The Role of Urine cytology in the investigation of Haematuria? B Barrass Audit Meeting 17 th May 2006

Overview Urine Cytology The Role of cytology in haematuria assessment Audit Standards Aims Methods Results Comparison with Audit stanards Discussion Recommendations

Atypical Malignant

Urine Cytology 1864-Exfoliated urothelial cells first described 1945-First used to diagnose urothelial malignancy Graded I-V (Papanicolaou & Marshal 1945) I-II normal IIIsuspicious IV-Vmalignant Sensitivity 42% - 66% Specificity up to 97%

Problems with Urine Cytology Low grade malignancy less likely shed cells Patients with suspicious cytology faced with: Anxiety over undiagnosed cancer Several invasive investigations and F/U False positive common Stones UTI Radiotherapy Urinary Instrumentation Only 50% with positive cytology have cancer – who should be investigated?

How Should Suspicious Cytology be Followed-up? 2005 Nabi et al followed up 70 patients with haematuria & C3-C5 cytology & normal investigations 25 had normal repeat cytology 4 had persistent suspicious cytology 41 developed cancer in mean 5.6 months 37 had positive repeat cytology 8 had recurrent haematuria 4 had prostate cancer Recommends investigate: Persistent positive cytology Symptoms

Audit Standards 1. Was cytology repeated? 2. Was repeat abnormal cytology investigated? 3. Were investigations thorough Lower tract: -GA cystoscopy Upper tract:-IVU -Retrograde & washing -Ureteroscopy retrograde abnormal

Aims 1. Review the investigations & diagnosis for positive cytology 2. Review additional Investigations to investigate for positive cytology 3. Review if these investigations generated additional diagnosis 4. What was the cost & morbidity of additional tests? 5. How did the results compare with the audit standards? 6. Recommend use and follow-up of cytology in the investigation of haematuria

Methods All urine cytology was reviewed between 01/10/2001 and 31/06/2004 Patients were identified who had C3-5 cytology either No histological diagnosis No repeat cytology Notes were obtained and reviewed Data was recorded regarding Investigations & associated morbidity Diagnosis Follow-up and survival

Results: Patient identification 1829 urine samples analysed 9% were atypical 11% were inadequate 80% were benign. Of the 164 (9%) atypical samples 53 (32%) had urothelial neoplasia 33 (20%) had repeat cytology 14 (8.5%) had other urological / gynaecological malignancy 61 (42.7%) had no further sample or biopsy 3 had missing records 65 (40%) had either no biopsy, no repeated cytology or persistently abnormal cytology

Results: Positive Cytology & Cancer 187 biopsy following urine cytology 53 TCC with benign cytology Atypical cytology identified 42 TCC 1 breast met (bladder) 11 prostate cancer 1 endometrial cancer 1 penile cancer INADEQUATEBENIGNATYPICAL BENIGN CIS/TCC sensitivitySpecificity This study 47%93% Keir&Womak %72% Beyer Boon %92% Raitanen % primary 34% recurrent 90% Amberson & Laino %99%

Results – reason for checking cytology Reason for investigatingNumber% Unknown812.3 microscopic haematuria irritative LUTS34.6 to investigate mets11.5 to investiagte haematuria non specified57.7 to investigate frank haematuria f/u TCC710.8 to investigate haemospermia11.5 to investigate vaginal discharge11.5

Results – Initial Investigation INVESTIGATIONNo.% unknown710.8 Nil34.6 Cystoscopy23.1 flexible cystoscopy GA cyst23.1 USS23.1 CT11.5 INVESTIGATIONNo.% unknown812.3 Nil57.7 IVU46.2 USS / KUB CT23.1 KUB11.5 USS Lower tract Upper tract

Results – Initial Diagnosis Of those with a diagnosis: 7 (33%) had a tumour 14 (66.7%) had a benign diagnosis DIAGNOSISNUMBER% Diagnosis Normal Unknown1624.6

Results – Additional Lower Tract Investigation & diagnosis 11 patients (16.9%) had further investigation 1 (10%) aspirated after GA cystoscopy The remaining 54 (83.1%) had either no further imaging of the lower urinary tract (47) or were unknown (7 ) Initial DiagnosisAdditional InvestigationFindingNo. cystitisGA cystoscopynormal2 GA cystoscopynormal3 Other DiagnosisGA cystoscopyConfirmed5 v-v FistulaMRI / USSNormal1 CTNormal1

Results – Additional Upper Tract Investigation & Diagnosis 9 (13.8%) underwent further upper tract investigations 2 (22.2%) had a diagnosis (ureteric stones) causing stones positive cytology 1 (11.%) had diagnosis (duplex) that did not cause abnormal cytology 6 (66.7%) either had a diagnosis confirmed or were confirmed to be normal. Additional InvestigationNo.% Unknown710.8 Ureteroscopy, retrograde, biopsy, washing11.5 Retrograde23.1 IVU46.2 IVU & retrogrades11.5 IVU RGP ureteroscopy11.5 Nil4975.4

Results: Follow-up Cytology Finding on cytologyNumberInvestigation normal1Not investigated abnormal1 Fully investigated (no diagnosis) abnormal1 Fully investigated (diagnosis) abnormal2Not investigated inadequate1Fully investigated Six patients (9.2%) also had repeat cytology

Results: Overall Additional Diagnostic Yield of Investigating Cytology Lower tract diagnosis Nil Upper tract diagnosis 2 upper ureteric stones 3.1% of total, 22.2% of those investigated (found on retrogrades) No additional malignancies were detected one patient had a serious complication (aspiration) There were four false positives (6.2%) detected on re- investigation 3 found on lower tract imaging and 1 found on cytology

Results: Final Diagnosis after all Investigations 3 patients have unexplained positive cytology of which only one underwent further investigations 54 (83.1%) had no further lower tract imaging and 49 (75.4%) had no further upper tract imaging. DiagnosisNumber% Diagnosis Normal Unknown1624.6

Results: Significance of Frank Haematuria Diagnosis % with frank haematuria Normal35.4 Any diagnosis52.4 Cancer71.4 (100% frank haematuria, non-specified or known cancer)

Follow-up and Outcome The median follow-up 30 months ( months). Mortality 13.8% (9 patients) Disease specific mortality 6.2% (4 patients) All disease specific deaths occurred in patients diagnosed with TCC on initial assessment 2 (50%) had C3-4 cytology and 2 (50%) had C5 cytology 1 recurrence during follow-up (2.3% of those found to be normal or benign on initial assessment) Previous TCC with C5 cytology. An initial flexible cytoscopy was normal Disease free interval 40 months Grade & stage G1Pta TCC This patient did not contribute to the mortality.

Comparison with Audit Standard StandardResult Was cytology repeated?36 (37%) of 97 with no diagnosis had repeat cytology Was abnormal cytology investigated 2 (50%) of 4 with persistently abnormal cytology were investigated Were additional lower tract investigations sufficient 10 (15.4%) had a GA cystoscopy Were additional upper tract investigations sufficient 9 (13.8%) had upper tract investigation and 5 (7.7%) had retrograde or ureteroscopy

Discussion The results were below the standard in terms of repeating positive cytology Investigating positive cytology The investigation of positive cytology was variable Investigation of cytology didn't yield many additional diagnosis over all (3.1%) Did not yield any additional cancers Did yield a high number of diagnosis among those investigated (22.2%) Retrograde yielded all additional diagnosis The presence of frank haematuria seemed to correlate with malignancy C3-4 cytology does not rule out finding tumour The recurrence rate was low and there were no new cancers during follow- up, suggesting most patients were unlikely to have significant cancer Most diagnoses were benign (70% C5 and 93.1 C3/4)

Recommendations 1. Cytology does not seem to increase the diagnosis of malignancy through the haematuria clinic but… Few were investigated Low rate of malignancy during F/U 2. Atypical cytology should be repeated and investigated only if persistently abnormal 3. A prospective study of the long-term follow-up of atypical cytology is needed 1. Do patients with benign diagnosis or cytology that normalises on F/U have any increase in risk? 2. What is the diagnostic yield of full investigation for positive cytology –does it add to the haematuria assessment? 3. Are there any reliable clinical markers that can be used to identify those who should be investigated e.g. frank bleeding?