Journal of Cytology
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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 29  |  Issue : 1  |  Page : 16-19
Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India


1 Department of Pathology, Institute of Nephro Urology, Victoria Hospital Campus, Bangalore, India
2 Department of Microbiology, Institute of Nephro Urology, Victoria Hospital Campus, Bangalore, India
3 Department of Biochemistry, Institute of Nephro Urology, Victoria Hospital Campus, Bangalore, India

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Date of Web Publication27-Feb-2012
 

   Abstract 

Background: Regardless of the availability of newer and more sophisticated modalities of investigation, urinary tract cytology still remains the most commonly used non-invasive test for the diagnosis of bladder cancer.
Aims: As hematuria is the commonest presenting symptom in patients with malignancy of urinary tract, we undertook this study to know the usefulness of urine cytology in evaluation of the hematuric patients for malignancy.
Materials and Methods: A total of 21,557 fresh voided urine samples received at our tertiary care referral centre over a period of three years were included in the study. Of these, 1428 cases had hematuria, criteria of either gross or microscopic.
Results: Among these hematuric cases included in the study, 32.5% (464 cases) were found to have positive finding of atypical cells. In these cases with atypia, 9.5% (136 cases) were proved to have malignancy both with the histopathological biopsy and cystoscopic findings. Other cases of atypia were found to be of reactive origin, either due to instrumentation or foreign body. A large number of hematuric cases, that is, 964 cases (67.5%) were negative for atypical cells.
Conclusions: The limited ability of urine cytology to detect low grade bladder tumors, its subjectivity and lack of uniformity in reporting, all render urine cytology a less than perfect tool. With added collaboration between clinician and cytopathologist, urine cytology can be used an adjunct tool in evaluation of patients with hematuria.

Keywords: Atypical cells; hematuria; urine cytology

How to cite this article:
Siddappa S, Mythri K M, Kowsalya R. Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India. J Cytol 2012;29:16-9

How to cite this URL:
Siddappa S, Mythri K M, Kowsalya R. Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India. J Cytol [serial online] 2012 [cited 2014 Oct 20];29:16-9. Available from: http://www.jcytol.org/text.asp?2012/29/1/16/93211



   Introduction Top


Bladder cancer is one of the most common malignancies occurring worldwide. It represents 13 th most common cause of all cancer deaths worldwide. [1] Though a high annual incidence of approximately 13,000 cases is seen, majority of the patients have a curable and controllable disease. [2] Most of the bladder cancers are non-muscle invasive or muscle invasive transitional cell carcinoma (TCC) of low histological grade. These cancers have a better outcome when treated by endoscopic resection or intravesical therapies. However, still 23% to 35% of bladder cancer is of the high histological grade which has already invaded the muscularis propia or metastasized by the time of diagnosis. [3] Patients with these muscle invading tumors have poor prognosis, with only 30% surviving 5 years despite extensive treatments. [4],[5] Thus, early detection and reliable diagnosis are of utmost importance in this subset of population for a favorable outcome.

Several techniques for screening and diagnosis of bladder cancer have emerged of which cytomorphology still remains the mainstay. [6] Cytological examination of a urine specimen is a simple, safe, and inexpensive method to uncover hidden urothelial tumors. As most of the bladder cancers produce hematuria, even at non-invasive stages, screening of those at risk could provide a means of early detection, thus reducing cancer related morbidity and mortality. [7] Hence, we undertook this study to evaluate the utility of urinary cytology in hematuric cases among routine voided urine samples.


   Materials and Methods Top


This study was undertaken over a period of three years from September 2007 to August 2010 in our tertiary care referral centre. During this period a total of 21,557 fresh voided urine samples selected from patients (both urologic and non-urologic) attending the outpatient services of our institution were included.

Around 50 mL of urine was collected in a clean container. A sterile container was used if additional microbiological examination was required. The urine samples were usually the freshly voided morning sample, since sediments are best preserved in this specimen.

The processing of the samples was done in 3 parts:

  1. Physical examination: Volume, color, appearance, odor.
  2. Chemical analysis with the dip sticks for leukocytes, nitrite, urobilinogen, protein, pH, blood, specific gravity, ketone, bilirubin, glucose.
  3. Microscopic evaluation
    1. Wet mount: A column of 10 mL of urine was centrifuged at 800 revolutions per minute (rpm) for 30 minutes. The supernatant was discarded, and wet mount preparation was studied under ×40 for sediments.
    2. For cytologic evaluation: The sample was centrifuged in a Rotofix 32A at 800 rpm for 30 minutes, and the slide stained by Papanicolaou method along with a direct sweep preparation. Cytological details such as presence of inflammatory cells, non inflammatory cells, and atypical cells-India ink cells, necrosis, nuclear-cytoplasmic (N/C) ratio, cytoplasmic details, hyperchromasia and chromatin abnormalities were noted.



   Results Top


Out of the 21,557 urine samples included in the study, 1428 cases (6.6%) had either microscopic (>3 RBCs/hpf)[8] or gross hematuria. The average age of the hematuric cases was 46 years (range 6 to 80 years) with 1069 males and 359 female cases. These hematuria cases were further evaluated and the samples were processed for cytology. Based on the presence or absence of atypical cells (urothelial cells exhibiting a N/C ratio exceeding 50% were considered as atypical) on cytology, these cases were classified into two broad classes as: negative and atypia. Majority of the cases i.e. 964 cases (67.5%) were negative for atypical cells whereas, 464 cases (32.5%) showed presence of atypical cells.

The cases under atypia were further reviewed and compared with histological biopsy and cystoscopy study data. After the review, 136 cases (9.5%) turned out to be malignant (true positive). The most consistent features in the malignant atypical cells were presence of high nuclear and cytoplasmic (N/C) ratio, nuclear pleomorphism, India ink cells (single cells with deep black structureless nucleus) and chromatin abnormalities which correlated with histological findings of the tumor. [Figure 1] shows tumor cells exhibiting features of increased N/C ratio and hyerchromatic nucleus with irregular margins.
Figure 1: Loosely cohesive clusters of high grade transitional cell carcinoma seen. These cells exhibit features of increased nuclear cytoplasmic ratio and hyerchromatic nucleus with irregular margins. The background is hemorrhagic with focal necrosis (Pap, ×600)

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28 cases with atypia were placed under category of suspicious of malignancy and later proved histologically to be cases of follicular cystitis. The remaining 300 cases of atypia were categorized as probably benign due to presence of predisposed history of instrumentation, calculi, crystalluria and indwelling catheter for long time. In the cases classified as negative, 478 cases (33.6%) showed signs of acute inflammation with presence of some reactive degenerated cells and the remaining 484 cases (33.9%) showed presence of non-specific pathology without any contributory clinical, radiological and cystoscopy data.

Two cases (false negative) had papillary growth on cystoscopic examination, thus the urine specimens were processed for cell block and found positive for malignant cells. These cases were further confirmed to be transitional cell carcinoma on biopsy. In our study, sensitivity and specificity for urine cytology was 98.5% and 74.5% respectively, with an overall accuracy of 76.8%. The summary of the various categories of the cytological lesions is shown in [Figure 2]. There are many causes of hematuria e.g cystitis, inflammation of prostate and infections which can present in more than one category.
Figure 2: Summary of the various categories of cytological lesions

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   Discussion Top


Most bladder cancers are detected because they produce hematuria; additionally, 10% of the patients with bladder cancer have asymptomatic microscopic hematuria and are positive for urine cytology. [9] Thus the mainstay for diagnosis of bladder cancer is combination of cystoscopy, biopsy and voided urine cytology. Among these, urine cytology is a non-invasive technique suitable for screening, diagnosis and follow-up. [10] It can detect cases of carcinoma in-situ, low grade non invasive tumor, and also the most aggressive neoplasm. An important diagnostic principle in urine cytology is that higher the grade of the tumor, the more accurate the diagnosis. [11],[12] Also, it has been shown that patients with negative cytological findings have a very low risk of recurrence, while high-grade cytological abnormalities predict an aggressive tumor course. [13] Apart from these, urine cytology is also a better indicator of the presence of concomitant urothelial atypia, and indicator for bladder wash or mucosal biopsies. [14]

In our study, we found that about 9.5% (136 out of 1428 cases) of hematuria patients were positive (true positive) for malignant cells in urine cytology. These patients were later histologically proven to have malignancy of urothelial tract. An overall specificity of 75% was found for malignancy in our study. Though the specificity is high, still it is not possible to localize cancer based on urine cytology alone. A positive test warrants further evaluation and investigation of the patient. [15]

A variety of lesions can lead to exfoliation of transitional cells including stones, infection, post surgical/instrumentation trauma and inflammatory process. Thus, false positive diagnosis is higher in urinary cytology compared to other cytodiagnostic techniques. In addition, transition cells can show marked variation in sizes and shape, nucleation and exhibit nuclear and cytoplasmic degenerative changes that can mimic malignancy. [15],[16] In our study, 300 cases had atypical cells of reactive origin. These are the cases of less consequence and should be correlated by clinical data and confirmed histologically. Thus, interpretation of urine cytology should always be used as an adjunct to clinical data along with other diagnostic tools.

Additionally, in our study 28 cases which were false positive, showed cellular atypia on urine cytology, however, were histologically proven to be follicular cystitis. These cases should be dealt with great caution, as there are documented evidences of presence of pleomorphic cells in urine samples of these cases. [17]

A negative cytology doesn't always exclude malignancy. There are several reasons for these diagnostic inaccuracies, as urine is an inhospitable environment for cells, consequently cells undergo degenerative changes which can make diagnosis difficult. [18] As often quoted, the paradox of urine cytology is that pleomorphic cells with enlarged hyperchromatic nuclei with prominent nucleoli can be benign, whereas cancer cells can be composed of nearly normal looking monomorphic cells with benign nuclei. Thus, the number of false-negative diagnosis is higher in urinary cytological specimen and more of clinical consequence.

Regarding screening of the patients with hematuria, many clinical questions persist. Many times hematuria will be intermittent/microscopic, hence its detection itself is beset with multiple problems. Some studies have raised doubts about the utility of urinary cytology in evaluation of hematuria. [19] According to American urological association (AUA) recommendations, urine cytology is reserved only for patients with risk for TCC. [20] Others consider it as a good tool for screening in middle-aged or elderly patients. [21] Due to its subjectivity and lack of uniformity in reporting, urinary cytology is considered less than a perfect technique, even among experts. All these inconsistencies can be eliminated if the clinicians and cytopathologists meet eye to eye and use a practical clinical approach.

 
   References Top

1.Parkin DM. The global burden of urinary bladder cancer. Scand J Urol Nephrol Suppl 2008;218:12-20.  Back to cited text no. 1
    
2.Petersen RO, Sesterhenn IA, Davis CJ Jr. In: Robert O Petersen, editor. Urologic pathology. 3 rd ed. Philadelphia: Lippincott Williams and Wilkins; 2009. p. 209-51.  Back to cited text no. 2
    
3.Messing EM, Young TB, Hunt VB, Gilchrist KW, Newton MA, Bram LL, et al. Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology 1995;45:387-96; discussion 396-7.  Back to cited text no. 3
    
4.Pagano F, Bassi P, Galetti TP, Meneghini A, Milanic C, Artibani W, et al. Results of contemporary radical cystectomy for invasive bladder cancer: A clinico-pathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol 1992;145:45-50.  Back to cited text no. 4
    
5.Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Nichols P, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 1991;145:459-64.  Back to cited text no. 5
    
6.Bhatia A, Dey P, Kakkar N, Srinivasan R, Nijhawan R. Malignant atypical cell in urine cytology: A diagnostic dilemma. Cytojournal 2006;3:28-33.  Back to cited text no. 6
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7.Messing EM, Vaillancourt A. Hematuria screening for bladder cancer. J Occup Med 1990;32:838-45.  Back to cited text no. 7
    
8.Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: The American Urological Association best practice policy-part I: Definition, detection, prevalence, and etiology. Urology 2001;57:599-603.  Back to cited text no. 8
    
9.Messing EM, Young TB, Hunt VB, Roecker EB, Vaillancourt AM, Hisgen WJ, et al. Home screening for hematuria: Results of a multiclinic study. J Urol 1992;148:289-92.  Back to cited text no. 9
    
10.Thompson RA Jr, Campbell EW Jr, Kramer HC, Jacobs SC, Naslund MJ. Late invasive recurrence despite long-term surveillance for superficial bladder cancer. J Urol 1993;149:1010-1.  Back to cited text no. 10
    
11.Wiener HG, Vooijs GP, van't Hof-Grootenboer B. Accuracy of urinary cytology in the diagnosis of primary and recurrent bladder cancer. Acta Cytol 1993;37:163-9.  Back to cited text no. 11
    
12.Zein TA, Milad MF. Urine cytology in bladder tumors. Int Surg 1991;76:52-4.  Back to cited text no. 12
    
13.Harving N, Wolf H, Melsen FL. Positive urinary cytology after tumor resection: An indicator for concminant carcinoma in situ. J Urol 1988;140:495-7.  Back to cited text no. 13
    
14.Soloway MS. International consultation on bladder tumor. Urology 2005;68:40-1.  Back to cited text no. 14
    
15.Farrow GM. Urine cytology in the detection of bladder cancer: A critical approach. J Occup Med 1990;32:817-21.  Back to cited text no. 15
    
16.Koss LG, Deitch D, Ramanathan R, Sherman AB. Diagnostic value of cytology of voided urine. Acta Cytol 1985:29:810-6.  Back to cited text no. 16
    
17.Ro JY, Staerkel GA, Ayala AG. Cytologic and histologic features of superficial bladder cancer. Urol Clin North Am 1992;19:435-53.  Back to cited text no. 17
    
18.Frable WJ, Paxson L, Barksdale JA, Koontz WW Jr. Current practice of urinary bladder cytology. Cancer Res 1977;37:2800-5.  Back to cited text no. 18
    
19.Nakamura K, Kasraeian A, Iczkowski KA, Chang M, Pendleton J, Anai S, et al. Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria. BMC Urol 2009;9:12.  Back to cited text no. 19
    
20.Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: The American Urological Association best practice policy - part 2. Urology 2001;57:604-10.  Back to cited text no. 20
    
21.Viswanath S, Zelhof B, Ho E, Sethia K, Mills R. Is routine urine cytology useful in the haematuria clinic? Ann R Coll Surg Engl 2008;90:153-5.  Back to cited text no. 21
    

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Correspondence Address:
Sujatha Siddappa
Laboratory In Charge, Department of Pathology, Institute of Nephro Urology, Victoria Hospital Campus, Bangalore - 56002
India
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DOI: 10.4103/0970-9371.93211

PMID: 22438611

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