© 1991 S. Karger AG, Basel 0378-7346/91/0321 -0055S2.75/0
Gynecol Obstet Invest 1991;32:55-58
Clinical Significance of Squamous Cell Carcinoma Antigen in Cancer of the Human Uterine Cervix Comparison with CEA and CA-125 H. Verlooy3, P. Devos3, J. Janssensb, L. Mortelmans3, M. Gents3, J. Bonteh, M. De Roo3 “Department of Nuclear Medicine and bDepartment of Gynecologic Oncology, University Hospital Gasthuisberg, Leuven, Belgium
Key Words. Squamous cell carcinoma antigen • Squamous cell carcinoma • Cancer of the uterine cervix Abstract. Serum squamous cell carcinoma antigen (SCCa) concentrations were determined by a radioimmunoas say kit before and during the treatment of 50 patients with cervical carcinoma: 44 with squamous cell carcinoma (SCC) and 6 with adenocarcinoma. The positivity rate of SCCa was 50% (52% for SCC and 33% for adenocarcino ma). The sensitivity of SCCa for SCC was twice as high as that of CEA and CA-125. Low serum concentrations were observed in early-stage carcinoma, indicating that SCCa is not useful for diagnosis. In advanced cases, serum levels were directly and significantly correlated with the stage of the disease.
Squamous cell carcinoma antigen (SCCa) is a subfrac tion of the tumor antigen TA-4, which was first de scribed by Kato and Torigoe [1], TA-4 is a glycoprotein with a molecular weight of 48,000 daltons. It is found both in normal and malignant squamous cell tissue and at times also in adenocarcinomas of the female genital tract. Consisting of two fractions with different isoelec tric points, the neutral TA-4 is detectable in nonmalignant squamous cell tissue, whereas the acid TA-4 is found in the tissue and serum of patients with cervical SCC [2], The aim of the present study is to evaluate the relative value of SCCa as compared to CEA and CA-125 in cancer of the uterine cervix.
Material and Methods Our study population consisted of 50 patients with cervical can cer -4 4 patients with squamous cell carcinoma (SCC) and 6 with adenocarcinoma - and a control group of 103 patients (32 healthy women, 42 patients with ovarian cancer and 29 with endometrial
carcinoma). Clinical staging of the patients with SCC was done at the time of the first SCCa determination. A modified F1GO classi fication was used with three groups (table 1). In order to evaluate the relative value of SCCa, two other tumor markers were compared: CEA and CA-125. Serum concentrations were determined by a radioimmunoassay (RIA) kit from Abbott: SCCa-RIA, CEA-IRMA and CA-125-IRMA. The cut-off values for normal used in this study were 2.5 ng/ml for SCCa, 5 ng/ml for CEA and 65 U/ml for CA-125. For statistical analysis, nonparameteric tests were employed using a significance level of p < 0.01.
.
Table 1 Patients with SCC according to stage Stage group
n
Group I
St 0 and IA = carcinoma in situ and microinvasive carcinoma
3
Group 11
St IB and II = early invasive carcinoma
20
Group III
St III, IV and recurrence = advanced carcinoma
21 Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
Introduction
56
Verlooy/Devos/Janssens/Mortelmans/Gerits/Bonte/De Roo
Table 2. Positivity rates of SCCa
Results
Healthy controls Ovarian cancer Endometrial cancer Cervical carcinoma SCC Adenocarcinoma
n
Positive, %
32 42 29 50 44 6
9 12 0 50 52 33
Table 2 demonstrates SCCa positivity in cervical can cer as well as in the control group. The positivity rate was 50% in cervical carcinoma (52% in SCC and 33% in adenocarcinoma). The false positives in the control group varied between 0 and 12%. In the SCC subgroup, the positivity rate was 22% for CEA and 26% for CA125. The combination assay of the three tumor markers showed a combined positivity (i.e. each marker positive in the same patient) of 9% (fig. 1). Figure 2 gives the individual results for all the pa tients as a function of stage and histological subgroup for the three tumor markers: SCCa, CEA, and CA-125. These frequency distributions clearly show that SCCa performed best. Figure 3 shows the sensitivity of the tumor markers. In the SCC subgroup, SCCa seemed to be the best mark er. Within the adenocarcinoma subgroup, the perfor mance of all three markers was similar. The statistical analysis did not reveal a significant difference between the two histological classes. Figure 4 demonstrates the relationship between stage of disease and serum positivity (percentage above cut-off value) for each of the three tumor markers. There were no patients with elevated SCCa levels in group 1. The
Fig. 1. Combination assay of SCCa, CA-125 and CEA in cervical SCC.
•
40-
20-
•
•
1 O) c
CO
•
8
•• •
•
•
•
•
15-
> 200-
•
< O
2 0 -
o
1° -
150-
IO CM
• 100-
• •
•
•
•
•
•
% A • m H is to lo g y
•*
10-
•
• %
• •
••
• • •
•
• •
• t
V»
•
7*
S q u a m o u s c e ll c a r c in o m a A d e n o carcin o m a
H is to lo g y
• • • • •
•
A
S q u a m o u s c e ll c a r c in o m a A d e n o carcin o m a
H is to lo g y
V
4
!
•
• • «•
••
1 1
S q u a m o u s c e ll c a r c in o m a A d o n o carcin o m a
S t a g e g ro u p
I
II
III
U n s ta g e d
S t a g e g ro u p
1
II
in
U n s ta g e d
S ta g e g ro u p
1
II
III
U n s ta g e d
P a tie n ts , n
3
20
21
6
P a tie n ts , n
3
20
21
6
P a tie n ts , n
3
20
21
6
E le v a te d , n
0
8
15
2
E le v a te d , n
1
4
5
2
E le v a te d , n
1
3
7
2
E le v a te d , %
0
40
71
33
E le v a te d . %
33
20
24
33
E le v a te d . %
33
15
33
33
Fig. 2. Frequency distribution data of SCCa, CEA and CA-125 in cervical carcinoma.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
•
5-
57
SCCa in Cervical Carcinoma
positivity rate was 40% in early invasive carcinoma and increased to 71 % in advanced disease. The statistical analysis of our results concerning stage and serum concentrations showed a significant differ ence between the stage groups for SCCa (Kruskal-Wallis test, p = 0.003) but not for CEA and CA-125.
Discussion Our results concerning sensitivity and specificity agree with data that have been published previously [3-6], Kato et al. [3] noted a sensitivity of 55% for SCC and Maruo et al. [4] found a sensitivity of 54% and 6% false positive cases. In our material and also in other studies, SCCa alone appeared to be a better discriminator for SCC than the combination assay with other tumor markers [7]. Contrary to other authors such as Crombach et al. [8], the difference we found between SCC and adenocarci noma for SCCa was rather small, 52 versus 33%, one reason being the small number of patients with adeno carcinoma. According to Wells and Brown [9], however, glandular and squamous lesions often coexist. A reliable tumor marker should have increasing inci dence of positivity (percentage above cut-off value) and increasing serum levels with advancing disease [10]. Our results showed that stage and serum SCCa levels/positivity were directly and significantly related. This finding is also in agreement with data from the literature [4, 1115], No significant difference could be detected for CEA and CA-125 concerning stage and serum antigen concen trations.
Fig. 4. Positivity of tumor markers versus stage of cervical SCC.
Conclusion SCCa is a tumor antigen with a high specificity for cervical SCC. It has a fairly low but anyway the best sensitivity in comparison with other tumor markers. A stage-related increase in SCCa concentrations and posi tivity was clearly demonstrated. The future potential of SCCa for cervical SCC appears promising, for serum SCCa determinations can provide noninvasive and reli able assessment of the extent of disease.
Acknowledgments The authors wish to thank Mrs. D. Schepers and Mrs. M.J. Vangoetsenhoven for the secretarial work.
References 1 Kato H, Torigoe T: Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 1977;41: 1621-1628. 2 Kato H, Nagaya T, Torigoe T: Heterogenity of a tumor antigen TA-4 of squamous cell carcinoma in relation to its appearance in the incubation. Gann 1984;75:433-435. 3 Kato H, Morioka H, Aramaki SH, Torigoe T: Radioimmunoas say for tumor-antigen of human cervical squamous cell carcino ma. Cell Mol Biol 1979;25:51-56. 4 Maruo T, Shibata K, Kimura A, Hoshina M, Mochizuki M: Tumor-associated antigen, TA-4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Cancer 1985;56:302-308. 5 Gosselin P, Cazin JL, Dehaut JP, Sulman Ch, Bazanzelli MC, Démaillé MC Intérêt du dosage de l’antigène «squamous cell
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
Fig. 3. Positivity of tumor markers versus histology in cervical carcinoma.
Verlooy/Devos/Jansscns/Mortelmans/Gerits/Bonte/De Roo
6
7
8
9
10
11
12
carcinoma» dans le cancer du col utérin. Presse Méd 1987; 16: 1677-1679. Molina R, Filella X, Torres MD, Ballesta AM, Mengual P, Casis A, Balaque A: SCC antigen measured in malignant and nonmalignant diseases. Clin Chem 1990;36:251-254. Komafel J, Wawrzkiewicz M: Evaluation of diagnostic useful ness of CEA, hCG and SCC antigen in cervical cancer patients. E urJ Gynaecol Oncol 1989;10:319-322. Crombach G, Würz H, Boite A: Determination of SCC antigen in the serum of patients with cervical cancer. Geburtshilfe Frauenheilkd 1987;47:439-445. Wells M, Brown U R : Glandular lesions of the uterine cervix: The present state of our knowledge. Histopathology 1986; 10: 777-792. Paulick R, Caffier H, Homer G, Lang K, Filbry E: Clinical sig nificance of different serum tumor markers in gynecological malignancies. Cancer Detect Prev 1985;8:115-120. Kato H, Morioka H, Torigoe T: A radioimmunoassay for a tumor-antigen (TA) of squamous cell carcinoma: Pretreatment serum TA-4 levels and the extent of cervical cancer. AACR abstracts 1980:237. Kato H, Morioka H, Aramaki S, Ouchi Y, Torigoe T: A radioim munoassay for a tumor antigen (TA-4) of squamous cell carcino ma: Pretreatment serum levels and the extent of disease. Proc of the 32nd Annu Sei Meet. Acta Obstet Gynaecol Jpn 1980;32: 2087-2088.
13 Schmidt-Rhodc P, Schulze KD, Sturm G, Hafner H, Prinz H, Kunzig HJ: Squamous cell carcinoma antigen for monitoring cervical cancer. Int J Biol Markers 1988;3(2):87—94. 14 Kato H, Morioka H, Tsutsui H, Aramaki Sh, Torigoe T: Value of tumor-antigen (TA-4) of squamous cell carcinoma in predicting the extent of cervical cancer. Cancer 1982:50:1294—1296. 15 Hsieh CY, Chang DY, Huang SC, Yen ML, Juang GT, Ouyang PC: Serum squamous cell carcinoma antigen in gynecologic ma lignancies with special reference to cervical cancer. Taiwan I Hsueh Hui Tsa Chih 1989;88:797-800.
Received: August 27, 1990 Accepted in revised form: February 14. 1991 H. Verlooy Department of Nuclear Medicine University Hospital Gasthuisberg B-3000 Leuven (Belgium)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
58
Gynecol Obstet Invest 1991;32:55-58
Clinical Significance of Squamous Cell Carcinoma Antigen in Cancer of the Human Uterine Cervix Comparison with CEA and CA-125 H. Verlooy3, P. Devos3, J. Janssensb, L. Mortelmans3, M. Gents3, J. Bonteh, M. De Roo3 “Department of Nuclear Medicine and bDepartment of Gynecologic Oncology, University Hospital Gasthuisberg, Leuven, Belgium
Key Words. Squamous cell carcinoma antigen • Squamous cell carcinoma • Cancer of the uterine cervix Abstract. Serum squamous cell carcinoma antigen (SCCa) concentrations were determined by a radioimmunoas say kit before and during the treatment of 50 patients with cervical carcinoma: 44 with squamous cell carcinoma (SCC) and 6 with adenocarcinoma. The positivity rate of SCCa was 50% (52% for SCC and 33% for adenocarcino ma). The sensitivity of SCCa for SCC was twice as high as that of CEA and CA-125. Low serum concentrations were observed in early-stage carcinoma, indicating that SCCa is not useful for diagnosis. In advanced cases, serum levels were directly and significantly correlated with the stage of the disease.
Squamous cell carcinoma antigen (SCCa) is a subfrac tion of the tumor antigen TA-4, which was first de scribed by Kato and Torigoe [1], TA-4 is a glycoprotein with a molecular weight of 48,000 daltons. It is found both in normal and malignant squamous cell tissue and at times also in adenocarcinomas of the female genital tract. Consisting of two fractions with different isoelec tric points, the neutral TA-4 is detectable in nonmalignant squamous cell tissue, whereas the acid TA-4 is found in the tissue and serum of patients with cervical SCC [2], The aim of the present study is to evaluate the relative value of SCCa as compared to CEA and CA-125 in cancer of the uterine cervix.
Material and Methods Our study population consisted of 50 patients with cervical can cer -4 4 patients with squamous cell carcinoma (SCC) and 6 with adenocarcinoma - and a control group of 103 patients (32 healthy women, 42 patients with ovarian cancer and 29 with endometrial
carcinoma). Clinical staging of the patients with SCC was done at the time of the first SCCa determination. A modified F1GO classi fication was used with three groups (table 1). In order to evaluate the relative value of SCCa, two other tumor markers were compared: CEA and CA-125. Serum concentrations were determined by a radioimmunoassay (RIA) kit from Abbott: SCCa-RIA, CEA-IRMA and CA-125-IRMA. The cut-off values for normal used in this study were 2.5 ng/ml for SCCa, 5 ng/ml for CEA and 65 U/ml for CA-125. For statistical analysis, nonparameteric tests were employed using a significance level of p < 0.01.
.
Table 1 Patients with SCC according to stage Stage group
n
Group I
St 0 and IA = carcinoma in situ and microinvasive carcinoma
3
Group 11
St IB and II = early invasive carcinoma
20
Group III
St III, IV and recurrence = advanced carcinoma
21 Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
Introduction
56
Verlooy/Devos/Janssens/Mortelmans/Gerits/Bonte/De Roo
Table 2. Positivity rates of SCCa
Results
Healthy controls Ovarian cancer Endometrial cancer Cervical carcinoma SCC Adenocarcinoma
n
Positive, %
32 42 29 50 44 6
9 12 0 50 52 33
Table 2 demonstrates SCCa positivity in cervical can cer as well as in the control group. The positivity rate was 50% in cervical carcinoma (52% in SCC and 33% in adenocarcinoma). The false positives in the control group varied between 0 and 12%. In the SCC subgroup, the positivity rate was 22% for CEA and 26% for CA125. The combination assay of the three tumor markers showed a combined positivity (i.e. each marker positive in the same patient) of 9% (fig. 1). Figure 2 gives the individual results for all the pa tients as a function of stage and histological subgroup for the three tumor markers: SCCa, CEA, and CA-125. These frequency distributions clearly show that SCCa performed best. Figure 3 shows the sensitivity of the tumor markers. In the SCC subgroup, SCCa seemed to be the best mark er. Within the adenocarcinoma subgroup, the perfor mance of all three markers was similar. The statistical analysis did not reveal a significant difference between the two histological classes. Figure 4 demonstrates the relationship between stage of disease and serum positivity (percentage above cut-off value) for each of the three tumor markers. There were no patients with elevated SCCa levels in group 1. The
Fig. 1. Combination assay of SCCa, CA-125 and CEA in cervical SCC.
•
40-
20-
•
•
1 O) c
CO
•
8
•• •
•
•
•
•
15-
> 200-
•
< O
2 0 -
o
1° -
150-
IO CM
• 100-
• •
•
•
•
•
•
% A • m H is to lo g y
•*
10-
•
• %
• •
••
• • •
•
• •
• t
V»
•
7*
S q u a m o u s c e ll c a r c in o m a A d e n o carcin o m a
H is to lo g y
• • • • •
•
A
S q u a m o u s c e ll c a r c in o m a A d e n o carcin o m a
H is to lo g y
V
4
!
•
• • «•
••
1 1
S q u a m o u s c e ll c a r c in o m a A d o n o carcin o m a
S t a g e g ro u p
I
II
III
U n s ta g e d
S t a g e g ro u p
1
II
in
U n s ta g e d
S ta g e g ro u p
1
II
III
U n s ta g e d
P a tie n ts , n
3
20
21
6
P a tie n ts , n
3
20
21
6
P a tie n ts , n
3
20
21
6
E le v a te d , n
0
8
15
2
E le v a te d , n
1
4
5
2
E le v a te d , n
1
3
7
2
E le v a te d , %
0
40
71
33
E le v a te d . %
33
20
24
33
E le v a te d . %
33
15
33
33
Fig. 2. Frequency distribution data of SCCa, CEA and CA-125 in cervical carcinoma.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
•
5-
57
SCCa in Cervical Carcinoma
positivity rate was 40% in early invasive carcinoma and increased to 71 % in advanced disease. The statistical analysis of our results concerning stage and serum concentrations showed a significant differ ence between the stage groups for SCCa (Kruskal-Wallis test, p = 0.003) but not for CEA and CA-125.
Discussion Our results concerning sensitivity and specificity agree with data that have been published previously [3-6], Kato et al. [3] noted a sensitivity of 55% for SCC and Maruo et al. [4] found a sensitivity of 54% and 6% false positive cases. In our material and also in other studies, SCCa alone appeared to be a better discriminator for SCC than the combination assay with other tumor markers [7]. Contrary to other authors such as Crombach et al. [8], the difference we found between SCC and adenocarci noma for SCCa was rather small, 52 versus 33%, one reason being the small number of patients with adeno carcinoma. According to Wells and Brown [9], however, glandular and squamous lesions often coexist. A reliable tumor marker should have increasing inci dence of positivity (percentage above cut-off value) and increasing serum levels with advancing disease [10]. Our results showed that stage and serum SCCa levels/positivity were directly and significantly related. This finding is also in agreement with data from the literature [4, 1115], No significant difference could be detected for CEA and CA-125 concerning stage and serum antigen concen trations.
Fig. 4. Positivity of tumor markers versus stage of cervical SCC.
Conclusion SCCa is a tumor antigen with a high specificity for cervical SCC. It has a fairly low but anyway the best sensitivity in comparison with other tumor markers. A stage-related increase in SCCa concentrations and posi tivity was clearly demonstrated. The future potential of SCCa for cervical SCC appears promising, for serum SCCa determinations can provide noninvasive and reli able assessment of the extent of disease.
Acknowledgments The authors wish to thank Mrs. D. Schepers and Mrs. M.J. Vangoetsenhoven for the secretarial work.
References 1 Kato H, Torigoe T: Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 1977;41: 1621-1628. 2 Kato H, Nagaya T, Torigoe T: Heterogenity of a tumor antigen TA-4 of squamous cell carcinoma in relation to its appearance in the incubation. Gann 1984;75:433-435. 3 Kato H, Morioka H, Aramaki SH, Torigoe T: Radioimmunoas say for tumor-antigen of human cervical squamous cell carcino ma. Cell Mol Biol 1979;25:51-56. 4 Maruo T, Shibata K, Kimura A, Hoshina M, Mochizuki M: Tumor-associated antigen, TA-4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Cancer 1985;56:302-308. 5 Gosselin P, Cazin JL, Dehaut JP, Sulman Ch, Bazanzelli MC, Démaillé MC Intérêt du dosage de l’antigène «squamous cell
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
Fig. 3. Positivity of tumor markers versus histology in cervical carcinoma.
Verlooy/Devos/Jansscns/Mortelmans/Gerits/Bonte/De Roo
6
7
8
9
10
11
12
carcinoma» dans le cancer du col utérin. Presse Méd 1987; 16: 1677-1679. Molina R, Filella X, Torres MD, Ballesta AM, Mengual P, Casis A, Balaque A: SCC antigen measured in malignant and nonmalignant diseases. Clin Chem 1990;36:251-254. Komafel J, Wawrzkiewicz M: Evaluation of diagnostic useful ness of CEA, hCG and SCC antigen in cervical cancer patients. E urJ Gynaecol Oncol 1989;10:319-322. Crombach G, Würz H, Boite A: Determination of SCC antigen in the serum of patients with cervical cancer. Geburtshilfe Frauenheilkd 1987;47:439-445. Wells M, Brown U R : Glandular lesions of the uterine cervix: The present state of our knowledge. Histopathology 1986; 10: 777-792. Paulick R, Caffier H, Homer G, Lang K, Filbry E: Clinical sig nificance of different serum tumor markers in gynecological malignancies. Cancer Detect Prev 1985;8:115-120. Kato H, Morioka H, Torigoe T: A radioimmunoassay for a tumor-antigen (TA) of squamous cell carcinoma: Pretreatment serum TA-4 levels and the extent of cervical cancer. AACR abstracts 1980:237. Kato H, Morioka H, Aramaki S, Ouchi Y, Torigoe T: A radioim munoassay for a tumor antigen (TA-4) of squamous cell carcino ma: Pretreatment serum levels and the extent of disease. Proc of the 32nd Annu Sei Meet. Acta Obstet Gynaecol Jpn 1980;32: 2087-2088.
13 Schmidt-Rhodc P, Schulze KD, Sturm G, Hafner H, Prinz H, Kunzig HJ: Squamous cell carcinoma antigen for monitoring cervical cancer. Int J Biol Markers 1988;3(2):87—94. 14 Kato H, Morioka H, Tsutsui H, Aramaki Sh, Torigoe T: Value of tumor-antigen (TA-4) of squamous cell carcinoma in predicting the extent of cervical cancer. Cancer 1982:50:1294—1296. 15 Hsieh CY, Chang DY, Huang SC, Yen ML, Juang GT, Ouyang PC: Serum squamous cell carcinoma antigen in gynecologic ma lignancies with special reference to cervical cancer. Taiwan I Hsueh Hui Tsa Chih 1989;88:797-800.
Received: August 27, 1990 Accepted in revised form: February 14. 1991 H. Verlooy Department of Nuclear Medicine University Hospital Gasthuisberg B-3000 Leuven (Belgium)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/7/2018 8:12:01 AM
58
