Treatment of Papillomatosis of the Bladder with Phenol and Glycerin: A Clinical and Laboratory Study

Vol, ll9, May Printed in U,S,A,

THE JOURNAL OF UROLOGY

Copyright© 1968 by The Williams & Wilkins Co,

TREATMENT OF PAPILLOlVIATOSIS OF THE BLADDER WITH PHENOL AND GLYCERIN: A CLINICAL AKD LABORATORY STUDY VINCENT VERMOOTEN, PAUL C, PETERS

AND

DONALD K JOHNSON

From the Southwestern 111 eclical School, University of Texa8, Dalla8, Texas

Multiple papillomatosis or diffuse non-infiltrati11g papillary carcinoma of the bladder is an infrequently encountered condition, The number and location of individual lesions make the disease difficult to control transurethrally, Staging of individual lesions is possible, but at times the growths are so numerous that correct staging is difficult and it may reveal surprising differences between the clinical appearance and the true stage of the neoplasm, Figure l shows a papillomatous growth which histologically would be classified as grade l, Jewett stage O endoscopically, However, on microscopic examination of the base of the lesion, vascular invasion is present, necessitating the classification at least of Jewett stage C, Marshall estimates that 17 per cent of 188 patients had carcinoma of the bladder within 5 years after initial biopsy revealing papilloma. The cancer was much more likely to occur in those who had papilloma with atypical celb, Only 200 of 500 cases of papilloma reviewed by Marshall showed metastases and invasion. Because of the relatively benign nature of papillomatosis, urologists have been unwilling to refer their patients for radiation therapy since a small dose is often ineffective and a tumoricidal dose results ultimately in diminished bladder capacity, Therefore, urologists have generally preferred an open operation with cystectomy and diversion or fulguration and chemical cauterization of individual lesions in the treatment of multiple papillomatosis. In an excellent review on the use of chemotherapeutic agents in destruction of bladder papillomas, Abbassian and Wallace showed that in general the use of these agents has been disappointing as far as local destruction of individual bladder neoplasms is concerned. 1 Still another problem is the occasional step-up of clinical grade of the neoplasm with the passage of Accepted for publication June 27, 1967. Read at annual meeting of American Urological Association, Inc,, New York, New York, May 29-June 1, 1967. 1 Abbassian, A, and Wallace, D. M,: Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. .J, Urol., 96: 4fil-465, 1966, 588

time. unless each individual lesion is removed and staged, the individual variation in potential of the various papillomas cannot be accurately a.,sessed, Because of these difficulties workers have sought a suitable chemical agent to produce non-selective complete destruction of the bladder mucosa in the hope that the newly regenerated epithelium would not show the neoplastic tendency, This theory was based on two observations: 1) Kirwin proposed the theory that bladder papillomatosis is possibly due to a virus, and that virus particles similar to those seen in the common verruca vulgaris of the skin have been demonstrated in bladder papilloma cells, 2 2) It was believed that if the neoplasm was secondary to a change induced in the bladder mucosa by a chemical carcinogen, it might be some time before the new mucosa could become sensitized to the carcinogen, It was known that in the aniline dye industry workers many years of exposure to the carcinogen was necessary before the subsequent appearance of the neoplasm. Certain characteristics of an intracavitary agent for use in destruction of bladder tumor seemed necessary. The effect of the agent must be peripheral, it must not be absorbed into the bloodstream to cause systemic side effects such as leukopenia, thrombocytopenia and bone marrow depression. Local irritative symptoms should be minimal, There should be no late sequelae, such as mucosa! atrophy, telangiectasia, bladder wall fibrosis, The treatment should be repeatable over the years for recurrence, and the agent should be absorbed into the cell, but not into the bloodstream, Therefore, the agent should have a high fat solubility to be rapidly absorbed into a cell. It should have a low molecular weight to increase its absorption rate. Vermooten, modifying a suggestion used by Kirwin, has reported successful use of phenol for chemical cauterization of bladder mucosa! tumors in 13 cases of papillomatosis (see table), He found that there were no deaths directly attributable to filling the bladder with phenol, that the chemical 2 Kirwin, T. J.: Tumors of the bladder. J. Intern at. Coll. Surg,, 13: 1-19, 1950.

PAPILLO:IIATOSIS OF BLADDER TREATED WFrH PHENOL AND GLYCERIN

appeared efficient in ridding the bladder mucosa of papillary lesions and that recurrences 1Yere much less frequeut, though occasionally present, after cmnplete destruction of the bladder mucosa,. This would suggest that after some time the newly regenerated mucma again bc:comes sensitized

Frn. l. Rma.11 papilloma grossly benign low grade, but on microscopic examination shows 1,U· mor cells in vessel.

the continued appearance of the carcinogen 111 the urine. Several questions which were not, answered in the c:linical study required investiga. tion in the laboratory: 1) What is the depth ol penetration of the agent in the method u,,ed clinically? 2) Is destruction of the bladder mu~· culature extensive? :3) What is the effect upon tfw urcterovesical junetion? 4) fa reflux produced cauterization of the bladder mucma? ii) VVhat i~ tbe time required for regeneration of the bladder epithelium? Two groups of experiments were ~et up in tbe laboratory. The first was to determine the rate oi' regeneration of tbe bladder epithelium and the second was to cletcrrni11e the effect of adding colon patch with mucosa cauterized by phenoJ the bladder at the time of the c,hcmical cautcriza, tion, to determine if ultimate bladder would be satisfacto1y and to determine if the cauterized colon epithelium would be replaced transitional epithelium, thus avoicliug the lem of secretion of mucus into the bladder lumen by the colon epithelium. Group 1. Pentobarbital general anesthesia w1Lh enclotracheal intubation was used in .5 dogs. The animals were opened throngh a miclline incision after preparation of the skin with The bladder was mobilized up into the incision, inciRed and evacuated of its co11tent,,,. The ti:-;sue.c surrounding the bladder were carefully packed off and AIiis forceps were used to hold up the bladder so that its cavity could he filled witb a mixture of

Swnmary of nm.1.lt.s of /reaimeni of paiients w1:th papillrmwtosis of the bladder /JJJ the use of phenol and glycerin

ratient

580 H.R.H. 303G E.R. 305fJ A.F.W. :3329 ;3373 3;3;33 G444

A.F.W.

M.A. T.S.

54/M 57/M fi0/7\I 45/M

7G:36 8462 85Gl 8709

H.C. RJ. M.C. C.D.

59/1< 74/M 5fl/F 55/11

A.E.

57

GO 45 5D (i9

59 5,5

Frequency of Recurrence Before Phenol

Length of Interval \Vithout Recurrence

10-15 monthly for 6 mos. Once Annual

HJ yrs. 9 yrs.

Initial diagnosis Initial diagnosis fnitial diagnosis

3 yrs. 11 yrs. 3 yrs.

In i( ial Every Every Initial

diagnosis 6 mos. Ci mos. diagnosis

5 yrs.

5 yrs. Expired 1 yr. 2 yrs. 2 yrs.

Bladder Capaci !.y

III/A I/A ll/A II/B, If/B,

>200 cc ::ioo cc 480 cc

II/A

III/A II/B, II/B II/A II/B II/A

Normal Me(.a,stases 8 yrs. :100 CG

No :-;tagc

3()0

C<'

590

VER'.\100TEN, PETERS AND JOHNSON

FIG. 2. Ureterovesical junction at 5 days after phenolization shows intact ureteral epithelium and eschar covering bladder muscle.

FIG. 3. Sigmoid colon patch attached to bladder with vascular pedicle attached.

150 cc pure phenol and glycerin in equal parts. The bladder was filled to the brin.1 of the cystotomy and the solution was allowed to remain in place for 2 minutes. The phenol-glycerin mixture was then sucked out and the bladder was washed with 95 per cent alcohol. The wounds were closed with no drains, and the animals were returned to their cages. The animals were sacrificei at .5, 7, 9, 14 and 21 clays respectively. There were no postoperative deaths in this group. The dogs ate a regular diet, and though the frequency of their voiding was not measured, they seemed well clinically when sacrificed for bladder study. Results: In the animal sacrificed 5 days after phenolization, the intravesical ureter and ureteral orifice have an intact epithelium covering them (fig. 2). The eschar on the bladder mucosa away from the orifice involves the superficial bladder

epithelium, but does not extend deep enough to involve the intravesical ureter. A fibro-purulent eschar replaces the destroyed bladder mucosa epithelium, but edema and infiltration do not extend to the muscular coat. At 7 days, the epithelium is just starting to regenerate from the ureteral orifice and superficially on the mucosa! surface replacing the eschar. Inflammation is still seen in the lamina propria. At 10 days, a normal vesical epithelium is present and there is no evidence of damage to the intramural ureter by the phenol. At 14 days, there is a normal appearing ureteral orifice and regenerated bladder epithelium is seen near the ureteral orifice. The bladder mucosa is thin, but there is regenerating bladder epithelium and there is very little inflammation and edema left. At the time of sacrifice of the animal, the bladder did appear thickened and contracted. At 21 days, the bladder mucosa epithelium is completely regenerated to its normal thickness, with some nodularity due to n:iasses of regenerating epithelium. No neoplastic formation was noted. Inflammation and edema have disappeared. No dysplastic epithelial changes were noted. The dog appeared to be in good health. Group 2. Three mongrel dogs were handled in a similar manner as those in group 1 except, that at the time of completion of cauterization of the mucosa with phenol, a patch of sigmoid colon, approximately 10 by 5 cm. was attached with its vascular pedicle intact to the anterior surface of the bladder after cauterization of the colonic

PAPILL0l1IAT0S1S OF BLA llDER TREATED v\Tl'H PHENOL A :-;D GliYCEIUN

;,!J J.

FIG. 4. il 11onnal excretory mogrnm G months aJter phcnolization of blnduer and colon pMcb. U, eystognm1 no evidence of reflnx G months after phenolization.

Fm. 5. l'ho(ornicrograph dcmo11strn1es regencrn1ion oI colonic and bladder epithelium with slight overgrowth of bladder epiU1elium at anastomotic site.

mucosa Viit.h th<' phenol (fig. 3). The pakh waf anastomo"ed to the bladder with 2 layers of 3-0 chromic: catg,1t and the wmmd was closed without. drain.,. l-'o8toperativel:v, all animab did well. It was decided not to obtain a biopsy from these animab until definitive ]waling had occurred. At 6 n1onth.c;, rystograrn., and excretory urograms were and a biopsy was taken of the bladder and of the colon patch to asse~s thr degree of reand appearance of the bladder and to

drtrnnine whethr,r the colon epithelium had been replaced hy bladder mucosa or whether regrowth of colonic mucosa had occmTrrl. The1·e wa" no evidence of any clifficuliy iu the postoperative course with any of these animals and there was no evidence of anemia or bone marrow dppres~ion. Res1ilts: Tht> excretmy urogram shows 110 evidence of bydronephrosis or hydrnureter (fig. 4, J.). Renal function is prompt bilaterally. reveab no evidence of reflux (fig. 4,

592

VERMOOTEN, PETERS AND JOHNSON

cal examination reveals normal bladder epithelium, and the colon patch had regenerated a normal colonic epithelium, slightly overgrown by the vesical mucosa (fig. 5). The absence of reflux is attributed to the lack of damage to the intramural ureter by the phenol at the time of the cauterization. It is likely that the intramural ureter remains intact because the thick phenolglycerin solution is poured in through the open cystotomy and intravesical pressure is not increased at the time of its application to the mucosa! surface. CONCLUSIONS

The use of phenol for chemical cauterization of the bladder mucosa appears to be clinically safe.

Laboratory and clinical studies have been made. Reflux is not produced by the method used in the laboratory or in the clinical patient. Regeneration of the vesical mucosa occurs from periureteral and vesical neck epithelium. Bladder capacity is diminished at first, but later adequate. Destruction of the mucosal layer with preservation of the muscle of the bladder, under the conditions of the experiment, appears feasible. Colonic epithelium, used as a bladder patch in this experiment, regenerates. The bladder epithelium did not have time to overgrow the colon muscle before colon mucosa regeneration occurred.