the betweenurinary infection, · fiftybladderbiopsiesweretaken, after full explana-tion and...

J. clin. Path., 1974, 27, 297-307

The relationship between urinary infection,cystoscopic appearance, and pathology of thebladder in manF. P. MARSH, R. BANERJEE, AND P. PANCHAMIA

From the Departments of Nephrology and Morbid Anatomy, The London Hospital, London

I Lymphocytes in the lamina propria

SYNOPSIS Studies of bladder histology were made in patients with recurrent urinary infection or

symptoms of cystitis, with a view to establishing its relationship to symptoms, cystoscopicappearance,and bacilluria. Bladder biopsies were taken from the patients and compared with control materialobtained at necropsy. Acute inflammatory changes were inconstant and sometimes sparse. Chronicinflammatory changes were often marked, and were ranked by severity into four grades. There was

a statistically significant correlation between the more severe grades and the finding of bacilluria,which was not dependent on sex or age. The grades in patients with recurrent non-bacterial dysuria('urethritis') lay between those of the controls and the infected patients, and were statisticallydifferent from both. There was no correlation between these grades and either symptoms or thefinding of trigonal hyperaemia during cystoscopy. However, heavy lymphocytic infiltration, andparticularly germinal follicle formation, frequently resulted in macroscopic tubercle-like noduleswhich were visible on cystoscopy. Such germinal follicles may contribute to local antibacterialdefences by their production of immunoglobulins, and may explain the high antibacterial antibodytitres sometimes found in the sera of subjects with infection confined to the lower urinary tract.

During a prospective study of women with recurrenturinary infection we could not relate the cystoscopicappearance of the bladder either to the patients'symptoms or to the presence of bacilluria. Becauseof this, and because the literature concerning bladderpathology in cystitis is scanty and inadequate, weperformed bladder biopsies in an attempt to relateclinical, cystoscopic, bacteriological, and immuno-logical findings to the histological changes. Wereporthere our findings concerning lymphocytes in thelamina propria.

Clinical Material and Methods

PATIENTSFifty bladder biopsies were taken, after full explana-tion and discussion, from 37 female and four malepatients suspected or known to have urinary infec-tions. Thirty-one patients had recurrent cystitis,five painless frequency, and one abdominal pain.

Received for publication 13 December 1973.

Three others had symptoms associated with neuro-pathic bladders and a fourth had a vesical calculus.The patients' ages ranged from 21 to 76 years.

Cystoscopy was performed under general anaes-thesia. After examination of the bladder a biopsywas taken with a resectoscope or Riches forceps,usually from the middle of the interureteric bar. Ifany local abnormality was noted, this was biopsiedinstead. In a few cases the biopsy was taken fromthe vault or bladder neck in the absence of anylocal abnormality. Haemorrhage immediately afterthe initial biopsy made a second attempt at the samecystoscopy impossible. Repeat biopsies were madein some patients at a later date. Although transientpostoperative haematuria was common the onlypotentially serious complication was the develop-ment in one patient of abdominal pain with signs ofperitoneal irritation, which subsided after two daysof catheter drainage.

Patients with bacilluria were given antibiotics for48 hours before cystoscopy, unless they were alsoundergoing ureteric catheterization to locate infection.

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F. P. Marsh, R. Banerjee, and P. Panchamia

In this event, chemotherapy was commencedimmediately afterwards. Non-bacilluric patientswere not routinely given antibiotics.

CONTROLSAdequate human control material for histologicalstudy is difficult to obtain, for bladder biopsy ofpatients with no urological complaints would beunjustified. Therefore we studied vertical sections ofthe trigone taken at necropsy as soon after deathas possible, so as to reduce changes due to autolysis.In some cases additional sections were taken fromthe bladder vault. Material was obtained from 30

e ,O"

NW

Fig 1 Section of bladder from uninfected controlshowing grade I subepithelial histology. The transitionalepithelium is partly autolysed. H & E x 140.

JIT14/4 4-

,.r Jea *;A #Fig 3 Bladder biopsy from patient showing a diffuseincrease in the number of lymphocytes in the laminapropria, and, to the right, a focal accumulation oflymphocytes without a germinal centre (grade III).H&E x 140.

subjects (17 female, 13 male) whose ages ranged from0 (stillbirth) to 76 years, whom we called 'non-infected controls'. There had been no clinicalevidence of urinary infection in these. They had notreceived steroids or immunosuppressives, or beencatheterized before death, and at necropsy had noevidence of any condition predisposing to urinaryinfection.

Similar tissue from seven female and five malesubjects (aged 21 to 79 years) with documentedclinical or necropsy evidence suggesting antemortemurinary infection was also examined. These werecalled 'infected controls'.

-~~~~~~~3.,*y > fl

'41*.,4,.

Fig 2 Bladder biopsy from patient showing grade IHsubepithelial changes (oedema of the lamina propriawith a doubtful increase in lymphocytes). H & E x 140.

Fig 4 Bladder biopsy from patient showing asubepithelial germinal follicle (grade IV). H & E x 53.

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The relationship between urinary infection, cystoscopic appearance, and pathology of the bladder in man 299

HISTOLOGICAL CLASSIFICATIONThe degree of lymphocytic infiltration in the laminapropria was assessed as falling into one of fourgrades:

I Scattering of lymphocytes (fig 1)II Subepithelial oedema ± a minor increase in

the number of lymphocytes (fig 2)III Definite focal or diffuse lymphocytic infiltrate

(fig 3) but no germinal centresIV Germinal follicle formation (fig 4).

ASSESSMENT OF THE BACTERIOLOGICAL STATEOF THE PATIENTS

Patients were seen, and their urine cultured, monthly.If they developed symptoms of urinary infection,cultures were made before they took antibacterialagents. Bacterial urinary infections were diagnosedin 24 of the patients (bacilluric patients), who pro-vided 29 of the biopsies, according to any of thefollowing criteria: (1) two successive midstreamurine specimens culturing over 100 000 of thesame bacteria (not serotyped) per ml of fresh orrefrigerated urine; (2) one midstream specimenculturing over 100 000 bacteria per ml, with over 10leucocytes per cmm of uncentrifuged urine; (3) onemidstream urine culturing over 100 000 bacteriaper ml urine, collected when there was pain duringmicturition; (4) any number of bacteria cultured froma suprapubic aspirate.

Fifteen biopsies were taken from 11 patients whowere regarded as non-bacilluric because theyexhibited none of the above features during followup for at least six months. Six biopsies came fromsix patients who were regarded as of uncertainbacilluric status because, although no evidence ofbacilluria had been obtained, the duration of followup was less than six months.

SEROLOGICAL STUDIES

Serial agglutination studies were performed in 21patients using sera stored at - 20°C, tested inbatches by the method of Percival, Brumfitt, and de

Louvois (1964). The normal range of titres in ourlaboratory was up to 1:320. 0 antigens from 11 E.coli (0-1, 2, 4, 5, 6, 7, 9, 11, 18, 39, 75), includingthose known to cause urine infections frequently(Rantz, 1962), were used to determine titres in non-bacilluric patients, but in bacilluric ones antigenprepared from the homologous infecting E. coli wasused.

STATISTICAL METHODSChi square, Fisher's exact probability, and Mann-Whitney U tests were used where applicable (Siegel,1956; Finney, Latscha, Bennet, and Hsu, 1963).Analysis of the ranked data concerning the degreeof lymphocytic infiltration was performed by theallotment of normal scores (David, Barton,Ganeshalingham, Harter, Kim, Merrington, andWalley, 1968) and calculation of a t statistic withinfinite degrees of freedom.

Results

URINARY INFECTION (TABLE I)Significantly higher grades of lymphocytic infiltra-tion were found in bacilluric than in non-bacilluricpatients, and in non-bacilluric ones than in non-infected controls. Sections from the trigones ofinfected controls were graded significantly higherthan those from non-infected controls. Germinalfollicles (grade IV) were found in 12 of the 29biopsies from bacilluric patients and in two of 12infected controls but were not found in any sectionsfrom non-infected controls or non-bacilluric patients.The differences between groups were still highlysignificant when only sections from female subjectswere considered.The grading of 31 biopsies taken from 24 women

with recurrent cystitis who had undergone closefollow up for over six months is also shown intable I. In this more homogeneous group, bacilluricpatients again tended to have higher grades thannon-bacilluric ones (0-005 > p > 00025), who in

Origin of Biopsy No. of Biopsies Suibepithelial Grade

I II III IV

A Uninfected controls 30 (17) 23 (13) 3 (1) 4 (3) 0B Infected controls 12 (7) 3 (2) 1 (0) 6 (4) 2 (1)C Non-bacilluric patients 15 (12) 1 (0) 9 (7) 5 (5) 0D Bacilluric patients 29 (19) 2 (1) 4 (2) 11 (5) 12 (11)

Table I Histology and urinary infection''Figures not in parentheses refer to trigonal sections from controls or (in patients) to biopsies from those of known bacilluric status, whethermale or female. Figures in parentheses refer to trigonal sections from female controls or biopsies from female patients ofknown bacilluric statuswho had recurrent cystitis.For figures not in parentheses: A v B, t = -3550, p < 0 0005; A v C, t = -37154,p < 0 0005; A v D, t = -5-6333,p < 0-0005; C v D,t= -29624, 0-0025 > p > 0.0005 (a = 0-05).3


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Origin of Biopsy Sex No. of Biopsies Subepithelial Grade

I lI 111 IV

A Uninfected controls F 17 13 1 3 0M 13 10 2 1 0

B Uninfected controls plusnon-bacilluric patients F 32 14 10 8 0

M 13 10 2 1 0C All subjects F 70 19 16 23 12

M 22 11 3 5 3

Table II Histology and sexMales v females: group A t = 0-2749; group B t = -15224, group C t = -14935; p > 0 05 (2 = 0 05).

turn had higher grades than the uninfected femalecontrol subjects (0-0025 > p> 0'0005). Urinecultureshad been made from all but one of the non-bacilluricpatients during an attack of 'cystitis' before any

chemotherapy. Such patients are often said to havea 'urethritis'.

SEX (TABLE II)The biopsies from several groups of subjects werestudied to see if males and females differed withregard to their grading: those from uninfectedcontrols by themselves and together with non-bacilluric patients, and those from all patients andcontrols irrespective of bacilluria, were considered.In none of these groups was there any significantdifference between males and females in this regard.

SITE OF BIOPSY

Sections from both vault and trigone were taken in17 controls; their grading agreed in 14 but differedby one grade in two cases and by two grades in one

case. The histology in patients is compared with thesite of biopsy in table III. Trigonal and bladderneck biopsies tended to be of higher grade than didbiopsies taken from outside the trigone, the differencebeing statistically significant. However, as the ratioof trigonal to extratrigonal biopsies in bacilluric andnon-bacilluric patients was almost identical thisdid not invalidate our conclusions concerning the

Site of Biopsy1 No. of Subepithelial GradeBiopsies

I II III IV

Extratrigonal 14 4 5 2 3Trigonal or

bladder neck 35 0 11 15 9

Table III Histology and site of biopsy in patients'The biopsy site was uncertain in one case.t = -2-2681, 0-025 > p > 0-02 (2a = 0 05)

relationship between infection and lymphocyticinfiltration.

SYMPTOMSIn 25 women (33 biopsies) symptoms present at thetime of biopsy were recorded by one observer on asix-point scale, allowing one point for each of thefollowing: pain during voiding, pain after voiding,frequency, urgency, nocturia, and suprapubic pain.The mean score per biopsy in each histological grade,and the distribution of scores, did not suggest anyrelationship between symptoms and histologicalclassification.The frequency of the above symptoms during the

pre-biopsy observation period was considered inrelation to the histological grade. Two points wereawarded for each symptom present at 50% or moreof pre-biopsy visits; one for each symptom presentat 25 to 49% of visits; and none for symptoms

Subepithelial Grade

I II III IV

No. of cystocopies 4 15 18 13Focal abnormalities seen during 1 Localized oedema 1 Focal mucosal 5 Pink or grey nodules 7 Pink or grey nodules

cystoscopy resembling elevation 13 Nil 6 Nilpapilloma 14 Nil

1 White film on trigone2 Nil

Degree of trigonal hyperaemial a 2 9 10 8b 0 3 4 2c 2 3 4 3

Table IV Focal abnormalities and trigonal hyperaemia on cystoscopyla = Absent, b = moderate, c = severe. (a) v (b + c): t = 0-2639, p > 0 05 (x = 0-05).

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The relationship between urinary infection, cystoscopic appearance, and pathology of the bladder in man 301

occurring less frequently. Consideration of the meanscores and the distribution of scores did not suggestthat such symptoms occurred more frequently inpatients with the highest grades.

CYSTOSCOPIC APPEARANCE (TABLE IV)The appearance of the trigone was allotted to one ofthree grades, according to the presence and severityof hyperaemia as seen on cystoscopy. The higherhistological grades were commonly found inbladders without trigonal hyperaemia and vice versa.Neither were trigonal hyperaemia and subepithelialhistology related when only biopsies taken from thetrigone itself were considered.A special note was made of the presence or

absence of focal abnormalities. The finding of smallpink or grey nodules on cystoscopy corresponded tohistological grades III and IV, but the latter were

often found when no local abnormality had beenfound at cystoscopy.

SEROLOGICAL STUDIESOnly patients with biopsies graded II, III, and IVwere studied.

Sera from all five non-bacilluric patients gavenormal titres when tested against the 11 standard 0antigens.

Sixteen bacilluric patients were studied. Three ofthe seven whose biopsies showed grade III changeshad high titres at the time of infection but two ofthese had clinical evidence of upper urinary tractinfection. Agglutination titres in the third patient(S.G.) rose from 1:640 to 1:1280 at the time ofbiopsy; she had no clinical or radiological evidenceof upper urinary tract infection, and bilateralureteric catheterization performed according toStamey, Govan, and Palmer (1965) suggested thatthe infection was confined to the lower urinary tract.

Seven of the nine bacilluric patients whosebiopsies showed grade IV changes had abnormaltitres (high, or not less than a four-fold rise in titrewithin the 'normal' range); however, all except one

had good evidence of upper urinary infection. Theexception was the patient (S.G.) referred to above,who had a second biopsy.Thus in only one patient, from whom two biopsies

were taken, was there a suggestion that heavylymphocytic infiltration of the bladder by itself couldresult in abnormal agglutination titres in serum.

OBSERVER ERROR IN HISTOLOGICAL CLASSIFI-CATIONTwo authors independently classified 32 of thebiopsies from patients, the source of the biopsybeing concealed. They agreed over all but threebiopsies, differing in their assessment of these by onlyone grade.3*

Blind examination of sections from controlsubjects mixed with similarly sized biopsies frompatients provided no evidence that knowledge of theorigin of control sections (which had sometimesseemed identifiable by their larger size) had favouredbias to a lower grade assessment.

Discussion

There has been disagreement for many years aboutthe significance of collections of lymphocytes in thebladder wall. Some authors have thought themnormal (Hamburger, 1879; Weischselbaum, 1881;Alexander, 1893; Asschoff, 1894; and Bohm andVon Davidoff, 1895) but Chiari (1881) and Przewoski(1889) believed that they signified infection. This isimplied in the term 'cystitis follicularis', used todenote subepithelial lymphoid follicles and con-sidered by some to be a common sequel to prolongedurinary infection (Hinman and Cordonnier, 1935;Stirling and Ash, 1941). However, Kretschmer(1952) believed that infection was common, butfollicular changes were rare. Mitchell and Andrews(1953) found lymph follicles in most patients withbladder neck obstruction but did not attribute themto infection. Pugh (1967) grouped cystitis folliculariswith other varieties of 'hyperplastic cystitis' which hebelieved were not genuine types of cystitis.These opinions were based on inadequate bac-

teriological methods, for the importance of quanti-tative cultures of urine was not recognized. Ourresults suggest that the lamina propria of the normalbladder contains relatively few lymphocytes. How-ever, biopsies from bacilluric patients nearly alwayscontained a heavy diffuse or focal lymphocyticinfiltrate and germinal follicles were seen in almosthalf. Biopsies from patients with a long history of'cystitis', but without significant bacilluria duringprolonged follow up (often said to have a 'urethri-tis'), showed a degree of lymphocytic infiltrationwhich was intermediate in severity between that ofthe uninfected controls and the bacilluric patients.This might suggest a less frequent or intense anti-genic stimulation than occurs in bacilluric patients,which might be of unrecognized bacterial, oreven viral, origin (Numazaki, Shigeta, Kumasaka,Miyazawa, Yamanaka, Yano, Takai, and Ishida,1968).Comparison of necropsy material with that

obtained from patients could lead to fallaciousconclusions. Although there were more males in ourcontrol than in our patient groups, we found noevidence that women have more lymphocytes in thelamina propria of the bladder than do men, otherthan as a result of their increased susceptibility tourinary infection. Age distribution might be impor-


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tant, for old age impairs ability to synthesize anti-body (Raffel, 1961). We found no evidence of anyreduction in lymphocytic infiltration with increasingage, and the distribution of ages in patient andcontrol groups was similar. Theages ofthe uninfectedsubjects (35'7 ± 22-4 years) were significantly lowerthan those of infected subjects (46-4 ± 17-1 years;0-05 > p > 0-025), a tendency commented onelsewhere (Marsh, Murray, and Panchamia, 1972).The process of dying might produce some lympho-cyte depletion. However, the modes of death of theinfected controls were comparable to those of theuninfected controls, although their sections showedmuch more lymphocytic infiltration.We found no evidence that the histological changes

discussed were directly associated with symptoms,either at the time of biopsy or when considered overa period of time before biopsy. Neither were theyrelated to the degree of trigonal hyperaemia observedat cystoscopy. However, the changes were those ofchronic inflammation (predominantly lymphocytic,although plasma cells were occasionally prominent)rather than acute inflammation.

Cystoscopy of bladders whose biopsies showedmarked lymphocytic infiltration or germinal follicles(grades III and IV) often revealed pink or pinkish-grey nodules, presumably composed of focal collec-tions of lymphocytes, although the latter were oftenfound without cystoscopically visible nodulation.Similar nodules were described at necropsy byChiari (1881), Przewoski (1889), and Alexander(1893). Hinman and Cordonnier (1935) noted themto be particularly prominent over the trigone atcystoscopy, with which we agree. Ziegler (1886)noted that such nodules may resemble tubercles.They led to a suggested diagnosis of tuberculosis inone of our patients, and we know of another inwhom their visualization at cystoscopy resulted inantituberculous chemotherapy being incorrectlyinstituted.The function of these lymphocyte collections is not

established. If bursa-dependent, they may beconcerned in the production of humoral antibodyand its transfer into urine (via the luminal surfaceof the bladder) or blood. The epithelium overlyingthe germinal follicles was often thinned, and some-times apparently absent (fig 4). IgA (s) (includingantibodies to E. coli) has been found in normalurine (Bienenstock and Tomasi, 1968). Its concen-tration is significantly higher in urine from childrenwith recurrent urinary infection than from thosewithout infection (Uehling and Steihm, 1971), andit can be produced in the bladder (Kaufman, Katz,and McIntosh, 1970) where it might be locallyprotective. There is also evidence that a secretoryform of IgE may be produced locally in the urinary

tract (Burdon, 1973). Our findings provide ahistological basis for these concepts. Althoughprotection against lower urinary tract infection maypredominantly involve hydrokinetic mechanisms,many other factors can be invoked (Marsh, 1973).The antibacterial activity of intact bladder tissuemay inhibit bacterial multiplication between voiding.However, its mechanism and its importance areuncertain. The local antibacterial activity of thebladder is not related to serum agglutination titresagainst the infecting bacteria (Norden, Green, andKass, 1968).Although renal parenchymal infection is reputed

to cause high agglutination or haemagglutinationtitres to the 0 antigen of homologous infecting E.coli, while lower urinary tract infection is said toresult in low titres (Percival et al, 1964; Andersen,Hanson, Lincoln, 0rskov, 0rskov, and Winberg,1965; Vosti, Monto, and Rantz, 1965), unless othertissues such as prostate are involved, this has beenfound unreliable (Gower, Taylor, Koutsaimanis,and Roberts, 1972) and it cannot be the wholestory. E. coli infection in the isolated bladder pouchof the dog results in 0 haemagglutination titres com-parable to those reached in renal infections (Darwish,Staubitz, Scheuller, Rubin, and Neter, 1968). In onepatient out of those whose sera we studied usingserial agglutination techniques, the abnormally hightitres found could not be attributed to renal infec-tion. This case suggests that bacterial cystitis inman may sometimes cause high titres in serum.

References

Alexander, S. (1893). Some observations respecting the pathology andpathological anatomy of nodular cystitis. J. Cutan. genito-urinary Dis., 11, 245-262.

Andersen, H. J., Hanson, L. A., Lincoln, K., 0rskov, I., 0rskov, F.,and Winberg, J. (1965). Studies of urinary tract infections ininfancy and childhood. IV Relation of the coli antibody titreto clinical picture and to serological type of the infecting E.coli in acute uncomplicated urinary tract infections. Actapaediat. scand., 54, 247-259.

Asschoff, L. (1894). Ein Beitrag zur normalen und pathologischenAnatomie der Schleimhaut der Harnwegc und ihrer drusigenAnbinge. Virchows Arch. path. Anat., 138, 119-161.

Bienenstock, J., and Tomasi, T. B., Jr. (1968). Secretory yA in normalurine. J. clin. Invest., 47, 1162-1171.

Bohm, A. A., and Von Davidoff, M. (1895). Lehrbuch der histologiedes menschen einschliesslich der mikroskopischen technick.(Bergman, Weisbaden).

Burdon, D. W. (1973). Immunoglobulins in the urinary tract; dis-cussion on a possible role in urinary tract infection. In UrinaryTract Infection, edited by W. Brunfitt and A. W. Asscher,pp. 148-158. Oxford University Press, London.

Chiari, H. (1881). Ueber das vorkommen lymphatischen gewebes inder schleimhaut des harnlcitenden apparates des menschen,Med. Jb,. pp. 9-19.

Darwish, M. E., Staubitz, W. J., Scheuller, E. F., Rubin, M. I., andNeter, E. (1968). Antibody response of dogs to experimentalinfection of bladder pouch. Invest. Urol., 6, 66-72.

David, F. N., Barton, D. E., Ganeshalingham, S., Harter, H. L., Kim,P. J., Merrington, M., and Walley, D. (1968). Normal Cen-troids, Medians and Scores for Ordinal Data. CambridgeUniversity Press, London

Finney, D. J., Latscha, R., Bennet, B. M., and Hsu, P. (1963). Tables

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for Testing Significance in a 2 x 2 Contingency Table. CambridgeUniversity Press, London.

Gower, P. E., Taylor, P. W., Koutsaimanis, K. G., and Roberts, A.P. (1972). Serum bactericidal activity in patients with upperand lower urinary tract infections. Clin. Sci., 43, 13-22.

Hamburger, A. (1879). Zur Histologie des Nierenbeckens und desharnleiters. Arch. mikr. Anat., 17, 14-20.

Hinman, F., and Cordonnier, J. (1935). Cystitis follicularis. J. Urol.(Baltimore), 34, 302-308.

Kaufman, D. B., Katz, R., and McIntosh, R. M. (1970). SecretoryIgA in urinary tract infections. Brit. med. J., 4, 463-465.

Kretschmer, H. L. (1952). On the occurrence of lymphoid tissue in theurinary organs. J. Urol. (Baltimore), 68, 252-260.

Marsh, F. P. (1973). Urinary tract infection. Med. Ann., 91,456-461.Marsh, F. P., Murray, M., and Panchamia, P. (1972). The relation-

ship between bacterial cultures of the vaginal introcitus andurinary infection. Brit. J. Urol., 44, 368-375.

Mitchell, J. P., and Andrews, G. S. (1953). Clinical aspects andpathology of bladder neck obstruction. Proc. roy. Soc. Med.,46, 549-555.

Norden, C. W., Green, G. M., and Kass, E. H. (1968). Antibacterialmechanisms of the urinary bladder. J. clin. Invest., 47, 2689-2700.

Numazaki, Y., Shigeta, S., Kumasaka, T., Miyazawa, T., Yamanaka,M., Yano, N., Takai, S., and Ishida, N. (1968). Acute haemor-rhagic cystitis in children. Isolation ofadenovirus type 11. NewEngl. J. Med., 278, 700-704.

Percival, A., Brumfitt, W., and de Louvois, J. (1964). Serum-antibodylevels as an indication of clinically inapparent pyelonephritis.Lancet, 2, 1027-1033.

Przewoski, E. (1889). Ueber nodulare oder folliculare Entzundung derSchleimhaut der Harnwege (Cystitis, urethritis et pyelitisgranulosa s. follicularis v. nodularis). Virchows Arch. path.Anat., 116, 516-536.

Pugh, R. C. B. (1967). Pathology of urinary tract infection. Hosp.Med., 1, 1001-1007.

Raffel, S. (1961). Immunity, 2nd ed., p. 1 5. Appleton-Century-Crofts,New York.

Rantz, L. A. (1962). Serological grouping of Escherichia coli. Arch.intern. Med., 109, 37-42.

Siegel, S. (1956). Non-Parametric Statistics for the BehaviouralSciences. McGraw-Hill, New York.

Stamey, T. A., Govan, D. E., and Palmer, J. M. (1965). The localizationand treatment of urinary tract infections: the role ofbactericidalurine levels as opposed to serum levels. Medicine (Baltimore), 44,1-36.

Stirling, C., and Ash, J. E. (1941). Chronic proliferative lesions of theurinary tract. J. Ulrol., 45, 342-360.

Uehling, D. T., and Steihm, E. R. (1971). Elevated urinary secretoryIgA in children with urinary tract infection. Pediatrics, 47, 40-46.

Vosti, K. L., Monto, A. S., and Rantz, L. A. (165). Host-parasiteinteraction in patients with infections due to Escherichia coli.II Serologic response of the host. J. Lab. clin. Med., 66, 613-626.

Weischselbaum, A. (1881). Ueber das Vorkommen lymphatischenGewebes in dernormalen Harnblasenschleimhaut des Menschen.Allg. Wien. Med. Zeit., 26, 346.

Ziegler, E. (1886). A Textbook of Pathological Anatomy and Patho-genesis, translated and edited by D. MacAlister, Sect. IX-XIi, p. 82. MacMillan, London.

II Squamous change in the bladder epithelium

SYNOPSIS The occurrence of squamous change in the bladder epithelium was studied in bladderbiopsies from patients with recurrent urinary infections or symptoms of cystitis and comparisonswere made with sections taken at necropsy from control subjects. Two types of squamous change,termed 'vaginal' and 'cornified', are described. Vaginal change was frequent in females, and seemedto be a normal finding in them, but was not observed in males. It did not seem to be caused byurinary infection. Cornified change was also common in females and was found in one (infected)man. Like vaginal change it was most often found in sections from the trigone. Urinary infectionmay predispose to its formation but we were unable to prove this. Squamous change did not seemto cause symptoms, and could not usually be recognized at cystoscopy. The varieties described areso common that they are unlikely to be markedly precarcinomatous.

The literature concerning the significance of squa-mous epithelial change in the bladder is inadequate.During a prospective study of women with recurrenturinary infections we took 50 bladder biopsies(usually from the trigone) from 41 patients whopresented with recurrent or persistent symptomssuggesting infection. Twenty-four developed urinaryinfection during follow up but in 11 there was noevidence of infection throughout prolonged obser-vation; six were regarded as of uncertain bacilluricstatus as they were observed for too short a time.Only one biopsy was taken at each cystoscopy. Thefrequency with which squamous change was foundin these biopsies, and its nature, was compared withthat in sections made at necropsy from the trigones,

and in some cases the vaults also, of bladders from42 control subjects. We could find no evidence ofprevious urinary infection in 30 of these but 12 hadsuggestive evidence of antemortem infection.

Details of patients and controls, and our bacterio-logical and statistical methods, have been given else-where (Marsh, Banerjee, and Panchamia, 1974).

Histological Classification

Two types of squamous epithelium were found:

1 VAGINAL SQUAMOUS EPITHELIUM (FIG 1)This thick epithelium was composed largely ofpolygonal cells with clear cytoplasm; the epithelial


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