Acta Oto-Laryngologica. 2015; 135: 295–301
ORIGINAL ARTICLE
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Prognostic significance of serum squamous cell carcinoma antigen in patients with head and neck cancer
RYUSUKE IMAI, YUKINORI TAKENAKA, TOSHIMICHI YASUI, SUSUMU NAKAHARA, YOSHIFUMI YAMAMOTO, ATSUSHI HANAMOTO, NORIHIKO TAKEMOTO, TAKAHITO FUKUSUMI, HIRONORI CHO, MASASHI YAMAMOTO & HIDENORI INOHARA Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Abstract Conclusions: Serum squamous cell carcinoma antigen (SCC-Ag) level was an independent prognostic factor for survival in patients with head and neck squamous cell carcinoma (HNSCC), and the prognostic value depended on the carcinoma site. Objectives: To assess the value of SCC-Ag as a prognostic indicator in patients with HNSCC and to determine the effect of primary tumor site on prognosis. Methods: We reviewed 493 patients with HNSCC between 2004 and 2012. The chi-squared test was used to assess associations between SCC-Ag levels and TNM classification. A Cox proportional hazard model was used to assess the hazard ratio of SCC-Ag at different sites for death, and it was analyzed as a continuous variable. Results: The median serum level of SCC-Ag was 1.1 ng/ml (range 0–20). SCC-Ag was significantly higher in patients with advanced T and N classification tumors. Primary sites in the oral cavity, in the hypopharynx, advanced T and N classification, distant metastasis, and SCC-Ag were negatively associated with survival in univariate analysis. Multivariate analysis revealed that SCC-Ag was a significant risk factor for overall survival in cancers of the oral cavity, hypopharynx, and larynx, but not in oropharyngeal cancer.
Keywords: Prognosis, tumor marker, oral cavity, hypopharynx, larynx, oropharynx
Introduction Various serum tumor markers have been used in clinical settings. The main purpose of tumor marker measurements is for early detection of recurrence or metastasis after treatment. Generally, serum levels of tumor markers increase as tumors progress; therefore, tumor markers are potential prognostic markers. Several biomarkers, including tissue biomarkers and serum tumor markers, have been used to predict prognosis of patients with cancer [1]. However, serum tumor markers are more easily and less invasively obtained than tissue biomarkers. Squamous cell carcinoma (SCC) antigen (SCCAg) was biochemically isolated from SCC tissue of the
uterine cervix by Kato and Torigoe in 1977 [2]. SCCAg has been explored as a serum tumor marker of human SCCs originating in various organs, such as the lung [3], anus [4], esophagus [5], and bladder [6]. Krimmel et al. investigated the association between SCC-Ag and clinicopathological parameters in head and neck SCC (HNSCC) and found that tumor thickness correlated with elevated levels of SSC-Ag [7]. Lin et al. demonstrated that preoperative SCCAg in patients with oral SCC correlated with pathological lymph node metastasis, advanced tumor stage, distant metastasis, and disease-free survival [8]. On the contrary, Lara et al. reported that pretreatment SCC-Ag in patients with laryngeal and hypopharyngeal cancer did not have any impact on mortality [9].
Correspondence: Yukinori Takenaka, Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0874, Japan. Tel: +81 6 6879 3951. Fax: +81 6 6879 3959. E-mail: [email protected]
(Received 26 May 2014; accepted 23 July 2014) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2014.951454
296
R. Imai et al.
Therefore, the prognostic significance of pretreatment SCC-Ag in patients with HNSCC remains to be elucidated. The purpose of this study was to assess the value of pretreatment serum SCC-Ag level as an independent prognostic factor in patients with HNSCC and to determine the effect of primary tumor site on prognosis. Material and methods
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Patients and data extraction A retrospective chart review was performed of all patients with newly diagnosed and histologically confirmed HNSCC who were treated at the Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Hospital, between January 2005 and December 2012. A total of 684 patients were identified. Among them, 6 patients without initial staging, 41 patients with follow-up periods 1000
282
57
35
45
68
60
98
25
57
58
24
38
N/A
19
4
3
4
3
3
7
5
2
2
4
6
< 0.001
SCC (ng/ml) Median
1.1
1.0
1.3
1.4
1.0
1.4
Range
0–20
0–11.5
0–19.8
0–19.3
0–20
0–20
< 0.001
Treatment modality (C)RT
351
71
7
9
86
76
122
87
86
88
50
78
Surgery
103
21
64
82
15
13
7
5
6
6
11
18
Other
39
8
7
9
12
11
11
8
6
6
3
5
< 0.001
(C)RT, (chemo-)radiation therapy; N/A, not available.
Thus, elevated SCC-Ag was associated with poor prognosis. To further investigate the role of SCC-Ag in the prognosis of patients with HNSCC, we used a Cox proportional hazard model to examine the prognostic value of the clinicopathological variables by univariate analysis (Table III). When hazard ratios for overall survival were estimated, oral cavity primary (p = 0.01), hypopharyngeal primary (p < 0.001), T classification (p < 0.001), N classification (p < 0.001), distant metastasis (p < 0.001), and pretreatment SCC-Ag
level (p < 0.001) were significant risk factors for overall survival. The hazard ratio of (chemo-) radiation therapy was comparable to that of surgery (p = 0.090). Similarly, primary site, TNM classification, and SCC-Ag significantly affected diseasespecific survival. The patients with different primary site tumors had different backgrounds. Therefore, we stratified the subjects by primary site and calculated the hazard ratios of pretreatment SCC-Ag for each primary site (Table IV). The hazard ratios were adjusted for TNM
298
R. Imai et al.
Table II. Association of SCC-Ag and TNM classification. SCC-Ag
Median
First quartile-third quartile
T1, T2
1.0
0–2.0
T3, T4
1.3
0–2.4
Classification
p value
T classification 0.004
N0, N1
1.0
0–1.7
N2, N3
1.5
0–2.8
M0
1.1
0–2.0
M1
1.6
1.0–5.0
< 0.001
M classification 0.073
classification and age. In the analysis of overall survival, the adjusted hazard ratios of SCC-Ag for the oral cavity, oropharynx, hypopharynx, larynx, and other sites were 1.21, 1.01, 1.10, 1.27, and 1.08, respectively, and all were statistically significant except for the oropharynx and other sites. Similar results were obtained in the analysis of diseasespecific survival. SCC-Ag was a significant risk factor for disease-specific survival in oral cavity cancer and hypopharyngeal cancer.
Discussion The prognostic significance of SCC-Ag has been investigated for tumors of various organs [10–13]. Strauss et al. showed that SCC-Ag was an independent prognostic factor in operable SCC of the cervix [10]. Williams et al. showed that SCC-Ag was a potentially useful prognostic marker in SCC of the anal canal [11]. For esophageal SCC, preoperative SCC-Ag concentrations were shown to provide predictive information for tumor progression and survival [12]. Preoperative SCC-Ag levels in patients with lung cancer and decreases after surgery have prognostic significance [13]. On the other hand, A
B
Overall survival 1.0
0.5
0
SCC-Ag ≥ 1.1
0
12
24 36 Months
48
Diease-specific survival 1.0
SCC-Ag < 1.1 Survival
Survival
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N classification
findings for the prognostic value of SCC-Ag in patients with HNSCC have been contradictory. In the present study, we demonstrated that the prognostic significance of pretreatment SCC-Ag level depended on the primary tumor sites. Specifically, SCC-Ag had prognostic value for cancers of the oral cavity, larynx, and hypopharynx but not for oropharyngeal cancer. The results presented here are consistent with those of some previous reports. Molina et al. reported that elevated SCC-Ag levels in patients with HNSCC were a significant independent predictor of poor prognosis [14]. Lin et al. showed that the preoperative SCC-Ag level of the oral cavity SCC predicted overall survival [8]. In contrast, several previous reports have come to the opposite conclusion. Meyer et al. reported that SCCAg did not improve the predictive reliability for cancer recurrence or overall mortality [15]. However, the subjects in those studies only had stage I and II tumors, which may account for the negative results. Chen et al. reported that SCC-Ag level did not have prognostic value, whereas the combined measurement of SCC-Ag and C-reactive protein was capable of predicting prognosis [16]. Their study subjects only had oropharyngeal and hypopharyngeal cancers, and more than half had oropharyngeal cancer. The difference in the primary site distribution may explain the differences in prognostic values between that study and ours. Kimura et al. reported that the overall survival rate in the SCC-Ag-positive group was significantly lower than that in the SCC-Ag-negative group, but the prognostic value of SCC-Ag could not be proved on multivariate analysis [17]. Their multivariate analysis did not include the location of the carcinoma, which may have led to the negative result in multivariate analysis. Moreover, previous reports have used different cut-off values for SCCAg, which also may have led to discrepancies [8,14– 17]. To avoid different results caused by differences in cut-off values, we analyzed the SCC-Ag level as a continuous variable in the present study. There are several reasons that explain why high serum SCC-Ag level is associated with worse
60
SCC-Ag < 1.1
0.5
0
SCC-Ag ≥ 1.1
0
12
24 36 Months
48
60
Figure 1. (A) Overall survival and (B) disease-specific survival by serum squamous cell carcinoma antigen (SCC-Ag) level.
Prognostic significance of SCC antigen
299
Table III. Overall and disease-specific survival according to clinicopathologic variables. Overall survival Clinicopathologic variable
Hazard ratio
Disease-specific survival
95% confidence interval
p value
0.71–1.57
0.716
Hazard ratio
95% confidence interval
p value
0.81–1.91
0.282
Sex Male
Ref
Female
1.08
Ref 1.25
Age (years) 20
1.13
Ref
Drinking (unit-years) £1000
Ref
Ref
>1000
1.30
0.96–1.78
0.086
1.12
0.80–1.59
0.502
SCC-Ag (ng/ml)
1.09
1.05–1.12
< 0.001
1.10
1.05–1.14
< 0.001
Treatment modality (C)RT
Ref
Ref
Surgery
0.80
0.52–1.17
0.256
0.67
0.40–1.06
0.090
Other
7.72
5.17–11.25
< 0.001
8.77
5.69–13.18
< 0.001
(C)RT, (chemo-)radiation therapy.
prognosis. In our results, SCC-Ag levels were higher in the advanced T classification group and advanced N classification group. The T classification describes the tumor volume and invasiveness of the primary tumor. It is reasonable that elevated SCC-Ag is associated with advanced T classification because a larger number of tumor cells secrete larger amounts of SCCAg. In addition, the association of SCC-Ag and lymph node metastasis is plausible because secreted SCC-Ag from tumor cells in lymph nodes is easily detected in
the bloodstream [8]. Similarly, there should be an association between elevated SCC-Ag and distant metastasis because circulating tumor cells in the bloodstream enable easy detection of secreted SCC-Ag by blood tests. However, the relevance of distant metastasis and elevated SCC-Ag did not reach statistical significance in our analysis, probably because of the very small number of patients with distant metastasis. In this study, multivariate analyses using a Cox proportional hazard model revealed that
300
R. Imai et al.
Table IV. Hazard ratios of SCC-Ag for each primary site. Overall survival Primary site
Hazard ratio
Disease-specific survival
95% confidence interval
p value
Hazard ratio
95% confidence interval
p value
Oral cavity
1.21
1.03–1.39
0.025
1.21
1.03–1.41
0.024
Oropharynx
1.01
0.92–1.09
0.787
1.73
0.22–8.44
0.564
Hypopharynx
1.10
1.01–1.18
0.036
1.11
1.01–1.20
0.032
Larynx
1.27
1.11–1.43
0.002
1.21
0.88–1.49
0.196
Other
1.08
0.97–1.18
0.160
1.09
0.97–1.20
0.135
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The hazard ratio was adjusted for T, N, M classifications and age.
elevated SCC-Ag level was a prognostic factor independent of T, N, and M classification. This result suggests that there may be a specific role of SCC-Ag in tumor progression. Lin et al. demonstrated that preoperative SCC-Ag level could predict extracapsular spread of lymph node metastasis [8], which was evidenced by the observation in vitro that SCC-Ag stimulated production of MMP-9 resulting in promotion of cell invasion [18]. Collectively, elevated serum SCC-Ag level represents the following: (1) increased tumor cells in the primary site and lymph node and (2) invasiveness of the tumor cells. These features explain why serum SCC-Ag is a good prognostic marker. The prognostic value of serum SCC-Ag invites consideration of its clinical applications. Lin et al. suggested that elective neck dissection should be considered for patients with clinical N0 oral cancer who demonstrated elevated preoperative SCC-Ag levels [8]. Denge et al. suggested intensified treatment and rigorous follow-up after treatment for patients with higher levels of SCC-Ag [19]. Further investigations, including failure patterns, are required for determination of adequate treatment protocols for patients with elevated serum SCC-Ag. In the present study, pretreatment SCC-Ag level was not associated with survival in oropharyngeal cancer. One of the possible reasons is the existence of human papilloma virus (HPV)-associated cancer. It is well known that a substantial proportion of oropharyngeal cancer is HPV-associated cancer, and the proportion has been increasing worldwide. The presence of HPV is the most influential factor in the mortality of patients with oropharyngeal cancer [20]. Therefore, stratification by HPV status or the inclusion of HPV status as a covariate in multivariate analysis is indispensable for survival analysis of oropharyngeal cancer. Recently, Deng et al. reported the prognostic values of HPV and SCC-Ag mRNA in HNSCC [19]. They demonstrated that the ratio of SCC-Ag subtypes was predictive of recurrence-free survival of HPV-negative HNSCC patients [19].
These findings indicate that HPV status should be considered when planning future studies. There were some limitations in the present study. First, we could not obtain some important information because of the retrospective nature of this study. We analyzed only 77% of newly diagnosed HNSCC patients because of missing data on pretreatment serum SCC-Ag levels. In addition, we could not include data on performance status, a well-known prognostic factor for HNSCC. Second, the numbers of patients and thus the statistical power differed for each HNSCC site. Third, we did not include the treatment modality as a variable in statistical analyses because this type of subdivision leads to very small subgroups and precludes multivariate analyses. Finally, as described earlier, HPV status should have been required for the analysis of oropharyngeal cancer. Conclusion We found that SCC-Ag level was an independent prognostic factor for survival in patients with HNSCC, and the prognostic value depended on the HNSCC site. Further studies are required for future clinical applications. Acknowledgment We would like to thank Naomi Kawasaki for retrieving data. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Polanska H, Raudenska M, Gumulec J, Sztalmachova M, Adam V, Kizek R, et al. Clinical significance of head and neck squamous cell cancer biomarkers. Oral Oncol 2014;50: 168–77.
Acta Otolaryngol Downloaded from informahealthcare.com by West Virginia University on 03/08/15 For personal use only.
Prognostic significance of SCC antigen [2] Kato H, Torigoe T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 1977;40: 1621–8. [3] Margolis ML, Hyzy JB, Schenken LL, Schepart BS. Serum tumor markers in non-small cell lung cancer. A comparative analysis. Cancer 1994;73:605–9. [4] Petrelli NJ, Shaw N, Bhargava A, Daufeldt J, Herrera L, Stulc JP, et al. Squamous cell carcinoma antigen as a marker for squamous cell carcinoma of the anal canal. J Clin Oncol 1988;6:782–5. [5] Kawaguchi H, Ohno S, Miyazaki M, Hashimoto K, Eqashira A, Saeki H, et al. CYFRA 21-1 determination in patients with esophageal squamous cell carcinoma: clinical utility for detection of recurrences. Cancer 2000;89:1413–17. [6] Pectasides D, Bafaloucos D, Antoniou F, Gogou L, Economides N, Varthalitis J, et al. TPA, TATI, CEA, AFP, beta-HCG, PSA, SCC, and CA 19-9 for monitoring transitional cell carcinoma of the bladder. Am J Clin Oncol 1996;19:271–7. [7] Krimmel M, Hoffmann J, Krimmel C, Cornelius CP, Schwenzer N. Relevance of SCC-Ag, CEA, CA 19.9 and CA 125 for diagnosis and follow-up in oral cancer. J Craniomaxillofac Surg 1998;26:243–8. [8] Lin WH, Chen IH, Wei FC, Huang JJ, Kang CJ, Hsieh LL, et al. Clinical significance of preoperative squamous cell carcinoma antigen in oral-cavity squamous cell carcinoma. Laryngoscope 2011;121:971–7. [9] Lara PC, Cuyas JM. The role of squamous cell carcinoma antigen in the management of laryngeal and hypopharyngeal cancer. Cancer 1995;76:758–64. [10] Strauss HG, Laban C, Lautenschlager C, Buchmann J, Schneider I, Koelbl H. SCC antigen in the serum as an independent prognostic factor in operable squamous cell carcinoma of the cervix. Eur J Cancer 2002;38:1987–91. [11] Williams M, Swampillai A, Osborne M, Mawdsley S, Hughes R, Harrison M, et al. Squamous cell carcinoma antigen: a potentially useful prognostic marker in squamous cell carcinoma of the anal canal and margin. Cancer 2013; 119:2391–8.
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[12] Shimada H, Nabeya Y, Okazumi S, Matsubara H, Shiratori T, Gunji Y, et al. Prediction of survival with squamous cell carcinoma antigen in patients with resectable esophageal squamous cell carcinoma. Surgery 2003;133: 486–94. [13] Vassilakopoulos T, Troupis T, Sotiropoulou C, Zacharatos P, Katsaounou P, Parthenis D, et al. Diagnostic and prognostic significance of squamous cell carcinoma antigen in non-small cell lung cancer. Lung Cancer 2001; 32:137–44. [14] Molina R, Torres MD, Moragas M, Perez-Villa J, Filella X, Jo J, et al. Prognostic significance of SCC antigen in the serum of patients with head and neck cancer. Tumour Biol 1996;17:81–9. [15] Meyer F, Samson E, Douville P, Duchesne T, Liu G, Bairati I. Serum prognostic markers in head and neck cancer. Clin Cancer Res 2010;16:1008–15. [16] Chen HH, Wang HM, Fan KH, Lin CY, Yen TC, Liao CT, et al. Pre-treatment levels of C-reactive protein and squamous cell carcinoma antigen for predicting the aggressiveness of pharyngolaryngeal carcinoma. PLoS ONE 2013;8:e55327. [17] Kimura Y, Fujieda S, Takabayashi T, Tanaka T, Sugimoto C, Saito H. Conventional tumor markers are prognostic indicators in patients with head and neck squamous cell carcinoma. Cancer Lett 2000;155:163–8. [18] Sueoka K, Nawata S, Nakagawa T, Murakami A, Takeda O, Suminami Y, et al. Tumor-associated serpin, squamous cell carcinoma antigen stimulates matrix metalloproteinase-9 production in cervical squamous cell carcinoma cell lines. Int J Oncol 2005;27:1345–53. [19] Deng Z, Hasegawa M, Yamashita Y, Matayoshi S, Kiyuna A, Agena S, et al. Prognostic value of human papillomavirus and squamous cell carcinoma antigen in head and neck squamous cell carcinoma. Cancer Sci 2012;103:2127–34. [20] Rainsbury JW, Ahmed W, Williams HK, Roberts S, Paleri V, Mehanna H. Prognostic biomarkers of survival in oropharyngeal squamous cell carcinoma: systematic review and meta-analysis. Head Neck 2013;35:1048–55.
ORIGINAL ARTICLE
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Prognostic significance of serum squamous cell carcinoma antigen in patients with head and neck cancer
RYUSUKE IMAI, YUKINORI TAKENAKA, TOSHIMICHI YASUI, SUSUMU NAKAHARA, YOSHIFUMI YAMAMOTO, ATSUSHI HANAMOTO, NORIHIKO TAKEMOTO, TAKAHITO FUKUSUMI, HIRONORI CHO, MASASHI YAMAMOTO & HIDENORI INOHARA Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Abstract Conclusions: Serum squamous cell carcinoma antigen (SCC-Ag) level was an independent prognostic factor for survival in patients with head and neck squamous cell carcinoma (HNSCC), and the prognostic value depended on the carcinoma site. Objectives: To assess the value of SCC-Ag as a prognostic indicator in patients with HNSCC and to determine the effect of primary tumor site on prognosis. Methods: We reviewed 493 patients with HNSCC between 2004 and 2012. The chi-squared test was used to assess associations between SCC-Ag levels and TNM classification. A Cox proportional hazard model was used to assess the hazard ratio of SCC-Ag at different sites for death, and it was analyzed as a continuous variable. Results: The median serum level of SCC-Ag was 1.1 ng/ml (range 0–20). SCC-Ag was significantly higher in patients with advanced T and N classification tumors. Primary sites in the oral cavity, in the hypopharynx, advanced T and N classification, distant metastasis, and SCC-Ag were negatively associated with survival in univariate analysis. Multivariate analysis revealed that SCC-Ag was a significant risk factor for overall survival in cancers of the oral cavity, hypopharynx, and larynx, but not in oropharyngeal cancer.
Keywords: Prognosis, tumor marker, oral cavity, hypopharynx, larynx, oropharynx
Introduction Various serum tumor markers have been used in clinical settings. The main purpose of tumor marker measurements is for early detection of recurrence or metastasis after treatment. Generally, serum levels of tumor markers increase as tumors progress; therefore, tumor markers are potential prognostic markers. Several biomarkers, including tissue biomarkers and serum tumor markers, have been used to predict prognosis of patients with cancer [1]. However, serum tumor markers are more easily and less invasively obtained than tissue biomarkers. Squamous cell carcinoma (SCC) antigen (SCCAg) was biochemically isolated from SCC tissue of the
uterine cervix by Kato and Torigoe in 1977 [2]. SCCAg has been explored as a serum tumor marker of human SCCs originating in various organs, such as the lung [3], anus [4], esophagus [5], and bladder [6]. Krimmel et al. investigated the association between SCC-Ag and clinicopathological parameters in head and neck SCC (HNSCC) and found that tumor thickness correlated with elevated levels of SSC-Ag [7]. Lin et al. demonstrated that preoperative SCCAg in patients with oral SCC correlated with pathological lymph node metastasis, advanced tumor stage, distant metastasis, and disease-free survival [8]. On the contrary, Lara et al. reported that pretreatment SCC-Ag in patients with laryngeal and hypopharyngeal cancer did not have any impact on mortality [9].
Correspondence: Yukinori Takenaka, Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0874, Japan. Tel: +81 6 6879 3951. Fax: +81 6 6879 3959. E-mail: [email protected]
(Received 26 May 2014; accepted 23 July 2014) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2014.951454
296
R. Imai et al.
Therefore, the prognostic significance of pretreatment SCC-Ag in patients with HNSCC remains to be elucidated. The purpose of this study was to assess the value of pretreatment serum SCC-Ag level as an independent prognostic factor in patients with HNSCC and to determine the effect of primary tumor site on prognosis. Material and methods
Acta Otolaryngol Downloaded from informahealthcare.com by West Virginia University on 03/08/15 For personal use only.
Patients and data extraction A retrospective chart review was performed of all patients with newly diagnosed and histologically confirmed HNSCC who were treated at the Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Hospital, between January 2005 and December 2012. A total of 684 patients were identified. Among them, 6 patients without initial staging, 41 patients with follow-up periods 1000
282
57
35
45
68
60
98
25
57
58
24
38
N/A
19
4
3
4
3
3
7
5
2
2
4
6
< 0.001
SCC (ng/ml) Median
1.1
1.0
1.3
1.4
1.0
1.4
Range
0–20
0–11.5
0–19.8
0–19.3
0–20
0–20
< 0.001
Treatment modality (C)RT
351
71
7
9
86
76
122
87
86
88
50
78
Surgery
103
21
64
82
15
13
7
5
6
6
11
18
Other
39
8
7
9
12
11
11
8
6
6
3
5
< 0.001
(C)RT, (chemo-)radiation therapy; N/A, not available.
Thus, elevated SCC-Ag was associated with poor prognosis. To further investigate the role of SCC-Ag in the prognosis of patients with HNSCC, we used a Cox proportional hazard model to examine the prognostic value of the clinicopathological variables by univariate analysis (Table III). When hazard ratios for overall survival were estimated, oral cavity primary (p = 0.01), hypopharyngeal primary (p < 0.001), T classification (p < 0.001), N classification (p < 0.001), distant metastasis (p < 0.001), and pretreatment SCC-Ag
level (p < 0.001) were significant risk factors for overall survival. The hazard ratio of (chemo-) radiation therapy was comparable to that of surgery (p = 0.090). Similarly, primary site, TNM classification, and SCC-Ag significantly affected diseasespecific survival. The patients with different primary site tumors had different backgrounds. Therefore, we stratified the subjects by primary site and calculated the hazard ratios of pretreatment SCC-Ag for each primary site (Table IV). The hazard ratios were adjusted for TNM
298
R. Imai et al.
Table II. Association of SCC-Ag and TNM classification. SCC-Ag
Median
First quartile-third quartile
T1, T2
1.0
0–2.0
T3, T4
1.3
0–2.4
Classification
p value
T classification 0.004
N0, N1
1.0
0–1.7
N2, N3
1.5
0–2.8
M0
1.1
0–2.0
M1
1.6
1.0–5.0
< 0.001
M classification 0.073
classification and age. In the analysis of overall survival, the adjusted hazard ratios of SCC-Ag for the oral cavity, oropharynx, hypopharynx, larynx, and other sites were 1.21, 1.01, 1.10, 1.27, and 1.08, respectively, and all were statistically significant except for the oropharynx and other sites. Similar results were obtained in the analysis of diseasespecific survival. SCC-Ag was a significant risk factor for disease-specific survival in oral cavity cancer and hypopharyngeal cancer.
Discussion The prognostic significance of SCC-Ag has been investigated for tumors of various organs [10–13]. Strauss et al. showed that SCC-Ag was an independent prognostic factor in operable SCC of the cervix [10]. Williams et al. showed that SCC-Ag was a potentially useful prognostic marker in SCC of the anal canal [11]. For esophageal SCC, preoperative SCC-Ag concentrations were shown to provide predictive information for tumor progression and survival [12]. Preoperative SCC-Ag levels in patients with lung cancer and decreases after surgery have prognostic significance [13]. On the other hand, A
B
Overall survival 1.0
0.5
0
SCC-Ag ≥ 1.1
0
12
24 36 Months
48
Diease-specific survival 1.0
SCC-Ag < 1.1 Survival
Survival
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N classification
findings for the prognostic value of SCC-Ag in patients with HNSCC have been contradictory. In the present study, we demonstrated that the prognostic significance of pretreatment SCC-Ag level depended on the primary tumor sites. Specifically, SCC-Ag had prognostic value for cancers of the oral cavity, larynx, and hypopharynx but not for oropharyngeal cancer. The results presented here are consistent with those of some previous reports. Molina et al. reported that elevated SCC-Ag levels in patients with HNSCC were a significant independent predictor of poor prognosis [14]. Lin et al. showed that the preoperative SCC-Ag level of the oral cavity SCC predicted overall survival [8]. In contrast, several previous reports have come to the opposite conclusion. Meyer et al. reported that SCCAg did not improve the predictive reliability for cancer recurrence or overall mortality [15]. However, the subjects in those studies only had stage I and II tumors, which may account for the negative results. Chen et al. reported that SCC-Ag level did not have prognostic value, whereas the combined measurement of SCC-Ag and C-reactive protein was capable of predicting prognosis [16]. Their study subjects only had oropharyngeal and hypopharyngeal cancers, and more than half had oropharyngeal cancer. The difference in the primary site distribution may explain the differences in prognostic values between that study and ours. Kimura et al. reported that the overall survival rate in the SCC-Ag-positive group was significantly lower than that in the SCC-Ag-negative group, but the prognostic value of SCC-Ag could not be proved on multivariate analysis [17]. Their multivariate analysis did not include the location of the carcinoma, which may have led to the negative result in multivariate analysis. Moreover, previous reports have used different cut-off values for SCCAg, which also may have led to discrepancies [8,14– 17]. To avoid different results caused by differences in cut-off values, we analyzed the SCC-Ag level as a continuous variable in the present study. There are several reasons that explain why high serum SCC-Ag level is associated with worse
60
SCC-Ag < 1.1
0.5
0
SCC-Ag ≥ 1.1
0
12
24 36 Months
48
60
Figure 1. (A) Overall survival and (B) disease-specific survival by serum squamous cell carcinoma antigen (SCC-Ag) level.
Prognostic significance of SCC antigen
299
Table III. Overall and disease-specific survival according to clinicopathologic variables. Overall survival Clinicopathologic variable
Hazard ratio
Disease-specific survival
95% confidence interval
p value
0.71–1.57
0.716
Hazard ratio
95% confidence interval
p value
0.81–1.91
0.282
Sex Male
Ref
Female
1.08
Ref 1.25
Age (years) 20
1.13
Ref
Drinking (unit-years) £1000
Ref
Ref
>1000
1.30
0.96–1.78
0.086
1.12
0.80–1.59
0.502
SCC-Ag (ng/ml)
1.09
1.05–1.12
< 0.001
1.10
1.05–1.14
< 0.001
Treatment modality (C)RT
Ref
Ref
Surgery
0.80
0.52–1.17
0.256
0.67
0.40–1.06
0.090
Other
7.72
5.17–11.25
< 0.001
8.77
5.69–13.18
< 0.001
(C)RT, (chemo-)radiation therapy.
prognosis. In our results, SCC-Ag levels were higher in the advanced T classification group and advanced N classification group. The T classification describes the tumor volume and invasiveness of the primary tumor. It is reasonable that elevated SCC-Ag is associated with advanced T classification because a larger number of tumor cells secrete larger amounts of SCCAg. In addition, the association of SCC-Ag and lymph node metastasis is plausible because secreted SCC-Ag from tumor cells in lymph nodes is easily detected in
the bloodstream [8]. Similarly, there should be an association between elevated SCC-Ag and distant metastasis because circulating tumor cells in the bloodstream enable easy detection of secreted SCC-Ag by blood tests. However, the relevance of distant metastasis and elevated SCC-Ag did not reach statistical significance in our analysis, probably because of the very small number of patients with distant metastasis. In this study, multivariate analyses using a Cox proportional hazard model revealed that
300
R. Imai et al.
Table IV. Hazard ratios of SCC-Ag for each primary site. Overall survival Primary site
Hazard ratio
Disease-specific survival
95% confidence interval
p value
Hazard ratio
95% confidence interval
p value
Oral cavity
1.21
1.03–1.39
0.025
1.21
1.03–1.41
0.024
Oropharynx
1.01
0.92–1.09
0.787
1.73
0.22–8.44
0.564
Hypopharynx
1.10
1.01–1.18
0.036
1.11
1.01–1.20
0.032
Larynx
1.27
1.11–1.43
0.002
1.21
0.88–1.49
0.196
Other
1.08
0.97–1.18
0.160
1.09
0.97–1.20
0.135
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The hazard ratio was adjusted for T, N, M classifications and age.
elevated SCC-Ag level was a prognostic factor independent of T, N, and M classification. This result suggests that there may be a specific role of SCC-Ag in tumor progression. Lin et al. demonstrated that preoperative SCC-Ag level could predict extracapsular spread of lymph node metastasis [8], which was evidenced by the observation in vitro that SCC-Ag stimulated production of MMP-9 resulting in promotion of cell invasion [18]. Collectively, elevated serum SCC-Ag level represents the following: (1) increased tumor cells in the primary site and lymph node and (2) invasiveness of the tumor cells. These features explain why serum SCC-Ag is a good prognostic marker. The prognostic value of serum SCC-Ag invites consideration of its clinical applications. Lin et al. suggested that elective neck dissection should be considered for patients with clinical N0 oral cancer who demonstrated elevated preoperative SCC-Ag levels [8]. Denge et al. suggested intensified treatment and rigorous follow-up after treatment for patients with higher levels of SCC-Ag [19]. Further investigations, including failure patterns, are required for determination of adequate treatment protocols for patients with elevated serum SCC-Ag. In the present study, pretreatment SCC-Ag level was not associated with survival in oropharyngeal cancer. One of the possible reasons is the existence of human papilloma virus (HPV)-associated cancer. It is well known that a substantial proportion of oropharyngeal cancer is HPV-associated cancer, and the proportion has been increasing worldwide. The presence of HPV is the most influential factor in the mortality of patients with oropharyngeal cancer [20]. Therefore, stratification by HPV status or the inclusion of HPV status as a covariate in multivariate analysis is indispensable for survival analysis of oropharyngeal cancer. Recently, Deng et al. reported the prognostic values of HPV and SCC-Ag mRNA in HNSCC [19]. They demonstrated that the ratio of SCC-Ag subtypes was predictive of recurrence-free survival of HPV-negative HNSCC patients [19].
These findings indicate that HPV status should be considered when planning future studies. There were some limitations in the present study. First, we could not obtain some important information because of the retrospective nature of this study. We analyzed only 77% of newly diagnosed HNSCC patients because of missing data on pretreatment serum SCC-Ag levels. In addition, we could not include data on performance status, a well-known prognostic factor for HNSCC. Second, the numbers of patients and thus the statistical power differed for each HNSCC site. Third, we did not include the treatment modality as a variable in statistical analyses because this type of subdivision leads to very small subgroups and precludes multivariate analyses. Finally, as described earlier, HPV status should have been required for the analysis of oropharyngeal cancer. Conclusion We found that SCC-Ag level was an independent prognostic factor for survival in patients with HNSCC, and the prognostic value depended on the HNSCC site. Further studies are required for future clinical applications. Acknowledgment We would like to thank Naomi Kawasaki for retrieving data. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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