The Role of Urine cytology in the investigation of Haematuria?

B Barrass

Audit Meeting 17th 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 III suspicious IV-V malignant

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

INADEQUATE BENIGN ATYPICAL

BENIGN 2 68 11

CIS/TCC 11 53 42

sensitivity Specificity

This study 47% 93%

Keir&Womak 2002 28% 72%

Beyer Boon 1978 70% 92%

Raitanen 2002 57% primary

34% recurrent

90%

Amberson & Laino 1993

72% 99%

Results – reason for checking cytology

Reason for investigating Number %

Unknown 8 12.3

microscopic haematuria 16 24.6

irritative LUTS 3 4.6

to investigate mets 1 1.5

to investiagte haematuria non specified 5 7.7

to investigate frank haematuria 23 35.4

f/u TCC 7 10.8

to investigate haemospermia 1 1.5

to investigate vaginal discharge 1 1.5

Results – Initial Investigation

INVESTIGATION No. %

unknown 7 10.8

Nil 3 4.6

Cystoscopy 2 3.1

flexible cystoscopy 48 73.8

GA cyst 2 3.1

USS 2 3.1

CT 1 1.5

INVESTIGATION No. %

unknown 8 12.3

Nil 5 7.7

IVU 4 6.2

USS / KUB 34 52.3

CT 2 3.1

KUB 1 1.5

USS 11 16.9

Lower tract Upper tract

Results – Initial Diagnosis

Of those with a diagnosis:

7 (33%) had a tumour

14 (66.7%) had a benign diagnosis

DIAGNOSIS NUMBER %

Diagnosis 21 32.3

Normal 28 43.1

Unknown 16 24.6

C3/4 89.20%

C5 10.80%

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 Diagnosis Additional Investigation Finding No.

cystitis GA cystoscopy normal 2

normal GA cystoscopy normal 3

Other Diagnosis GA cystoscopy Confirmed 5

v-v Fistula MRI / USS Normal 1

Normal CT Normal 1

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 Investigation No. %

Unknown 7 10.8

Ureteroscopy, retrograde, biopsy, washing 1 1.5

Retrograde 2 3.1

IVU 4 6.2

IVU & retrogrades 1 1.5

IVU RGP ureteroscopy 1 1.5

Nil 49 75.4

Results: Follow-up Cytology

Finding on cytology Number Investigation

normal 1 Not investigated

abnormal 1Fully investigated (no diagnosis)

abnormal 1Fully investigated (diagnosis)

abnormal 2 Not investigated

inadequate 1 Fully 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.

Diagnosis Number %

Diagnosis 20 30.1

Normal 29 44.6

Unknown 16 24.6

Results: Significance of Frank Haematuria

Diagnosis% with frank haematuria

Normal 35.4

Any diagnosis 52.4

Cancer 71.4

(100% frank haematuria, non-specified or known cancer)

Follow-up and Outcome

The median follow-up 30 months (1 - 54 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

Standard Result

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?