J Clin Pathol 1988;41:1277-1280

Clinicopathological importance of primary dysplasia ofbladderR J ZUK,* H S ROGERS,t J E MARTIN,* S I BAITHUN*

From the University Departments of*Morbid Anatomy and tUrology, The London Hospital, Whitechapel,London

SUMMARY A retrospective study of 15 patients with primary dysplasia of bladder urothelium wasperformed in an attempt to clarify some of the clinical and histopathological features. The lesionoccurs predominantly in middle aged men who present with irritative bladder symptoms with orwithout haematuria and show no evidence of bacteriological urinary tract infection. Appearances atcystoscopy are non-specific. Thirteen patients showed no progression to carcinoma in situ after a longperiod of follow up, but primary dysplasia cannot be regarded as an entirely innocuous condition asthe remaining two patients did develop carcinoma in situ. The grade of dysplasia on presentationbears no relation to the final outcome. Regular cytological analysis of urine seems to be the bestmeans of follow up, and more active treatment does not seem to be justified.

Over the past 30 years, following early work byMelicow and Hollowel in 1952' and Melamed, Voutsa,and Grabstald in 1962,2 interest in bladder carcinomahas focused on the early stages of tumour develop-ment. These stages included dysplasia (or "atypicalhyperplasia")3 and transitional cell carcinoma in situ(CIS). Experimental studies on animals suggest thatbladder cancers usually grow slowly through severalstages of increasing dysplasia to invasive tumours.4

In patients with overt bladder cancer or patientsundergoing follow up of previously treated tran-sitional cell carcinoma a complete search of thebladder mucosa often shows that macroscopicallynormal epithelium is histologically abnormal, withchanges varying from minor degrees of dysplasia toCIS" This concomitant or secondary dysplasia or CISis much more common than that found in the absenceof exophytic bladder cancer-that is, primary dys-plasia and primary CIS.

Little is known about the clinical presentation,natural history, or incidence of primary dysplasia ofthe bladder. We performed a retrospective study onpatients with this condition in an attempt to assess thefeatures of primary vesical urothelial dysplasia.

Accepted for publication 23 June 1988

Material and methods

Cases ofbladder urothelial dysplasia were found in thefiles ofour pathology and urology departments. Fortycases of dysplasia were identified. From this group 25cases were excluded because the histological featureswere not those of dysplasia, or the patient hadconfirmed bladder carcinoma.

Multiple mucosal biopsy specimens had been takenon each of the remaining 15 cases, the histology ofwhich was reviewed by three pathologists withoutknowledge ofthe clinical history. Histological featureswere graded according to the criteria used by Nagy,Frable, and Murphy9:(a) Mandatory features degree of change of uro-thelial polarisation; presence or absence of superficialcells; variation in nuclear size; presence of nuclearcrowding; degree of nuclear irregularity; chromatinstructure.(b) Non-critical features mitotic activity; promin-ence of nucleoli; cytoplasmic glycogen; absence orpresence of inflammation in the underlying connectivetissues.

Using these guidelines the histological material wasdivided into four groups-mild, moderate, severedysplasia, and CIS (figs 1 to 4). The clinical historieswere then reviewed in the 15 cases, with particularattention paid to age, sex, symptoms on presentation,and the appearance of the bladder mucosa on cyto-scopy. Subsequent clinical course, including the

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Fig 1 Mild dysplasia: urothelium shows slight change ofpolarisation, superficial cells are present, and there is slightenlargement, minimal crowding and slight irregularity ofnuclei. Nuclear chromatin is.finely granular and evenlydistributed. No mitoses are visible. (Haematoxylin andeosin).

Zuk, Rogers, Martin, Baithun

Eight cases were classified as mild, six as moderate andone as severe dysplasia. All cases were followed up byregular cytological analysis of the urine. Two malepatients developed CIS the first three months afterpresenting with mild dysplasia and the second threeyears after presenting with severe dysplasia. In bothcases the onset of CIS was detected by cytology andconfirmed histologically on biopsy. No other patientshad positive urine cytology for CIS at any stage and nopatients developed papillary or invasive tumours.

Discussion

Little is known of the clinical presentation, biologicalimportance, and incidence of dysplasia of the uro-thelium. Most information has been gained frompatients on follow up for bladder cancer. Dysplasticepithelium is found in selected or random mucosalbiopsy specimens from patients with previously resec-ted superficial bladder carcinoma and is also a recog-nised finding in bladders removed for multifocalcarcinoma."'

In the groups with secondary or concomitant dys-plasia most patients are middle-aged men with noevidence of bacteriological urinary tract infection whopresent with frequency, dysuria, or haematuria, or a

development or not offurther urothelial abnormalitiesand duration of follow up were noted.

Results

AGE AND SEXThere were 11 male and four female patients (ratio2-75:1). The male patients ranged from 49 to 70 yearswith a mean of 58 5 years; the female patients rangedfrom 55 to 66 years with a mean of 60-8 years (table).

CLINICAL HISTORYOfthe 15 patients, four presented with haematuria andthe remainder with irritative bladder symptoms. Noneof the patients had evidence of bacteriological urinarytract infection. In eight patients cytoscopy showed anerythematous bladder mucosa and in the remainingseven the epithelium looked normal. Follow up on allpatients was obtained and ranged from two to eightyears (mean 4-8 years). Two patients developed CISwith no clinically important change in their symptoms.Two patients went on to develop the clinical syndromeof chronic interstitial cystitis.

PATHOLOGYAll 15 cases were graded using the criteria described.

AM.

Fig 2 Moderate dysplasia: urothelium shows changedpolarisation. Superficial cells are stillpresent. Nuclear sizeexhibits more variation, and nuclear crowding and nuclearirregularity are more prominent than in mild dysplasia.Chromatin structure in some nuclei is coarsely granular.(Haematoxylin and eosin).

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Primary dysplasia ofbladder

i T T.0Fig 3 Severe dysplasia: urothelium shows severely changedpolarisation. Superficial cells are present but abnormal inappearance. Bizarre nuclei are present with nuclear crowdingandprominent nuclear irregularity. Chromatin is coarselygranular and irregularly distributed. (Haematoxylin andeosin).

combination." 2 These findings are similar to ours inthat primary dysplasia chiefly affects middle-agedmen, most presenting with irritative bladder symp-toms but occasionally with haematuria. There was noevidence of bacteriological urinary tract infection inany of the cases but two patients progressed to theclinical syndrome of "chronic interstitial cystitis".Table Case details

Fig 4 Carcinoma in situ: there is complete loss ofurothelialpolarisation. There are no superficial cells. Nuclear size,crowding irregularity, and chromatin structure are the sameas visualised in severe dysplasia. (Haematoxylin and eosin).

Cytoscopic examination performed on patients withsecondary dysplasia usually shows no obviousmacroscopic abnormality apart from occasionalslightly raised irregular areas of mucosa." The cyto-scopic findings in our study were mostly non-specific,varying from a slightly erythematous to a normalappearing mucosa.

Primary CIS of the bladder is now generally recog-

Case Sex/age History on Cystoscopy Histology on Length of Details ofNo (year) presentation on presentation original biopsy follow up (year)follow up

1 M 69 Frequency Erythema Mild dysplasia 6 Cytology negative2 M 49 Haematuria Erythema Severe dysplasia - Developed CIS after three years,

detected by urine cytology,confirmed histologically

3 M 51 Frequency; haematuria Normal Mild dysplasia 8 Cytology negative4 M 64 Frequency Normal Mild dysplasia 2 Developed chronic interstitial

cystitis5 F 64 Haematuria Erythema Mild dysplasia 2 Cytology negative6 M 57 Frequency; urgency Erythema Mild dysplasia 7 Cytology negative7 M 57 Frequency Normal Mild dysplasia - Developed CIS after three months,

detected by urine cytology,confirmed histologically

8 M 70 Frequency Normal Moderate dysplasia 4 Cytology negative9 F 58 Frequency Erythema Moderate dysplasia 3 Cytology negative10 F 55 Frequency Normal Mild dysplasia 3 Cytology negative11 M 58 Frequency Nornal Moderate dysplasia 8 Developed chronic interstitial

cystitis12 F 66 Haematuria Erythema Mild dysplasia 2 Cytology negative13 M 58 Frequency Normal Moderate dysplasia 3 Cytology negative14 M 55 Haematuria Erythema Moderate dysplasia 8 Cytology negative15 M 55 Frequency Erythema Moderate dysplasia 7 Cytology negative

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nised as a potentially lethal condition and if untreatedwill progress to invasive bladder carcinoma.'3 14 As it isthought to be preceded by lesser degrees of urothelialdysplasia514 active treatment with intravesicalchemotheraphy, intravesical bacillus Calmette-Guerin, radiotherapy or cystectomy have beenvariously advocated as prophylactic measures whenprimary dysplasia is found. Our results show thatprimary dysplasia progressed to CIS in only two casesdespite the relatively long period of follow up for allthe cases. If all dysplasia ultimately evolves into CISthere must be a long latent interval before itsappearance. At this time the best and most reliablefollow up procedure is urinary cytology which candetermlne accurately the appearance of CIS.'5Definitive diagnosis still depends on histologicalanalysis, however, and cystoscopy with rebiopsyshould be performed when cytological examination ofthe urine shows malignant cells. When CIS developsthen treatment by one of the many established tech-niques in use today is recommended.'6The results also show that of the two patients who

developed CIS during follow up one presented withsevere dysplasia and CIS was found three years later;the other presented with mild dysplasia and developedCIS three months later. This would suggest that thegrade ofdysplasia on presentation bears no relation tothe final outcome. It may be argued that in the secondcase with mild dysplasia an area ofCIS was missed oninitial biopsy due to sampling error. This seemsunlikely as multiple biopsy specimens had been takenon presentation and cytology performed at this timewas negative for CIS.From this study it is impossible to ascertain if (a)

dysplastic urothelium can revert back to normalappearances or (b) once initiated the affected uro-thelium must progress through the stages of mild tomoderate, to severe dysplasia, and ultimately to CISand invasive carcinoma. The numerous detailedstudies ofcervical intraepithelial neoplasia (CIN) haveshown not only that lesser degrees of dysplasticcervical epithelium can revert back to normal withouttreatment but also that mildly dysplastic cervicalepithelium can progress to invasive carcinoma albeitin a very small percentage of patients.'718 Futurestudies may show that urothelium may behavesimilarly.

In conclusion, primary dysplasia of bladder uro-thelium is found predominantly in middle-aged menwho present with irritative bladder symptoms with orwithout haematuria. There is no evidence of con-current bacteriological urinary tract infection. Cytos-copy shows a normal or slightly erythematous

mucosa. Primary dysplasia cannot be regarded as anentirely innocuous condition as it did progress to CISin two of 15 patients. The grade of dysplasia onpresentation bears no relation to the final outcome.Careful follow up and regular cytological analysis ofurine are required to detect CIS, when more activetreatment is justified.

RefeCes

1 Melicow MM, Hollowell JW. Intraurotheial cancer, carcinoma insitu, Bowen's disease of the urinary system: discussion of thirtycases. J Urol 1952;6S:763-72.

2 Melamed MR, Voutsa NG, Grabstald H. Natural history andclinical behaviour of in situ carcinoma of the human urinarybladder. Cancer 1964;17:1522-45.

3 Eisenberg RB, Roth RB, SchweinsbergMH. Bladder tumours andassociatedproliferative mucosal lesions. J Urol 1960;84:544-50.

4 Ito N, Matayoshi K, Arai M, et al. Effect of various factors oninduction ofurinary bladder tumours in animals by N-butyl-N-(4-hyroxybutyl) nitrosamine. Gan Jap J Cancer Res1973;64:l51-9.

5 Schade ROK, Swinney J. Pre-cancerous changes in bladderepithelium. Lancet 1968;5:943-6.

6 Koss LG, Tiamson EM, Robbims MA. Mapping cancerous andpre-cancerous bladder changes. JAMA 1974;227:281-6.

7 Farrow GM, Utz DC, Rife CC. Morphological and clinicalobservations of patients with early bladder cancer treated withtotal cystectomy. Cancer Res 1976;36:2495-501.

8 Kakizoe T, Matumoto K, Nishio Y, Ohtani M, Kishi K.Significance of carcinoma in situ and dysplasia in associationwith bladder cancer. J Urol 1985;133:395-8.

9 Nagy GK, Frable WJ, Murphy WM. The classification ofpremalignant urothelial abnormalities: a Delphi study of theNational Bladder Cancer Collaborative Group A. Pathol Annu1982;17:219-33.

10 Soloway MS, Murphy WM, Rao MK, Cox C. Serial multiple-sitebiopsies in patients with bladder cancer. J Urol 1978;120:57-9.

11 Murphy WM, Soloway MS. Urothelial dysplasia. J Urol1982;127:849-54.

12 Murphy WM, Soloway MS. Developing carcinoma (dysplasia) ofthe urinary bladder. Pathol Annu 1982;17:197-217.

13 Utz DC, Farrow GM, Rife CC, Segura JW, Zincke H. Carcinomain situ of the bladder. Cancer 1980;45:1842-6.

14 Zincke H, Utz DC, Farrow MD. Review of Mayo Clinicexperience with carcinoma in situ. Urology 1985;26:(Sqpl 4);39-46.

15 Highman WJ. Flat in situ carcinoma of the bladder: cytologicalexamination of urine in diagnosis, follow up, and assessment ofresponse to chemotherapy. J Clun Pathol 1988;41:540-6.

16 Jenkins BJ, England HR, Fowler CG, et al. Chemotherapy forcarcinoma in situ of the bladder. Br J Urol 1988;61:326-9.

17 Petersen 0. Spontaneous course of cervical precancerous condi-tions. Am J Obstet Gynecol 1956;72:1063-71.

18 Fox CH. Biologic behaviour of dysplasia and carcinoma in situ.Am J Obstet Gynecol 1967;99:960-74.

Requests for reprints to: Dr R J Zuk, Department ofMorbidAnatomy, The London Hospital, Whitechapel, LondonEl IBB, England.

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