Biopsy and Clinical Course After Cryosurgery for Prostatic Cancer

0022-534 7/78/1203-0308$02. 00/0 Vol. 120, September

THE JOURNAL OF UROWGY

Printed in U .SA.

Copyright © 1978 by The Williams & Wilkins Co.

BIOPSY AND CLINICAL COURSE AFTER CRYOSURGERY FOR PROSTATIC CANCER DAVIDS. PETERSEN, LEO A. MILLEMAN, EARL F. ROSE, WILLIAM W. BONNEY,* JOSEPH D. SCHMIDT, CHARLES E. HAWTREY AND DAVID A. CULP From the Departments of Urology and Pathology, University of Iowa and Veterans Administration Hospitals, Iowa City, Iowa

ABSTRACT

Open perinea! cryosurgical prostatectomy has been reported previously in 154 consecutive prostatic cancer patients at our center. In 37 of these patients post-cryosurgery biopsies of the prostate were obtained. In the present report we compare this tissue to the preoperative biopsies. The data suggest that well differentiated cancers are associated with advantageous survival in cryosurgery patients. Lymphoid and eosinophilic cell infiltrates may represent post-cryosurgical local immune responses, with improved survival. Estrogen therapy seems to suppress this local immune response. One month or more after cryosurgery cancer in the biopsy correlates with palpable local recurrence but .prior to 1 month it does not correlate. Cryosurgery by the open perineal approach has been an effective method to eliminate the primary lesion in localized and extensive prostatic cancer. Cryosurgery of the prostate was first reported by Soanes and associates for relief of bladder neck obstruction in benign prostatic hypertrophy or prostatic carcinoma. 1 Soanes2 and GurseP and their associates emphasized the further possibility of a systemic antitumor response in their reports on spontaneous regression of distant metastases after cryosurgery of the primary prostatic carcinoma. However, the cryo-destruction of the primary cancer was not documented histologically. Hansen and Wanstrup studied biopsies taken at various intervals after transurethral prostatic cryosurgery in 110 patients, 19 of whom had carcinoma. 4 Their report described local tissue reaction without reference to residual cancer cells. The use at our center of cryosurgery for prostatic carcinoma was prompted by the previous reports of metastatic regression after transurethral cryosurgery. However, we have used the open perineal route because it provides complete exposure, acmrate local staging and the greatest possibility for complete cryo-destruction of the primary tumor. Between 1969 and October 1974, 154 patients had open perineal cryosurgical prostatectomy with results previously reported. 5 There was complete destruction of the local lesion in 86 per cent of these patients, as assessed by rectal examination 3 months postoperatively. Of the total series hormone treatment had failed in 78 cases before cryosurgery and 46 additional patients had received it at the time of the operation. In the present study we have reviewed the pathology of prostatic tissue removed after cryosurgery in 37 patients. The histological findings were compared to preoperative biopsies and analyzed in regard to initial tumor stage and grade, hormone treatment, postoperative clinical course and evidence of a local immune response. It must be emphasized that these 37 patients include all of our known local cancer recurrences, while 86 per cent of the 154 patients have remained free of local disease. 5 METHODS AND MATERIALS

Of the 154 patients who underwent open perineal cryosurgical prostatectomy 39 had prostatic tissue removed in the postoperative period. Two of these cases were done at autopsy. In every other case there was a clinical indication for biopsy, either voiding difficulty or a nodule on rectal examination. Accepted for publication October 21, 1977. * Requests for reprints: University of Iowa Hospital, Iowa City, Iowa 52240. 308

Tissue is now available for microscopic review in 37 of these patients. There were 42 procedures in all, 28 done 10 days to 3 months postoperatively and 14 done 4 to 43 months postoperatively. The procedures were transurethral resection of the prostate in 31 cases (repeated in 3 cases)-positive for carcinoma in 22, percutaneous transperineal biopsy in 3 casespositive in 1, transurethral resection of the prostate and percutaneous transperineal biopsy in 1 case - positive for carcinoma and autopsy in 2 cases, subsequent to transurethral resection of the prostate in 1 case and positive in 1. At the time of this report all patients had been followed for 18 months or longer after cryosurgery, with survival reported to the present time (that is 1¼ to 6 years). In each case postoperative examinations were made either by our staff or by the referring physician. For purposes of correlation with biopsy findings a local recurrence was defined as a clinically significant mass detectable on rectal examination at biopsy or at some later time. Among the 37 patients under consideration hormone therapy was given as follows: preoperative orchiectomy- 6 cases (additional estrogen-4 cases) with only 1 survivor, orchiectomy at the time of cryosurgery-20 cases (additional estrogen -10 cases) with 12 survivors and orchiectomy postponed (3 cases) or withheld (8 cases) with 10 survivors. Initial tumor stage was assigned on the basis of preoperative evaluation and surgical assessment of the primary cancer as follows: stage B- 2 patients, stage C - 20 patients and stage D-15, patients. Preoperative histological grade was determined as follows: well differentiated-12 cases, moderately differentiated-10 cases, poorly differentiated- 9 cases, undifferentiated-! case and cribriform-3 cases. Because of similarities in survival data and incidence of local cancer postoperatively the well and moderately differentiated cases were combined into 1 group and the poorly differentiated and undifferentiated cases were combined into another for presentation. The same classification was applied to postoperative biopsy material. RESULTS

To date 14 patients have died (tables 1 and 2). The cause of death was cardiovascular disease in 2 patients, with bronchopneumonia and acute renal failure contributing factors in 1, and the remaining 12 patients died of carcinoma, with azotemia from ureteral obstruction a contributing factor in 5.

BIOPSY AFTER CRYOSURGERY TABLE

1. Tumor stage, survival and carcinoma in

post-cryosurgical biopsy Initial Stage

Ca Present*

Ca Absent*

Totals*

0 9/15 4/10 13/25

1/2 5/5 4/5 10/12

1/2 14/20 8/15 23/37

B C D All stages

* No. pts. surviving/No. pts. biopsied.

TABLE

2. Initial histological grade, survival and carcinoma in post-cryosurgical biopsy* Grade

Well differentiated and moderately well differentiated Poorly differentiated and anaplastic Cribriform All grades

Ca Presentt Ca Absentt

Totalt

9/12

8/10

17/22

1/9 2/2 12/23

1/1 1/1 10/12

2/10 3/3 22/35

* Patients with available pre-treatment biopsy slides. t No. pts. surviving/No. pts. biopsied. TABLE

3. Prostatic tissue reaction after cryosurgery

Histology Acute necrosis Eosinophilic infiltration Lymphocytic and plasmacytic infiltration Granuloma Fibrosis Squamous metaplasia Tissue unchanged from pre-cryosurgery

Mos. After Cryosurgery

No. Pts.

Ca Present

0-3 0-3 0-3

10* 7t 15:j:

7 3 8

1 1-31 1-43 1-22

1 13 5§

0 8 3 7

8

309

peared in the first 3 months, while fibrqsis was seen during this period and later, therefore probably representing the eventual healing phase in all cases. The inflammatory reactions (granuloma, eosinophils and lymphocytes or plasma cells) were confined to the first 3 months except for some minimal infiltration in 2 cases at 17 and 43 months. Squamous metaplasia was seen early and late, and the biopsies with no evident tissue reaction appeared sporadically. The inflammatory infiltrates correlated with 3 favorable findings. 1) They were associated with superior survival- 73 per cent of the patients with lymphocytes or plasma cells (11 of 15) and 86 per cent of patients with eosinophils (6 of 7), while in patients without these infiltrates the survival rate was approximately 50 per cent. 2) These infiltrates were seen only in patients with well differentiated, moderately well differentiated or cribriform patterns. 3) Inflammatory infiltration correlated with the absence of cancer in the post-cryosurgical biopsy in the following way: cancer was present in 43 per cent of patients with eosinophils (3 of7), 53 per cent of patients with lymphocytes or plasma cells (8 of 15), absent in the 1 patient with classical granuloma, yet present in 88 per cent of patients with tissue unchanged (7 of 8). Typical inflammatory infiltrates are depicted in figures 1 and 2. Tissue reaction also correlated with hormone treatment. Squamous metaplasia was associated closely with orchiectomy and estrogen therapy. Lymphocyte and plasma cell infiltrates occurred predominantly in patients given no estrogen (table 4), yet this association was not true for eosinophils. Clinically evident local cancer recurrence (nodule on rectal examination) was studied in relation to microscopic cancer in the post-cryosurgical biopsy of 19 surviving patients available

* Including 1 biopsy at 12 months. t Two patients with orchiectomy plus estrogen and 2 with orchiectomy alone. Survival 6 of 7 patients. :j: Including 2 biopsies that showed minimal infiltration at 17 and 43 months. Survival 11 of 15 patients. § All had orchiectomy and 4 on estrogen.

Among the 23 survivors the 8 patients with stage D disease, of course, have metastatic cancer. Of the 15 surviving patients with stages Band C disease 10 are free of cancer, 4 have local recurrence and only 1 has clinically evident metastases. Initial tumor stage did not correlate with survival rates, which were essentially the same in patients with stages C and D disease. Carcinoma was found on post-cryosurgical biopsy in 25 of the 37 patients. There was no significant difference between patients with stages C and D disease in this regard. However, a negative biopsy did correlate with good survival in patients with all stages of disease. Initial histological grade was compared to other parameters in each case. Well differentiated and poorly differentiated tumors were distributed equally between patients with stages C and D disease. In the post-cryosurgical biopsy cancer was present in 90 per cent of the patients with poorly differentiated tumors (9 of 10) but in only 56 per cent of the patients with better differentiated or cribriform patterns (14 of25). Furthermore, the histological grade correlated with survival: well differentiated 77 per cent (17 of 22), cribriform 100 per cent (3 of 3) but poorly differentiated 20 per cent (2 of 10). In 6 cases the postoperative carcinoma appeared to have a histological grade different from that seen on initial biopsymore poorly differentiated in 4 cases and better differentiated in 2 cases. The significance of this finding is not known. A variety of histological reactions was seen in the cancer and in the normal prostatic tissue after cryosurgery. These are presented as changes in comparison to preoperative histology (table 3). There were 28 biopsies done 10 days to 3 months postoperatively, while 14 biopsies were done later. This interval correlated with the tissue reaction. Acute necrosis ap-

Fm. 1. Prostatic biopsies from patient 1. A, preoperative, moderately well differentiated adenocarcinoma. Reduced from x 100. B, post-cryosurgical, eosinophils and mononuclear cell infiltrate. Reduced from x200.

310

PETERSEN AND ASSOCIATES

F'rq_. 2. Prostatic biopsies from patient 2. A, preoperative, well differentiated adenocarcinoma. Reduced from x40. B, post-cryosrirgical, granulomatous reaction with giant cell, eosinophils and mononuclear cell infiltrate-no cancer present. !{educed trom x:wu. TABLE

4. Hormone treatment related to lymphocytic infiltration after cryosurgery Lymphoid Infiltrate*

Hormone Treatment

Estrogen plus orchiectomy Estrogen alone Orchiectomy alone None Totals

Heavy With Aggregates

Minimal

Absent

2 0

1 2

9 7 6 0

5

22

2 0 6 2 10

* Includes plasmacytes and other mononucl~ar cells.

for late followup examination at our hospital (table 5). Local recurrence followed all positive biopsies taken 4 weeks or longer after cryosurgery, whereas the earlier positive biopsies did not correlate. DISCUSSION

Cryosurgery produces tissue death by intracellular dehydration and toxic electrolyte concentrations, crystallization with secondary membrane rupture, denaturation of proteins, thermal shock and vascular stasis. 6 • 7 In our series the postcryosurgical changes began with necrosis, edema and inflammatory cell response, reaching a peak after 1 month and lasting as long as 3 months. Hansen and Wanstrup noted edema and necrosis for 1 to 10 weeks after transurethral cryosurgery for bladder neck obstruction, mostly benign prostatic hyperplasia. 4 This process seems surprisingly -long but vascular damage and thrombosis may prolong the tissue destruction and delay healing. We would agree with the

concept of a slowly evolving lesion that is gradually replaced by fibrosis. The presence of carcinoma in the post-cryosurgical biopsy as a prognostic sign may, therefore, depend upon how soon the biopsy is taken. Cancer seen prior to 1 month may be destined to undergo further necrosis and does not necessarily mean incomplete destruction of the local tumor. This concept is supported by our data (table 5), in which the presence of carcinoma beyond 1 month post-cryosurgery was a more reliable predictor of subsequent local recurrence. Tissue showing no change, obtained by transurethral resection in most cases, perhaps can be explained by incomplete penetration of the cold from the posterior capsule and, therefore, protection of the periurethral tissue during cryosurgery. We have modified our technique to use a pointed probe inserted into the tissue, a colder temperature (minus 190C) and multiple applications during the same operation in an attempt to destroy completely the local cancer. Our few instances of apparent change in histological grade after cryosurgery also warrant explanation and may represent random sampling error in either the preoperative or postcryosurgical biopsy. Another possibility is that the postcryosurgical cancer has regenerated from a few surviving glands originally of a different histological pattern. Initial tumor stage did not appear to be a good predictor of survival in our series. However, even with advanced stage the patients with well differentiated cancers did have better survival after cryosurgery. Therefore, the better differentiated cancers appear to have less aggressive natural tendencies or lend themselves to generation of host resistance in conjunction with cryosurgery-especially since nearly all of the lymphocyte-plasma cell infiltrates were seen in association with well differentiated tumors. The inflammatory infiltrates may represent a local antitumor immune reaction. Our patients with these findings have done well with 1 exception, a patient with marked eosinophil infiltration (and a change of histological grade toward better differentiation) but a rather rapid downhill clinical course. Eosinophils generally are associated with allergic reactions and previous investigators have called attention to the inverse correlation between clinical allergy and cancer. 8 • 9 Furthermore, eosinophilic infiltrates within cancers have been associated previously with a favorable outcome. 10 Therefore, we conclude that our data do contain evidence of a local immune response and a suggestion that this might have benefited some patients. Estrogen therapy may be immunosuppressive in the prostatic cancer patient. Estrogens are not directly immunosuppressive in rodents 11 but do cause thymic atrophy in mice 12 and have been reported to suppress in vitro reactions. i:i Data from the present paper suggest that a local immune response develops primarily in patients without any estrogen. Therefore, we conclude that estrogen therapy does suppress immune reactions in the cryosurgery site. It is difficult to determine whether this non-estrogen immune response has any survival value. In our total experience of 154 patients there has been a better over-all prognosis whenever orchiectomy and estrogen treatment were omitted or delayed until after cryosurgery. However, the patients who had received hormone therapy were quite naturally the ones with most advanced disease. TABLE

5. Local cancer recurrence related to biopsy results* Biopsy

Ca Present

Wks. After Cryosurgery

Yes Yes No

2-3 4-76 2-10

Subsequent Local Recurrence

No. Pts.

No Yes No

6 5 8

* Nineteen patients available for late followup visit after cryosurgery. Local recurrence det.ected by rectal examination.

BlOPSY }\FTEP, CR-YOSUR-GERY

The m-,~ccmT data further suggest that squamous metaplasia is caused by estrogen therapy. However, an alternative cause may have been cryo-induced tissue infarction. Previous investigations have shown squamous metaplasia in regenerating marginal prostatic glands after cryosurgery alone in humans 4 and in animals. 14 In our series of preoperative and post-cryosurgical biopsies of prostatic cancer favorable prognostic signs would appear to be 1) well differentiated carcinoma in the initial biopsy, 2) absence of cancer in biopsies after cryosurgery and 3) any evidence of post-cryosurgical inflammatory response, such as granuloma formation or infiltration with eosinophilic, lymphocytic or plasmacytic cells. Although this is the largest series reviewing biopsy changes after cryosurgery for prostatic carcinoma and the only series done by the perineal approach, it represents a relatively small group, especially when subdivided for purposes of comparison. Furthermore, tissue was obtained in a non-random way for specific clinical indication- undoubtedly a cause for bias because these were the patients already showing signs of local recurrence while the large majority of patients, not biopsied a second time, remains free of local disease. Histological changes are at best circumstantial evidence of host immunological activity. For these reasons some caution must accompany any conclusions at present. Cryosurgery of the prostate via the open perinea} approach has been highly effective in eradicating the local lesion. Its possible role in stimulating an immunologic response warrants further investigation. REFERENCES

1. Soanes, VV. A., Gonder, M. J. and Shuln1.an, S.: Apparatus and

technique for cryosurgery of the prostate. J. Urol., 96: 508,

311

1966. 2. Soanes, W. A., Ablin, R. J. and Gonder, M. J.: Remission of metastatic lesions following cryosurgery in prostatic cancer: immunological considerations. J. Ural., 104: 154, 1970. 3. Gursel, E., Roberts, M. and Veenema, R. J.: Regression of prostatic cancer following sequential cryotherapy to the prostate. J. Urol., 108: 928, 1972. 4. Hansen, R. I. and Wanstrup, J.: Cryoprostatectomy. Histological changes elucidated by serial biopsies. Scand. J. Urol. Nephrol., 7: 100, 1973. 5. O'Donoghue, E. P. N., Milleman, L.A., Flocks, R.H., Culp, D. A. and Bonney, W.W.: Cryosurgery for carcinoma of prostate. Urology, 5: 308, 1975. 6. Cooper, I. S.: Cryogenic surgery of the basal ganglia. J.A.M.A., 181, 600, 1962. 7. Gonder, M. J., Soanes, W. A. and Smith, V.: Experimental prostate cryosurgery. Invest. Urol., 1: 610, 1964, 8. Mackay, W. D.: The incidence of allergic disorders and cancer. Brit. J. Cane., 20: 434, 1966. 9. Fisherman, E. W.: Does the allergic diathesis influence malignancy? J. Allergy, 31: 74, 1960. 10. Haskill, J. S., Yamamura, Y. and Radov, L.: Host responses within solid tumors: non-thymus-derived specific cytotoxic cells within a murine mammary adenocarcinoma. Int. J. Cane., 16: 798, 1975. 11. Bonney, W. W., Feldbush, T. L. and Neufeld, S. E.: Effectiveness and toxicity of immunosuppressive agents: inhibition of the rat popliteal node graft-vs.-host reaction. J. Pharmacol. Exp. Ther., 190: 576, 1974. 12. Thompson, J. S., Reilly, R. W., Crawford, M. and Russe, H.P.: The effect of estradiol and estriol on the survival of sublethally and lethally irradiated mice. Rad. Res., 26: 567, 1965. 13. Guinan, P., Ablin, R. J., Bruns, G. R., Sadoughi, N. and Bush, I. M.: Suppression ofin vitro blast transformation by estrogen. Surg. Forum, 25: 540, 1974. 14. Bonney, W.W.: Unpublished data.