataCorp LP, College Station, Texas, USA).
The association between cyclin D1 overexpression and lymph nodal metastasis was reported by 14 studies. The total number of included subjects was 1211. Cyclin D1 overexpression significantly correlated with high risk of lymph node metastasis (OR 2.25; 95 % CI 1.76–2.87; p = 0.024; Fig. 2); results showed moderate heterogeneity I-squared = 47.7 %. Subgroup analysis showed the effect for different observation endpoints as follows: 7 studies and 634 patients were included in the laryngeal cancer group (OR 2.26; 95 % CI 1.61–3.16; p = 0.009), results showed moderate heterogeneity I-squared = 65.0 %; 5 are the number of studies and 468 the patients included in subgroup of oral cancer (OR 2.60; 95 % CI 1.75–3.75; p = 0.668), results showed no heterogeneity I-squared = 0.0 %; 2 studies and 109 patients were included in the group of nasopharyngeal cancer (OR 1.01; 95 % CI 0.41–2.49; p = 0.181), results showed moderate heterogeneity I-squared = 44.1 %. Concerning DFS, the total number of included subjects was 1245, cyclin D1 overexpression was a predictor for patients with head and neck cancer (OR 3.06; 95 % CI 2.42–3.87; p = 0.005; Fig. 3) with assessment by Peto method for pooling time-to-event data; results showed large heterogeneity I-squared = 60.0 %. Subgroup analysis showed the effect for different observation endpoints as follows: 4 studies and 400 patients were in the laryngeal cancer group (OR 2.87; 95 % CI 1.87–4.38; p = 0.215), results were moderate heterogeneity I-squared = 32.9 %; 3 studies and 429 patients formed the oral cancer group (OR 2.73; 95 % CI 1.85–4.04; p = 0.343), results showed no heterogeneity I-squared = 6.5 %; 2 studies and 91 patients were in the nasopharyngeal cancer group (OR 4.44; 95 % CI 1.89–10.42; p = 0.001), results showed extreme heterogeneity I-squared = 91.2 %. In the 15 studies reporting OS, the random effect OR was pooled for comparison of cyclin D1 overexpression with cyclin D1 low expression, the total number of included subjects was 1466, (OR 3.14; 95 % CI 2.52–3.93; p = 0.205 not statistically significant; Fig. 4) with assessment by Peto method for pooling time-to-event data, results showed no heterogeneity I-squared = 22.4 %.
Results Results of the search In all, 724 potentially relevant titles were identified during the initial search, of which 43 studies were subjected to full review, and 22 were included in the final selection. Reasons for exclusion are detailed in Fig. 1. Table 1 summarizes the characteristics of the 22 studies reporting a total of 1929 samples with head and neck cancer. All the 22 studies used the immunohistochemistry (IHC) method to detect cyclin D1 expression.
Mean of quality scores was 9.1 ± 1.68. Scores ranged from 4 to 11, out of a maximum possible score of 12 (data are not shown). Common areas of weakness included: failure to adjust for confounding factors such as smoking, alcohol intake, performance score, and treatment; and the use of an arbitrary or data-dependent cut-point.
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Eur Arch Otorhinolaryngol Fig. 1 Flow diagram of articles selection
Table 1 Baseline characteristics of included studies
HNC head and neck cancer, LC laryngeal cancer, OPC oropharyngeal cancer, OC oral cavity cancer, NPC nasopharyngeal cancer, LNM lymph nodes metastasis, DFS disease-free survival, OS overall survival a
Percentual of nuclei stained
References
Country
Pathological characteristic
Cyclin D1 assay
Cut-off levela
Investigation objective
Fracchiolla et al. [35]
Italy
58
LC
IHC
[1 %
LNM
Kyomoto et al. [36]
Japan
45
HNC
IHC
[10 %
OS
Michalides et al. [37]
Holland
115
HNC
IHC
[5 %
DFS
Pignataro et al. [16]
Italy
147
LC
IHC
[5 %
LNM, DFS. OS
Mineta et al. [38]
Japan
94
OC
IHC
[50 %
LNM, OS
Dong et al. [15]
Japan
102
LC
IHC
[25 %
LNM, DFS. OS
Goto et al. [39]
Japan
41
OC
IHC
Score
LNM, OS
Carlos de Vicente et al. [40]
Spain
35
OC
IHC
[50 %
LNM, OS
Lai et al. [41]
China
64
NPC
IHC
[10 %
LNM, DFS. OS
Mielcarek-Kuchta et al. [42]
Poland
73
LC
IHC
[1 %
LNM
Miyamoto et al. [43] Vielba et al. [19]
Japan Spain
41 62
OC LC
IHC IHC
[10 % [5 %
DFS. OS DFS, OS
Kumar et al. [44]
India
64
LC
IHC
[5 %
LNM
Jayasurya et al. [45]
India
125
OC
IHC
Score
DFS, OS
130
Morshed et al. [46]
Poland
LC
IHC
[5 %
LNM, DFS. OS
Lin et al. [47]
USA
27
NPC
IHC
[5 %
DFS
Maahs et al. [18]
Brazil
45
OC
IHC
Score
LNM, OS
Fu et al. [48]
China
58
LC
IHC
[10 %
LNM
Zhang et al. [49]
China
92
LC
IHC
[50
OS
Huang et al. [9]
Taiwan
264
OC
IHC
[10 %
LNM, DFS. OS
Acikalin et al. [50]
Turkey
45
NPC
IHC
[10 %
LNM
Scantlebury et al. [51]
USA
202
OPC
IHC
[10 %
DFS, OS
Subgroup analysis showed the effect for different observation endpoints as follows: 5 studies and 517 patients were included in the laryngeal cancer group (OR 2.55; 95 % CI 1.74–2.76; p = 0.17), results were moderate
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Patients
heterogeneity I-squared = 37.7 %; 7 studies and 638 patients were included in the oral cancer group (OR 2.80; 95 % CI 1.99–3.93; p = 0.625), results showed no heterogeneity I-squared = 0.0 %.
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Fig. 2 Results of meta-analysis with all evaluable studies for lymph nodes metastasis. OR odds ratio, CI confidence interval. Squares represent the effect size of results of each included study. Horizontal lines represent the 95 % CI of each effect size. Most of them are on
the left of vertical line indicating that cyclin D1 overexpression is correlated with the lymph node metastasis. The diamond represents the aggregate effect size and 95 % CI
Discussion
Zhao et al. [28] reported that cyclin D1 expression level detected by IHC is associated with worst clinico-pathological features and prognosis for esophageal squamous cell carcinoma. On the basis of their meta-analysis Li et al. [29] concluded that cyclin D1 overexpression is significantly associated with poor OS as well as DFS in colorectal cancer. On the other hand, Ren et al. [31] in their meta-analysis found that increased cyclin D1 expression level detected by immunohistochemistry is associated with good progression-free survival for bladder cancer. In the recent years the presence of human papillomavirus (HPV) has been associated with some important implications in oropharyngeal squamous cell carcinoma (SCC) evolution. In particular, a recent meta-analysis [33] clarified that patients with oropharyngeal SCC have a better outcome when the tumoral tissue results positive for HPV. Concerning the relationship between cyclin D1 and HPV, Hong et al. [34] showed as in oropharyngeal cancers the better prognostic outcomes were obtained for patients with HPVpositive/cyclin D1-negative tumors.
Cyclin D1 has been extensively investigated in cancer development and is seen as an important regulator of the G1- to S-phase transition in the cell cycle [23]. In addition, it also has been shown that cyclin D1 mediates DNA repair [24]. Wang et al. [25] investigated the role of cyclin D1 in the metastasis of breast cancer. Their results showed that cyclin D1 expression was clearly related to the metastasis of breast cancer, and breast cancer with low cyclin D1 expression had a poor capability of metastasis when compared with its parental cells. Liang et al. [26] in their study on endometrioid carcinoma found that cyclin D1’s overexpression was positively correlated with the lymph node metastasis and poor prognosis. Wang et al. [27] in their recent study reported that an overexpression of cyclin D1 was positively related to pathological grade and survival rate in ovarian serous carcinomas. The prognostic value of cyclin D1 expression has been investigated for various cancers also by reviews and metaanalysis [28–32].
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Fig. 3 Results of meta-analysis with all evaluable studies for diseasefree survival (DFS). OR odds ratio, CI confidence interval. Squares represent the effect size of results of each included study. Horizontal lines represent the 95 % CI of each effect size. Most of them are on
the left of vertical line indicates that cyclin D1 overexpression increases mortality compared with cyclin D1 low expression. The diamond represents the aggregate effect size and 95 % CI
Fig. 4 Results of meta-analysis with all evaluable studies for overall survival (OS). OR odds ratio, CI confidence interval. Squares represent the effect size of results of each included study. Horizontal lines represent the 95 % CI of each effect size. Most of them are on
the left of vertical line indicates that cyclin D1 overexpression increases the mortality compared with cyclin D1 low expression but not statistically significant. The diamond represents the aggregate effect size and 95 % CI
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Eur Arch Otorhinolaryngol Table 2 Subgroup results of meta-analysis and heterogeneity test Subgroup
No. of studies
OR (95 % CI)
5
Oral cancer 7 Disease-free survival
Heterogeneity test p
I-squared (%)
2.55 (1.74–2.76)
0.170
37.7
2.80 (1.99–3.93)
0.625
0.0
2.87 (1.87–4.38)
0.215
32.9
Overall survival Laryngeal cancer
Laryngeal cancer
4
Oral cancer
3
2.73 (1.85–4.04)
0.343
6.5
Nasopharyngeal cancer
2
4.44 (1.89–10.42) 0.001
91.2
Laryngeal cancer
7
2.26 (1.61–3.16)
0.009
65.0
Oral cancer
5
2.60 (1.75–3.85)
0.668
0.0
Nasopharyngeal cancer
2
1.01 (0.41–2.49)
0.181
44.1
Lymph node
OR odds ratio, CI confidence interval
Our study supports the evidence that cyclin D1 overexpression in tumor tissues is a valid risk factor for predicting poor survival in patients with head and neck cancer. Although this meta-analysis suggested that cyclin D1 overexpression is an available prognostic factor in patients with head and neck cancer, we could not identify the independent prognostic role of cyclin D1 because only univariate effect sizes were used to synthesize data. So, the prognostic effect of cyclin D1 overexpression could be influenced by other factors such as clinical stage, differentiation, or lymph node metastasis. Multivariate results were not used to estimate the pooled effect size in our meta-analysis due to the absence of unified risk factors in different studies. Overall our results showed a strong and statistically significant positive correlation between cyclin D1 expression and lymph node metastasis in patients with head and neck SCC subtypes. Subgroup analyses (Table 2) failed to show any association between cyclin D1 overexpression and lymph node metastasis in the oral and nasopharyngeal cancer group. This result may be explained by the scarce number of studies reported. On the basis of this observation, others studies are needed to better clarify this conception. Nevertheless for laryngeal cancer, the result suggested a potential positive association of cyclin D1 expression with lymph node metastasis. Also concerning DFS our analysis showed a statistically significant positive correlation with cyclin D1 expression in patients with head and neck cancer. Examining the individual subgroups of patients (Table 2) it appears that only the group of nasopharyngeal cancer showed a statistically significant association. Our results showed a
positive correlation trend between high cyclin D1 expression and poor survival in patients affected by laryngeal cancer, but we could not find a statistically significant association. That may be explained by the limited number of available studies. Regarding possible limitations of our meta-analysis, two may have altered our data and so hinder us from evaluating precisely the prognostic value of cyclin D1. The first is the method used for extrapolating HR. When survival curves were used to obtain available variables, the whole process was only based on the graphical representation. So, we considered that censored observations presented a potential source of variability of the HR estimates. To decrease the variability, two authors independently estimated each Kaplan–Meier curve and obtained the final HR and its variances. Secondly, studies measuring cyclin D1 gene or mRNA level by reverse transcriptase-polymerase chain reaction (RT-qPCR) method were not yet included in this meta-analysis. Third, the number of selected studies was still relatively small.
Conclusion In conclusion, our meta-analysis indicated as cyclin D1 expression may be considered as a valid survival predictor for patients with head and neck cancer. In particular on the basis of our results cyclin D1 expression could have a significant impact for patients with laryngeal cancer while the association with oral cancer remained uncertain. Conflict of interest
None.
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Eur Arch Otorhinolaryngol 48. Fu ZJ, Ma ZY, Wang QR et al (2008) Over expression of cyclin D1 and under expression of p16 correlate with lymph node metastases in laryngeal squamous cell carcinoma in Chinese patients. Clin Exp Metastasis 25(8):887–892 49. Zhang YY, Xu ZN, Wang JX, Wei DM, Pan XL (2012) G1/Sspecific cyclin-D1 might be a prognostic biomarker for patients with laryngeal squamous cell carcinoma. Asian Pac J Cancer Prev 13(5):2133–2137 50. Acikalin MF, Etiz D, Gurbuz MK, Ozudogru E, Canaz F, Colak E (2012) Prognostic significance of galectin-3 and cyclin D1
expression in undifferentiated nasopharyngeal carcinoma. Med Oncol 29(2):742–749 51. Scantlebury JB, Luo J, Thorstad WL, El-Mofty SK, Lewis JS Jr (2013) Cyclin D1-a prognostic marker in oropharyngeal squamous cell carcinoma that is tightly associated with high-risk human papillomavirus status. Hum Pathol 44(8):1672–1680
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REVIEW ARTICLE
The prognostic value of cyclin D1 expression in head and neck squamous cell carcinoma Federico M. Gioacchini • Matteo Alicandri-Ciufelli Shaniko Kaleci • Giuseppe Magliulo • Livio Presutti • Massimo Re
•
Received: 9 October 2014 / Accepted: 1 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract The correlation between cyclin D1 overexpression and the clinical outcome of head and neck cancer is not defined. The aim of this meta-analysis was to evaluate the prognostic value of cyclin D1 in patients with head and neck cancer. A search thorough Ovid MEDLINE was performed to enroll all eligible articles. Twenty-two studies comprising a total of 1,929 patients with different head and neck cancers were included. Cyclin D1 overexpression was significantly associated with lymph node metastasis [OR 2.25; 95 % confidence interval (CI) 1.76–2.87] and worse disease-free survival (OR 3.06; 95 % CI 2.42–3.87]. Subgroup analysis revealed that cyclin D1 overexpression correlated significantly with nodal metastasis for laryngeal cancer (OR 2.26; 95 % CI 1.61–3.16) and was a significant poor predictor for nasopharyngeal cancer (OR 4.44; 95 % CI 1.89–10.42). Our meta-analysis suggests that cyclin D1 overexpression could represent an important prognostic indicator for patients with head and neck cancer.
F. M. Gioacchini (&) M. Alicandri-Ciufelli L. Presutti Otolaryngology Department, University Hospital of Modena, Via del Pozzo 71, 41100 Modena, Italy e-mail: [email protected] S. Kaleci Department of Diagnostic Medicine, Clinical and Public Health University Hospital of Modena, Modena, Italy G. Magliulo Department of Otorhinolaryngology ‘‘G. Ferreri’’, ‘‘La Sapienza’’ University, Rome, Italy M. Re Otorhinolaryngology Department, Marche Polytechnic University, Ancona, Italy
Keywords Cyclin D1 Head and neck cancer Biomarkers Survival Prognosis
Introduction Head and neck cancers are the tenth most common type of human cancer and comprise a heterogeneous group of tumors with different clinical and biological behavior, causing an annual mortality of more than 17,960 cases in the world [1]. Despite a rapid development in diagnosis and treatment modalities, the survival rate of patients affected by some of these cancers is still not significantly improved [2]. Traditional prognostic factors, such as tumor stage, histological grade, perineural invasion, and positive surgical margins, are currently used to predict the outcome of head and neck cancer. However, they are inadequate to determine individual patient’s prognosis after systemic treatment. So, the raising question concerning the patients prognosis is whether there is a correlation between the tumor’s behavior and any biological parameter that may help the clinician to make therapeutical decisions [3]. During the recent decades there has been increasing of interest in assessing cancer progression and predicting its course using different molecular markers [4, 5]. However, until recently, studies have not successfully identified clinically useful biomarkers of prognosis. This has been mainly due to the use of small sample sizes from single institutions, with tumors from heterogeneous head and neck subsites that have received a variety of treatments. The most critical point in cell cycle regulation is the G1 checkpoint which determines whether the cell will exit the cell cycle and go into a quiescent state (G0) or enter into the S phase and proceed with cell division [6].
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Regulation of G1-S transition of the cell cycle is tightly controlled by phosphorylation of the retinoblastoma protein (pRb) resulting in the release of essential transcription factors such as E2F-1 [7]. Moreover, the phosphorylation of pRb is regulated by a large number of regulatory proteins such as cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors [8]. Among the cyclins involved in G1 phase, Cyclin D1 appears to be most strongly implicated in human carcinogenesis. The cyclin D1 gene (CCND1) located on chromosome 11q13 is a positive regulator of the cell cycle. It encodes a nuclear protein that forms complexes with cyclin-dependent kinases 4 and 6, which phosphorylate and inactivate the retinoblastoma protein (pRb). Inactivation of pRb allows cell cycle progression from G1 to S phase [9]. The interest about cyclin D1 is greatly increased after the findings of Akervall et al. [10, 11] who observed the association between 11q13 amplification and poor prognosis in patients with squamous cell carcinoma of head and neck regions. An increased level of cyclin D1 expression has been reported in a number of malignancies including esophageal, ovarian, breast, uterine, colon, lung, prostate, lymphoma, as well as head and neck cancers [12]. Moreover, in vitro and in vivo experiments have shown that cyclin D1 overexpression is correlated with tumor growth, lymphangiogenesis, and distant metastasis [13, 14]. Therefore, cyclin D1 might be a potential prognostic factor to predict worse survival in patients’ cancer. There is some evidence suggesting that cyclin D1 overexpression is a potential predictor for poor overall survival (OS) and disease-free survival (DFS) in patients with head and neck cancer, [9, 15, 16] whereas other studies reported the contrary results [17] or any significant associations [18, 19]. The aim of our study was to perform a systematic review and meta-analysis to evaluate the prognostic value of cyclin D1 for patients with head and neck cancer.
Materials and methods Search methods for identification of studies In March 2014, a computerized MEDLINE search was performed from the start of the database until the end of February 2014 using the PubMed service of the US National Library of Medicine and the following search string was run: ‘‘Cyclin D1’’[Mesh] AND (‘‘Head and Neck Neoplasms’’[Mesh] OR ‘‘Laryngeal Neoplasms’’[Mesh] OR ‘‘Salivary Gland Neoplasms’’[Mesh] OR ‘‘Lip Neoplasms’’[Mesh] OR ‘‘Mouth Neoplasms’’[Mesh] OR ‘‘Tongue Neoplasms’’[Mesh] OR ‘‘Nasopharyngeal
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Neoplasms’’[Mesh] OR ‘‘Pharyngeal Neoplasms’’[Mesh]) Reference lists from relevant articles were hand searched for further studies. Inclusion/exclusion criteria Abstracts identified by the search were reviewed independently by two reviewers (F.M.G., M.R.), after appropriate training and piloting. Training in critical appraisal was carried out by the senior author (G.M.) to ensure that selected articles were reviewed to an appropriate standard. Articles were selected for full review in accord with the following a priori eligibility criteria: (a) studies that recruited patients with a proven diagnosis of head and neck cancer were included (b) studies that correlated cyclin D1 expression with patient survival were included, (c) only English-language studies were included, and (d) articles were included if histological samples were used to detect cyclin D1 status (excluding serum cyclin D1 and continuous variable). The full texts of selected articles were retrieved for detailed scrutiny. Studies were excluded based on the following criteria: (a) survival data not specifically reported, (b) tumors originating from thyroid gland cancer, lymphoma, and occult primary cancer, (c) in vitro studies, (d) cross-sectional studies and case–control studies, (e) studies with fewer than ten patients, (f) included patients with distant metastases or recurrent disease, (g) inadequate survival data for calculation of relative risk (RR), or data duplicated elsewhere. Data extraction and management Two authors (FMG and MR) independently reviewed articles for quality assessment and extracted data. The following data were collected from each study: first author’s last name, publication date, country of origin, characteristics of pathology, number of patients, cyclin D1 assays (cut-off level, methods of determination), and observation endpoints (OS, DFS, and lymph node metastasis). Each reviewer also scored the studies for methodological quality in accord with criteria formulated using the guidelines published by Hayden and the REMARK (REporting recommendations for tumor MARKer) guidelines for prognostic studies [20, 21]. The factors assessed included study participation and attrition; prognostic factor under study; outcome and confounding factor measurement; and the quality of the analysis. In accordance with the methodology described by Hayden and colleagues, each of the 17 quality criterion has up to 6 characteristics that define it.
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Studies were allocated a score depending on whether they did not meet (0 points), partly met (1 point), or completely met (2 points) the characteristics of each criterion. The reader is directed to Hayden et al. for further details of the descriptors for each quality criterion. Quality assessment generated a score out of 12, with low-scoring papers likely to contain greater possibility of bias. Differences of opinion were resolved by discussion, then adjudication to the senior author.
Quality assessment, risk of bias, and heterogeneity in included studies
Statistical analysis
Meta-analysis
We performed meta-analysis using a random-effects model and the heterogeneity between study was assessed by the v2 based Cochran’s Q statistic test and I2 metric. Heterogeneity was considered significant at p \ 0.01 for the Q statistic (to assess whether observed variance exceeds expected variance). And for the I2 metric (I2 = 100 % 9 (Q - df)/Q), the following cut-off points were used: I2 = 0–25 %, no heterogeneity; I2 = 25–50 %, moderate heterogeneity; I2 = 50–75 %, large heterogeneity; I2 = 75–100 %, extreme heterogeneity. Pooled effect size was considered to be significantly different if its 95 % CI did not include 1. By convention, effect size [1 implied a worse prognosis for the cycline D1 overexpression group. For OS and DFS, odds ratio (OR) and its 95 % confidence interval (95 % CI) were combined to give the effect measure. We used Peto method for pooling time-to-event data reported by the book of ‘‘systematic Reviews in health care’’ by Egger et al. [22] to extract them. Our primary objective was to evaluate the prognostic role of cyclin D1 overexpression for OS and DFS in patients with head and neck cancer. The secondary objective was to investigate whether high cyclin D1 expression was related to lymph node metastasis. The p values were two-sided, and significant difference was defined as p value less than 0.05. All statistical analyses were performed using STATA version 13 (StataCorp LP, College Station, Texas, USA).
The association between cyclin D1 overexpression and lymph nodal metastasis was reported by 14 studies. The total number of included subjects was 1211. Cyclin D1 overexpression significantly correlated with high risk of lymph node metastasis (OR 2.25; 95 % CI 1.76–2.87; p = 0.024; Fig. 2); results showed moderate heterogeneity I-squared = 47.7 %. Subgroup analysis showed the effect for different observation endpoints as follows: 7 studies and 634 patients were included in the laryngeal cancer group (OR 2.26; 95 % CI 1.61–3.16; p = 0.009), results showed moderate heterogeneity I-squared = 65.0 %; 5 are the number of studies and 468 the patients included in subgroup of oral cancer (OR 2.60; 95 % CI 1.75–3.75; p = 0.668), results showed no heterogeneity I-squared = 0.0 %; 2 studies and 109 patients were included in the group of nasopharyngeal cancer (OR 1.01; 95 % CI 0.41–2.49; p = 0.181), results showed moderate heterogeneity I-squared = 44.1 %. Concerning DFS, the total number of included subjects was 1245, cyclin D1 overexpression was a predictor for patients with head and neck cancer (OR 3.06; 95 % CI 2.42–3.87; p = 0.005; Fig. 3) with assessment by Peto method for pooling time-to-event data; results showed large heterogeneity I-squared = 60.0 %. Subgroup analysis showed the effect for different observation endpoints as follows: 4 studies and 400 patients were in the laryngeal cancer group (OR 2.87; 95 % CI 1.87–4.38; p = 0.215), results were moderate heterogeneity I-squared = 32.9 %; 3 studies and 429 patients formed the oral cancer group (OR 2.73; 95 % CI 1.85–4.04; p = 0.343), results showed no heterogeneity I-squared = 6.5 %; 2 studies and 91 patients were in the nasopharyngeal cancer group (OR 4.44; 95 % CI 1.89–10.42; p = 0.001), results showed extreme heterogeneity I-squared = 91.2 %. In the 15 studies reporting OS, the random effect OR was pooled for comparison of cyclin D1 overexpression with cyclin D1 low expression, the total number of included subjects was 1466, (OR 3.14; 95 % CI 2.52–3.93; p = 0.205 not statistically significant; Fig. 4) with assessment by Peto method for pooling time-to-event data, results showed no heterogeneity I-squared = 22.4 %.
Results Results of the search In all, 724 potentially relevant titles were identified during the initial search, of which 43 studies were subjected to full review, and 22 were included in the final selection. Reasons for exclusion are detailed in Fig. 1. Table 1 summarizes the characteristics of the 22 studies reporting a total of 1929 samples with head and neck cancer. All the 22 studies used the immunohistochemistry (IHC) method to detect cyclin D1 expression.
Mean of quality scores was 9.1 ± 1.68. Scores ranged from 4 to 11, out of a maximum possible score of 12 (data are not shown). Common areas of weakness included: failure to adjust for confounding factors such as smoking, alcohol intake, performance score, and treatment; and the use of an arbitrary or data-dependent cut-point.
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Eur Arch Otorhinolaryngol Fig. 1 Flow diagram of articles selection
Table 1 Baseline characteristics of included studies
HNC head and neck cancer, LC laryngeal cancer, OPC oropharyngeal cancer, OC oral cavity cancer, NPC nasopharyngeal cancer, LNM lymph nodes metastasis, DFS disease-free survival, OS overall survival a
Percentual of nuclei stained
References
Country
Pathological characteristic
Cyclin D1 assay
Cut-off levela
Investigation objective
Fracchiolla et al. [35]
Italy
58
LC
IHC
[1 %
LNM
Kyomoto et al. [36]
Japan
45
HNC
IHC
[10 %
OS
Michalides et al. [37]
Holland
115
HNC
IHC
[5 %
DFS
Pignataro et al. [16]
Italy
147
LC
IHC
[5 %
LNM, DFS. OS
Mineta et al. [38]
Japan
94
OC
IHC
[50 %
LNM, OS
Dong et al. [15]
Japan
102
LC
IHC
[25 %
LNM, DFS. OS
Goto et al. [39]
Japan
41
OC
IHC
Score
LNM, OS
Carlos de Vicente et al. [40]
Spain
35
OC
IHC
[50 %
LNM, OS
Lai et al. [41]
China
64
NPC
IHC
[10 %
LNM, DFS. OS
Mielcarek-Kuchta et al. [42]
Poland
73
LC
IHC
[1 %
LNM
Miyamoto et al. [43] Vielba et al. [19]
Japan Spain
41 62
OC LC
IHC IHC
[10 % [5 %
DFS. OS DFS, OS
Kumar et al. [44]
India
64
LC
IHC
[5 %
LNM
Jayasurya et al. [45]
India
125
OC
IHC
Score
DFS, OS
130
Morshed et al. [46]
Poland
LC
IHC
[5 %
LNM, DFS. OS
Lin et al. [47]
USA
27
NPC
IHC
[5 %
DFS
Maahs et al. [18]
Brazil
45
OC
IHC
Score
LNM, OS
Fu et al. [48]
China
58
LC
IHC
[10 %
LNM
Zhang et al. [49]
China
92
LC
IHC
[50
OS
Huang et al. [9]
Taiwan
264
OC
IHC
[10 %
LNM, DFS. OS
Acikalin et al. [50]
Turkey
45
NPC
IHC
[10 %
LNM
Scantlebury et al. [51]
USA
202
OPC
IHC
[10 %
DFS, OS
Subgroup analysis showed the effect for different observation endpoints as follows: 5 studies and 517 patients were included in the laryngeal cancer group (OR 2.55; 95 % CI 1.74–2.76; p = 0.17), results were moderate
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Patients
heterogeneity I-squared = 37.7 %; 7 studies and 638 patients were included in the oral cancer group (OR 2.80; 95 % CI 1.99–3.93; p = 0.625), results showed no heterogeneity I-squared = 0.0 %.
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Fig. 2 Results of meta-analysis with all evaluable studies for lymph nodes metastasis. OR odds ratio, CI confidence interval. Squares represent the effect size of results of each included study. Horizontal lines represent the 95 % CI of each effect size. Most of them are on
the left of vertical line indicating that cyclin D1 overexpression is correlated with the lymph node metastasis. The diamond represents the aggregate effect size and 95 % CI
Discussion
Zhao et al. [28] reported that cyclin D1 expression level detected by IHC is associated with worst clinico-pathological features and prognosis for esophageal squamous cell carcinoma. On the basis of their meta-analysis Li et al. [29] concluded that cyclin D1 overexpression is significantly associated with poor OS as well as DFS in colorectal cancer. On the other hand, Ren et al. [31] in their meta-analysis found that increased cyclin D1 expression level detected by immunohistochemistry is associated with good progression-free survival for bladder cancer. In the recent years the presence of human papillomavirus (HPV) has been associated with some important implications in oropharyngeal squamous cell carcinoma (SCC) evolution. In particular, a recent meta-analysis [33] clarified that patients with oropharyngeal SCC have a better outcome when the tumoral tissue results positive for HPV. Concerning the relationship between cyclin D1 and HPV, Hong et al. [34] showed as in oropharyngeal cancers the better prognostic outcomes were obtained for patients with HPVpositive/cyclin D1-negative tumors.
Cyclin D1 has been extensively investigated in cancer development and is seen as an important regulator of the G1- to S-phase transition in the cell cycle [23]. In addition, it also has been shown that cyclin D1 mediates DNA repair [24]. Wang et al. [25] investigated the role of cyclin D1 in the metastasis of breast cancer. Their results showed that cyclin D1 expression was clearly related to the metastasis of breast cancer, and breast cancer with low cyclin D1 expression had a poor capability of metastasis when compared with its parental cells. Liang et al. [26] in their study on endometrioid carcinoma found that cyclin D1’s overexpression was positively correlated with the lymph node metastasis and poor prognosis. Wang et al. [27] in their recent study reported that an overexpression of cyclin D1 was positively related to pathological grade and survival rate in ovarian serous carcinomas. The prognostic value of cyclin D1 expression has been investigated for various cancers also by reviews and metaanalysis [28–32].
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Fig. 3 Results of meta-analysis with all evaluable studies for diseasefree survival (DFS). OR odds ratio, CI confidence interval. Squares represent the effect size of results of each included study. Horizontal lines represent the 95 % CI of each effect size. Most of them are on
the left of vertical line indicates that cyclin D1 overexpression increases mortality compared with cyclin D1 low expression. The diamond represents the aggregate effect size and 95 % CI
Fig. 4 Results of meta-analysis with all evaluable studies for overall survival (OS). OR odds ratio, CI confidence interval. Squares represent the effect size of results of each included study. Horizontal lines represent the 95 % CI of each effect size. Most of them are on
the left of vertical line indicates that cyclin D1 overexpression increases the mortality compared with cyclin D1 low expression but not statistically significant. The diamond represents the aggregate effect size and 95 % CI
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Eur Arch Otorhinolaryngol Table 2 Subgroup results of meta-analysis and heterogeneity test Subgroup
No. of studies
OR (95 % CI)
5
Oral cancer 7 Disease-free survival
Heterogeneity test p
I-squared (%)
2.55 (1.74–2.76)
0.170
37.7
2.80 (1.99–3.93)
0.625
0.0
2.87 (1.87–4.38)
0.215
32.9
Overall survival Laryngeal cancer
Laryngeal cancer
4
Oral cancer
3
2.73 (1.85–4.04)
0.343
6.5
Nasopharyngeal cancer
2
4.44 (1.89–10.42) 0.001
91.2
Laryngeal cancer
7
2.26 (1.61–3.16)
0.009
65.0
Oral cancer
5
2.60 (1.75–3.85)
0.668
0.0
Nasopharyngeal cancer
2
1.01 (0.41–2.49)
0.181
44.1
Lymph node
OR odds ratio, CI confidence interval
Our study supports the evidence that cyclin D1 overexpression in tumor tissues is a valid risk factor for predicting poor survival in patients with head and neck cancer. Although this meta-analysis suggested that cyclin D1 overexpression is an available prognostic factor in patients with head and neck cancer, we could not identify the independent prognostic role of cyclin D1 because only univariate effect sizes were used to synthesize data. So, the prognostic effect of cyclin D1 overexpression could be influenced by other factors such as clinical stage, differentiation, or lymph node metastasis. Multivariate results were not used to estimate the pooled effect size in our meta-analysis due to the absence of unified risk factors in different studies. Overall our results showed a strong and statistically significant positive correlation between cyclin D1 expression and lymph node metastasis in patients with head and neck SCC subtypes. Subgroup analyses (Table 2) failed to show any association between cyclin D1 overexpression and lymph node metastasis in the oral and nasopharyngeal cancer group. This result may be explained by the scarce number of studies reported. On the basis of this observation, others studies are needed to better clarify this conception. Nevertheless for laryngeal cancer, the result suggested a potential positive association of cyclin D1 expression with lymph node metastasis. Also concerning DFS our analysis showed a statistically significant positive correlation with cyclin D1 expression in patients with head and neck cancer. Examining the individual subgroups of patients (Table 2) it appears that only the group of nasopharyngeal cancer showed a statistically significant association. Our results showed a
positive correlation trend between high cyclin D1 expression and poor survival in patients affected by laryngeal cancer, but we could not find a statistically significant association. That may be explained by the limited number of available studies. Regarding possible limitations of our meta-analysis, two may have altered our data and so hinder us from evaluating precisely the prognostic value of cyclin D1. The first is the method used for extrapolating HR. When survival curves were used to obtain available variables, the whole process was only based on the graphical representation. So, we considered that censored observations presented a potential source of variability of the HR estimates. To decrease the variability, two authors independently estimated each Kaplan–Meier curve and obtained the final HR and its variances. Secondly, studies measuring cyclin D1 gene or mRNA level by reverse transcriptase-polymerase chain reaction (RT-qPCR) method were not yet included in this meta-analysis. Third, the number of selected studies was still relatively small.
Conclusion In conclusion, our meta-analysis indicated as cyclin D1 expression may be considered as a valid survival predictor for patients with head and neck cancer. In particular on the basis of our results cyclin D1 expression could have a significant impact for patients with laryngeal cancer while the association with oral cancer remained uncertain. Conflict of interest
None.
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