GRÁFICO DE PRÉSTAMOS OTORGADOS
COOPERATIVA DE AHORRO Y CRÉDITO “15 DE ABRIL LTDA.”
(5a). Sharply circumscribed, rounded masses of almost solid cribiform tumour, usually with central necrosis (comedocarcinoma).
(5b). Ragged masses of anaplastic cancer with only enough gland formation or vacuoles to identify it as adenocarcinoma.
GLEASON SUM OR GLEASON SCORE
The five basic grade patterns are used to generate a Gleason score which can range from 2-10, by adding the primary grade pattern and the secondary grade pattern.
The primary pattern is the one that is predominant in area, by simple visual inspection. The secondary is the second most common pattern.
If only one grade is in the tissue sample, that grade is multiplied by two to give the score.
According to the Gleason approach of 1977, if the second grade is less than 3% of the total tumour, it is ignored, and the primary grade is again doubled to give the Gleason score.87 When more than two patterns are present in needle biopsy, and the worse grade is neither the predominant nor the secondary grade, the predominant and the highest grade should be added to arrive at a score.89
Gleason scores provide useful prognostic information.8,31 The higher the Gleason score, the more aggressive the cancer and more likely it is to spread.90
Well differentiated tumours have a Gleason score of 2-4. Moderately differentiated tumours have a Gleason score of 5-6 and poorly differentiated tumours have a Gleason score of 8-10.
The Gleason score is extremely useful as the tumour grade is closely associated with biologic activity (rate pattern of growth) and the likelihood of metastases. 38
The well differentiated tumours, Gleason score 2-4 tend to grow slowly and take a long time to become clinically significant, their doubling time is measured in years.15 In the VACURG series of 5,000 prostate cancer patients in a prospective randomized study, Gleason score 2 adenocarcinoma comprised <1% of all cases. The diagnosis of Gleason score 2-4 carcinoma in needle biopsy almost always represents undergraded intermediate-grade carcinoma.86 Pattern 1 in Gleason scores of 2 and 3 is usually a focal finding involving less than 5-10% of prostatic tissue.87, 91
Moderately differentiated cancers have moderate Gleason score of 5-6. These cancers may become clinically significant if they occur in younger men below the ages of 70-75
years. Over the age, of 80 years, the patient is more likely to die of other causes than prostate cancer.15
Poorly differentiated cancers are described as Gleason score of 8, 9 or 10. These tumours are very aggressive, have poor results with most treatments and have a doubling time measured in a matter of weeks or months. 15 Gleason score 9 and 10 are seen associated with high clinical stage disease with clinically detectable cancer outside the prostate, either locally or in the form of metastatic disease.87.
Patients with Gleason score of 7 who have primary Gleason grade of 4 (4+3) tend to have worse prognosis than those who have a primary Gleason grade of 3 (3+4).4, 8, 90
Gleason score 7, currently one of the most commonly assigned Gleason scores are in between moderate and high grade cancers and must be considered significant, but not incurable cancers.
In a recent study of 767 men with localized prostate cancer, there was a high correlation between the risk of dying from prostate cancer and the Gleason score. Patients with a score of 2-4 have a 4-7% chance of dying within 15 years of diagnosis. In contrast, patients with a score of 8-10 had a 60-87% chance of death from prostate cancer.31
A 10 year likelihood of metastases of local progression is shown in table II below:31
Gleason score Histological characteristic
Ten-year likelihood of local progression(%)
≤4 Well differentiated 25
5-7 Moderately differentiated 50
>7 Poorly differentiated 75
Table II Showing a 10 year likelihood of local progression of CaP in relation to histological characteristics
A meta-analysis of patients being managed by active surveillance, found that the annual rate of developing metastasis correlates well with Gleason scores. This is shown in table III. 31 Gleason score Rate of developing metastasis (%)
< 4 2.1
5-7 5.4
>7 13.5
Table III Showing annual rate of developing CaP metastasis in relation to Gleason score
CORRELATION BETWEEN SERUM PSA AND GLEASON SCORE
Many prostate cancers are indolent and may never cause a problem, but it is as at now impossible to identify such tumours with certainty.92 Currently, prostate-specific antigen, Gleason score, and stage at diagnosis are the most reliable markers of prostate cancer prognosis and tumour aggressiveness.93 It has been suggested that prostate cancer cells produce more PSA than normal cells; and, it is proposed that poorly differentiated prostate cancer cells may secrete and release greater amounts of PSA than well-differentiated ones.94 In a population study of 65 men with prostate cancer at the University of Kentucky Medical Centre, Lexington Kentucky, pre biopsy and pre digital rectal examination serum prostate-specific antigen were measured. The Gleason scores were obtained and divided into two groups of high Gleason scores (6 to 10) and Low Gleason scores (2 to 5). Forty two patients had high Gleason scores with mean PSA of 134.39ng/ml. Twenty three patients had low Gleason scores with mean PSA of 23.62ng/ml.
The high Gleason score group exhibited significantly high PSA values compared with the low Gleason score group. 94
In a retrospective study of 67 men with prostate adenocarcinoma diagnosed and treated at UCH Ibadan, there was a positive correlation between serum PSA and Gleason grade or score. PSA levels were significantly lower in patients with stage B disease than in patients with stage D disease.1
In a similar retrospective study of correlation between PSA level, Gleason score and bone scan in staging of prostate cancer patients, it was found that well differentiated tumours have low PSA levels (PSA < 10 ng/ml) and low positivity rate for bone metastasis while those patients who had moderate to poor differentiated tumours have high PSA levels (PSA >
20 ng/ml) and high positivity rate for bone metastasis. 95
Freeland et al 96 showed that the pathological Gleason score was significantly associated with death from prostate cancer. Patients with Gleason scores of 8–10 were more likely to die from prostate cancer than those with Gleason scores of ≤ 7. Both the pathological stage and the Gleason score are established important predictors of biochemical recurrence after radical retropubic prostatectomy (RRP). There is a statistically significant correlation between disease-free survival after RRP, the PSA level beforehand and the final pathological Gleason score in most series.97
The histological grade of prostate cancer, usually assessed using the Gleason system is one of the key prognostic markers for predicting biochemical recurrence (BCR), systemic recurrence and overall patient survival. Whereas patients with high-grade tumours have higher rate of progression, patients with low-grade tumours generally have a favourable prognosis and a low risk of recurrence after therapy.98 In a study of 1,354 patients with pathological features of Gleason score 6, patients were divided into two groups of low PSA
levels; <4ng/ml and intermediate range of PSA levels; 4-10ng/ml. It was found that at Gleason score of 6, there was a statistically significant higher rate of BCR in the high PSA group than in the low PSA group.99
Although there is positive correlation between serum PSA and Gleason grade as well as Gleason score in most studies done within and outside Nigeria, Ellis and associates, found a negative correlation between histopathologic differentiation and PSA levels.100 Despite the fact that PSA, Gleason score and stage at diagnosis are currently the most reliable markers of prostate cancer prognosis and tumour aggressiveness,93 the correlation between PSA levels and Gleason score has not been studied in the UCTH Calabar. Findings from this study will therefore not only help to prognosticate and take appropriate decisions in treatment of patients with prostate cancer in this centre, but will compare the previous reports from other centres within and outside Nigeria.
CHAPTER THREE PATIENTS AND METHODS PLACE AND PERIOD OF STUDY
This prospective study was carried out in the University of Calabar Teaching Hospital (UCTH) Calabar, over a 12 month period (September 2011 to August 2012). Approval for this study was obtained from the ethical committee of the hospital.
CATCHMENT AREA (see Figure 4)
The University of Calabar Teaching Hospital is a 410-bed hospital, currently operating on two sites (old and new sites) about 5 kilometres apart, in Calabar South and Calabar Municipal Local Government areas of Cross River State, Nigeria. It is a teaching centre for both undergraduate medical students and resident (postgraduate) doctors, as well as a referral centre for hospitals in Cross River and Akwa Ibom States of Nigeria. This centre also often receives referrals from Benue, Abia, Rivers and Ebonyi states, as well as the Republic of Cameroon. On the average, it subserves an approximate population of over 8 million people.
There are 4 consultants, three of whom are professors in the urology unit of this hospital.
The catchment area is shown as the shaded portion of the map of West Africa in figure 4 below.
STUDY POPULATION
During the period of study, all adult male patients 40 years and above with Lower Urinary Tract Symptoms (LUTS), retention of urine, and other symptoms suggestive of prostate cancer, seen or referred to the urology unit, and in whom pre-biopsy PSA estimations and digitally guided transrectal prostate biopsies were obtained were included in the study based on the inclusion criteria below:
INCLUSION CRITERIA a). All adult patients 40 years and above with clinical findings suggestive of carcinoma of the
prostate.
b). Patients with or without elevated prebiopsy PSA in addition to (a) above.
c). Patients with prostate biopsies positive for prostate cancer with Gleason scores reported.
EXCLUSION CRITERIA
1. All patients who were on, or had been on, medical treatment with finasteride, dutasteride and aspirin.
2. Patients who had commenced hormonal treatment for prostate cancer.
3. Patients whose biopsy specimens were not reported or reported to be BPH were also excluded from the study.
SCOPE OF THE STUDY
This was a hospital based study to find out if there was a correlation between biopsy Gleason scores and prostate specific antigen levels in patients with histologically proven carcinoma of the prostate seen at the University of Calabar Teaching Hospital. It was a prospective, observational and purely descriptive study.
SAMPLE SIZE ESTIMATION
The sample size was calculated using the Leslie Kish formula for single proportion;101 n = z2pq/d2
Where n = sample size
z = 1.96 at 95% confidence level
p = the prevalence of high PSA value among histologically confirmed CaP cases for one year.
q = 1- p
d = the difference between the true population rate and the sample (precision) = 0.05.
For this Study,
p = 0.97 (Being the prevalence of significantly high PSA (52 patients) among histologically confirmed cases of CaP (50 patients) presenting at UCTH for 1 year)
q=0.03
From a pilot study of cases at the Urology clinic, UCTH, Calabar between January 2009 to January, 2010.
Substituting in the formula n = (0.97)x(0.03)(1.96)2 (0.050)2 n = 44.7 ~ 45
Therefore the minimum sample size was 45. However, 60 patients who met the inclusion criteria were recruited for the study.
THE PROCEDURE
An investigator-administered proforma (Appendix 1) was designed to record details of patient’s personal and clinical data as well as findings from relevant investigations.
Every patient seen in the urology unit with LUTS characterised by nocturia, frequency, urgency, sensation of incomplete bladder emptying, weak urinary stream,, low back ache, bone pain, weight loss, paraparesis, paraplegia e.t.c. suggestive of prostate cancer in the University of Calabar Teaching Hospital was clerked and examined by the author following the proforma designed for this study. Patients that were not sure of their ages had their age estimated from the age of their first child, popularly remembered historical events, and contributions from their relations.
A carefully performed clinical examination of each patient was done. Particular attention was paid to DRE to assess the prostate gland for size, symmetry, presence or absence of median groove and lateral sulci, consistency, nodularity, induration, fixation and tenderness.
Their prebiopsy baseline PSA level estimation, full blood count and platelets, serum electrolytes, urea and creatinine, fasting blood sugar, and abdominopelvic ultrasonography were done. Those patients that presented with acute retention of urine, had their blood samples collected for PSA before they were catheterized to prevent significant rise in PSA levels that may be caused by urethral catheterization and acute retention of urine.
Before blood samples were collected for PSA, patients were asked to abstain from ejaculation, riding a bicycle, and TRUS examination for at least 72 hours to minimize a rise in serum PSA levels
Measurement of Serum tPSA Concentration
a) Sample Collection, Processing and Preservation
Patients were in a sitting position and well-rested before 5mls of blood was collected from the antecubital vein into plain tubes which were then spun at 3000rpm for 5 minutes. The supernatant sera were transferred to storage tubes and stored at -20oC for a maximum of 2 weeks before analysis. Total PSA assays were carried out in batches of 20 samples each.
Total PSA (tPSA) concentration was estimated using a Commercially available enzyme-linked immunosorbent assay (ELISA) kit manufactured by DR G Diagnostics (18,D-35039, Marburg, Germany). Reference number E/A-3882 and batch number of 20120728.
b) Assay Procedure
In the determination of tPSA done with the help of a consultant chemical pathologist, all reagents, samples and controls were brought to room temperature before analysis. 25µl of PSA standards and serum samples are pipetted into appropriate microwells. 100µl of enzyme conjugate was then added into all microwells. The microwell plate is mixed gently for 30s, covered and then incubated for 30mins at room temperature. Thereafter, the microwells content were decanted and washed 3times with 300µl of washing solution. 100µl of 3,3’,5,5’-tetramethyl-bendizine (TMB) substrate solution is added into all microwells which were then covered and incubated for 15mins at room temperature in the dark.
Thereafer 100µl of stop solution is added to all microwells to stop the chemical reactions and the microwells content are gently mixed and their absorbance read at 450nm using microwell reader.
c) Calculation
The microwell reader plots the standard curve and reads out the total PSA concentrations expressed in ng/ml from the curve.
Prostate biopsy procedure
Patients with abnormal DRE and abdominopelvic ultrasound findings with or without total PSA elevation had informed consent obtained from them for prostate biopsy. Oral ciprofloxacin 500mg stat dose was given 30 minutes to the procedure as prophylactic antibiotic. Six patients that had bleeding either from the urethra or rectum and one patient who had fever had their oral ciprofloxacin 500mg twice daily extended to one week.
The patients were placed in the left lateral (Sims’s) position with the right lower limb flexed at the knee and the left lower limb semi-extended with the buttocks projecting over the edge of the couch. The left index finger, well lubricated with K-Y jelly was used to guide a size 16G biopsy needle mounted on an automated spring loaded biopsy gun into the rectum to access the prostate. Four to six cores of prostatic tissue from suspicious part(s) of the gland obtained from the biopsy of each patient were preserved in Bouin’s solution (which is said to better outline nuclear features than formaldehyde)102 and sent for histology.
Histology Report
Slides of prostatic tissue stained with H&E, positive for malignancy were assigned Gleason grades by matching their histologic features with those of the template shown in Figure 3 by a histopathologist. The Gleason grading system defines five histological patterns or grades with decreasing differentiation. In grades 1 to 3, there is retained epithelial polarity with luminal differentiation in virtually all glands. In grade 4, there is partial loss of normal polarity and in grade 5, there is an almost total loss of polarity with only occasional luminal
differentiation. The grade is the highest histological pattern present. The primary and secondary pattern, i.e. the most prevalent and the second most prevalent pattern are added to obtain a Gleason score or sum.
Relevant data were collected from all patients found to be positive for carcinoma of the prostate on biopsy with Gleason score reported and prebiopsy serum PSA levels estimation done.
Other necessary investigations such as X-rays of the lumbosacral region and chest and liver function tests were only done for selected patients because of cost. At present there are no functional facilities for imaging with transrectal ultrasonography, MRI and CT at UCTH Calabar.
STATISTICAL ANALYSIS
A spreadsheet was developed using data obtained from patients’ case notes as represented on the proforma. Data analysis was conducted using SPSS (Statistical Package for Social Sciences) Statistic 17.0 and Microsoft Excel 2007. Data was summarized as frequencies, percentages, means, and standard deviations. Relevant tests of significance such as; chi-square (x2), ANOVA, correlation and regression analysis were conducted at a 95% confidence limit, and a p-value of ≤ 0.05. Spearman’s rho Correlation Coefficient was used to test for correlation of Gleason scores and serum PSA levels. Data were presented in tables and bar charts.
CHAPTER FOUR RESULTS
During the 12 months study period, 90 patients suspected to have cancer of the prostate were biopsied. Histology report confirmed 22 patients (24.4%) to have BPH, 8 patients (8.9%) as having high-grade prostatic intraepithelial neoplasia (HGPIN) and they were not included in the study. Sixty patients (66.7%) with histologically reported adenocarcinoma of the prostate, with Gleason scores assigned, and who met other inclusion criteria constituted the studied population.
Age of patients at presentation
The patients’ age ranged from 49-95 years with a mean (± standard deviation) of 67.4±10.8 years. Almost half of the patients, 29 (48.3%) in this study were in their sixth decade of life. Only one patient (1.7%) was less than 50 years old and only one patient (1.7%) was above 90 years old. Figure 5.
Family and social history (Table IV)
Fifty patients (83.3%) were married and six (10%) were divorced. Three patients (5%) were widowers and only one patient (1.7%) was separated. Two patients had first degree relatives with prostate cancer.
Most of these patients resided in the urban areas, mainly Calabar and Ikom in Cross River State and Uyo in Akwa Ibom State. These constituted 37 (61.7%) cases, while 23 (38.3%) patients were from rural areas.
Nineteen patients (31.7%) were retirees, 12 (20%) manual/agricultural workers, 9 (15%) traders while 3 patients (5%) were factory workers with a cement manufacturing company.
Mode of admission
Majority of the patients, 47(78.3%), were admitted through the Surgical Out-Patients Department (SOPD), while 13 patients presented as emergencies and were admitted through the Casualty/Accident and Emergency unit.
Presenting symptoms
Nineteen patients (31.7%) had lower urinary tract symptoms (LUTS) with retention of urine, 17 (28.3%) had LUTS alone, 14 (23.3%) had LUTS with low back pain, 3 (5.0%) had LUTS with swelling of the lower limbs, 2 (3.3%) had LUTS with haematuria, 1 (1.7%) had LUTS with Haemospermia. The order of prevalence of the presenting symptoms is as shown in Table V. Most of these patients were being managed in private clinics or General Hospitals for Lower urinary symptoms before referral to our centre.
Past medical history (Table VI)
Two patients (3.3%) had previous enucleation of the prostate for benign prostatic enlargement while 23 patients (38.3%) had previous surgeries unrelated to the urinary tract which include 16 patients that had previous herniorrhaphy, 2 patients that had previous hydrocelectomy and 5 patients that had previous haemorrhoidectomy which predated the onset of symptoms. Nineteen patients (31.7%) had urethral catheterizations that were removed at least eight weeks before presenting in our clinic. Three patients (5.0%) had UTI.
Thirteen patients (21.7%) had no relevant past medical history.
Findings on physical examination
Twenty four patients (40.0%) had no obvious abnormality discovered. Twelve patients (20%) had palpable urinary bladder. Seven patients (18.3%) had hernia /haemorrhoids. Eleven patients (11.7%) had pallor. Two patients (3.3%) had pallor and Paraparesis of the lower limbs. Four patients (6.7%) had palpable inguinal lymph nodes with associated leg swellings.
Findings on clinical examination are presented in Table VII
Digital rectal examination
Digital rectal examination (DRE) of the prostate showed an enlarged prostate in 56 patients (93.3%) while four patients (6.7%) had no prostatic enlargement. The prostate was firm to hard and nodular in 27 patients (45.0%), initially assed as clinically benign in nine patients (15.0%), with obliteration of the median sulcus in 8 patients (13.3%). Three patients (5%) had obliteration of the lateral sulci while 5 patients (8.3%) had firm to hard prostate, no nodule. Four patients (6.7%) had their gland fixed to the rectal mucosa. Table VIII shows the findings on DRE.
PROSTATE-SPECIFIC ANTIGEN (PSA) RESULTS
The PSA was elevated in 55 patients (91.7%) while the PSA level of 5 patients (8.3%) was within normal range.
The mean pre-biopsy PSA level was 43.97±28.87ng/ml; the highest value being 117ng/ml and the lowest was 0.8ng/ml. Six patients (10%) had serum PSA levels of 5-9.9 ng/ml and another six patients (10%) had 70-74ng/ml in this study.
At slightly elevated PSA level of 5 – 9.9 ng/ml, 6 patients (10%) had adenocarcinoma of the prostate while 5 patients (8.3%) had adenocarcinoma of the prostate at moderately elevated PSA of 10 – 19.9 ng/ml. At significantly elevated PSA level of 20ng/ml and above, 44 patients (73.4%) had adenocarcinoma of the prostate. Table IX and Figure 6 illustrate PSA results.
BIOPSY RESULTS Gleason grade
The mean Gleason grade was 3.3±0.77, with a range of 2 to 5. Thirty two patients (53%) were in Gleason grade-3 category. Seventeen patients (28.3%) had Gleason grade 4 tumours while 7 patients (11.7%) had well differentiated Gleason grade-2 tumours. Four patients (6.7%) had Gleason grade 5 tumours. (Figure7).
Gleason score
The mean Gleason score (± standard deviation) was 6.53±1.40, with a range of 4 to 9.
Twenty five patients (41.7%) had Gleason scores 5-6, sixteen patients (26.7%) had Gleason score 8-10 and fourteen patients (23.3%) had Gleason score 7. Five patients (8.3%) had well differentiated tumours - Gleason score 2-4. The modal Gleason score was 6. (Figure 8).
RELATIONSHIP OF GLEASON GRADES WITH PSA
Seven patients (11.7%) had Gleason grade 2 with mean PSA level of 15.41ng/ml. Thirty two patients (53.3%) had Gleason grade 3 with a corresponding mean PSA level of 39.76ng/ml while seventeen patients (28.3%) had Gleason grade 4 with mean PSA level of 57.09ng/ml. Four patients (6.7%) had Gleason grade 5 with a mean PSA level of 71.85ng/ml.
Table X illustrates the distribution of Gleason grade with PSA results.
RELATIONSHIP OF GLEASON SCORES WITH PSA
Five patients (8.3%) had a Gleason score of 4 with mean PSA level of 9.6ng/ml. Nine patients (15%) had a Gleason score of 5 with a corresponding mean PSA level of 28.5ng/ml while sixteen patients (26.7%) had a Gleason score of 6 with mean PSA level of 43.9ng/ml.
Nine patients (15%) had a Gleason score of 7 with a predominant Gleason grade 3 and a mean PSA level of 41.33 ng/ml while five patients (8.3%) had a Gleason score of 7 with a predominant Gleason grade 4 and a mean PSA level of 62.62 ng/ml. Eleven patients (18.3%) had a Gleason score of 8 with a mean PSA level of 53.1ng/ml while five patients (8.3%) had a Gleason score of 9 with a mean PSA level of 72.16ng/ml.
Table XI illustrates the distribution of Gleason score with PSA results.
CORRELATION BETWEEN BIOPSY GLEASON SCORES AND PSA LEVELS There was a positive correlation between pre-biopsy serum PSA levels and Gleason grade. The Spearman’s rho Correlation Coefficient was 0.341 and this was statistically significant (p=0.008). There was a statistically significant regression of Gleason grade to
serum PSA levels (R2=0.137, p=0.004), showing that the pre-biopsy PSA accounted for 14%
of the total variance in Gleason grade. Figure 9.
Similarly, there was statistically significant positive correlation between pre-biopsy serum PSA levels and Gleason scores. The Spearman’s rho Correlation Coefficient was 0.345 and this was statistically significant (p =0.006). Regression analysis showed a predictive accuracy of 15% (R2=0.146) for the variance of Gleason score using the pre-biopsy serum PSA level, and this was statistically significant (p=0.003).
The mean serum PSA level for patients with Gleason scores of 2-4 was 28.8ng/ml (±22.78) and this was statistically lower than those of patients with Gleason scores of 8-10 which was 59.1ng/ml (±31.76). Figure 10.
COMPLICATIONS OF BIOPSY
Fifty three patients (88.3%) had no complications following the procedure. Three patients (5%) bled per urethram while two patients (3.3%) bled per rectum. A patient (1.7%) had both urethral and rectal bleeding. Another patient (1.7%) who tested human immunodeficiency virus (HIV) positive had fever after 48 hours of the procedure. The complications that followed this procedure are shown in Table XII.
0 5 10 15 20 25 30 35
40-49 yrs 50-59 yrs 60-69 yrs 70-79 yrs 80-89 yrs >90 yrs NO. OF PATIENTS
AGE GROUP (YEARS)
Figure 5. DISTRIBUTION OF PATIENTS BY AGE
TABLE IV. DISTRIBUTION OF PATIENTS BY FAMILY AND SOCIAL HISTORY
Variable No of patients Percentage
Marital status
Married 50 83.3
Divorced 6 10.0
Separated 1 1.7
Widower 3 5.0
Total 60 100
Occupations
Professional/Managerial 7 11.6
Civil servants/Teachers 9 15.0
Factory workers Traders
3 9
5.0 15.0
Manual and Agricultural 12 20.0
Retired 19 31.7
Others 1 1.7
Total 60 100
Domicile
Urban 37 61.7
Rural 23 38.3
Total 60 100
Religion
Christianity 59 98.3
Islam 0 0
Others 1 1.7
Total 60 100
Family history of prostate cancer
Yes 2 3.3
No 58 96.7
Total 60 100
FIGURE 6 : PRE BIOPSY SERUM PSA LEVEL
TABLE V. PRESENTATION
Variable No. of patients Percentage
LUTS + Urinary retention 19 31.7
LUTS Alone 17 28.3
LUTS + Low back pain 14 23.3
LUTS + Weight loss 4 6.7
LUTS + Swelling of lower limb 3 5.0
UTS + Haematuria 2 3.3
LUTS + Haemospermia 1 1.7
Total 60 100