Carcinoma in Situ of the Bladder in Workers Exposed to Xenylamine: Diagnosis by Ultraviolet Light Cystoscopy

Vol. 99, Feb. Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1968 by The Williams & Wilkins Co.

CARCIKOl\IA IN SITU OF THE BLADDER IN WORKERS EXPOSED TO XENYLAl\IINE: DIAGNOSIS BY ULTRAVIOLET LIGHT CYSTOSCOPY

w.

F. MELICK

AND

J. J. NARYKA

From the Department of Urology, St. Louis Universi·ty School of il1edicine, St. Louis, Missouri

In 1955 we reported on a group of chemical workers who had been exposed to a new chemical bladder carcinogen.1 In 1954, Walpole and associates reported on the production of bladder tumors in dogs after the ingestion of the same chemical 4-aminodiphenyl (xenylamine) ;2 this work was later confirmed by Deichmann and associates. 3 Initially all of the exposed workers were subjected to routine observation cystoscopy if they were found free of tumors at the initial cystoscopy. Eighteen men had bladder tumors on the first cystoscopy. These patients usually underwent cystoscopy every 3 months after removal of the tumor until they had been free of the tumor for 1 year, then every 6 months for the second year, and tln.en yearly, unless new tumors appeared. At the end of 5 years there were 25 men in whom bladder tumors had developed. 4 It has been shown by direct bladder implantation into rats that the actual bladder carcinogen is a metabolite, most likely 3-amino-4-biphenyl. 5 Most of the tumors were managed by transurethral resection. We have attempted to keep records of the sites of tumor development and the dates when the diagnosis was made. It is indeed unfortunate that the term recurrent tumor is used so loosely. We believe that the term recurAccepted for publication February 3, 1967. Read at annual meeting of South Central Section, American Urological Association, Inc., Mexico City, Mexico, October 16-22, 1966. 1 Melick, W. F., Escue, H. M., Naryka, J. J., Mezera, R. A. and Wheeler, E. P.: The first reported cases of human bladder tumors due to a new carcinogen-xenylamine. J. Urol., 74: 760, 1955. 2 Walpole, A. L., Williams, M. H. C. and Roberts, D. C.: Tumours of the urinary bladder in dogs after ingestion of 4-aminodiphenyl. Brit. J. Indust. Med., 11: 105, 19.54. 3 Deichmann, W. B., Coplan, JVI. M., Woods, F. M., Anderson, W. A. D., Heslin, J. and Radomski, J.: The carcinogenic action of p-aminobiphenyl in the dog. Arch. Indust. Health, 13: 8, 19.~6. 4 Melick, W. F. and Naryka, J. J.: Xenylamine (para-aminobiphenyl) bladder tumors in man. Acta Un. Int. Cancer, 16: 277, 1960. 5 Bonser, G. JVI., Clayson, D. B., Juli, J. W. and Pyrah, L. N.: Experimental aspects of industrial bladder cancer. Brit. J. Urol., 26: 49, 1954.

rent tumor should be reserved for cases in which the tumor is found in the same or adjacent marginal sites on subsequent cystoscopic examinations. It would, of course, imply inadequate tumor removal, which may happen to anyone if he removes enough tumors transurethrally. If the tumor is found on subsequent examination in a totally different area, it is, in our opinion, a new growth. It is also possible that this tumor was missed on the previous cystoscopy. The size of the tumor would allow an honest evaluation of whether it might have been present on the previous cystoscopy. In the few patients in this group in whom total cystectomy has been done, plus all other cystectomies we have done for carcinoma, total bladder sections have been made, and almost without exception, other tumor changes have been found in areas widely apart from the primary tumor. This is not original with us and much has been written about this particular problem with bladder tumors, 6 but we are in agreement with the multifocal theory of bladder carcinoma in the majority of cases. We do know that in this group of patients, tumors most certainly have appeared at different times and at widely different places in the bladder. Given equal exposure to a known potent chemical carcinogen we have no idea why tumors should appear at different sites at different times, but our observations during the past 13 years permit no other concept. There are many clinical examples of individual susceptibility or resistance. In some of the workers who were equally exposed, as far as it is possible to determine tumors have not developed, while in others who worked far briefer periods in this particular depart1nent, tumors have developed. 1Ve hesitate to mention single exam.pies of environment, but two of the workers who worked in the department as partners, lived next door to each other and took their vacations together: in one, tumors developed that were invasive enough to require cystectomy while the other has had a normal bladder to date. 6 Hinman, F.: The recurrence of bladder tumors. J. Urol., 83: 294, 1960.

178

IN SITU BLADDER CARCINOMA IN WORKERS EXPOSED TO XENYLAMISE

FIG. 1. Cai:cinoma in situ, biopsy specimen. Les10n approximately 3 mm. in diameter.

With the perfection and use of the Papanicolaou smear as an additional diagnostic aid in similar chemical workers in England, 7 this routine examination was also added as part of the followup evaluation of this group of patients. We are particularly fortunate to get Drs. Koss and JVIelamed from the cytology service of the Memorial Hospital for Cancer and Allied Diseases to review the urinary sediment slides as well as the slides of the removed tumors in this group of workers. In 1960 the results of the preliminary study to correlate the effectiveness of the Papanicolaou urinary smears with observation cystoscopy on these workers was published by .IVIezera and associates. 8 There is no problem when patients with a positive PAP smear have a tumor visible by v\ ,ouvuvC'fJ y. Those with a positive smear and a negative cystoscopy, however, present vastly different problems. :Four possibilities are obvious: 1) the urinary sediment was mis-read; 2) the n"'"'·········""·' missed a visible tumor; 3) the tumor is a tiny carcinoma in situ and, with tin1e, will grow big enough to become visible cystoscopically or 4) a carcinoma in situ could undergo spontaneous remission. Koss and associates have attempted to answer some of these possibilities. 9 In 1965 records were 7 Crabbe, J. G. S., Cresdee, W. C., Seott, T. S. and Williams, M. H. C.: Cytological diagnosis of bladder tumours amongst dvestuff workers. Brit. J. Inclust. ;.\[eel., 13: 2i0, rniG. 8 Mezera, R., Melick, W. a11d Xarvlrn J.: Correlation of the Papanicolaou 11rinaq;· sm~ius with obscrvat10n cystoscopy 011 some workers exposed to a chemical carcinogen. J. Urol.. 84: :317. HJGO. 9 Koss, L. G., :Vlelamed, 1\I. ·R., Ricci, A. JVlelick, W. F. and Kelly, R. E.: Carcinogenesis ir:: the human urmarv bladder. Ne,,; Engl. J. :\led., 272: 767, 1965.

reviewed of 22 patients whose urinarv scdi.men t in 1960 contained cells interpreted a; or positive, but who had no cystoscopic eviclellce of bladder cancer. Between 1960 and 1964 in three of the suspicious group and eight ol" 'the positive group, histologically proven -carci11oma of the bladder developed. Four of the suspicimrn group and one of the positive group have not had tumors that can be seen cystoscopically ti., although their cytology remains abnormal. One patient in this group died of unrelated disease, in 2 patients diagnostic errors were found on reviewing the cytology and in 3 patients followup was not possible. vVhen Whitmore and associates presented their work on the use of fluorescence and the ultraviolet light cystoscopy in patients with bladder ean cer, 10 • 11 its application to our problem was e,"ident. Through the years our high index of suspicion on this group of workers had enabled us to detect some exceedingly small carcinomas in situ of the bladder. One is shown in figure l; the lesion was not raised above the mucosa and appeared as a small red patch only a few millimeters in diameter. It should also be mentioned that many such lesions which were removed showed only chronic inflammatory reaction. A review of different pathologists' ideas of chronic inflammation, cellular dysplasia and carcinoma in situ does, of course, indicate that there are areas of disagreement as to just where the lille is drawn with beginning malignancy. The clinical problem remains, however, for those patients with a positive urinarv sediment and a normal, conventional cystos:'.opy. The alternative solution of "multiple random has not appealed to us since we feel that there is a real clanger of implanting viable tumor cells iL the traumatized and denuded area left b-1· such biopsies. We were grateful to A1neriean scope :Yiakers, Inc. for providing the equipment when it became commerciallv awl particularly to Mr. Frank ·· who mstruct~,(1 us in its operation. The routine described by V\!l1itmore and Bw,h has been carefully followed. Two methods mn.v be used; in one tetracycline is given orallv, 25() '. 0 Whit,more, W. F., Jr., BLtSh, I. ~\I. mid Esqmvel, E.: Tetracycline ultraviolet f-luoresc811ce in bladder carcinoma.. Cancer 17: . 11 Whitmore, W. F., Jr. v10let cystoscopy in patients with J. Urol., 95: 201, HJGG.

180

MELICK AND N A.RYKA

TABLE

Case

I I

G.F.

I

I

W.M.

G.V.

E.S. R.T.

H.D.

R.B.

G.V.

M.C. T.B.

I

E.S.

A.H.

I I I

1* i

Papanicolaou Test

Ultraviolet

Previous History

ND 4-55 12-55 1-57 2-58 10-58 5-60 1-61 6-61 No 1-62 4-62 4-63 No 5-66 No 4-63 7-64 No 12-65 5-54 1-58 No 2-61 No 5-62 6-63 No 8-64 No 8-65 6-53 12-54 5-58 8-58 11-59 No 2-65 No 4-66 5-53 No 3-58 12-59 No 9-60 1-61 9-62 9-63 3-64 3-65 No 11-65 No 4-63 11-63 No 7-65 2-65 No 12-65 No 6-66 No 2-66 No 10-57 5-60 11-60 No 12-61 1-62 No 12-62 No 12-63 No 9-64 4-65 10-65 1-66 No 2-63 No 2-65 No 4-66 No 12-65 No 4-66

NEG

I

SUSP

POS

I

Cystoscopy

Disease

on

X X X

or

0 II (I.R..) In situ CI In 8itu

X X X X X X X X X X X

OII OII

SM In situ

Fl

0 I-II

on NEG

X X

0I In situ

X X X X X

CI

NEG

X

OI SM

X X X X

5-28 CI 8-58 0 III

X X

Fl

X

In situ OIII

X

on X X

Ca in situ X X X X

In situ S'vl

OI Fl

X X X X X

Fl Fl

Papilloma. CI In situ In sit.u CI

NEG NEG

X X X X X X X X X X

CI

0 I-II

A III

OII NEG NEG

X X

X X

X

Fl

I

I I

CD

NEG NEG

* ND-not done; NEG-negative; SUSP-suspicious; POS-positive; S"1i-squa.mous metaplasia; CI-chronic infla.n1n1ation; CD-celJular dysplasia; Fl-fluorescence with ultraviolet light; No-no change seen by ordinary cystoscopy.

I:-.l SITU BLADDJDR CARCINOJ\B IN WORKERS EXPONED 'l'O XEKY LANlil'>iE

mg, every G hourn for at least ;3 and dis-continued 24 hours l;c:fore exarninatio11. 1'hc: aJ(,emate procedure i" to instill a solution of acridine orange into the: bladder and, when this is a special blnc filter is used instead of 1he ultrm·iolet filter i1t the fiber optic bundle. Tml lem s_r;;tems :ire the J\!cCarthy furoblique lens and the conventional right angle approximatcl)· a lGF Tetraercli11e fluorescence lmcfor ultraviolet light appear,; as b1ight yellowish-green. To rn; it is more yello\\" through the right lens, which has a built-in yellow filter. With acricli11l' orange iu~tillations the

I,'),

fiuoresce11ce in abnmmal areas appearn as a orange Io brown against, the blue (green 1\"lH·n the right angle lens with i1s filter i,; rnecl). .-'1.8 V\l1itmorc aud Dw,h han, nientio!l('d, examination of the bladder removed cpl.c,c: tomy provides an excellent UJJJJOJ'tunitv tu experience with this inst.rument. in a recenL casr· of ourn au area of fluorescence was seen in tile remon,cl bladder in a sncond area apart from l.he original tumor, afl-c:r a Cull course nf Co-60, ,d1ich prnved to he marked cellular dysplasia. -~ seeoml bladder iYith a 111.as~in,' initinl

Fro. 2. Carcinoma in 8itu diagnosed hy ultraviolet fh10rcscence. ;J, rnncoso almost illt,w(, ovc"t lesion.

182

MELICK AND NARYKA TABLE

Case

F.H.

A.B.

2. Non-chemical bladder tumors

Previous History

1962 1962 8-63 5-65 No 4-66 4-65 6-65 10-65 No 4-66 2-66 5-66

Papanicolaou Test*

Disease

ND NEG SUSP POS

X X X X X X X X X X

ND ND ND ND Fl ND ND ND Fl ND Flt

O IVt OIIt O Ill-IV In situ

on O IIt O IIIt O III! 0 I-II 0-A II-III 0-A II-III

* ND-not done; No--no change seen by ordinary cystoscopy; Fl-fluorescence with ultraviolet light; NEG-negative; SUSP-suspicious; POS-positive. t Done elsewhere. t Additional areas of fluorescence beyond that seen with regular cystoscopy.

tumor showed multiple carcinomas apart from the initial tumor. One can also gain valuable experience using ultraviolet cystoscopy to examine known tumors. With the ultraviolet foroblique lens one can have, without the filter, approximately the equal of visible light, but can shift the filters to determine if all of the areas of fluorescence have been resected. RESULTS

The results have been summarized in tables 1 and 2. Case R. T. is an example of a positive urinary sediment for more than 1 year before the tumor could be detected even by ultraviolet fluorescence. Case H. D. had a positive urinary sediment beginning in September 1962, but ordinary light cystoscopy remained normal. A fluorescent area was picked up in November 1965 and even then, because of the benign appearance on microscopic examination, the diagnosis was papilloma. Case R. B. had a positive urine sediment in 1963; conventional cystoscopy remained normal until an in situ carcinoma was picked up by ultraviolet light in July 1965. Case T. B. had a positive urinary sediment in 1957;

however, an area of chronic irritation was found by conventional cystoscopy in May 1960, and a definite tumor was seen in November 1960. A second, more malignant tumor was found in January 1962, and the urine has remained positive for malignant cells since that time. To the present time no areas of fluorescence have been noted with ultraviolet light. Case G. F. represents another carcinoma found by fluorescence which was not visible on conventional cystoscopy. Figure 2 shows typical carcinoma in situ diagnosed by ultraviolet lightfluorescence. CasesG. V. and E. S. represent areas of fluorescence to chronic inflammatory and cellular dysplasia respectiYely. Such findings might, of course, be expected since any cellular activity ,vould also fluoresce. Three cases among the general population have been found, in 2 cases the lesion was found by ultraviolet light when it could not have been seen with ordinary light cystoscopy. In the third case additional extent of the tumor was found with the ultra-violet light after resection of all visible tumor by ordinary light. SUMMARY

In our initial experience with the ultraviolet cystoscope, 6 cases of bladder tumors have been found and proven by histological study when the site of tumor ,vas not -visible by conventional cystoscopy. In 1 case cellular dysplasia is seen to the extent that there is disagreement whether it is an early carcinoma in situ. Use of the ultraviolet cystoscope seems to provide valuable help in the diagnosis of early cases of bladder tumor and should be even more valuable when utilized in conjunction with periodic Papanicolaou sm.ears of the urinary sediment. Use of the ultraviolet panendoscopic lens during transurethral removal of bladder tumors may give additional information as to the true extent of the tumor. 3720 TV ashing/on Avenue, St. Louis, Niissouri 63108