- Email: [email protected]
Delayed Cutaneous Hypersensitivity in Patients with Prostatic Adenocarcinoma
Vol. 114, July Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
DELAYED CUTANEOUS HYPERSENSITIVITY IN PATIENTS WITH PROSTATIC ADENOCARCINOMA JOHN C. HUUS, ELROY D. KURSH, PETER POOR
AND
LESTER PERSKY
From the Department of Urology, University Hospitals, Case Western Reserve University, Cleveland, Ohio
ABSTRACT
Cell-mediated immunocompetence of patients seen for followup of adenocarcinoma of the prostate is evaluated using dinitrochlorobenzene as a contact sensitizing agent. The immune status is correlated with the presence or absence of metastatic disease. A highly significant correlation is found between the lack of immune response and the presence of metastatic carcinoma, suggesting that immunotherapy will be useful in the treatment of carcinoma of the prostate. Tumor immunology has attracted much attention recently and has been stimulated by an interest in eventually achieving immunologic treatment of malignant disease. Tumor-specific antigens are known to exist 1 and development of tumors is enhanced in patients with immunodeficient states. 2 For example renal transplant recipients taking immunosuppressive drugs have been found to have an increased incidence of malignancy. 3 • • The prognosis in certain malignancies has been correlated with the degree of immunologic competence present. 5 In fact, prevention of bladder carcinoma recurrence by immunologic stimulation has been reported. 6 Investigation of prostatic carcinoma has been restricted to evaluation of the patient's immune status at the time of initial diagnosis. 1 • 8 Catalona and associates used dinitrochlorobenzene (DNCB) to evaluate cell-mediated immunocompetence and found that 52 per cent of prostatic carcinoma patients had depressed reactivity. 7 McLaughlin and associates evaluated lymphocyte activity in relation to the stage of prostatic adenocarcinoma and found decreased lymphocyte activity in stages B, C and D. 8 Our study was undertaken to determine if patients with metastases from prostatic carcinoma at a remote time after the initial diagnosis and treatment were immunologically different from those who did not have metastases.
flare, scaling or itching. This method has been found to be effective in judging immunologic competence. 9 • 10 Patients selected for the study consisted of a control group with a pathologic diagnosis of benign prostatic hyperplasia and an experimental group comprised of patients seen for followup care of prostatic adenocarcinoma. Patients in the experimental group were evaluated 4 months to 23 years after the initial diagnosis and treatment. Excluded from the study were patients with other malignan cies, patients taking steroids and patients with immunologic disease . The decrease in immunologic activity with increasing age was compensat ed for by having an age-matched control group. The experimental group of patients was objectively evaluated for metastatic activity by means of serum acid phosphatase, metastatic bone survey, radioisotope bone scan and/or tissue biopsy. T his group was then divided into 2 sub-groups: those with metastatic carcinoma and t hose without. RESULTS
The results are summarized in the table. A delayed cutaneous hypersensitivity to DNCB was noted in 92 per cent of the control group. Of the 15 patients with metastatic carcinoma 14 were unable to develop an immune response to DNCB. Conversely, 14 of the 15 patients free of metastatic disease developed an immune response or exhibited cutaneous hypersensit ivity. Chi-square analysis showed that p was less than 0.001. The mean age for the 3 groups was similar.
METHOD
DNCB was used as a contact sensitizing antigen to evaluate cell-mediated immunocompetence. A test dose of 2 mg. DNCB in an acetone vehicle was placed on the patient's forearm . Two weeks later the test site was inspected for delayed cutaneous hypersensitivity manifested by an erythematous
DISCUSSION
Catalona and McLaughlin and their associates demonstrated impaired immunocompetence in patients with adenocarcinoma of the prostate. 7 • 8 T heir studies indicated that a correlation existed at the t ime of diagnosis between the presence of carcinoma of the prostate and depressed immuno-
Accepted for publication November 22, 1974. Read at annual meeting of North Central Section, American Urological Association, Columbus, Ohio, September 18- 21, 1974. 86
HYPERSENSITIVITY IN PATIENTS WITH PROSTATIC ADENOCARCINOMA
Results Control Group
J
l I! \
i
I f j
l
.....--r •II
I
:
1
I
No. pts. DNCB reactive DNCB non-reactive Mean age
25 23 2
66 ± 12 yrs.
Metastatic Ca Prostate 15 l* 14
71 ± 10 yrs.
Remote (inactive) Ca Prostate 15 14 1
73 ± 9yrs .
* Chi-square shows p less than 0.001 comparing the metastatic group to the control and remote groups.
logic reactivity but there was no correlation to the extent or stage of disease. In the study by Catalona and associates the incidence of impaired immunocompetence was similar in patients with localized tumor (60 per cent with subnormal reactivity) and patients with metastatic disease (47 per cent with subnormal reactivity). McLaughlin and associates also failed to show a significant difference in immunocompetence in patients with stages B, C or D adenocarcinoma of the prostate. The results of our study agree with their findings regarding the relationship of impaired immunocompetence in patients with adenocarcinoma of the prostate but differ in that we found a significant correlation in the demonstration of immunocompetence compared to the extent of disease. Fourteen of 15 patients with metastatic carcinoma of the prostate (93 per cent) were unable to develop an immune response to DNCB. In contrast, 14 of 15 patients with documented adenocarcinoma of the prostate but free .of metastatic disease (93 per cent) demonstrated immunocompetence. The differences in our results as compared to their findings might be explained by the fact that all patients were evaluated for immunocompetence after the diagnosis of carcinoma of the prostate had been established (varying from 4 months to 23 years). This possibly allowed for better and more accurate staging and better separation of the study groups. Some of the patients initially thought to have stage A, B or C disease were later found to have extensive metastasis. The percentage of skin reactivity in our control group is in agreement with the previous control populations tested. 10 Our study suggests that if a patient's immune mechanism can be stimulated to achieve normal competency, the development of metastatic disease may be prevented. Much research in immunotherapy has been done with a variety of other malignancies. 11 Since carcinomas of the bladder and prostate have now been shown to be associated with immunologic deficiency, it is possible that we may be able to use immunotherapeutic techniques that have been useful in other types of malignancy.
87
Hopefully, this will lead to improved survival rates for both diseases . REFERENCES
l. Hellstrom, I., Hellstrom, K. E. , Sjogren, H. 0. and Warner, G. A.: Demonstration of cell-mediated immunity to human neoplasms of various histological types. Int. J. Cancer, 7: 1, 1971. 2. Alexander, J. W. and Good, R. A.: Immunobiology for Surgeons. Philadelphia: W. B. Saunders Co., 1970. 3. Starzl, T. E., Porter, K. A., Andres, G., Halgrimson, C. G., Hurwitz, R., Giles, G., Terasaki, P. I., Penn, I., Schroter, G. T., Lilly, J., Starkie, S. J. and Putnam, C. W.: Long-term survival after renal transplantation in humans: (with special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy). Ann. Surg. , 172: 437, 1970. 4. Kay, S., Frable, W. J. and Hume, D. M.: Cervical dysplasia and cancer developing in women on immunosuppression therapy for renal homotransplantation. Cancer, 26: 1048, 1970. 5. Eilber, F. R. and Morton, D. L.: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer, 25: 362, 1970. 6. Olsson, C. A., Chute, R. and Rao, C. N .: Immunologic reduction of bladder cancer recurrence rate. J. Urol. , Ill: 173, 1974. 7. Catalona. W. J., Chretien, P . B. and Trahan, E. E.: Abnormalities of cell-mediated immunocompetence in genitourinary cancer. J. Urol., Ill: 229, 1974. 8. McLaughlin, A. P., III, Kessler, W. 0. , Triman, K. and Gittes, R. F .: Immunologic competence in patients with urologic cancer. J. Urol., I 11: 233, 1974. 9. Catalona, W. J. and Chretien, P. B.: Correlation among host immunocompetence and tumor stage, tumor grade and vascular permeation in transitional carcinoma. J. Urol., 110: 526, 1973. 10. Catalona, W. J., Taylor, P . T. and Chretien, P. B. : Quantitative dinitrochlorobenzene contact sensitization in a normal population. Clin. Exp. Immunol., 12: 325, 1972. 11. Morton, D. L.: Immunotherapy of cancer: present status and future potential. Cancer, 30: 1647, 1972.
COMMENT This study provides further documentation of the defect in immunologic reactivity demonstrable in patients with prostatic cancer. However, in the study by Catalana and associates t here was no correlation between the lack of immunologic reactivity and the presence of metastases, 53 per cent of patients with metastases having normal reactivity compared to 40 per cent reactivity among patients with localized tumors. W.W.S.
THE JOURNAL OF UROLOGY
Copyright© 1975 by The Williams & Wilkins Co.
DELAYED CUTANEOUS HYPERSENSITIVITY IN PATIENTS WITH PROSTATIC ADENOCARCINOMA JOHN C. HUUS, ELROY D. KURSH, PETER POOR
AND
LESTER PERSKY
From the Department of Urology, University Hospitals, Case Western Reserve University, Cleveland, Ohio
ABSTRACT
Cell-mediated immunocompetence of patients seen for followup of adenocarcinoma of the prostate is evaluated using dinitrochlorobenzene as a contact sensitizing agent. The immune status is correlated with the presence or absence of metastatic disease. A highly significant correlation is found between the lack of immune response and the presence of metastatic carcinoma, suggesting that immunotherapy will be useful in the treatment of carcinoma of the prostate. Tumor immunology has attracted much attention recently and has been stimulated by an interest in eventually achieving immunologic treatment of malignant disease. Tumor-specific antigens are known to exist 1 and development of tumors is enhanced in patients with immunodeficient states. 2 For example renal transplant recipients taking immunosuppressive drugs have been found to have an increased incidence of malignancy. 3 • • The prognosis in certain malignancies has been correlated with the degree of immunologic competence present. 5 In fact, prevention of bladder carcinoma recurrence by immunologic stimulation has been reported. 6 Investigation of prostatic carcinoma has been restricted to evaluation of the patient's immune status at the time of initial diagnosis. 1 • 8 Catalona and associates used dinitrochlorobenzene (DNCB) to evaluate cell-mediated immunocompetence and found that 52 per cent of prostatic carcinoma patients had depressed reactivity. 7 McLaughlin and associates evaluated lymphocyte activity in relation to the stage of prostatic adenocarcinoma and found decreased lymphocyte activity in stages B, C and D. 8 Our study was undertaken to determine if patients with metastases from prostatic carcinoma at a remote time after the initial diagnosis and treatment were immunologically different from those who did not have metastases.
flare, scaling or itching. This method has been found to be effective in judging immunologic competence. 9 • 10 Patients selected for the study consisted of a control group with a pathologic diagnosis of benign prostatic hyperplasia and an experimental group comprised of patients seen for followup care of prostatic adenocarcinoma. Patients in the experimental group were evaluated 4 months to 23 years after the initial diagnosis and treatment. Excluded from the study were patients with other malignan cies, patients taking steroids and patients with immunologic disease . The decrease in immunologic activity with increasing age was compensat ed for by having an age-matched control group. The experimental group of patients was objectively evaluated for metastatic activity by means of serum acid phosphatase, metastatic bone survey, radioisotope bone scan and/or tissue biopsy. T his group was then divided into 2 sub-groups: those with metastatic carcinoma and t hose without. RESULTS
The results are summarized in the table. A delayed cutaneous hypersensitivity to DNCB was noted in 92 per cent of the control group. Of the 15 patients with metastatic carcinoma 14 were unable to develop an immune response to DNCB. Conversely, 14 of the 15 patients free of metastatic disease developed an immune response or exhibited cutaneous hypersensit ivity. Chi-square analysis showed that p was less than 0.001. The mean age for the 3 groups was similar.
METHOD
DNCB was used as a contact sensitizing antigen to evaluate cell-mediated immunocompetence. A test dose of 2 mg. DNCB in an acetone vehicle was placed on the patient's forearm . Two weeks later the test site was inspected for delayed cutaneous hypersensitivity manifested by an erythematous
DISCUSSION
Catalona and McLaughlin and their associates demonstrated impaired immunocompetence in patients with adenocarcinoma of the prostate. 7 • 8 T heir studies indicated that a correlation existed at the t ime of diagnosis between the presence of carcinoma of the prostate and depressed immuno-
Accepted for publication November 22, 1974. Read at annual meeting of North Central Section, American Urological Association, Columbus, Ohio, September 18- 21, 1974. 86
HYPERSENSITIVITY IN PATIENTS WITH PROSTATIC ADENOCARCINOMA
Results Control Group
J
l I! \
i
I f j
l
.....--r •II
I
:
1
I
No. pts. DNCB reactive DNCB non-reactive Mean age
25 23 2
66 ± 12 yrs.
Metastatic Ca Prostate 15 l* 14
71 ± 10 yrs.
Remote (inactive) Ca Prostate 15 14 1
73 ± 9yrs .
* Chi-square shows p less than 0.001 comparing the metastatic group to the control and remote groups.
logic reactivity but there was no correlation to the extent or stage of disease. In the study by Catalona and associates the incidence of impaired immunocompetence was similar in patients with localized tumor (60 per cent with subnormal reactivity) and patients with metastatic disease (47 per cent with subnormal reactivity). McLaughlin and associates also failed to show a significant difference in immunocompetence in patients with stages B, C or D adenocarcinoma of the prostate. The results of our study agree with their findings regarding the relationship of impaired immunocompetence in patients with adenocarcinoma of the prostate but differ in that we found a significant correlation in the demonstration of immunocompetence compared to the extent of disease. Fourteen of 15 patients with metastatic carcinoma of the prostate (93 per cent) were unable to develop an immune response to DNCB. In contrast, 14 of 15 patients with documented adenocarcinoma of the prostate but free .of metastatic disease (93 per cent) demonstrated immunocompetence. The differences in our results as compared to their findings might be explained by the fact that all patients were evaluated for immunocompetence after the diagnosis of carcinoma of the prostate had been established (varying from 4 months to 23 years). This possibly allowed for better and more accurate staging and better separation of the study groups. Some of the patients initially thought to have stage A, B or C disease were later found to have extensive metastasis. The percentage of skin reactivity in our control group is in agreement with the previous control populations tested. 10 Our study suggests that if a patient's immune mechanism can be stimulated to achieve normal competency, the development of metastatic disease may be prevented. Much research in immunotherapy has been done with a variety of other malignancies. 11 Since carcinomas of the bladder and prostate have now been shown to be associated with immunologic deficiency, it is possible that we may be able to use immunotherapeutic techniques that have been useful in other types of malignancy.
87
Hopefully, this will lead to improved survival rates for both diseases . REFERENCES
l. Hellstrom, I., Hellstrom, K. E. , Sjogren, H. 0. and Warner, G. A.: Demonstration of cell-mediated immunity to human neoplasms of various histological types. Int. J. Cancer, 7: 1, 1971. 2. Alexander, J. W. and Good, R. A.: Immunobiology for Surgeons. Philadelphia: W. B. Saunders Co., 1970. 3. Starzl, T. E., Porter, K. A., Andres, G., Halgrimson, C. G., Hurwitz, R., Giles, G., Terasaki, P. I., Penn, I., Schroter, G. T., Lilly, J., Starkie, S. J. and Putnam, C. W.: Long-term survival after renal transplantation in humans: (with special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy). Ann. Surg. , 172: 437, 1970. 4. Kay, S., Frable, W. J. and Hume, D. M.: Cervical dysplasia and cancer developing in women on immunosuppression therapy for renal homotransplantation. Cancer, 26: 1048, 1970. 5. Eilber, F. R. and Morton, D. L.: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer, 25: 362, 1970. 6. Olsson, C. A., Chute, R. and Rao, C. N .: Immunologic reduction of bladder cancer recurrence rate. J. Urol. , Ill: 173, 1974. 7. Catalona. W. J., Chretien, P . B. and Trahan, E. E.: Abnormalities of cell-mediated immunocompetence in genitourinary cancer. J. Urol., Ill: 229, 1974. 8. McLaughlin, A. P., III, Kessler, W. 0. , Triman, K. and Gittes, R. F .: Immunologic competence in patients with urologic cancer. J. Urol., I 11: 233, 1974. 9. Catalona, W. J. and Chretien, P. B.: Correlation among host immunocompetence and tumor stage, tumor grade and vascular permeation in transitional carcinoma. J. Urol., 110: 526, 1973. 10. Catalona, W. J., Taylor, P . T. and Chretien, P. B. : Quantitative dinitrochlorobenzene contact sensitization in a normal population. Clin. Exp. Immunol., 12: 325, 1972. 11. Morton, D. L.: Immunotherapy of cancer: present status and future potential. Cancer, 30: 1647, 1972.
COMMENT This study provides further documentation of the defect in immunologic reactivity demonstrable in patients with prostatic cancer. However, in the study by Catalana and associates t here was no correlation between the lack of immunologic reactivity and the presence of metastases, 53 per cent of patients with metastases having normal reactivity compared to 40 per cent reactivity among patients with localized tumors. W.W.S.