B n m h Journaf of Urology (1981). 53, 115-1 18 1981 Britibh Association of Urological Surgeon,

oOo7-1331/81/067 101 15$02.00

The Role of N-nitrosamine in Carcinogenesis a t the Ureterocolic Anastomosis

M. STEWART, M. J. HILL, R. C. B. PUGH and J. P. WILLIAMS

St Peter‘s Hospitals, London

Summary-Seven cases of colonic tumours occurring at t he ureterocolic anastomosis (UCA) in patients diverted for benign disease are presented and comparisons made with existing literature.

There appears t o be a definite increase in the incidence o f colonic malignancy in patients with this diversion. A theory of carcinogenesis involving bacterial activation o f endogenously formed N-nitrosamine is suggested. Preliminary results of rectal urine analysis support th is theory in that high concentrations of N-nitrosamine have been found and mutagens demonstrated.

In 1851 Lloyd, at St Bartholomew’s Hospital, London, first described the use of the ureterocolic fistula in a child with exstrophy. Many ingenious attempts at urinary diversion followed, but it was not until 191 1 that the first successful transplant of the ureter into intact colon was performed by Stiles.

The ureterocolic diversion was (and, with the Leadbetter modification, still is) widely used throughout the world. In 1950, Bricker reported the use of the isolated loop of ileum as a urinary conduit. The disappointing long-term results of ureterocolic diversions, coupled with the excellent initial results of the ileal loop, turned most sur- geons away from colonic diversions. The ileal loop soon became, and remains today, the diver- sion of choice for both benign and malignant disease of the lower urinary tract (Fig. 1).

The complications of ureterosigmoidostomies are well known. Despite improved surgical tech- niques and modern chemotherapy, stricture, hyperchloraemic acidosis and the sequelae of reflux of faecal material into the upper urinary tracts remain major problems.

The first case of carcinoma at the site of the ureterocolic anastomosis was reported by Hammer in 1929 (Fig. 2) but even now, 50 years later, the risk of colon cancer in these patients remains an uncommon hazard. We have studied this par- ticular malignancy in patients diverted for benign disease. Part of this study has been concerned

Read at the 36th Annual Meeting of the Britihh Association ol Urological Surgeons In Liverpool, June 1980.

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i u o o - l q i o 1920 1910 iq4n 1150 LBGO 1970 ,gin 1990

Fig. 1 diversions in diagrammatic form (not t o scale).

with the analysis of rectal urine in an attempt to identify a possible carcinogen.

The total dietary nitrate is excreted by the kid- neys into the urine. When urine is diverted into the colon it comes into contact with endogenous secondary amine. In the presence of a mixed bac- terial flora it has been shown that nitrate plus secondary amine leads to the formation and acti- vation of large amounts of N-nitroso compounds. One of these, N-nitrosamine, is a powerful car-

Relative popularity of ureterocolic and ureteroileal

, X DIVERSIONS 7 PLRPORYED FOR BLNICN ‘ DISEASE

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1900 1910 1920 1930 1940 A o 1960 1970 19a0 i g z

1929 l a t Report of CARCINOMA AT UCA (H*MIER)

Fig. 2 First case of carcinoma at UCA.

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116 BRITISH JOURNAL OF UROl.OGY

cinogen to which no laboratory animal has proved resistant. Although there is, as yet, no proof of its carcinogenic action in man, the series of cases presented here suggests that it might, in fact, have such a potential.

Patients and Methods Three groups of patients, all of whom have under- gone ureterocolic diversion for benign disease, have been studied.

Group I Seven patients with tumour at the anastomotic site treated at the St Peter's Hospitals during the last 30 years. Details of 3 of these cases have been reported previously (Whitaker et a/ . , 1971). Fifty-four cases with tuniour at the ariastomotic site reported in the world literature.

Group I l l Eighty-one patients diverted at the St Peter's Hospitals since 1954.

GIoups I and 11 have been analysed with regard to age a i tuniour diagnosis, latency of the tumour and its histology.

Group I l l is a prospective survey. The case notes of X I patients were examined; the patients were then contacted and invited to attend for follow-up examination. Forty-six of the 8 1 have so far been seen and 29 of these have provided rectal urines for biochemical investigations, in- cluding N-nitrosamine assay. The other findings will form the basis of a later publication.

Rectal urine samples were transferred to a pro- tective transport broth and frozen for bacterio- logical analysis and the remainder of the sample frozen for biochemical analysis. The sample

Group I I

assayed bacteriologically was cultured for total anaerobic bacteria, total aerobes and mean pro- bable number of nitrate-reducing organisms.

Part of the sample for biochemical analysis was assayed for nitrate and nitrite ion concentra- tion. A further part was assayed using a chemi- luminescence analyser for N-nitroso compounds and a further portion was filtered through a milli- pore filter (pore size 0.22 p) and then assayed for mutagens by the Salmonella mutagenesis assay system (Ames, 1972).

Results

The findings in Groups I and I1 are summarised in Table 1. Exstrophy was the single commonest antecedent in both groups and, in the majority of cases, diversion was carried out within the first few years of life. In contrast, diversion for other causes (such as incontinence and interstitial cys- titis) tended to be carried out in adult life.

In the 61 patients in Groups I and 11, the mean latent period between diversion and tuniour de- velopment was the same (24 years).

Adenocarcinoma was the most common tumour (70% of Group I and 70% of Group 11 patients). Thirteen (21%) of the 61 tumours were polyps, the majority of which were adenomas, allhough some were described as reactive and juvenile types.

There was an interesting difference in the latent period according to type of tumour (Table 2 ) when Groups I and I1 are considered together; the mean ages at diagnosis of polyps and car- cinomas were very similar, whereas the mean latency was strikingly different, being 19.8 years for polyps and 25 .8 years for adenocarcinomas.

Table 1 Turnours at Ureterocolic Anastomosih (Benign Antcccdctits)

Sr Peter's cuws Liierarure review (Croup I ) (Group I / )

Ape ;if tun lour diagnosis

I alcncq

Exsliophy Others

Polyp Adc.iiocarcicionia Ti aiisiiioiial cell carciiioiiia Carcinoma of indctcrminatc origin

4 3

22-77 yr\ (Incan 46)

15-40 yrs (mean 24.3)

1 5

I

41 I

13-70 yra (mean 32.9)

10-50 yrc (mean 24.5)

12 38

1 3

THE ROLE OF N-NITROSAMINE IN CARCINOGENESIS AT THE URETEROCOLIC ANASTOMOSIS 117

Table 2 Mean Age and Latency of Adenocarcinomata and Polyps Arising at the Ureterocolic Anastomosis

Tumours at ureterocolic Mean age at Mean anastomosis diagnosis latency

Polyps 33.5 19.8

Adenocarcinorna 34.7 25.8

X DIVERSIONS PERFORYED FOR BENIGN DISEASE

Biochemical Assays in Group III Patients Assays were complete in 7 of the 29 urines studied and uniformly high levels of nitrate, nitrite and N-nitroso compounds have been found and muta- gens demonstrated. In the remaining 22 urines, the presence of mixed bacteria and large amounts of nitrates and nitrites was confirmed and muta- gens demonstrated. Given the normal secondary amine production in the colon, N-nitrosamine formation could reasonably be expected.

Discussion The risk of colonic malignancy complicating ure- terocolic diversion has been calculated at between 180 and 7000 times that of the population at large depending on age (Table 3). It is an under-diag- nosed malignancy and the clinician should be aware of the high risk group of patients, diverted in the fifties and sixties, who are now in danger.

Analysis of Group I and I1 cases confirms that this is a malignancy which occurs in the under-50 age group, where colon cancer is rare. The ap- parent discrepancy between the ages at tumour diagnosis in Groups I and I1 is probably a reflec- tion of the high percentage of Group 1 patients who were diverted in adult life.

The constant latency of 24 years before tumour development is reminiscent of that found in indus- trial bladder cancer, where a carcinogen is known to be active.

Polyps occurring at the ureterocolic anasto- mosis have a 6-year shorter mean latency than carcinomas. It would not be unreasonable to sug-

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1900 1910 1920 1930 1940 1950 1960 1970 1980 1990

1929:lst REPORT OF 1978: 1st REPORT OF '

CARCINOMA A T UCA CARCINOMA I N I L E A L uy)P (SHOUSA e t aL) (HAHMER)

Fig. 3 First case of carcinoma at UCA and first case of car- cinoma in ileal loop.

gest that, if adenomatous polyps were to undergo malignant change, this process would occur over a period of 5 to 10 years.

The demonstration of N-nitroso compounds in the rectal urine is highly significant, in that these compounds are not normally found, other than in trace amounts, either in human urine or faeces. In fact, N-nitroso compounds have been demon- strated in only 2 other locations in the human body: firstly, in the achlorhydric stomach, when they have been associated with gastric cancer, and secondly, in the mixed urinary tract infection associated with bilharzia when, again, they have been incriminated in local carcinogenesis.

The detection of mutagens in these rectal urines is a further very strong indication that a carci- nogen is present.

Because ureterocolic diversions are no longer commonly performed in this country, it may be argued that this tumour is of minor significance. Before accepting this, certain points should be considered.

Firstly, in Third World countries, where ex- ternal urinary appliances are impracticable or unacceptable, the ureterocolic diversion remains the operation of choice for a great many people.

Secondly, if we accept the likelihood of a power- ful, locally active carcinogen at the anastomotic site, it may be that colon loops, currently gaining

Table 3

Author No. of cases No. of cases Incidence per lO0,OOO Risk

Estimated Risk of Colon Cancer at the Ureterocolic Anastomosis in Patients Diverted for Benign Disease

folio wed up of carcinoina population

Urdaneta el al. (1966) 83 3 13,000/ 100,000 550 x normal population

Parsons et al. (1977) 29 2 6900/ 100,000 280 x normal population

Eraklis and Folkman (1978) 82 4 4.9/100 181 x whole population 7000 x of population aged 25 and under

118 I3K1'11511 J O U R N A I OF 1JKOl.OGL

popularity among paediatric urologists, carry a similar risk of colon cancer.

In 1978 Shousa el af. rcported an adenocar- cinonia :it the ureteroileal anastomosis in a patient diverted for cxstrophy 20 years prior to thc diag- nosis of' his tumour (Fig. 3 ) . Assuming a latent period similar t o that of malignancy occurring at the ureterocolic anastomosis, and the fact that ileal loops liavc been performed in significant nuinbcrs only in the last 20 ycars, this case may be the warning of many more to come.

Lastly, the recently reported long-term results of itreter.osigtiioidostomies over the last 30 years, pcrfornied with the benefit of better surgical tech- niqucs, powerful antibiotics and a clcarcr under- standing of metabolic disturbances, compare favour a bl y the di sap poin t i ng 1 o t i g - t er m results of thc ileal loop diversions. 11 niay well be that the wheel may tu rn full cycle and many urolugisls will turn their attention back to thc colon ah a urinary conduir .

We ttiereforc contend that, thougli rare, car- cinoma at the ureterocolic anastomosis is an ini- portant nialignancy which offers u s the chance to idcntify a human carcinogen and we feel that the question of nitrosamine-induced carcinogenesis requires further study.

wit h

Hrirkrr, b;. M . ( 1950). Syrnpositini on clinical siirpcry: blaildei substitution after pelvic evisceration. Surgrcnl CImic~ (</ Nor-/h /l/,lericU, 30, 151 1-1521.

Eraklib, A. .I. and Folkman, M. J . (1978). Adenocai-ciriutri:~ at t h e site 0 1 the iireterosigmoidostomio for csstrophy 01' the hladder. .lournu/ of Pediatric Surgery, 13. 730-734.

Hammrr, I-:. (1029). Cancer dti colon 5igtiioYdc dili t i t i \ ap r& irnplantatioii des urcicrec d'une vessic cxstiopliiCc. Joi/rtirrl d'l/ro/oyic, 28 ~ 260-263,

I h y d , Mr ( 1 x 5 1 ) . Ectopia vesicae (absciicc of the anterior walls of the bladder), opci-ation, subsequent death. Laricrr. 2, 370-372.

Parsons, C. I>., 'I'lioittas, M. H. nnd <;arrett, H. A . (1977). Colonic ;idenocarcinoina: a dclayed complication 0 1 ' iiiclci o- signioiilostoin)'. Jourtiu/ (?f Urology, 11X, 31 -34.

Shoiisa, S. . Scott, J. aiid Polak, J . (1978). llcal loop car- cinoma aficr cysteciomy for bladder c\;strophy. Dri/tsh Mcdicrrl Joirrtrtrl, 2, 397-398.

Stiles, M. , I . (191 1). Epispadias i n the feniale i i i id its \tirgic:il treatnienr. Surgery, G.vnecolog.v unrl Obrtctrrc.$, 13, 127- 130.

Urdnneta, 1,. F,, Diiffell, I)., Creevy, C. I). and AIISI. . I . 1%. (1966). 1.ate developnicn~ of primary cnrcinomtr of' t l i c colui~ I'ollowinp ti1 etcrosigiiiaidostorny; repoi t 01' t l i t ee c i i m ;incI literature revicw. Annuls oj'.Surgery, 164, 503-513.

Whilakrr, K. 13.. Pugh, It. C . B. and lkw. I ) . (1971 ). C(iioriii. t i i m o ~ i I \ lollowing urctcrosigmoidosioiii~. Bri/I5/i .Jor/r/iu/ of (J~Ol~ i ,~ ,V . 43. 562-575.

The Authors M . Sicwiirt, TRCS, Ho~ioIai-y Research Rcpisti-ai. M. J . Hill, Phl), MRCPath, Dircctoi-, lkicterial Mci;tbol iw

Rehearch L.aboratory, Central Public Health Laboratoric\, ('01 indal e , N W 9.

R . C. 13. l'iigli, MI), FRCPath, Cutisulranr Pntholoyi>~. I . 1'. Williariia, MCliii . tKCS, Consultitiit Llrologizt .

Reque& 1'01 icprinic to: M. Slewart. St Paul's Ho\pit~tI. 24 1:ndcll Street, I-oriclon WC2H 9AE.