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Papillomatosis of the Bladder: New Conceptions of Etiology and Treatment1
PAPILLOMATOSIS OF THE BLADDER: NEW CONCEPTIONS OF ETIOLOGY AND TREATMENT1 THOMAS J. KIRWIN From the Department of Urology, James Buchanan Brady Foundation, New York Hospital ' and from Department of Urology, New York City Hospital, New York, N. Y.
Vesical papillomata may be single or multiple. When many small growths occur together, or :in rapid sequence, the condition is termed papillomatosis. Histologically, there is no difference between the single and the multiple forms. HISTORY
The first description of vesical papillomatosis I have been able to find in the literature is that given by John Green Crosse in his 1833 Jacksonian Prize essay on Urinary Calculus. In the bladder of a male infant aged 18 months he found the "cavity filled with soft tumors ..... The fatal disease occupied the lining membrane of the bladder, which was loosely connected with the muscular coat and very abundant so as to fall into folds, also thicker than usual, and having a gelatinous appearance ..... One large tumor with a broad basis, was firmer than the rest, and placed near the termination of the left ureter ..... Several small detached tumors, from the size of a pea to that of a bean, were loose in the bladder .... all the tumors were covered with their proper membrane, continuous with the inner coat of the bladder ..... " In his treatise on Diseases of the Urinary Blad,der, first published in 1851, Samuel D. Gross, who may be ranked as the first American urologist, in our modem acceptance of that term, copied this "exceedingly instructive case" verbatim. He added several other instances of vesical neoplasm, taken from European literature, together with a description of what he called "a peculiar fungous growth, a species of vegetation of the mucous membrane [which] .... varies in its size from that of a pea to that of a pullet's egg, and is of a soft and spongy consistence, with rough, fimbriated, or villous surface. In some instances .... it occurs in considerable numbers, so as to stud the greater part of the surface of the bladder. Its form is generally globular, ovoidal, or pediculated, and its color is commonly a few shades redder than that of the mucous membrane upon which it rests, and from which it arises." Gross evidently did not think this "fungous" growth was in any way akin to the growths described by Crosse 10 years previously. Seven years after Gross's textbook appeared, John Birkett, surgeon to Guy's Hospital, read before the Medico-Chirurgical Society of London, the account of a case of "fibrous polypus of the urinary bladder," which he was careful to differentiate from both "papilloma" and "epithelioma." He failed, however, to provide us with the histological details which would have enabled modern pathologists correctly to classify the case which he proceeded to describe and compare 1 Read before the annual meeting of the American Urological Association, New York, N. Y., June 3, 1942. 1
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THOMAS J. KIRWIN
with that earlier reported by Crosse. Birkett's patient was a little girl of 5 years. At autopsy he found tumors "growing from the internal surface of the anterior wall of the bladder, reaching as low as the meatus, and extending on the sides to the junction of the anterior two-thirds with the inferior third of the viscus. They consisted .... of distinct growths, approximated together, and having more or less of the polypoid form .... taken together they formed a conical or pyriform mass, the apex of which was attached to the vesical orifice of the urethra, and the base was free in the bladder ..... All the growths had their seat in the mucous membrane and submucous connective tissue, the former extending over their surfaces." Pathologic differentiation had progressed far enough in 1879 to permit Robert S. Hudson, when he published his case in the Dublin Journal of Medical Science, to use the title "Villous Disease (Papillary Fibroma) of the Bladder." At autopsy upon a 54-year old man, there were found in the bladder "eight tumors, each connected by a narrow pedicle ..... When .... a portion of the tumor floated out in water, its true character was seen-delicate, lace-like growths springing from a firm fleshy pedicle .... " Hudson's object in reporting his case and citing others from the literature was to demonstrate the feasibility of operating for the removal of such tumors from the male bladder, as had already been done in female cases. In this connection he cited the work of 'Professor Simon of Heidelberg, who has scraped off papillary fibromas in three cases, with recovery in each, although in one the bladder was nearly two-thirds filled with these growths'. I have been unable to find any references to these cases in Simon's publications on bladder tumors, but feel they may be reasonably accepted on Hudson's authority. The entire subject of bladder tumors was, however, much misunderstood and neglected up to 1881, when Stein "brought together and classified 60 cases of benign papillomatous, villous and polypoid growths .... true villous structures., closely resembling the villi of the chorion .... placed in water the villiosities are floated out and present a beautiful and characteristic appearance .... the larger villi branch out from the central mass .... some being thick and short .... some appear as pendulous tumors hanging from a distinct stalk or pedicle, and terminate in numerous filamentous processes. Others are sessile and .... may appear as soft, loose, shaggy villous tufts, projecting more or less from the mucous surface, or they may have a more solid basic structure and present a warty or cauliflower-like appearance ..... Villous growths are usually benign. In structure they do not partake of the character of malignant tumors ..... They do not cause death by malignant cachexia, but from hemorrhage, or from the consequences of mechanical obstruction to the outflow of urine." Sir Henry Thompson's monograph on Tumours of the Bladder, though primarily surgical, still shows that the understanding of the pathology of these growths had greatly advanced by the date of its publication, 1884. "It may fairly beinferred,"he tells us, "that the commonest species of tumour affecting the adult bladder are papillomata ... [which] .... have certainly no malignant tendencies, but their disposition to increase and fill the cavity of the bladder, and
PAPILLOMATOSIS OF BLADDER
3
thus to disintegrate at their periphery, together with their vascularity and consequent strong disposition to bleed largely, render them sooner or later invariably fatal." The French urologists of the last years of the nineteenth century, chief among whom were Guyon and his pupil, Albarran, were careful to insist upon the histological benignity of vesical papillomata, though Guyon does speak of "pseudopapillomas (villous epitheliomas and carcinomas, fibrous polyps, etc.) .... among them many may be found which are of a malignant nature." During the last decade of the nineteenth century and the first of the twentieth, the study of all kinds of neoplastic growths made great strides, but the condition now known as vesical papillomatosis was seldom mentioned. Every sort of bladder growth was regarded as malignant, and it was not until the cystoscope in its more modern form became a regular part of the diagnostician's equipment that the existence of benign bladder growths was definitely established, and their differentiation from malignant tumors placed on a scientific basis. In.the year 1910, the late Reinhold Wappler designed, first for Edwin Beer and shortly thereafter for Edward L. Keyes, high frequency machines which employed electric current introduced through a specially designed cystoscope for the destruction of multiple growths in the urinary bladder. Within a comparatively short time this method became a standard for the treatment of bladder growths which were unquestionably benign, for it is simple enough to be readily employed by any physician who has had adequate training for this work. Thenceforward the history of vesical papillomatosis becomes a history of treatment. The surgeon is not so much concerned with pathological differentiation, he concentrates on methods of getting rid of the lesion, and looks forward to end-results rather than backward toward histological structure and etiology. ETIOLOGY
In common with other neoplastic growths, papilloma of the bladder has remained persistently an etiological mystery. Those who hold to the theory of local irritation point out the chemical and traumatic accidents to which the bladder is more or less constantly subjected as abundant reason why neoplastic growths are so often found in that cavity. From the outset of my medical career it has always seemed to me that new growths in the human body must arise from many different causes, depending upon factors of time, place or environment peculiar to each individual. No single etiological theory can be stretched to cover all these contingencies. To say that "cancer" is always due to any single cause is, to my mind, a logical impossibility. In regard to papillomatosis of the bladder, it has long been my conviction that it is due to afiltrable virus. The conception remained more or less nebulous in my mind until 1919, when Wile and Kingery published their investigation into the etiology of common warts. At the point of injection where they had introduced a filtrate made from curetted wart material these investigators obtained typical lesions of verruca. They concluded that these results, while not abolishing previous etiological conceptions, "definitely demonstrated that such changes can be
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THOMAS J. KIRWIN
caused by a :filtrable virus", and "when trauma and foreign bodies apparently are present as exciting factors, they may merely represent the point of entrance of an infectious agent." Applying these :(indings to the bladder wall, it is observable that papillomata have much in common with warts upon the cutaneous surface. The empty bladder lies in folds everywhere apposed, just as Crosse first described it; that is, presenting ideal conditions for tiontact infection, could it be established that these neoplasms have an infectious origin. Because we cannot examine the interior of the relaxed bladder in the living human subject, no positive confirmation has yet been possible, for experiments upon animals are · unsatisfactory. But considerable progress has been made upon the study of the problem, notably by Rous, Beard and Kidd at the Rockefeller Institute. In 1934 they began the investigation of the etiology of the so-called "Shope rabbit papilloma" (a growth known to be caused by a virus) with a view to determining whether it possessed the immediate characters and potentialities of a tumor. Shape's original description stated that "the growth as found on the skin of wild rabbits has the appearance of a papilloma and is devoid of inclusive bodies such as would indicate the presence of a virus." Rous and Beard found, however, that "rabbit papillomas developing on the skin as a result of virus inoculation can be readily transferred to the inner organs of favorable hosts by implanting bits of living tissue; that growths thus produced proliferate actively, and are often markedly invasive and destructive, tending to recur after excision. Most significant perhaps, is the statement, "Implantation growths of the papilloma in favorable hosts have the morphology of epidermoid tumors of greater or less malignancy. They behave as these do and elicit similar changes in the surrounding tissue." Rous, Beard and John G. Kidd extended these researches over a number of years. In 1936 they announced that all the strains of the virus causing rabbit papilloma which has been tested up to that time, if they give rise to vigorous, progressively enlarging papilloma in domestic rabbits,-could also be employed "as carcinogenic agents by way of these growths." They felt justified, therefore, in stating positively that "the virus-induced papilloma is not only a neoplasm in its immediate aspect and habit, but sometimes one that verges on malignancy." Beard has now been for some time at Duke University, where, with several associates, he has continued the endeavor to establish an infectious origin for certain types of papilloma. These investigators have recently succeeded in isolating from infectious extracts of growths from cotton-tail (wild) rabbits, a specific material exhibiting the biological characteristics of the recognized rabbit papilloma virus. "This macromolecular material .... behaves biologically as the virus responsible for the disease.'' In the findings just cited, I feel that my theory concerning the origin of bladder papilloma has received strong support. The impossibility of demonstrating these findings in the human subject necessarily lessens their value and weakens the strength of the hypothesis, but the conviction that in deciding upon treatment for papillomatosis of the bladder, we are seeking to conquer a virus, will influence our procedure and, it may be hoped, enable us to make greater headway in the control of neoplastic disease in general.
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THE EPITHELIUM. SUBEPITHELIAL CONNECTIVE TISSUE AND THE SUBMUCOSAL MUSCULATURE OF A URINARY BLADDER 15 MINUTES AFTER THE APPLICATION OF so% PHENOL IN GLY CERINE FOLLOWED BY ALCOHOL.
THE EPITHELIUM, SUBEPITHELIAL CONNECTIVE TISSUE ANO THE SUBMUCOSAL MUSCULATURE OF A NORMAL URINARY BLADDER.
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THE MUCOSA OF THE URINARY WEEK AFTER APPLICATION OF
BLADDER ONE PHENOL IN
THE MUCOSA OF T'HE URINARY BLADDER TWO WEEKS AFTER APPLICATION OF so % PHENOL IN GLYCERINE FOLLOWED BY ALCOHOL,
so'7o
GLYCERINE
FOLLOWED
BY
ALCOHOL.
3
6
THE
MUCOSA
OF
THE
URINARY
BLADDER
THREE
CROSS
WEEKS AFTER THE APPLICATION OF so% PHENOL IN GLYCERINE FOLLOWED BY ALCOHOL.
SECTION
OF
THE
WALL
OF
A
URIN A RY
BLADDER THREE WEEKS AFTER TREATMENT WITH PHENOL IN GLYCERINE FOLLOWED BY ALCOHOL.
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Fw. 1. Experimental results: E ffect upon dogs' bladders of phenol, glycerine a nd alcoh ol appli cations . 1, Epithelium , sub epithelia l connective tissue and submuco sal mu scul ature of a norma l urinary bladder. 2, M ucosa of urinary bladder 1 wee k aft er app lica t ion of 50 per cent phenol in glycerine followed by alcohol. 3, Mucosa of urina ry bladder 3 weeks after app li cation of 50 p er cent phenol in glycerine fo llowed by a lco hol. 4, E pithelium , sub epithelial connective tissue and submucosal musculature of urinary bladder 15 minutes a fter application of 50 per cent phenol in glycerine follo wed by a lcohol. 5, M ucosa of urinaryj bladd er 2 weeks after a pplication of 50 per ce nt phenol in glycerine fo ll owed by alco hol. •,;}6, Cross section of wall of urinary bladder 3 weeks after treatment with 50 p er cent phenol in glycerine fo llowed by alcohol . 5
FI X ATION
IN
10 %
F O RMALIN .
APPLI C ATI O N
OF 25 % PHEN O L IN FOR ONE MINUTE .
G LY C ERINE
2
4
A PPLI C ATION
OF so% PHEN O L IN F O R O NE M I NUTE .
G LY C ERINE
APPLI C ATION
OF 7 5 ';to PHENOL IN FOR ONE MINUTE .
GLYCERINE
APPLI C ATI O N OF PURE PHENOL FOR ONE MINUTE .
5
FIG . 2. E ff ect of p henol, 50 per cent , on papilloma of hum an bladder . 1, F ixation in 10 per cent fo rmalin . 2, Appli cation of 50 per cent p henol in glyce rine fo r 1 minute . 3, Applica tion of 25 per cen t p henol in glycerine fo r 1 m inu te. 4, Application of 75 per cent phenol in glycerine for 1 m in u te. 5, Application of pure p henol for 1 m inute. 6
PAPILLOMATOSIS OF BLADDER
7
ANI MAL EXPERIMEN TATION
If vesical papillomatosis be due to a virns, complete disinfection of all surfaces which may come in contact with the original disease is the logical way to prevent recurrence. To find out how such disinfection might best be accomplished, animal experimentation was undertaken, using phenol as the agent. The sections in figure 1 show: At upper left, normal bladder wall ; at upper right, epithelium, subepithelial connective tissue, and the submucosal musculature, 15 minutes after application of 50 per cent phenol in glycerine, followed by alcohol, 95 per cent. At loft center can be seen how the bladder wall appears one week following a similar treatment. The epithelium is absent, its place being t aken by acute inflammatory exudat e; mucosal connective tissue is t hick, edematous, hemorrhagic and profusely infiltrated with polyps; fibroblastic proliferation is active, but there is little inflammatory reaction in the musculature. At the middle right, 2 weeks after application, the acute inflammatory reaction has abated, and repair, characterized by regeneration of the epithelium, chronic inflammatory cell-infiltration, fibroblasti c proliferation, with superficial formation of collagen, is active. At lower loft and right a re 2 views of sections made 3 weeks after tho phenol-glycerine applications, followed by alcohol. In both horizontal and cross sections it can be seen that t he epithelium is completely regenerated, though small deposits of calcium are still visible in tho subepithelial connective tissue. Scarring and cellular infiltration of the mucosa are mild, while the regional musculature is quite normal. EFFECT ON HUMAN BLADDER
F igure 2 shows effect of phenol applications upon sections of human bladder wall and papillomatous growths after fixation in 10 per cent formalin . One minute exposure after 25, 50, 75, and 100 per cent phenol had been applied, is shown . TREATMENT
Up to tho t ime Edwin Beer instituted his treatment of benign bladder tumors by fulguration, there had been practically no means of combating t his frequently encountered vesical lesion. Beer's method became standard, and has remained so almost to the present day. But recurrences have been distressingly frequent and the method in other ways h as been far from satisfactory. In common with many other urologists, I have long sought for some way of gaining more effective control of this condition. If my conviction that bladder papillomatosis is due to infection by a filtrable virus is correct, t hen, I reasoned, our entire method of t reatment should be revised in conformity with it. Accordingly I have recently carried out complete removal of the papillary growths with the cutting current, instead of the fulguration technique commonly employed; that is, excision , rather than destruction in sil'u. The bladder is opened by a midline incision and the growths are removed with a wire electrode, the exposed bases being then cauterized by application of the ball
8
THOMAS J . KIRWIK
3
4
Tumor
5
Necros is
f'ollawin.S f'ul 8uralion.
FIG. 3. P a pilloma of t h e bla dder: Preoperative cystoscopic views. First 5 views sh ow sm all papillomata on anteri or vesical wall. Air bubble visible in 3, 4, 5 . At 6 a tumor is seen in an ar ea of necrosis at base, near ri ght ureter and trigone .
electrode. The next step is to apply a solution of 50 per cent phenol2 in glycerine, not only to the areas from which growths have been removed , but also t o the mucosa of the ureteral orifices, prostatic urethra and bladder cavity throughout, 2 We ar e now experimen t ing wit h other disinfectan ts, bu t so far have found none equal to phenol.
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PAPILLOMA'.rOSIS OF BLADDER
t hus st erilization of all possible sit es of recurrence is assured . Mr. Didusch 's excellent drawings depict a t ypical case with the various steps of operation. The colored plate (fig. 3) shows the anterior bladder wall scattered over with small papillomata (1 , 2, 3, 4, and 5) . At 6, a t umor can be seen on t he base of the bladder, near the trigone, at t he right ureteral orifice. T here is an area of necrosis on the surface of the growth. Figure 4 shows the procedure of removal and cauterization. T hrough the suprapubic incision (1 ) the bladder is opened with the straight wire electrode (2),
2
ln.rnin~ bladder with l ':>traibht. wire electrode I
I
I
'I
I
FIG. 4. Operation for remova l of vesical papilloma . 1, Midline suprapubic incision. 2, Bladder being opened with straight wire electrode, exposing sma ll t umors on anterior vesical wa ll, and la rger growth in necrotic area at bla dder base.
exposing several small tumors on the anterior vesical wall, and a large t umor with an area of necrosis at the base of the bladder. The edges of t he incision are shown protected by gauze, as an additional precaution against the spread of an infectious condition. In a personal communication, Elmer Belt suggested the substitution of rubber for the gauze, a practice which I intend in future to adopt. In figure 5, the wire elect rode is seen in use for the removal of one of the small growths. The large tumor at the base has been treated in the same manner. The wire loop removes neoplastic tissue down to t he muscularis; t he bleeding
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THOMAS J . KIRWIN
FIG. 5. Operation for removal of vesical papilloma. 1, Small papilloma being removed with wire loop electrode, tissue excised clown to muscula ris, bleeding points coagulated with ball electrode. (Large tumor at base has been treated in sam e manner. ) 2, Application of 50 per cent phenol in glycerine in prostatic urethra, entire wall and cut edges of bladder, to be followed by application of 95 per cent alcohol.
FIG. 6. Operation for removal of vesical papilloma. 1, Bladder is closed around drainage tube; another drain is placed in space of Retzius . 2, Final closure of wound with drain in place.
PAPILLOMATOSIS OF BLADDER
11
points are coagulated with the ball electrode (1) . No. 2 shows the tumor removed. A 50 per cent solution of phenol in glycerine is applied to the entire vesical wall, to the cut edge of the midline incision, and to the mucosa surrounding it. The solution is allowed to remain about t hree minutes. This is followed by the application of 95 per cent alcohol to the bladder wound. Figure 6 indicates the placing of drainage in the space of Retzius, with method of final closure (2), with drain in place. This completes a method of treatment
1
'B ladder' 1 f-ree ot lurnor
Condi lion. e,th.t mant~~ f o\\owi n. 0 ope.ration..
Fw. 7. Postoperative cystoscopic views. 1, Condition 6 weeks after removal of papillomata and application of phenol and alcohol. Cystitis is marked. 2 , Condition 8 months after operation; mucosa is slightly pale, but no evidence of recurrence.
carried out in accordance with the etiologic conception of a virus as the causal factor . Figure 7 shows the condition 6 weeks and also 8 months after operation. SUMMARY
1. Vesical papillomatosis is the t erm applied to a condition of the bladder wherein multiple papillomata appear upon the mucosa. Histologically, it does not differ from solitary growths of the same structure. 2. Though recognized clinically for more than a century, papilloma of the bladder was regarded as primarily malignant and seldom cured, until the high frequency current gave a treatment which produced some clinical cures early in the twentieth century, yet was far from entirely satisfactory.
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THOMAS J . KIRWIK
3. My conviction that vesical papillomatosis is due to a virus has received support and confirmation in the work of 'Wile and Kingery on the etiology of common warts, and the more recent demonstration of Beard and his co-workers at Duke University that a "specific material" exhibiting the biological characteristics of the virus responsible for rabbit papilloma could be obtained from extracts made from the growths themselves. 4. In accordance with this conception I undertook the treatment of four cases of vesical papillomatosis by excision of the growths with the wire-loop electrode, cauterization of the bases with the ball electrode, and sterilization of the bladder mucosa by application of a 50 per cent solution of phenol in glycerine, followed by alcohol 95 per cent, when the phenol solution has been in contact with the mucosa for about three minutes. The various steps of the operation are shown in illustrations by William P. Didusch. 5. This new etiologic conception and the method of treatment as an infectious condition are, so far as I am aware, now presented for the first time, as a contribution toward the control of neoplastic growths in the vesical cavity, and the suppression of neoplastic disease in general. CONCLUSION
From so few cases it is, of course, quite impossible to draw definite conclusions. I have no intention of claiming great originality in the application of this method. Neither do I wish to assume the position of having proved beyond doubt that my theory of the infectious nature of bladder papillomatosis has been demonstrated . But I do most sincerely hope that the results so far attained with the method will recommend it to competent urologists throughout the country so that it will be given sufficient clinical trial to prove its worth. For should the method fulfil the promise it has given in my hands, it will go far toward solving one of the most vexatious problems presented by vesical surgery. ACKNOWLEDGEMENT
The work reported in the preceding pages has been possible only through the never-failing ·courtesy of Dr. Oswald Swinney Lowsley, director of the Brady Foundation for Urology of the New York Hospital, who not only actively aided me, but placed all the facilities of his department at my disposal. I am most grateful also for the continued cooperation and assistance of Dr. Anthony N . Spinnelli of the Brady Foundation and the Urological Department of City Hospital; of Dr. Joseph Menning of the Brady Foundation; of Dr. James R. Lisa, pathologist at City Hospital; and of Dr. George M. Hass, assistant professor of pathology, Cornell University Medical School. It is a pleasure to acknowledge my indebtedness to these good friends and co-workers.
1 E. 63rd St., New York, N. Y. REFERENCES ALBARRAN , J .: Medecine operatoire des voies urinaires. Paris: Masson et Cie, 1909. BEARD, J. W. et al.: The nature of a virus associated with carcinoma in rabbits. Surg. , Gynec. , & Obst., 74: 509 , 1942. BEER, EDWIN: Removal of neoplasms of the urinary bladder; a new method, etc . J . A. M. A. , 54: 1768, 1910.
PAPILLOMATOSIS OF BLADDER
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BIRKETT, JoHN: A case of fibrous polypus of the urinary bladder, etc. Med.-Chir. Trans., 41: 311, 1858. CROSSE, J. G.: Urinary calculus. Jacksonian Prize Essay, 1833. GRoss, S. D.: Practical treatise on ... diseases of the bladder. Phila. Blanchard & Lea, 1855. GUYON, L. C. FELIX: Le9ons cliniques sur les maladies des voies urinaires. Paris: J. B. Baillaire et Fils, 2nd ed., 1885. HUDSON, R. S.: Villous disease (papillary fibroma) of the bladder. Dublin J. Med. Sc., 67: 490, 1879. KEYES, E. L.: Preliminary report on the treatment of bladder tumors by high frequency current. Trans. Am. Assoc. Genito-Urin. Surg., 5: 193, 1910. Rous, PEYTON: The virus tumors and the tumor problem. Am. J. Cancer, 28: 236, 1936. Rous, P., AND BEARD, J. W.: A virus-induced mamillian growth, with the character of a tumor (the Shope rabbit papilloma). J. Exp. Med., 60: 701, 1934. Rous, P., BEARD, J. W., AND KIDD, J. G.: Observations on the relation of the virus causing rabbit papilloma to the cancers deriving therefrom. II. The evidence provided by the tumor; general considerations. J. Exp. Med., 64: 401, 1936. STEIN, A. W.: Study of the tumors of the bladder. N. Y., Wm. Wood & Company, 1881. THOMPSON, Sm HENRY: Tumours of the bladder. London, 1884. WILE, U. J., AND KINGERY, L. B.: Etiology of common warts. J. A. M. A., 13: 970, 1919.
Vesical papillomata may be single or multiple. When many small growths occur together, or :in rapid sequence, the condition is termed papillomatosis. Histologically, there is no difference between the single and the multiple forms. HISTORY
The first description of vesical papillomatosis I have been able to find in the literature is that given by John Green Crosse in his 1833 Jacksonian Prize essay on Urinary Calculus. In the bladder of a male infant aged 18 months he found the "cavity filled with soft tumors ..... The fatal disease occupied the lining membrane of the bladder, which was loosely connected with the muscular coat and very abundant so as to fall into folds, also thicker than usual, and having a gelatinous appearance ..... One large tumor with a broad basis, was firmer than the rest, and placed near the termination of the left ureter ..... Several small detached tumors, from the size of a pea to that of a bean, were loose in the bladder .... all the tumors were covered with their proper membrane, continuous with the inner coat of the bladder ..... " In his treatise on Diseases of the Urinary Blad,der, first published in 1851, Samuel D. Gross, who may be ranked as the first American urologist, in our modem acceptance of that term, copied this "exceedingly instructive case" verbatim. He added several other instances of vesical neoplasm, taken from European literature, together with a description of what he called "a peculiar fungous growth, a species of vegetation of the mucous membrane [which] .... varies in its size from that of a pea to that of a pullet's egg, and is of a soft and spongy consistence, with rough, fimbriated, or villous surface. In some instances .... it occurs in considerable numbers, so as to stud the greater part of the surface of the bladder. Its form is generally globular, ovoidal, or pediculated, and its color is commonly a few shades redder than that of the mucous membrane upon which it rests, and from which it arises." Gross evidently did not think this "fungous" growth was in any way akin to the growths described by Crosse 10 years previously. Seven years after Gross's textbook appeared, John Birkett, surgeon to Guy's Hospital, read before the Medico-Chirurgical Society of London, the account of a case of "fibrous polypus of the urinary bladder," which he was careful to differentiate from both "papilloma" and "epithelioma." He failed, however, to provide us with the histological details which would have enabled modern pathologists correctly to classify the case which he proceeded to describe and compare 1 Read before the annual meeting of the American Urological Association, New York, N. Y., June 3, 1942. 1
2
THOMAS J. KIRWIN
with that earlier reported by Crosse. Birkett's patient was a little girl of 5 years. At autopsy he found tumors "growing from the internal surface of the anterior wall of the bladder, reaching as low as the meatus, and extending on the sides to the junction of the anterior two-thirds with the inferior third of the viscus. They consisted .... of distinct growths, approximated together, and having more or less of the polypoid form .... taken together they formed a conical or pyriform mass, the apex of which was attached to the vesical orifice of the urethra, and the base was free in the bladder ..... All the growths had their seat in the mucous membrane and submucous connective tissue, the former extending over their surfaces." Pathologic differentiation had progressed far enough in 1879 to permit Robert S. Hudson, when he published his case in the Dublin Journal of Medical Science, to use the title "Villous Disease (Papillary Fibroma) of the Bladder." At autopsy upon a 54-year old man, there were found in the bladder "eight tumors, each connected by a narrow pedicle ..... When .... a portion of the tumor floated out in water, its true character was seen-delicate, lace-like growths springing from a firm fleshy pedicle .... " Hudson's object in reporting his case and citing others from the literature was to demonstrate the feasibility of operating for the removal of such tumors from the male bladder, as had already been done in female cases. In this connection he cited the work of 'Professor Simon of Heidelberg, who has scraped off papillary fibromas in three cases, with recovery in each, although in one the bladder was nearly two-thirds filled with these growths'. I have been unable to find any references to these cases in Simon's publications on bladder tumors, but feel they may be reasonably accepted on Hudson's authority. The entire subject of bladder tumors was, however, much misunderstood and neglected up to 1881, when Stein "brought together and classified 60 cases of benign papillomatous, villous and polypoid growths .... true villous structures., closely resembling the villi of the chorion .... placed in water the villiosities are floated out and present a beautiful and characteristic appearance .... the larger villi branch out from the central mass .... some being thick and short .... some appear as pendulous tumors hanging from a distinct stalk or pedicle, and terminate in numerous filamentous processes. Others are sessile and .... may appear as soft, loose, shaggy villous tufts, projecting more or less from the mucous surface, or they may have a more solid basic structure and present a warty or cauliflower-like appearance ..... Villous growths are usually benign. In structure they do not partake of the character of malignant tumors ..... They do not cause death by malignant cachexia, but from hemorrhage, or from the consequences of mechanical obstruction to the outflow of urine." Sir Henry Thompson's monograph on Tumours of the Bladder, though primarily surgical, still shows that the understanding of the pathology of these growths had greatly advanced by the date of its publication, 1884. "It may fairly beinferred,"he tells us, "that the commonest species of tumour affecting the adult bladder are papillomata ... [which] .... have certainly no malignant tendencies, but their disposition to increase and fill the cavity of the bladder, and
PAPILLOMATOSIS OF BLADDER
3
thus to disintegrate at their periphery, together with their vascularity and consequent strong disposition to bleed largely, render them sooner or later invariably fatal." The French urologists of the last years of the nineteenth century, chief among whom were Guyon and his pupil, Albarran, were careful to insist upon the histological benignity of vesical papillomata, though Guyon does speak of "pseudopapillomas (villous epitheliomas and carcinomas, fibrous polyps, etc.) .... among them many may be found which are of a malignant nature." During the last decade of the nineteenth century and the first of the twentieth, the study of all kinds of neoplastic growths made great strides, but the condition now known as vesical papillomatosis was seldom mentioned. Every sort of bladder growth was regarded as malignant, and it was not until the cystoscope in its more modern form became a regular part of the diagnostician's equipment that the existence of benign bladder growths was definitely established, and their differentiation from malignant tumors placed on a scientific basis. In.the year 1910, the late Reinhold Wappler designed, first for Edwin Beer and shortly thereafter for Edward L. Keyes, high frequency machines which employed electric current introduced through a specially designed cystoscope for the destruction of multiple growths in the urinary bladder. Within a comparatively short time this method became a standard for the treatment of bladder growths which were unquestionably benign, for it is simple enough to be readily employed by any physician who has had adequate training for this work. Thenceforward the history of vesical papillomatosis becomes a history of treatment. The surgeon is not so much concerned with pathological differentiation, he concentrates on methods of getting rid of the lesion, and looks forward to end-results rather than backward toward histological structure and etiology. ETIOLOGY
In common with other neoplastic growths, papilloma of the bladder has remained persistently an etiological mystery. Those who hold to the theory of local irritation point out the chemical and traumatic accidents to which the bladder is more or less constantly subjected as abundant reason why neoplastic growths are so often found in that cavity. From the outset of my medical career it has always seemed to me that new growths in the human body must arise from many different causes, depending upon factors of time, place or environment peculiar to each individual. No single etiological theory can be stretched to cover all these contingencies. To say that "cancer" is always due to any single cause is, to my mind, a logical impossibility. In regard to papillomatosis of the bladder, it has long been my conviction that it is due to afiltrable virus. The conception remained more or less nebulous in my mind until 1919, when Wile and Kingery published their investigation into the etiology of common warts. At the point of injection where they had introduced a filtrate made from curetted wart material these investigators obtained typical lesions of verruca. They concluded that these results, while not abolishing previous etiological conceptions, "definitely demonstrated that such changes can be
4
THOMAS J. KIRWIN
caused by a :filtrable virus", and "when trauma and foreign bodies apparently are present as exciting factors, they may merely represent the point of entrance of an infectious agent." Applying these :(indings to the bladder wall, it is observable that papillomata have much in common with warts upon the cutaneous surface. The empty bladder lies in folds everywhere apposed, just as Crosse first described it; that is, presenting ideal conditions for tiontact infection, could it be established that these neoplasms have an infectious origin. Because we cannot examine the interior of the relaxed bladder in the living human subject, no positive confirmation has yet been possible, for experiments upon animals are · unsatisfactory. But considerable progress has been made upon the study of the problem, notably by Rous, Beard and Kidd at the Rockefeller Institute. In 1934 they began the investigation of the etiology of the so-called "Shope rabbit papilloma" (a growth known to be caused by a virus) with a view to determining whether it possessed the immediate characters and potentialities of a tumor. Shape's original description stated that "the growth as found on the skin of wild rabbits has the appearance of a papilloma and is devoid of inclusive bodies such as would indicate the presence of a virus." Rous and Beard found, however, that "rabbit papillomas developing on the skin as a result of virus inoculation can be readily transferred to the inner organs of favorable hosts by implanting bits of living tissue; that growths thus produced proliferate actively, and are often markedly invasive and destructive, tending to recur after excision. Most significant perhaps, is the statement, "Implantation growths of the papilloma in favorable hosts have the morphology of epidermoid tumors of greater or less malignancy. They behave as these do and elicit similar changes in the surrounding tissue." Rous, Beard and John G. Kidd extended these researches over a number of years. In 1936 they announced that all the strains of the virus causing rabbit papilloma which has been tested up to that time, if they give rise to vigorous, progressively enlarging papilloma in domestic rabbits,-could also be employed "as carcinogenic agents by way of these growths." They felt justified, therefore, in stating positively that "the virus-induced papilloma is not only a neoplasm in its immediate aspect and habit, but sometimes one that verges on malignancy." Beard has now been for some time at Duke University, where, with several associates, he has continued the endeavor to establish an infectious origin for certain types of papilloma. These investigators have recently succeeded in isolating from infectious extracts of growths from cotton-tail (wild) rabbits, a specific material exhibiting the biological characteristics of the recognized rabbit papilloma virus. "This macromolecular material .... behaves biologically as the virus responsible for the disease.'' In the findings just cited, I feel that my theory concerning the origin of bladder papilloma has received strong support. The impossibility of demonstrating these findings in the human subject necessarily lessens their value and weakens the strength of the hypothesis, but the conviction that in deciding upon treatment for papillomatosis of the bladder, we are seeking to conquer a virus, will influence our procedure and, it may be hoped, enable us to make greater headway in the control of neoplastic disease in general.
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THE EPITHELIUM. SUBEPITHELIAL CONNECTIVE TISSUE AND THE SUBMUCOSAL MUSCULATURE OF A URINARY BLADDER 15 MINUTES AFTER THE APPLICATION OF so% PHENOL IN GLY CERINE FOLLOWED BY ALCOHOL.
THE EPITHELIUM, SUBEPITHELIAL CONNECTIVE TISSUE ANO THE SUBMUCOSAL MUSCULATURE OF A NORMAL URINARY BLADDER.
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THE MUCOSA OF THE URINARY WEEK AFTER APPLICATION OF
BLADDER ONE PHENOL IN
THE MUCOSA OF T'HE URINARY BLADDER TWO WEEKS AFTER APPLICATION OF so % PHENOL IN GLYCERINE FOLLOWED BY ALCOHOL,
so'7o
GLYCERINE
FOLLOWED
BY
ALCOHOL.
3
6
THE
MUCOSA
OF
THE
URINARY
BLADDER
THREE
CROSS
WEEKS AFTER THE APPLICATION OF so% PHENOL IN GLYCERINE FOLLOWED BY ALCOHOL.
SECTION
OF
THE
WALL
OF
A
URIN A RY
BLADDER THREE WEEKS AFTER TREATMENT WITH PHENOL IN GLYCERINE FOLLOWED BY ALCOHOL.
so%
Fw. 1. Experimental results: E ffect upon dogs' bladders of phenol, glycerine a nd alcoh ol appli cations . 1, Epithelium , sub epithelia l connective tissue and submuco sal mu scul ature of a norma l urinary bladder. 2, M ucosa of urinary bladder 1 wee k aft er app lica t ion of 50 per cent phenol in glycerine followed by alcohol. 3, Mucosa of urina ry bladder 3 weeks after app li cation of 50 p er cent phenol in glycerine fo llowed by a lco hol. 4, E pithelium , sub epithelial connective tissue and submucosal musculature of urinary bladder 15 minutes a fter application of 50 per cent phenol in glycerine follo wed by a lcohol. 5, M ucosa of urinaryj bladd er 2 weeks after a pplication of 50 per ce nt phenol in glycerine fo ll owed by alco hol. •,;}6, Cross section of wall of urinary bladder 3 weeks after treatment with 50 p er cent phenol in glycerine fo llowed by alcohol . 5
FI X ATION
IN
10 %
F O RMALIN .
APPLI C ATI O N
OF 25 % PHEN O L IN FOR ONE MINUTE .
G LY C ERINE
2
4
A PPLI C ATION
OF so% PHEN O L IN F O R O NE M I NUTE .
G LY C ERINE
APPLI C ATION
OF 7 5 ';to PHENOL IN FOR ONE MINUTE .
GLYCERINE
APPLI C ATI O N OF PURE PHENOL FOR ONE MINUTE .
5
FIG . 2. E ff ect of p henol, 50 per cent , on papilloma of hum an bladder . 1, F ixation in 10 per cent fo rmalin . 2, Appli cation of 50 per cent p henol in glyce rine fo r 1 minute . 3, Applica tion of 25 per cen t p henol in glycerine fo r 1 m inu te. 4, Application of 75 per cent phenol in glycerine for 1 m in u te. 5, Application of pure p henol for 1 m inute. 6
PAPILLOMATOSIS OF BLADDER
7
ANI MAL EXPERIMEN TATION
If vesical papillomatosis be due to a virns, complete disinfection of all surfaces which may come in contact with the original disease is the logical way to prevent recurrence. To find out how such disinfection might best be accomplished, animal experimentation was undertaken, using phenol as the agent. The sections in figure 1 show: At upper left, normal bladder wall ; at upper right, epithelium, subepithelial connective tissue, and the submucosal musculature, 15 minutes after application of 50 per cent phenol in glycerine, followed by alcohol, 95 per cent. At loft center can be seen how the bladder wall appears one week following a similar treatment. The epithelium is absent, its place being t aken by acute inflammatory exudat e; mucosal connective tissue is t hick, edematous, hemorrhagic and profusely infiltrated with polyps; fibroblastic proliferation is active, but there is little inflammatory reaction in the musculature. At the middle right, 2 weeks after application, the acute inflammatory reaction has abated, and repair, characterized by regeneration of the epithelium, chronic inflammatory cell-infiltration, fibroblasti c proliferation, with superficial formation of collagen, is active. At lower loft and right a re 2 views of sections made 3 weeks after tho phenol-glycerine applications, followed by alcohol. In both horizontal and cross sections it can be seen that t he epithelium is completely regenerated, though small deposits of calcium are still visible in tho subepithelial connective tissue. Scarring and cellular infiltration of the mucosa are mild, while the regional musculature is quite normal. EFFECT ON HUMAN BLADDER
F igure 2 shows effect of phenol applications upon sections of human bladder wall and papillomatous growths after fixation in 10 per cent formalin . One minute exposure after 25, 50, 75, and 100 per cent phenol had been applied, is shown . TREATMENT
Up to tho t ime Edwin Beer instituted his treatment of benign bladder tumors by fulguration, there had been practically no means of combating t his frequently encountered vesical lesion. Beer's method became standard, and has remained so almost to the present day. But recurrences have been distressingly frequent and the method in other ways h as been far from satisfactory. In common with many other urologists, I have long sought for some way of gaining more effective control of this condition. If my conviction that bladder papillomatosis is due to infection by a filtrable virus is correct, t hen, I reasoned, our entire method of t reatment should be revised in conformity with it. Accordingly I have recently carried out complete removal of the papillary growths with the cutting current, instead of the fulguration technique commonly employed; that is, excision , rather than destruction in sil'u. The bladder is opened by a midline incision and the growths are removed with a wire electrode, the exposed bases being then cauterized by application of the ball
8
THOMAS J . KIRWIK
3
4
Tumor
5
Necros is
f'ollawin.S f'ul 8uralion.
FIG. 3. P a pilloma of t h e bla dder: Preoperative cystoscopic views. First 5 views sh ow sm all papillomata on anteri or vesical wall. Air bubble visible in 3, 4, 5 . At 6 a tumor is seen in an ar ea of necrosis at base, near ri ght ureter and trigone .
electrode. The next step is to apply a solution of 50 per cent phenol2 in glycerine, not only to the areas from which growths have been removed , but also t o the mucosa of the ureteral orifices, prostatic urethra and bladder cavity throughout, 2 We ar e now experimen t ing wit h other disinfectan ts, bu t so far have found none equal to phenol.
9
PAPILLOMA'.rOSIS OF BLADDER
t hus st erilization of all possible sit es of recurrence is assured . Mr. Didusch 's excellent drawings depict a t ypical case with the various steps of operation. The colored plate (fig. 3) shows the anterior bladder wall scattered over with small papillomata (1 , 2, 3, 4, and 5) . At 6, a t umor can be seen on t he base of the bladder, near the trigone, at t he right ureteral orifice. T here is an area of necrosis on the surface of the growth. Figure 4 shows the procedure of removal and cauterization. T hrough the suprapubic incision (1 ) the bladder is opened with the straight wire electrode (2),
2
ln.rnin~ bladder with l ':>traibht. wire electrode I
I
I
'I
I
FIG. 4. Operation for remova l of vesical papilloma . 1, Midline suprapubic incision. 2, Bladder being opened with straight wire electrode, exposing sma ll t umors on anterior vesical wa ll, and la rger growth in necrotic area at bla dder base.
exposing several small tumors on the anterior vesical wall, and a large t umor with an area of necrosis at the base of the bladder. The edges of t he incision are shown protected by gauze, as an additional precaution against the spread of an infectious condition. In a personal communication, Elmer Belt suggested the substitution of rubber for the gauze, a practice which I intend in future to adopt. In figure 5, the wire elect rode is seen in use for the removal of one of the small growths. The large tumor at the base has been treated in the same manner. The wire loop removes neoplastic tissue down to t he muscularis; t he bleeding
10
THOMAS J . KIRWIN
FIG. 5. Operation for removal of vesical papilloma. 1, Small papilloma being removed with wire loop electrode, tissue excised clown to muscula ris, bleeding points coagulated with ball electrode. (Large tumor at base has been treated in sam e manner. ) 2, Application of 50 per cent phenol in glycerine in prostatic urethra, entire wall and cut edges of bladder, to be followed by application of 95 per cent alcohol.
FIG. 6. Operation for removal of vesical papilloma. 1, Bladder is closed around drainage tube; another drain is placed in space of Retzius . 2, Final closure of wound with drain in place.
PAPILLOMATOSIS OF BLADDER
11
points are coagulated with the ball electrode (1) . No. 2 shows the tumor removed. A 50 per cent solution of phenol in glycerine is applied to the entire vesical wall, to the cut edge of the midline incision, and to the mucosa surrounding it. The solution is allowed to remain about t hree minutes. This is followed by the application of 95 per cent alcohol to the bladder wound. Figure 6 indicates the placing of drainage in the space of Retzius, with method of final closure (2), with drain in place. This completes a method of treatment
1
'B ladder' 1 f-ree ot lurnor
Condi lion. e,th.t mant~~ f o\\owi n. 0 ope.ration..
Fw. 7. Postoperative cystoscopic views. 1, Condition 6 weeks after removal of papillomata and application of phenol and alcohol. Cystitis is marked. 2 , Condition 8 months after operation; mucosa is slightly pale, but no evidence of recurrence.
carried out in accordance with the etiologic conception of a virus as the causal factor . Figure 7 shows the condition 6 weeks and also 8 months after operation. SUMMARY
1. Vesical papillomatosis is the t erm applied to a condition of the bladder wherein multiple papillomata appear upon the mucosa. Histologically, it does not differ from solitary growths of the same structure. 2. Though recognized clinically for more than a century, papilloma of the bladder was regarded as primarily malignant and seldom cured, until the high frequency current gave a treatment which produced some clinical cures early in the twentieth century, yet was far from entirely satisfactory.
12
THOMAS J . KIRWIK
3. My conviction that vesical papillomatosis is due to a virus has received support and confirmation in the work of 'Wile and Kingery on the etiology of common warts, and the more recent demonstration of Beard and his co-workers at Duke University that a "specific material" exhibiting the biological characteristics of the virus responsible for rabbit papilloma could be obtained from extracts made from the growths themselves. 4. In accordance with this conception I undertook the treatment of four cases of vesical papillomatosis by excision of the growths with the wire-loop electrode, cauterization of the bases with the ball electrode, and sterilization of the bladder mucosa by application of a 50 per cent solution of phenol in glycerine, followed by alcohol 95 per cent, when the phenol solution has been in contact with the mucosa for about three minutes. The various steps of the operation are shown in illustrations by William P. Didusch. 5. This new etiologic conception and the method of treatment as an infectious condition are, so far as I am aware, now presented for the first time, as a contribution toward the control of neoplastic growths in the vesical cavity, and the suppression of neoplastic disease in general. CONCLUSION
From so few cases it is, of course, quite impossible to draw definite conclusions. I have no intention of claiming great originality in the application of this method. Neither do I wish to assume the position of having proved beyond doubt that my theory of the infectious nature of bladder papillomatosis has been demonstrated . But I do most sincerely hope that the results so far attained with the method will recommend it to competent urologists throughout the country so that it will be given sufficient clinical trial to prove its worth. For should the method fulfil the promise it has given in my hands, it will go far toward solving one of the most vexatious problems presented by vesical surgery. ACKNOWLEDGEMENT
The work reported in the preceding pages has been possible only through the never-failing ·courtesy of Dr. Oswald Swinney Lowsley, director of the Brady Foundation for Urology of the New York Hospital, who not only actively aided me, but placed all the facilities of his department at my disposal. I am most grateful also for the continued cooperation and assistance of Dr. Anthony N . Spinnelli of the Brady Foundation and the Urological Department of City Hospital; of Dr. Joseph Menning of the Brady Foundation; of Dr. James R. Lisa, pathologist at City Hospital; and of Dr. George M. Hass, assistant professor of pathology, Cornell University Medical School. It is a pleasure to acknowledge my indebtedness to these good friends and co-workers.
1 E. 63rd St., New York, N. Y. REFERENCES ALBARRAN , J .: Medecine operatoire des voies urinaires. Paris: Masson et Cie, 1909. BEARD, J. W. et al.: The nature of a virus associated with carcinoma in rabbits. Surg. , Gynec. , & Obst., 74: 509 , 1942. BEER, EDWIN: Removal of neoplasms of the urinary bladder; a new method, etc . J . A. M. A. , 54: 1768, 1910.
PAPILLOMATOSIS OF BLADDER
13
BIRKETT, JoHN: A case of fibrous polypus of the urinary bladder, etc. Med.-Chir. Trans., 41: 311, 1858. CROSSE, J. G.: Urinary calculus. Jacksonian Prize Essay, 1833. GRoss, S. D.: Practical treatise on ... diseases of the bladder. Phila. Blanchard & Lea, 1855. GUYON, L. C. FELIX: Le9ons cliniques sur les maladies des voies urinaires. Paris: J. B. Baillaire et Fils, 2nd ed., 1885. HUDSON, R. S.: Villous disease (papillary fibroma) of the bladder. Dublin J. Med. Sc., 67: 490, 1879. KEYES, E. L.: Preliminary report on the treatment of bladder tumors by high frequency current. Trans. Am. Assoc. Genito-Urin. Surg., 5: 193, 1910. Rous, PEYTON: The virus tumors and the tumor problem. Am. J. Cancer, 28: 236, 1936. Rous, P., AND BEARD, J. W.: A virus-induced mamillian growth, with the character of a tumor (the Shope rabbit papilloma). J. Exp. Med., 60: 701, 1934. Rous, P., BEARD, J. W., AND KIDD, J. G.: Observations on the relation of the virus causing rabbit papilloma to the cancers deriving therefrom. II. The evidence provided by the tumor; general considerations. J. Exp. Med., 64: 401, 1936. STEIN, A. W.: Study of the tumors of the bladder. N. Y., Wm. Wood & Company, 1881. THOMPSON, Sm HENRY: Tumours of the bladder. London, 1884. WILE, U. J., AND KINGERY, L. B.: Etiology of common warts. J. A. M. A., 13: 970, 1919.