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Association of urine cytology and cystoscopy findings with histologic diagnosis of urinary bladder lesions
, Vijay Suri4, Jasmine Kaur5, Tamanna Kalra3, M. L. Dhar2
*Corresponding author: Saurabh Gupta, Department of General Surgery, Adesh Institute of Medical Sciences and Research, Bathinda, Punjab, India. drguptasaurabh@yahoo.co.in
-
Received: ,
Accepted: ,
How to cite this article: Goyal N, Gupta S, Gupta A, Suri V, Kaur J, Kalra T, et al. Association of urine cytology and cystoscopy findings with histologic diagnosis of urinary bladder lesions. Adesh Univ J Med Sci Res. doi: 10.25259/AUJMSR_61_2025
Abstract
Objectives:
Neoplastic urinary bladder lesions are responsible for significant morbidity and mortality throughout the world. The diagnostic armentarium used by the urologists for urinary bladder lesions includes urinary cytology, cystoscopy, and biopsy. This study aims at studying the histopathological spectrum of urinary bladder lesions and associating it with findings of precystoscopy urine cytology and cystoscopy.
Material and Methods:
This observational study was carried out for 18 months, including the patients presenting with urinary bladder complaints, who attended the hospital and underwent relevant procedures.
Results:
It was noted that maximum cases, that is, 36 (49.3%) in which biopsy/transurethral resection of bladder tumor was done were diagnosed as high-grade urothelial carcinoma and 31 cases (42.5%) were cases of low-grade urothelial carcinoma suggesting that intervention is normally done in cases with suspicion of malignancy or in later stages of the disease. The overall sensitivity of the urine cytology, taking histopathology as the gold standard, was seen to be 72% and specificity was seen to be 80%. Furthermore, it was noted that cystoscopy findings which suggested large lesions (>3 cm) or multiple lesions were seen to be malignant on histopathology, making the sensitivity of cystoscopy quite high.
Conclusion:
In the end, it was concluded that bladder carcinoma is most commonly seen in males and in the age group of 51–60 years, with hematuria being the most common complaint. Urine cytology, despite being used to correctly detect malignancy, could not be used to comment on the grade of malignancy. Although, urine cytology in conjunction with cystoscopy can work as a good diagnostic aid in differentiating malignant from non-malignant lesions. However, for commenting on the invasiveness and the typing of the malignancy, histopathology remains the gold standard.
Keywords
Cystoscopy
Histopathology
Transurethral resection of bladder tumour
Urine cytology
Urothelial carcinoma
INTRODUCTION
Neoplastic urinary bladder lesions are responsible for significant morbidity and mortality throughout the world. Around 90% of the carcinoma bladder diagnoses are made in the age group of 55 years and above, and these cancers are 4 times common in males as compared to females.[1] As per the Indian Cancer Registry, bladder carcinoma constitutes the ninth most common malignancy, which accounts for 3.9% of all cancers overall in India.[2]
Early detection of bladder cancer is crucial for achieving better outcomes. Voided urine cytology has a specificity of >93% and has a sensitivity of only 25–40% for low-grade tumours.[3] A more widely accepted method of surveillance and detection of bladder lesions is cystoscopy, which offers direct visualization of bladder mucosa and has high sensitivity, but, small size of the lesion or inaccessibility of the lesion may lead to false negative results.[4,5] Furthermore, it has a higher cost of device maintenance, equipment, and labour, and it is an invasive procedure. Therefore, histological evaluation of the systemic biopsy is the gold standard, which assesses the degree of differentiation and depth of the tumour in the region.[6] Many studies are available in the literature correlating these three different diagnostic modalities; still, data remain inconclusive.[7] In the present study, the histopathological spectrum of urinary bladder lesions resected by transurethral resection of bladder tumour (TURBT) was correlated with pre-cystoscopy urine cytology and cystoscopy findings of the patients presenting to the institute. This will help in assessing the role of screening by urine cytology and cystoscopy in the early detection of lesions and also the follow-up of patients for recurrence of treated lesions.
Aims and objectives
The aim of this study was to study the histopathological spectrum of urinary bladder lesions and associate them with pre-cystoscopy urine cytology and cystoscopy findings, and analyse the relationship between cystoscopy findings and pre-cystoscopy urine cytology.
MATERIAL AND METHODS
Study design and setting
This observational cross-sectional study was conducted in the department of pathology and the department of general surgery.
Ethical approval
Ethical approval for the study was obtained from the Institutional Ethics Committee before commencement.
Study period and population
The study included patients for 15 months from March 28, 2019, to June 28, 2020, who presented with urinary bladder lesions and underwent relevant diagnostic procedures.
Inclusion criteria
All the patients presenting with urinary bladder lesions on ultrasonography/computed tomography (CT) scan who underwent pre-cystoscopy urine cytology, cystoscopy, and histopathology, and gave consent to participate in the study.
Exclusion criteria
The cases in which the specimen was autolysed or the biopsy material that was not adequate were excluded from the study.
Methodology
Pre-cystoscopy urine cytology was performed, followed by cystoscopy.
Urine cytology smears were prepared using direct smears and centrifuged smears (centrifugation of 50 mL of urine for 10 min at 1200 rpm). Smears were diagnosed based on the Paris System for Urine Cytology.[8] Papanicolaou stain was used for close nuclear detail examination, and modified Wright-Giemsa stain was used to evaluate non-urothelial cell entities. The cytological examination of all the cases was carried out by at least two experienced cytologists in the pathology department.
Urine cytology was classified using the Paris System of Classification:
Negative for malignancy
Atypical/reactive cells
Suspicious for malignancy
Positive for low-grade malignancy
Positive for high-grade malignancy.
Cystoscopy findings were recorded by the consultant surgeon/urologist, and intra-procedural photographs were taken.
Findings were classified on the basis of observation of the urologist according to the number of lesions
Single
Multiple.
And the size of the lesion –
<3cm
>3 cm.
Tissue samples were obtained either through cystoscopy biopsy (punch/excisional) or TURBT using a cystoscope having a 30° Rod Lens System with a 25 French sheath.
Histopathological examination was performed using hematoxylin and eosin staining on paraffin-embedded tissue sections, and biopsies were classified into five broad classes according to the World Health Organization classification:[9,10]
Benign papilloma
Cystitis
Low-grade urothelial carcinoma (LGUC)
High grade urothelial carcinoma (HGUN)
Papillary urothelial neoplasm of low malignant potential
Papillary urothelial neoplasm of unknown malignant potential.
Other malignant tumors like clear cell carcinoma.
Statistical analysis
Comparison between histopathology, urine cytology, and cystoscopy findings was done. P-value and Chi-square test were used for statistical analysis.
RESULTS
Seventy-three cases of urinary bladder lesions with bladder lesions were studied. The majority of cases (29; 40.3%) were in the 51–60 years age group. Males (53; 73.6%) were more commonly affected than females (20; 27.8%).
Out of 73 cases reported, 23 cases (31.5%) were negative for malignancy on histopathological examination, 16 (21.9%) were suspicious of high-grade malignancy, 15 cases (20.5%) showed presence of atypical cells, 12 (16.4%) were positive for LGUC, and 7 (9.6%) were positive for HGUN [Table 1].
| Histopathology diagnosis | Cytology findings | Total | ||||
|---|---|---|---|---|---|---|
| Negative n(%) | Atypical cells n(%) | Suspicious for high-grade n(%) | Positive for low-grade n(%) | Positive for high-grade n(%) | ||
| Benign papilloma | 1 (4.3) | 0 (0.0) | 1 (6.2) | 0 (0.0) | 0 (0.0) | 2 |
| Cystitis | 3 (13) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 |
| LGUC | 15 (65.2) | 9 (60) | 5 (31.3) | 1 (8.3) | 1 (14.2) | 31 |
| HGUC | 4 (17.45) | 6 (40) | 10 (62.5) | 11 (91.7) | 5 (71.4) | 36 |
| Clear cell adenocarcinoma | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (14.2) | 1 |
| Total | 23 (100) | 15 (100) | 16 (100) | 12 (100) | 7 (100%) | 73 |
HGUC: High-grade urothelial carcinoma, LGUC: Low-grade urothelial neoplasia
Most of the cases, that is, 54 (75%) out of 73 cases studied, presented as single lesions, and 19 (26.4%) were seen as multiple lesions in the urinary bladder. Furthermore, 46 (63.9%) cases were reported to be of size <3 cm and 27 (37.5%) were of size greater than 3 cm. Out of 36 cases of HGUC, 14 (38.9%) were noted in the age group of 51– 60 years and 11 (30.5%) were noted in the age group of 61– 70 years. Similarly, 11 (35.4%) cases of LGUC were seen in the age group of 51–60 years, and 6 (19.3%) cases each were seen in age group of <40, 61–70 and >70 years of age, respectively. In males, out of 53 cases studied, 29 cases (54.7%) were that of HGUC and 21 cases (39.6%) were that of LGUC. Similarly, out of 20 cases reported in females, 10 (50%) were that of LGUC and 7 (35%) were that of HGUC.
The most common symptom of the urinary bladder lesions was hematuria. Out of 40 cases that presented with the chief complaint of hematuria, 22 (54.8%) were diagnosed as HGUC and 16 (21.9%) were diagnosed as LGUC. Dysuria followed by pain were the other two main complaints with which patient presented to the outpatient department. Twenty-seven (90%) of these cases were later diagnosed as positive for malignancy.
Association between cytological and histopathological diagnosis
It was observed that urine cytology is much more sensitive in the diagnosis of HGUC than LGUC. The cases of cystitis were negative on cytology; benign papilloma was diagnosed as both negative and suspicious on urine cytology [Figures 1-3]. Fifteen (48.3%) out of 31 cases of LGUC were diagnosed as negative for any malignant cells on urine cytology and rest 16 (51.6%) were either suspicious for atypical/malignant cells or positive for LGUC or HGUC. Out of 36 HGUC cases, 5 (13.8%) were positive for HGUC on cytology, 11 (30.5%) for LGUC, 10 (27.7%) were suspicious for high-grade malignancy, and 4 (11.1%) were totally negative [Table 1]. The specificity of the urine cytology for benign lesions was close to 80%, and the sensitivity was 72%. The overall positive predictive value of urine cytology was around 98% and non-predictive value was 17% [Table 2].
- Urine cytology: Giemsa stained slide (40×, 10×), showing presence of few atypical suspicious cells.
- Cystoscopy (10x) showing single, small papillary lesion.
- Histopathology: Hematoxylin and eosin stained slide (10×, 10×), showing benign papilloma.
| True positive | 49 |
| False positive | 01 |
| True negative | 04 |
| False negative | 19 |
| Sensitivity | 72% |
| Specificity | 80% |
| Accuracy | 72.6% |
| PPV | 98% |
| NPV | 17% |
PPV: Positive predictive value, NPV: Negative predictive value
Association between cystoscopy evaluation and histopathological diagnosis
All the lesions with cystoscopy presentation as multiple lesions or size >3 cm were diagnosed as malignant. Out of 19 cases with multiple lesions on cystoscopy, 15 (78.9%) were diagnosed as HGUC and 4 (21.1%) were diagnosed as LGUC. Out of 29 cases which were of size >3 cm, 23 (79.3%) cases were diagnosed as HGUC and 6 (20.6%) were diagnosed as LGUC. Hence, the sensitivity of cystoscopy is around 100% if the lesions are multiple and are >3 cm [Table 3 and Figures 4-6].
| Histopathological diagnosis | Cystoscopy findings number | Size | ||
|---|---|---|---|---|
| Multiple n(%) | Single n(%) | >3 cm (%) | <3 cm (%) | |
| Benign papilloma | 0 (0.0) | 2 (3.7) | 0 (0.0) | 2 (4.6) |
| Cystitis | 0 (0.0) | 3 (5.5) | 0 (0.0) | 3 (6.8) |
| LGUC | 4 (21.1) | 27 (50) | 6 (20.6) | 25 (56.8) |
| HGUC | 15 (78.9) | 21 (38.8) | 23 (79.3) | 13 (29.5) |
| Clear cell adenocarcinoma | 0 (0.0) | 1 (1.8) | 0 (0.0) | 1 (2.3) |
| Total | 19 (100) | 54 (100) | 29 (100) | 44 (100) |
| Chi-square value | 2.847 | 15.74 | ||
| P-value | 0.416 | 0.001 | ||
HGUC: High-grade urothelial carcinoma, LGUC: Low-grade urothelial carcinoma. P<0.05: Statistically significant.
- Urine cytology: Giemsa-staincd slide (40×, 10×). showing urine cytology with large atypical cells positive for high-grade urothelial carcinoma (yellow arrow).
- Cystoscopy (10x) showing large multiple lesions (>3 cm).
- Histopathology: Hematoxylin and eosin-staincd slide (40×, 10×), showing high grade urothelial carcinoma. Yellow arrow indicates mitotic figure.
Association between cystoscopy and urine cytology
Out of 29 cases with a lesion size of >3 cm, only three were given negative on urine cytology, with the sensitivity of cystoscopy in association with urine cytology being 79.3%. Furthermore, out of 19 cases with multiple bladder lesions on cystoscopy, all were given positive results on urine cytology, making the sensitivity of cytology almost 100% if the lesions are multiple [Table 4 and Figures 4-6]. Association of several lesions and cytology findings was statistically significant with a Chi-square value of 18.64 (P = 0.001), showing that the more the number of lesions, more are the chances of positive urine cytology.
| Cytoscopy findings | ||||||
|---|---|---|---|---|---|---|
| Cystoscopy findings | Atypical n(%) | Negative n(%) | Suspicious n(%) | Positive LGUC n(%) | Positive HGUC n(%) | Total |
| Number | ||||||
| Multiple | 4 (21.0) | 0 (0.0) | 5 (26.4) | 8 (42.1) | 2 (10.5) | 19 |
| Single | 11 (20.3) | 23 (42.5) | 11 (20.4) | 4 (7.5) | 5 (9.3) | 54 |
| Size | ||||||
| <3 cm | 8 (18.1) | 20 (45.4) | 8 (18.1) | 4 (9.1) | 4 (9.1) | 44 |
| >3 cm | 7 (24.1) | 3 (10.3) | 8 (27.6) | 8 (27.6) | 3 (10.4) | 29 |
HGUC: High-grade urothelial carcinoma, LGUC: Low-grade urothelial carcinoma
Cystoscopy and cytology findings of the cases with muscle invasion
There was no direct correlation between muscle-invasive tumours and cystoscopy findings, which suggests that cystoscopy cannot be considered a good diagnostic modality to differentiate between muscle-invasive and non-invasive tumours. The muscle-invasive tumours can present both as single or multiple lesions on cystoscopy. Furthermore, the size of the tumour cannot determine if the tumour will be muscle-invasive or not.
It was noted that out of 28 cases with muscle invasion, 10 (35.7%) were given as positive for LGUC on urine cytology, 7 (25%) were reported as suspicious for HGUC, 6 (21.5%) were given as positive for HGUC, 3 (10.7%) were given negative on urine cytology, and 2 (7.1%) were reported with the presence of atypical cells. Urine cytology was unable to comment on the muscle invasion of the bladder tumour.
DISCUSSION
In this study, maximum cases in which biopsy/TURBT was done, 36 (49.3%) were diagnosed as HGUC, 31 cases (42.5%) were cases of LGUC, 3 cases (4.1%) were of cystitis, 2 cases (2.7%) were of benign papilloma, and 1 case (1.4%) was that of clear cell adenocarcinoma. Hence, most cases (93%) with symptomatic bladder lesions were labelled as malignant and very few (6.8%) cases were benign.
The findings of our study were similar to the studies mentioned in the literature with neoplastic lesions being more predominant than non-neoplastic lesions being just. Among neoplastic lesions, LGUC were seen most commonly, followed by HGUC and adenocarcinoma.[11,12]
The main reason for neoplastic lesions being more predominant than non-neoplastic lesions in our study can be attributed to the fact that we included only those cases for which histopathology biopsy was sent, and TURBT is usually done only in cases that are suspicious of malignancy.[13]
HGUN is comparatively more common in our study, which can be attributed to late presentation and the presence of thermal power plants in our region, leading to more industrial exposure.
The histopathological diagnosis of the patients was considered the gold standard in our study, and the findings of pre-cystoscopy urine cytology were compared with it. The case that gave a false positive in our study can be attributed to the fact that the smears prepared from the urine sample of the patient had a moderate amount of inflammation. Furthermore, the atypical cells suggested could be reactive cells associated with the inflammation. Thus, in this case, it would have been advisable to repeat the sample after the control of infection.
The reason for urine cytology being underdiagnosed as positive for LGUC instead of HGUC can be low cellularity due to overhydration, subjective bias, or inflammation.[14]
The false negativity can be due to a number of causes, which include the hydration status of the patient, sampling error, instrumentation, or low-grade neoplasia in which little or no shedding of tumour cells occurs. To overcome this problem, it is advisable to repeat the urine cytology of each negative patient for 3 consecutive days to be completely sure of the absence of any tumour.
Thus, urine cytology can act as a good aid for the diagnosis of urinary bladder lesions and categorizing them as benign or malignant, as its sensitivity is good (72%). This value is comparable to the sensitivity seen in other studies, which ranged from 38% to 74.1%.[15,16]
P-value for the association between urine cytology and histopathology is 0.149, which makes it non-significant and hence, urine cytology cannot replace histopathology. The main reason for this can be the fact that negative urine cytology does not rule out urothelial carcinoma and radiological imaging and cystoscopy are still required to be sure about the negative findings.[17] Furthermore, positive results on urine cytology need cystoscopy for the confirmation of the diagnosis which makes the role of urine cytology questionable.
The sensitivity of cystoscopy in our study was concluded to be around 100% if the lesions are multiple and are >3 cm. It should be noted that if the lesion is of large size on cystoscopy, it is almost certain that it will be diagnosed as malignancy (either LGUC or HGUC).
P-value in case of cystoscopy lesion size and histopathology was seen to be significant, that is, 0.001, which signifies that the larger the size, the greater the chances of it being HGUC. Although it was noted that the urologist was not able to distinguish between LGUC and HGUC. Furthermore, invasive and non-invasive tumours could not be distinguished from each other on cystoscopy, for which histopathology remains the gold standard.
Similar findings were seen in another study which concluded that the cystoscopy evaluation can correctly discriminate between malignant and benign lesion with the sensitivity and specificity of 100%.[18] In our study, when cystoscopy was compared with urine cytology, it was noted that out of 29 cases with a lesion size of >3 cm, only three were given negative results on urine cytology, which makes the sensitivity of cystoscopy in correlation to urine cytology to be 79.3%. Out of 19 cases that presented with multiple bladder lesions on cystoscopy, none were given a negative result on urine cytology, which makes the sensitivity of cystoscopy almost 100% if the lesions are multiple and larger in size.
Association of urine cytology, cystoscopy, and histopathology
As described above, the urine cytology offered sensitivity and specificity of 72% and 80%, respectively, whereas cystoscopy yielded nearly 100% sensitivity and specificity to distinguish between benign and malignant lesions. However, none of them offered clear features to distinguish between LGUC and HGUC. Furthermore, it was difficult to differentiate invasive and non-invasive tumours on urine cytology and cystoscopy, especially when the muscle invasion was microscopic only.
A recent study done on 50 cases revealed that overall sensitivity of urine cytology and cystoscopy was 62% and 84% respectively. The statistical relationship between urine cytology and histopathology was significant. Similar significance was reported between cystoscopy and histopathology as well.[19]
After going through the literature and findings of our study, it was noted that cytological examination of urine specimens is a valuable aid in the diagnosis and follow-up study of cystoscopically visualized bladder tumours.
Cystoscopy was seen to be of more useful in diagnosing low-grade tumours which were missed by voided urine cytology. Furthermore, cystoscopy can differentiate well between malignant and benign lesion, but not between LGUC and HGUC.
Limitations
The cases which were reported negative on cytology, urine samples were not repeated for 3 consecutive days in the present study, which may be the reason for lower sensitivity and false negativity.
Tumour invasiveness cannot be commented upon by either cytology or cystoscopy, for which histopathology is indispensable
CONCLUSION
Cytological examination of urine specimens is a valuable aid in the diagnosis and follow-up study of cystoscopically visualized bladder tumours. However, a patient should not be labelled as negative for malignancy unless proven negative with first void urine samples for 3 consecutive days. Furthermore, the accuracy and sensitivity of urine cytology is more with high-grade tumours.
Cystoscopy is seen to be of more useful in diagnosing low-grade tumours which were missed by voided urine cytology and it can differentiate well between malignant and benign lesion, but not between LGUC and HGUC.
Hence, it can be suggested that voided urine cytological study is a valuable adjunct to the clinician in the evaluation of a urologic patient as it is simple, non-invasive with good accuracy in the diagnosis. However, histopathology cannot be replaced by any of the above two diagnostic modalities as none of them offers any help to differentiate well between invasive and non-invasive urothelial carcinoma specially in cases with microinvasion. Histopathology can also be used to for grading and differentiating between variants of malignancy which can help a urologist to decide the further treatment modalities such as radiation, chemotherapy, immunotherapy, or intravesical therapy.
Ethical approval:
The research/study approved by the Institutional Review Board at the Ethics Committee (EC), Adesh University, Bathinda, number AU/EC/FM/139/2018, dated 31st October 2018.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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