© 1990 S. Kargcr AG, Basel 0042-1138/90/0452-007 5$2.75/0
Urol Int 1990;45:75-77
HLA Antigens and Transitional Cell Carcinoma of the Bladder Murat Eryigit, Ziya Kirkali Department of Urology, Giilhane Military Academy and Faculty of Medicine, Ankara, Turkey
Keywords. Bladder tumors • HLA antigens • Transitional cell carcinoma • Major histocompatibility complex Abstract. A possible association between HLA antigens and transitional cell carcinoma of the bladder was searched for in 56 patients and 200 healthy kidney donors. Statistical analysis showed that HLA antigens A23, A25, A 28, B w 4, B w 2i , B w 22 and Cw4 are more common in bladder tumor patients, whereas B27 and Bw6 were more common in the control group. The relative risk for HLA Cw4 was 2.07 (95% confidence interval 1.51-2.48). Except for Cw4, these findings are inconsistent with previous reports. We believe this to be due to various misleading factors, and thus not conclusive. Even if such a statistical association exists, this appears to be clinically not relevant and, therefore, should not alter standard practice.
In the last two decades there has been a considerable search for an association between the human major his tocompatibility system and disease states. Diseases of unknown etiology, generally referred to as autoimmune diseases, and malignancies have been the major points of interest because of the many immunological aspects involved in the etiology, diagnosis and treatment of these disorders [1, 2], Although there have been several studies on HLA and bladder cancer, the results are inconsistent and practi cally not informative [2-8]. The latest study by Akda§ et al. [8] prompted us to look at this association in the same town, to see whether we could produce similar results. Materials and Methods Fifty-six consecutive patients (48 males, 8 females) with histo logically proven transitional cell carcinoma of the bladder, seen at our institution, were included in this study. Thirty-nine patients had superficial tumors (Ta-T 1), whereas 17 patients had invasive tumors (T i-T d. Patients were followed up with routine cystoscopies, but after 2 years 20 patients were lost to follow-up. Two hundred healthy kidney donors with no systemic disease or malignancy, who came for tissue typing during the study period,
constituted the control group. Blood was drawn from the patients and controls, and HLA typing was performed by the standard microlymphocytotoxicity technique using antisera for HLA A. B. C and DR antigens [9], The antigen frequency for both the patients and controls was recorded and compared by x2 test. The relative risk (RR), estimated as the odds ratio, and the etiological fraction (EF) values were also calculated for each antigen tested [10].
Results The results are summarized in table 1. When the anti gen frequency was tested statistically between patients with bladder tumors and controls, HLA antigens A23, A.25, A 28, B w 4, B w 2 i , BW22 and Cw4 were more common in bladder tumor patients, whereas B27 and Bw6 were more common in the control group. On the other hand, there were some antigens that appeared in one group but were absent in the other. No statistical conclusions were drawn for these antigens. The highest RR was for HLA A23 and A25, but this may be an incidental finding because the frequency of these two antigens in the con trol group is very low (0.5%). Statistically the most sen sitive RR was for HLA Cw4 (RR: 2.07, 95% confidence intervals 1.51-2.48).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 4:05:51 AM
Introduction
Eryigit/Kirkali
76
HLA
A! Aj Aj As A9 A 10 A| 1 a 23 a 25 A26 A28 A30 Asl A32 b5 b
7
b8
B12 B13 B|4 B| s B|7 B|8 Hi? B40 Bjj BW2 Bw4 Bw6 B w 21
BW22 Bw ,5 B w ,8 B w 44 B w 45 B w 4, B w 50
BwS| B w 56 B w 60 B w (,3 B w 73
Cw2 Cwj Cw4 DR, dr2 DR 3 dr4 dr5 dr6 dr7
Bladder tumors
Controls
n
%
n
%
8 39 2 0 12 0 6 3 10 11 37 0 0 5 27 7 7 8 9 7 1 4 4 5 6 0 0 24 8 7 5 13 2 1 2 7 1 0 2 0 0 0 4 2 18 0 3 0 0 1 2 0
14.3 69.6 3.6 0 21.4 0 10.7 5.4 17.9 19.6 66.1 0 0 8.9 48.2 12.5 12.5 14.3 16.1 12.5 1.8 7.1 7.1 8.9 10.7 0 0 42.9 14.3 12.5 8.9 23.2 3.6 1.8 3.6 12.5 1.8 0 3.6 0 0 0 7.1 3.6 32.1 0 5.4 0 0 1.8 3.6 0
47
23.5 75.0 3.0 0.5 21.5 14.5 4.0 0.5 0.5 23.5 48.5 6.0 6.0 0 52.5 20.0 5.0 6.5 11.0 4.5 0 6.5 11.0 54.5 9.5 3.0 0.5 24.5 47.0 1.5 1.0 35.0 0 0 0 0 0 3.0 0 1.0 5.0 3.0 3.0 4.0 15.5 1.0 1.0 1.0 0.5 1.0 0 2.0
150 6 1 43 29 8 1 1 47 97 12 12 0 105 40 10 13 22 9 0 13 22 109 19 6 1 49 94 3 2 70 0 0 0 0 0 6 0 2 10 6 6 8 31 2 2 2 1 2 0 4
P
RR
EF
> 0.05 > 0.05 > 0.05
0.61 0.93 1.20
0.091 0.052 0.006 0.002 0.067 0.049 0.174 0.040 0.175
-
> 0.05 -
-
0.99 -
2.67 > 0.05 0.05 > 0.05 > 0.05 > 0.05 > 0.05 -
> 0.05 > 0.05 0.05 0.05 0.05 > 0.05 -
-
0.180 0.333 0.110 0.079 0.119 -
Discussion Bladder tumors are common and, while some superfi cial tumors do not recur after treatment, 30-90% do, and 5-30% progress to higher stages [11], Studies have shown that host immune response plays a role in pro gression [12], Whether the major histocompatibility sys tem has any impact on these immune mechanisms re mains a point of interest. Studies by some authors disclosed no association be tween bladder cancer and HLA antigens [2, 4, 7], Arce et al. [3] found that HLA A9 was more frequent in patients with bladder cancer than controls. Terasaki et al. [5] reported a weak association between Bw35 and bladder tumors. Later a study from Britain showed that there was a twofold increase in the frequency of HLA B5 and Cw4 antigens in patients with transitional cell carcinoma [6]. Recently Akda§ et al. [8] reported a high frequency of HLA B5 antigen in 55 patients with transitional cell car cinoma of the bladder and a lower frequency of Bw35 compared to controls. This association, according to their findings, was more pronounced in patients with recurrent tumors. They therefore suggested more radical therapy and closer follow-up of patients with HLA B5 antigen [8]. Our findings are inconsistent with previous studies, except Cw4 antigen which was also found to be signifi cant by Herring et al. [6]. It was interesting to note that statistically this was the only antigen with a two-fold fre quency in bladder tumor patients. There was no similar ity between the results of the present study and another study from the same town [8], Although we have found a statistical significance for the frequency of some anti gens, we believe this to be by chance or due to other factors. Control group selection is always a problem in such studies, and we used 200 ‘healthy’ kidney donors as the control group who were typed for HLA antigens during the study period. Akda§ et al. [8] used 200 blood donors as the control group. Braf et al. [4] and Lytton et al. [7] used patients from another study as the control group. This obviously brings in some bias as many other fac tors, such as the number of antigens tested, use of differ ent techniques, equipment and examiners, are some of the problems in studies using historical controls [13]. Our institution is a general referal hospital, therefore it reflects a wide range of people from different parts of the country. This geographical non-representation may also be a cause for the uneven distribution of antigen frequencies. Another factor which may affect HLA de
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 4:05:51 AM
Table 1. HLA antigen frequencies in both groups, and RR and EF values for patients with bladder tumors
77
HLA and Bladder Tumors
termination is the fact that some drugs may lead to loss of some antigens [14], As none of the previous studies had mentioned this in their papers, we also did not assess this aspect in our patients and controls. We did not evaluate antigen frequencies in sub groups, such as the association of stage and grade of the tumors, because the figures would be less sensitive. We, however, would like to evaluate the HLA status accord ing to primary and recurrent tumors, but since we had a high rate of patients who were lost to follow-up, the data would cause statistically misleading results. Although our study showed some association between HLA antigens and transitional cell carcinoma of the bladder, we believe this to be dependent on many fac tors, and thus being nonconclusive. Even if such a statis tical association exists, this appears to be clinically nonrelevant and therefore should not alter standard prac tice.
6 Herring DW, Cartwright RA, Williams DDR: Genetic associa tion of transitional cell carcinoma. Br J Urol 1979;51:73-77. 7 Lytton B, O’Toole C, Tiptaft R, et al: Histocompatibility testing in patients with carcinoma of the bladder. Cancer 1983;52:645647. 8 Akda$ A, Tokuç R, Ôzerkan K, et al: Association between HLA antigens and bladder tumours. Eur Urol 1987;13:207-209. 9 Terasaki PI, Bernoco D, Parks MS, et al: Microdroplet testing for HLA- A, B, C and D. Am J Clin Pathol 1978;69:103-106. 10 Green A: The epidemiological approach to studies of association between HLA and disease. II. Estimation of absolute risk, étio logie and preventive fraction. Tissue Antigens 1982; 19:245258. 11 Herr HW, Laudrone VP, Whitmore WF Jr: An overview of intravesical therapy for superficial bladder tumours. J Urol 1987;138:1363-1368. 12 Droller MJ: Transitional cell cancer. Upper tracts and bladder; in Walsh PC, Gittes RF, Perlmutter AD, et a) (eds): Campbell’s Urology. Philadelphia, Saunders, 1986, pp 1343-1440. 13 Doll R, Peto R: Randomised controlled trials and retrospective controls. Br Med J 1980;280:44-47. 14 Svejgaard A, Platz P, Ryder LP, et al: HLA and disease associa tion. A survey. Transplant Rev 1975;22:3-9.
References
Received: March 22, 1989 Accepted: May 16, 1989 Murat Eryigit Department of Urology Giilhane Military Academy and Faculty of Medicine Ankara (Turkey)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 4:05:51 AM
1 Svejgaard A, Platz P, Ryder LP: HLA and disease 1982. A sur vey. Immunol Rev 1983;70:193-218. 2 Takasugi M, Terasaki PI, Hedersson B, et al: HLA antigens in solid tumours. Cancer Res 1973;33:648-650. 3 Arce S, Lopez R, Almaguer M, et al: HLA antigens and transi tional cell carcinoma of the bladder. Mater Med Pol 1978;35: 98-100. 4 Braf ZF, Gazit E, Many M: HLA-A and HLA-B antigens in tran sitional cell carcinoma of the bladder. J Urol 1979; 122:465466. 5 Terasaki PI, Perdue ST, Mickey MD: HLA frequencies in can cer. A second study; in Mulvihill JT, Miller RW, Franmeni JP (eds): Genetics of Human Cancer. New York, Raven Press, 1977, pp 321-328.
Urol Int 1990;45:75-77
HLA Antigens and Transitional Cell Carcinoma of the Bladder Murat Eryigit, Ziya Kirkali Department of Urology, Giilhane Military Academy and Faculty of Medicine, Ankara, Turkey
Keywords. Bladder tumors • HLA antigens • Transitional cell carcinoma • Major histocompatibility complex Abstract. A possible association between HLA antigens and transitional cell carcinoma of the bladder was searched for in 56 patients and 200 healthy kidney donors. Statistical analysis showed that HLA antigens A23, A25, A 28, B w 4, B w 2i , B w 22 and Cw4 are more common in bladder tumor patients, whereas B27 and Bw6 were more common in the control group. The relative risk for HLA Cw4 was 2.07 (95% confidence interval 1.51-2.48). Except for Cw4, these findings are inconsistent with previous reports. We believe this to be due to various misleading factors, and thus not conclusive. Even if such a statistical association exists, this appears to be clinically not relevant and, therefore, should not alter standard practice.
In the last two decades there has been a considerable search for an association between the human major his tocompatibility system and disease states. Diseases of unknown etiology, generally referred to as autoimmune diseases, and malignancies have been the major points of interest because of the many immunological aspects involved in the etiology, diagnosis and treatment of these disorders [1, 2], Although there have been several studies on HLA and bladder cancer, the results are inconsistent and practi cally not informative [2-8]. The latest study by Akda§ et al. [8] prompted us to look at this association in the same town, to see whether we could produce similar results. Materials and Methods Fifty-six consecutive patients (48 males, 8 females) with histo logically proven transitional cell carcinoma of the bladder, seen at our institution, were included in this study. Thirty-nine patients had superficial tumors (Ta-T 1), whereas 17 patients had invasive tumors (T i-T d. Patients were followed up with routine cystoscopies, but after 2 years 20 patients were lost to follow-up. Two hundred healthy kidney donors with no systemic disease or malignancy, who came for tissue typing during the study period,
constituted the control group. Blood was drawn from the patients and controls, and HLA typing was performed by the standard microlymphocytotoxicity technique using antisera for HLA A. B. C and DR antigens [9], The antigen frequency for both the patients and controls was recorded and compared by x2 test. The relative risk (RR), estimated as the odds ratio, and the etiological fraction (EF) values were also calculated for each antigen tested [10].
Results The results are summarized in table 1. When the anti gen frequency was tested statistically between patients with bladder tumors and controls, HLA antigens A23, A.25, A 28, B w 4, B w 2 i , BW22 and Cw4 were more common in bladder tumor patients, whereas B27 and Bw6 were more common in the control group. On the other hand, there were some antigens that appeared in one group but were absent in the other. No statistical conclusions were drawn for these antigens. The highest RR was for HLA A23 and A25, but this may be an incidental finding because the frequency of these two antigens in the con trol group is very low (0.5%). Statistically the most sen sitive RR was for HLA Cw4 (RR: 2.07, 95% confidence intervals 1.51-2.48).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 4:05:51 AM
Introduction
Eryigit/Kirkali
76
HLA
A! Aj Aj As A9 A 10 A| 1 a 23 a 25 A26 A28 A30 Asl A32 b5 b
7
b8
B12 B13 B|4 B| s B|7 B|8 Hi? B40 Bjj BW2 Bw4 Bw6 B w 21
BW22 Bw ,5 B w ,8 B w 44 B w 45 B w 4, B w 50
BwS| B w 56 B w 60 B w (,3 B w 73
Cw2 Cwj Cw4 DR, dr2 DR 3 dr4 dr5 dr6 dr7
Bladder tumors
Controls
n
%
n
%
8 39 2 0 12 0 6 3 10 11 37 0 0 5 27 7 7 8 9 7 1 4 4 5 6 0 0 24 8 7 5 13 2 1 2 7 1 0 2 0 0 0 4 2 18 0 3 0 0 1 2 0
14.3 69.6 3.6 0 21.4 0 10.7 5.4 17.9 19.6 66.1 0 0 8.9 48.2 12.5 12.5 14.3 16.1 12.5 1.8 7.1 7.1 8.9 10.7 0 0 42.9 14.3 12.5 8.9 23.2 3.6 1.8 3.6 12.5 1.8 0 3.6 0 0 0 7.1 3.6 32.1 0 5.4 0 0 1.8 3.6 0
47
23.5 75.0 3.0 0.5 21.5 14.5 4.0 0.5 0.5 23.5 48.5 6.0 6.0 0 52.5 20.0 5.0 6.5 11.0 4.5 0 6.5 11.0 54.5 9.5 3.0 0.5 24.5 47.0 1.5 1.0 35.0 0 0 0 0 0 3.0 0 1.0 5.0 3.0 3.0 4.0 15.5 1.0 1.0 1.0 0.5 1.0 0 2.0
150 6 1 43 29 8 1 1 47 97 12 12 0 105 40 10 13 22 9 0 13 22 109 19 6 1 49 94 3 2 70 0 0 0 0 0 6 0 2 10 6 6 8 31 2 2 2 1 2 0 4
P
RR
EF
> 0.05 > 0.05 > 0.05
0.61 0.93 1.20
0.091 0.052 0.006 0.002 0.067 0.049 0.174 0.040 0.175
-
> 0.05 -
-
0.99 -
2.67 > 0.05 0.05 > 0.05 > 0.05 > 0.05 > 0.05 -
> 0.05 > 0.05 0.05 0.05 0.05 > 0.05 -
-
0.180 0.333 0.110 0.079 0.119 -
Discussion Bladder tumors are common and, while some superfi cial tumors do not recur after treatment, 30-90% do, and 5-30% progress to higher stages [11], Studies have shown that host immune response plays a role in pro gression [12], Whether the major histocompatibility sys tem has any impact on these immune mechanisms re mains a point of interest. Studies by some authors disclosed no association be tween bladder cancer and HLA antigens [2, 4, 7], Arce et al. [3] found that HLA A9 was more frequent in patients with bladder cancer than controls. Terasaki et al. [5] reported a weak association between Bw35 and bladder tumors. Later a study from Britain showed that there was a twofold increase in the frequency of HLA B5 and Cw4 antigens in patients with transitional cell carcinoma [6]. Recently Akda§ et al. [8] reported a high frequency of HLA B5 antigen in 55 patients with transitional cell car cinoma of the bladder and a lower frequency of Bw35 compared to controls. This association, according to their findings, was more pronounced in patients with recurrent tumors. They therefore suggested more radical therapy and closer follow-up of patients with HLA B5 antigen [8]. Our findings are inconsistent with previous studies, except Cw4 antigen which was also found to be signifi cant by Herring et al. [6]. It was interesting to note that statistically this was the only antigen with a two-fold fre quency in bladder tumor patients. There was no similar ity between the results of the present study and another study from the same town [8], Although we have found a statistical significance for the frequency of some anti gens, we believe this to be by chance or due to other factors. Control group selection is always a problem in such studies, and we used 200 ‘healthy’ kidney donors as the control group who were typed for HLA antigens during the study period. Akda§ et al. [8] used 200 blood donors as the control group. Braf et al. [4] and Lytton et al. [7] used patients from another study as the control group. This obviously brings in some bias as many other fac tors, such as the number of antigens tested, use of differ ent techniques, equipment and examiners, are some of the problems in studies using historical controls [13]. Our institution is a general referal hospital, therefore it reflects a wide range of people from different parts of the country. This geographical non-representation may also be a cause for the uneven distribution of antigen frequencies. Another factor which may affect HLA de
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 4:05:51 AM
Table 1. HLA antigen frequencies in both groups, and RR and EF values for patients with bladder tumors
77
HLA and Bladder Tumors
termination is the fact that some drugs may lead to loss of some antigens [14], As none of the previous studies had mentioned this in their papers, we also did not assess this aspect in our patients and controls. We did not evaluate antigen frequencies in sub groups, such as the association of stage and grade of the tumors, because the figures would be less sensitive. We, however, would like to evaluate the HLA status accord ing to primary and recurrent tumors, but since we had a high rate of patients who were lost to follow-up, the data would cause statistically misleading results. Although our study showed some association between HLA antigens and transitional cell carcinoma of the bladder, we believe this to be dependent on many fac tors, and thus being nonconclusive. Even if such a statis tical association exists, this appears to be clinically nonrelevant and therefore should not alter standard prac tice.
6 Herring DW, Cartwright RA, Williams DDR: Genetic associa tion of transitional cell carcinoma. Br J Urol 1979;51:73-77. 7 Lytton B, O’Toole C, Tiptaft R, et al: Histocompatibility testing in patients with carcinoma of the bladder. Cancer 1983;52:645647. 8 Akda$ A, Tokuç R, Ôzerkan K, et al: Association between HLA antigens and bladder tumours. Eur Urol 1987;13:207-209. 9 Terasaki PI, Bernoco D, Parks MS, et al: Microdroplet testing for HLA- A, B, C and D. Am J Clin Pathol 1978;69:103-106. 10 Green A: The epidemiological approach to studies of association between HLA and disease. II. Estimation of absolute risk, étio logie and preventive fraction. Tissue Antigens 1982; 19:245258. 11 Herr HW, Laudrone VP, Whitmore WF Jr: An overview of intravesical therapy for superficial bladder tumours. J Urol 1987;138:1363-1368. 12 Droller MJ: Transitional cell cancer. Upper tracts and bladder; in Walsh PC, Gittes RF, Perlmutter AD, et a) (eds): Campbell’s Urology. Philadelphia, Saunders, 1986, pp 1343-1440. 13 Doll R, Peto R: Randomised controlled trials and retrospective controls. Br Med J 1980;280:44-47. 14 Svejgaard A, Platz P, Ryder LP, et al: HLA and disease associa tion. A survey. Transplant Rev 1975;22:3-9.
References
Received: March 22, 1989 Accepted: May 16, 1989 Murat Eryigit Department of Urology Giilhane Military Academy and Faculty of Medicine Ankara (Turkey)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 4:05:51 AM
1 Svejgaard A, Platz P, Ryder LP: HLA and disease 1982. A sur vey. Immunol Rev 1983;70:193-218. 2 Takasugi M, Terasaki PI, Hedersson B, et al: HLA antigens in solid tumours. Cancer Res 1973;33:648-650. 3 Arce S, Lopez R, Almaguer M, et al: HLA antigens and transi tional cell carcinoma of the bladder. Mater Med Pol 1978;35: 98-100. 4 Braf ZF, Gazit E, Many M: HLA-A and HLA-B antigens in tran sitional cell carcinoma of the bladder. J Urol 1979; 122:465466. 5 Terasaki PI, Perdue ST, Mickey MD: HLA frequencies in can cer. A second study; in Mulvihill JT, Miller RW, Franmeni JP (eds): Genetics of Human Cancer. New York, Raven Press, 1977, pp 321-328.
