Vol. 114, August

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright © 1975 by The Williams & Wilkins Co.

SKIN TESTING IN GENITOURINARY CARCINOMA: 2-YEAR FOLLOWUP J. MICHAEL DECENZO, RONALD ALLISON AND GUY W. LEADBETTER, JR.

From the University of Vermont College of Medicine, Burlington, Vermont

ABSTRACT

dinitrofluorobenzene was used with genitourinary cancer to test their to be immunized with a encountered antigen. In general, in whom a cutaneous response did not develop were more to have advanced tumors than patients whose immunocompetence was intact. A 2 to 3-year showed that patients with impaired cell-mediated immunity were more likely to undergo disease advancement than patients of similar stage whose immunity was normal. Unfortunately, these results cannot be extrapolated for application to a given patient. The cell-mediated immune response seems to have an important role in the host-tumor relationship. Although humoral antibodies are not changed in cancer patients' several investigators have demonstrated a decrease in cell-mediated immunocompetence in patients with neoplasms. 2 • 3 One method of quantitating a patient's cellmediated immunocompetence is to note his ability to exhibit cutaneous hypersensitivity to a dermally applied antigen. We herein present data on 115 patients with genitourinary carcinoma who were immunized with the compound 2,4 dinitrofluorobenzene (DNFB). This substance is a hapten that becomes antigenic by binding to skin proteins. Since it is unlikely that these patients would have come in contact previously with DNFB, we are testing their ability to react to a newly encountered antigen. The patients were studied at the time of immunization and at followup 2 to 3 years later. Certain clinical differences emerge between patients who had a hypersensitivity response to DNFB and those who did not. MATERIALS AND METHODS

Each patient with urological cancer admitted to the hospital between May 1970 and June 1971 was _sensitized with a 0.05 cc dose of 0.05 molar DNFB in acetone and corn oil. This dose, 8 to 10 drops from a 25 gauge needle, is placed on a regular size bandaid applied to the patient's upper arm and '.,left covered with an adhesive bandage for 8 to 12 hours. A test dose of 0.05 cc of 0.02 molar DNFB in acetone was similarly applied 10 to 14 days postthe skin sensitization. During the next 3 reaction was graded as follows: 0-no reaction, 1+-erythema, 2+-erythema and indmation, Accepted for publication November 22, 1974. Read at annual meeting of New England Section, American Urological Association, Southampton, Bermuda, September 29-0ctober 5, 1974.

3+-vesiculation and 4+-bullae or ulceration. A 2+, 3+ or 4+ reaction was regarded as evidence of DNFB sensitization. No systemic complications were encountered with this procedure. All grades and stages of tumors of the prostate, bladder, kidney and testis were studied. Patients ranged in age from 3 to 93 years, with a median of 67 years. No patient converted from positive to negative reactivity or vice versa on repeat testing 6 months later. Control sensitizations were done on 23 hospital personnel and patients with benign disease. Of these controls 15 were from 25 to 69 years old, with a median of 47 years and 8 were more than 70 years old. Followup was accomplished by reviewing the office and hospital records of all patients. Most patients received treatment during this interval. Treatment was primarily hormonal for the prostatic cancer patients. Patients with stages I and II renal carcinoma underwent radical nephrectomy. Patients with testis tumors underwent radical orchiectomy and retroperitoneal node dissection unless the tumor was a seminoma, in which case they underwent radical orchiectomy and radiotherapy. Patients with stage A bladder tumors were treated with transurethral or open excisional biopsy. Patients with stages B and C bladder tumors underwent radical cystectomy with pelvic node dissection. Patients whose tumors had distantly metastasized were treated palliatively. The patients were judged to have undergone disease progression if 1 of the following conditions occurred: 1) the tumor had advanced in clinical stage, 2) the patient died of effects attributable to the genitourinary cancer and 3) new cancer foci appeared in who already had metastatic foci at the time of sensitization but did not die during the followup period. The development of recurrent stage A bladder tumors was not consid·Nho ered disease advancement in those

272

DECENZO, ALLISON AND LEADBE'ITER

had stage A bladder tumors at the time they entered the study.

TABLE

2. Immunological reactivity versus tumor extent %

Capable of Sensitization

Tumor Extent DNCB

RESULTS

Of the control population 93 per cent (14 of 15) less than 70 years old displayed cutaneous hypersensitivity to DNFB. None of the 8 controls more than 70 years old showed reactivity. We cannot explain this fact since 45 per cent (25 of 55) of the cancer patients more than 70 years old were able to exhibit sensitization. Table 1 shows a definite correlation between immunological reactivity to DNFB and tumor stage as determined by accepted staging systems. Of the patients with lesion confined to the organ of origin 89 per cent (49 of 55) had an immune response to DNFB compared to 37 per cent (22 of 60) of patients with metastatic disease. Of the original 115 patients 75 were seen during an interval of 24 to 36 months post-immunization. Hypersensitivity developed in 48 of these 75 patients and only 29 per cent (14 of 48) experienced progression of the disease, according to the aforementioned criteria. The remaining 27 patients did TABLE

1. Immunological reactivity versus tumor stage

and subsequent clinical course Followup Data

Bladder: A B

Ability to be Sensitized

No. Pts.

Progression

No Progression

Lost to Followup

+

19

0

6

2 0

14 6

3 0

+

8 1

1 1

2 0

5 0

+

2 1

1 0

1 0

0 1

+

2 9

2 6

0 0

0 3

+

7 0

0 0

3 0

4 0

+

6 0

0 0

4 0

2 0

+

9 8

3 2

4 5

3 2

+

6 13

3 4

1 2

2 7

+

4 0

0 0

1 0

3 0

+

2 1

0 0

2 0

0 1

+

0 1

0 0

0 2

0 2

+

3 0

0 0

1 0

2 0

+

3 1

2 1

1 0

0 0

0

C

0

D

0

Prostate: A

0

B

0

C

0

D

0

Kidney: I

0

II

0

III

0

Testis: Local

0

Metastatic

0

Bladder: Local Metastatic Prostate: Local Metastatic Kidney: Local Metastatic Testis: Local Metastatic

DNFB

62 0

79 28

40 53

100 42

66 40

100 29

100 75

100 75

not have hypersensitivity and 52 per cent (14 of 27) underwent disease progression. If we exclude those patients more than 70 years old from the group who did not exhibit hypersensitivity, we still find that 50 per cent (6 of 12) underwent disease progression. DISCUSSION

Catalona and associates measured the ability of a group of patients with genitourinary tumors to become hypersensitive to the cutaneous injection of 2,4 dinitrochlorobenzene (DNCB), a compound chemically similar to the substance we used. 2 Their results were similar to ours for most tumor types (table 2). Limited sample sizes and differences in the potency of the antigenic stimuli used may suffice to explain the differences between our findings and those of Catalona and associates. Nonetheless, the generalization emerges that impaired immunocompetence as measured by testing with these 2 chemically related immunogens seems to correlate with higher clinical stage of genitourinary cancer at the time of testing. However, there is significant overlap and many patients with metastatic disease had an intact cell-mediated response. Postulating that cell-mediated immune surveillance impedes neoplastic transformation in the normal individual, Olsson and associates studied the skin test response of a group of patients with bladder cancer to certain commonly encountered antigens. 3 They found their patients to have defective cell-mediated immunity; this defect was most marked in the presence of active malignancy. They suggested that skin testing may be used to evaluate a bladder tumor patient for recurrence, since patients with active disease were anergic. A 2-year followup did not corroborate Olsson and associates' theory of anergy in the presence of active tumor.• However, they did note the absence of tumor recurrences among those patients who had delayed hypersensitivity to intracutaneous testing with the substance Keyhole-limpet hemacyanin (KLH). The only patients who had tumor recurrences during the followup period also had never exhibited delayed hypersensitivity to KLH. Although the majority of patients in their study

SKIN TESTING IN GENITOURINARY CARCINOMA

had no active tumor present at the time of immunization, Olsson and associates postulated that circulating tumor antigen was present and that the immunogen KLH may have coupled itself to the tumor antigen so that stimulation of the lymphoreticular system became specifically related to tumor antigens. Each time a focus of tumor recurrence appeared an arnnestic occurred with fore it grew to a ~~·J""""~cc~•~ size. Our results were different from those of Olsson and associates. In order to compare our data vvith their series of with stage B 1 or less bladder tumors we shall look at the followup data on our stage A tumors. None of the 6 patients who failed to exhibit hypersensitivity to DNFB happened to have invasive tumor in the period, although 2 had superficial recurrences. In those 16 patients who did have a hypersensitivity response, 4 were free of tumor for the fol!owup period, 2 had invasive cancer and the remaining 10 had l or more superficial recurrences. From another view, of these 22 patients with superficial bladder tumor followed for 2 years, 2 had invasive tumor and both had been sensitized to DNFB. There was no recurrence in 8 patients, of whom 4 had exhibited hypersensitivity and 4 had not. Superficial recurrences developed in 12 patients, of whom 10 were capable of sensitization and 2 were not. These results would indicate that the ability to be sensitized to DNFB afforded no protection subsequent tumor formation. In order to reconcile the data of Olsson and associates with ours, one would have to a

273

stimulation of the immune system by KLH but not by DNFB. It would be interesting if their followup data for the other antigens originally used are similar to our data for DNFB. We interpret our 2 to 3-year followup data to indicate that patients with normal cell-mediated immunocompetence generally have a better prognosis than patients whose cell-mediated immunity is impaired. The fact that this superior n~,.m,nc is not universal shows the importance of the intrinsic 2ggressiveness of the tumor itself. Since skin testi,1g with DNFB does not the future course of a given this tool is not useful in a clinical However, if further experience with immunogens such as KLH bears out that cutaneous sensitization exerts a effect against certain cancers, immunologic techniques may yet have some relevance for clinical urology. REFERENCES

Southam, C. M. and Moore, A. E.: Anti-virus antibody studies following induced infection of man with West Nile, Ilheus, and other viruses. J. Immunol., 72: 446, 1954. 2. Catalona, W. J., Chretien, P. B. and Trahan, E. E.: Abnormalities of cell-mediated immunocompetence in genitourinary cancer. J. UroL, Hl: 229, L

1974. 3. Olsson, C. A., Rao, C. N., Menzoian, J. 0. and Byrd, W. E.: Immunologic unreactivity in bladder cancer patients. J. UroL, 107: 607, 1972. 4. Olsson, C. A., Chute, Rand Rao, C. N.: Immunologic reduction of bladder cancer recurrence rate. J"

Ur~., Ill: 173, 1974.

Skin testing in genitourinary carcinoma: 2-year followup.

Compound 2,4 dinitrofluorobenzene was used to sensitize 115 patients with genitourinary cancer to test their ability to be immunized with a newly enco...
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