J Med Allied Sci 2018; 8(2):73-77 DOI: 10.5455/jmas.293731

Original article

A cyto-histo pathological correlation of bladder tumors in relation to smoking as a risk factor

Tanushree Satpathy1, Binapani Satpathy2, Sukumar Chakraborty3, Prasanna Kumar Satpathy3, Payala Vijayalakshmi4

Affiliation(s):

1Department of Pathology, GITAM Institute of Medical Sciences and Research, GITAM University, Vishakhapatnam-530045, Andhra Pradesh, India.

2Department of Obstetrics and Gynecology, Hi-Tech Medical College, Pandara, Rasulgarh, Bhubaneswar-751025, Odisha, India.

3Department of Pathology, Hi-Tech Medical College, Pandara, Rasulgarh, Bhubaneswar-751025, Odisha, India.

4Department of Microbiology, GITAM Institute of Medical Sciences and Research, GITAM University, Vishakhapatnam-530045, Andhra Pradesh, India.

Corresponding author: Dr. Tanushree Satpathy, Assistant Professor, Department of Pathology, GITAM Institute of Medical Sciences and Research, GITAM University, Vishakhapatnam-530045, Andhra Pradesh, India.

Phone: +91-8897002102 Email: jyothipgis@gmail.com

Abstract

Urinary bladder serve as an excretory dustbin, is exposed to all toxic and non toxic substances excreted by the body, thus it is a host to many metaplastic and neoplastic conditions apart from inflammatory changes. Urinary cytodiagnosis and biopsy studies are sufficient for confirmation in most cases. In this study also an attempt has been made to correlate smoking as a high risk factor. To correlate cytology and histology of different bladder tumors with smoking as a predisposing factor. This study was conducted on seventy four patients who were admitted to department of urology, Hi-Tech Medical College, Bhubaneswar between June 2012 to October 2014. Routine urinary cytology was done and stained by both diff quick and papanicoloke stain and biopsy specimen were stained by Hematoxylin and Eosin stains. By standard questionnaire the history of smoking was documented with consent from the patients who are included in the study. Out of 74 cases, 17 cases did not turn up for follow up. Samples were inadequate in 5 cases. 52 cases were included in the study. Strong correlation between cytodiagnosis and histology was observed with over all sensitivity 92.5% and specificity 80.0%. Out of 52 cases 21 were having history of smoking upto 10 cigarettes a day for a period of more than 20 years and 17 of them had high grade urothetial carcinoma 40.3% and 31 non smokers had 21.1% risk of developing bladder tumors. The present study concluded that urinary cytodiagnosis is well correlated with histopathology of patients of bladder tumors. This can be performed in centres where molecular marker study is not available. This is fairly cheap and accurate for early diagnosis and treatment. History of smoking habit is equally important to correlate with bladder tumors as a risk factor.

Key words: Bladder tumor, CECT, Cytodiagnosis, Fluorescence in-situ hybridization, Histopathology, Immune histochemistry, Smoking

Running title: Bladder tumor and smoking

Introduction

The urothetial neoplasms are known for their recurrence and morbidity than mortality. All types of neoplasms can be seen in bladder, but more than 95% of bladder tumors are of epithetial in origin and the rest are mesenchymal. Variants like squamour cell carcinoma and adenocarcinoma of urinary bladder carry worst prognosis where as prognosis of even high grade urothetical carcinoma stands better survival rate1. The challenge is that, early detection and treatment of new or recurrent cases are required to optimize bladder preservation, reduced patient morbidity and increase survival rate. Urinary cytodiagnosis and histopathological study are cost effective and have fairly accurate morphological assessment for early detection of bladder tumors as such patients present with history of painless hematuria2.

The first report in 1955 by Holsti & Ermalan suggested a relationship between bladder cancer and smoking. Since then few available literatures established a strong association of bladder tumor with smoking as a risk factor3. Though different investigation modalities are available in cases of suspected bladder tumor such as (a) ultrasonography, (b) cystoscopy (c) Computed tomography (CE-CT) scan (d) Magnetic resonance imaging (MRI) and (e) Molecular markers, yet urinary cytodiagnosis and morphological correlation with histopathology are cost effective and fairly accurate4.

Most of the published literature and data on urinary cytodiagnosis and histopathological correlation of bladder tumors specifically in relation to smoking as a risk factor are from research works outside the state and country, with occasional reference from our state. So this study was taken up.

Materials and methods

This study was approved by the ethical committee of Utkal University. All patients with complain of painless hematuria and suspicion of bladder tumor were included in the study. Those patients unwilling to co-operate were excluded from the study.

A.  Urine cytology was performed by standard procedure and slides fixed with 95% isopropyl alcohol were stained by Diff-quick stain, Haemotoxylene and eosin stain and also by papanicolaou stain separately. Cytology findings include hazy or turbid urine specimen, presence of numerous polymorphs, histiocytes, occasionally eosinophils, Inflammatory changes in epithelial cells, presence of pathogenic microorganisms and evidence of associated pathology may be seen. Histological grading of Invasive carcinomas of the bladder composed of orderly sheets of cells resembling normal urothelium (grade I tumors) are very rare. Essentially all invasive tumors are grade II, III, or IV, depending on the level of architectural and cytologic abnormality. Grade II tumors mimic papillary tumors of high grades and are composed of sheets of relatively uniform cancer cells separated from each other by bands of connective tissue. Grade III tumors are usually solid and are characterized by variability in the size of cancer cells and marked nuclear abnormalities. Grade IV tumors are either composed of large cancer cells, spindle and giant cells, or of small cancer cells.

B.  Biopsy samples as received from Transurethral resection of bladder tumors (TURBT) specimen were subjected to standard tissue processing, cutting and stained with haemotoxylene and eosin stain.

C.  History of addiction to smoking of cigarette, bidi and pica (as used by males and females in tribal belts of Odisha) 10 numbers a day for period of beyond 20 years were included in this study.

Statistical analysis

Data were statistically analyzed using SPPS software version 20.0.  Frequency and percentages were calculated for categorical and ordinal variables. Chi-square test was carried out and p value ≤0.05 were considered statistically significant.

Results

Total 74 patients with suspected bladder tumors presented with history of painless hematuria were subjected for urinary cytology. 17 cases were lost to follow up, 5 samples were inadequate and 52 cases were included. Total urinary cytosmears reported were listed in table 1. From the table 2, it was found that, out of 52 cases subjected to urinary cytodiagnosis, we received 51 TURBT biopsy specimen which were subjected for histopathological study. 46 cases were neoplastic, 30 malignant and 7 benign tomours. 5 cases were non-neoplastic. Of the 46 neoplastic cases, 37 were males (80%) and 9 were female patients (20%). In female, we had 1 benign and 8 were having malignant tumors (ratio 1:8) where as in males 6 were benign and 31 were malignant tumors (ratio 1:5). Other than the routine transitional cell carcinomas we had one case of adenocarcinoma in a 70 year old male and only one case of squamous cell carcinoma in a 60 year old female. The 39 malignant tumors included 26 were high grade tumors, 8 cases of low grade and 5 cases were tumors with low malignant potential. Of the 7 benign tumors we had 1 squamous papilloma, 1 Cavernous haemangioma and 5 cases were inverted papilloma. Amongst 26 malignant tumors, LVI found in 8 cases (31%), muscle invasion in 21 cases (81%) of low and intermediate grade malignant tumors 2 out of 13 (15%) showed LVI and 4 out of 13 (30%) showed muscle invasion (Fig 1a-d), (Fig 2 a-d). In our study incidence of bladder tumor is more amongst smokers (40.3%) in comparison to non smokers (21.1%) (Table 3).

Table 1: Total urinary cytosmears

Urinary cytosmears

N

Inadequate

05

Negative

Inflammatory-14

17

Catheter injury-3

Suspicious

05

Low intermediate grade tumor

06

High grade tumor

19

Total cases

52

 

Table 2: Statistical correlation of cytodiagnosis and histology

Histology

Tumor Present

Tumor Absent

Total

Cytology

Positive

25 (a)

05 (b)

30 (a+b)

Negative

02 (c)

20 (d)

22 (c+d)

 

 

27 (a+c)

25 (b+d)

52

Sensitivity of cytology = a/a+c = 25/27 = 92.5%

Specitivity of cytology = d/ptd = 20/25 = 80%

Positive predictive value = a/a+b = 25/30 = 83.3%

Chi-square = 25.13, df 1 and p<0.0001, which is significant

 

Table 3: Correlation of cytodiagnosis and histology in relation to smoking

Histology

Smokers

(n=21)

Non Smokers

(n=31)

Benign

Gr I

Gr II

Gr III

Benign

Gr I

Gr II

Gr III

Cytology

Positive (n=25)

-

-

1

17

-

-

2

5

Suspicious (n=5)

-

-

1

1

-

2

1

-

Negative (n=22)

-

1

-

-

-

-

1

-

 

52

-

1

2

18

-

2

4

5

 

c

b

d

a

Fig 1. Lymphovascular invasion and muscle invasion

d

c

b

a

Fig 2. Metaplasia and malignant cells

Discussion

Total number of patients admitted to urology department in two years were 2254, out of which bladder tumor was found in 46 cases, constitutes 2% of total patients which matches with study by shenoyu et al5. About 95% of bladder tumors are of epithelial origin, the remainder being mesenchymal tumors. Most epithelial tumors are composed of urothelial (transitional) type cells and are thus interchangeably called urothelial or transitional tumors, but squamous and glandular carcinomas also occur. Urothelial carcinoma (UC) is two to three times more common in men than women. Bladder neoplasm was mostly seen in elderly age group 83% of the patients which correlates with the finding of Nabi et al6. In our study male to female ratio is 4.2 : 1. In the study of Canter et al7 it was 4 :1 and the study by Nabi et al6. It was 3.5 : 1. Most common clinical presentation was gross haematuria, 71% of patients which almost matches with study Nabi et al6 i.e. 72%. Our study shows recurrence of bladder tumor in 8 patients within 1-3 years of treatment. Tumor recurrence or progression could be due to clinical under diagnosis as found by Chenko D8. It could also be due to the synchronous and metachronous multifocality of transional cell carcinoma9. So the patients are to be followed up by urinary cytology. Mitra et al10 in their study pointed out that it is unlikely for a single market to be sufficient for conclusion to improve the prognosis for patients with bladder tumors, but a combination of multiple markers are required for prognostication. This will be very expensive. Therefore urinary cytodiagnosis and correlation with histopathological study becomes the cheap as well as fairly accurate diagnosis criteria as mentioned by Steiner et al11 and Nabi et al6. Lympho vascular invasion (LVI) which is an important determinant of metastasis was seen in 31% high grade and 15% low grade tumors which almost matches with the study of Bolenz et al12. Incidences of muscular invasion in our study was found in 81% of high grade tumors and 31% in low grade tumors which shows our figures are higher than the study by Karakiewicz et al13. Tobacco smoking is the best established factor for bladder carcinoma in both men and women. As the composition of cigarettes has changed over the past 50 years, leading to reduction of levels of tar and nicotine concentrations in cigarette smoke and at the same time the concentration of some carcinogens like beta-napthylamine, a bladder carcinogen and tobacco-specific nitrosamines. Population attributable risks for tobacco smoking have been estimated to be 50-60% in men and 20-30% in women. The risk of bladder cancer is generally more in smokers than non-smokers. We found the history of tobacco addiction for smoking in 53.8% and 21.1% in non smokers. Pietzak et al14 suggested that smokers have three fold increased risk of developing bladder cancer than non smokers. Our study matches with study by Grotehivs et al15  showed (50.9% / 18.8%) and Rink et al16 (46.0% / 28.0%). Alberg et al17 showed the rate of bladder cancer was 22% in smokers and 52% in non-smokers whereas Tripathi et al18 reported 23% in smokers and 39% in non-smokers. Sturgeon et al19 found that risks of each stage of bladder cancer increased with number of cigarettes smoked per day, but the more advanced the stage the higher the relative risk. Similarly, in this study we found that smokers were proportionally more likely than nonsmokers to be diagnosed with invasive disease and this difference was statistically significant.

Conclusion

Early detection and treatment of new / recurrent cases is required to optimize bladder preservation, reduce patient morbidity and increase quality of life. We have evaluated in our study that urinary cytodiagnosis and subsequent histopathological correlation has high sensitivity and specificity 92.5% and 80% in our study.Even though many other modalities such as Immune Histochemistry (IHC), Flourescene-in-situ Hybridization (FISH), are available, these are expensive and requires specialised centres where these studies are available. While taking history, persons addicted to prolonged tobacco smoking 10 cigarettes / Picca / Bidi per day for a period of more than 20 years should be correlated with bladder tumor. Though smoking is not the only causative factor yet stands as a major risk factor for urinary bladder cancer.

Acknowledgments: None

Competing interest: Authors have declared that no competing interests exist.

References

1.    Chalasani V, Chin JL, Izawa JI. Histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer. Can Urol Assoc J. 2009 Dec; 3(6 Suppl 4):193-8. PMID: 20019984

2.    Goodison S, Rosser CJ, Urquidi V. Bladder cancer detection and monitoring: assessment of urine- and blood-based marker tests. Mol Diagn Ther. 2013 Apr; 17(2):71–84. PMID: 23479428 DOI: 10.1007/s40291-013-0023-x

3.    Lilienfeld AM. The relationship of bladder cancer to smoking. Am J Public Health Nations Health. 1964 Nov; 54(11):1864-75. PMID: 14227948

4.    Holsti LR,  Ermala P. Papillary carcinoma of the bladder in mice, obtained after peroral administration of tobacco tar. Cancer. 1955 Jul-Aug; 8(4):679-82. PMID: 13240647

5.    Shenoy UA, Colby TV, Schumann GB. Reliability of urinary cytodiagnosis in urothelial neoplasms. Cancer. 1985 Oct; 56(8):2041-5. PMID: 4027934

6.    Nabi G, Greene DR, O’Donnell M. How important is urinary cytology in the diagnosis of urological malignancies? Eur Urol.  2003 Jun; 43(6):632-6. PMID: 12767364

7.    Canter D, Guzzo T, Resnick M, Magerfleisch L, Sonnad S, Bergey M, Tomazewski J, Vaughn D, Van Arsdalen K, Malkowicz B. The presence of lymphovascular invasion in radical cystectomy specimens from patients with urothelial carcinoma portends a poor clinical diagnosis. BJU Int. 2008 Sep; 102(8):952-7. PMID: 18485042 DOI: 10.1111/j.1464-410X.2008.07732.x

8.    Daniltchenko DI, Riedl CR, Sachs MD, Koenig F, Daha KL, Pflueger H, Loening SA, Schnorr D. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol. 2005 Dec; 174(6):2129-33. PMID: 16280742 DOI: 10.1097/01.ju.0000181814.73466.14

9.    Eerguney S, Ali A, Gurbuz R, Gungor S, Dilek B. Urinary cytology in bladder cancer. Turk J Med Res. 1994; 12(6):232-5.

10.  Mitra AP, Birkhahn M, Cote RJ. p53 and retinoblastoma pathways in bladder cancer. World J Urol. 2007 Dec; 25(6):563-71. PMID: 17710407 DOI: 10.1007/s00345-007-0197-0   

11.  Steiner H, Bergmeister M, Verdorfer I, Granig T, Mikuz G, Bartsch G, Stoehr B, Brunner A. Early result of bladder-cancer screening in high-risk population of heavy smokers. BJU Int.  2008 Aug; 102(3):291-6. PMID: 18336612 DOI: 10.1111/j.1464-410X.2008.07596.x

12.  Bolenz C, Herrmann E, Bastian PJ, Michel MS, Wülfing C, Tiemann A, Buchner A, Stief CG, Fritsche HM, Burger M, Wieland WF, Höfner T, Haferkamp A, Hohenfellner M, Müller SC, Ströbel P, Trojan L. Lymphovascular invasion is an independent predictor of oncological outcomes in patients with lymph node-negative urothelial bladder cancer treated by radical cystectomy: a multicentre validation trial. BJU Int. 2010 Aug; 106(4):493-9. PMID: 20067452 DOI: 10.1111/j.1464-410X.2009.09166.x

13.  Karakiewicz PI, Benayoun S, Zippe C, Lüdecke G, Boman H, Sanchez-Carbayo M, Casella R, Mian C, Friedrich MG, Eissa S, Akaza H, Huland H, Hedelin H, Rupesh R, Miyanaga N, Sagalowsky AI, Marberger MJ, Shariat SF. Institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder. BJU Int. 2006 May, 97(5):997-1001. PMID: 16542342 DOI: 10.1111/j.1464-410X.2006.06036.x

14.  Pietzak EJ, Malkowicz SB. Does quantification of smoking history correlate with initial bladder tumor grade and stage? Curr Urol Rep. 2014 Jul; 15(7):416. PMID: 24832198 DOI: 10.1007/s11934-014-0416-3

15.  Grotenhuis AJ, Ebben CW, Aben KK, Witjes JA, Vrieling A, Vermeulen SH, Kiemeney LA. The effect of smoking and timing of smoking cessation on clinical outcome in non-muscle invasive bladder cancer. Urol Oncol. 2015 Feb; 33(2):65.e9-17. PMID: 25023787 DOI: 10.1016/j.urolonc.2014.06.002

16.  Rink M, Zabor EC, Furberg H, Xylinas E, Ehdaie B, Novara G, Babjuk M, Pycha A, Lotan Y, Trinh QD, Chun FK, Lee RK, Karakiewicz PI, Fisch M, Robinson BD, Scherr DS, Shariat SF. Impact of smoking and smoking cessation on outcomes in bladder cancer patients treated with radical cystectomy. Eur Urol. 2013 Sep; 64(3):456-64. PMID: 23206854 DOI: 10.1016/j.eururo.2012.11.039

17.  Alberg AJ1, Kouzis A, Genkinger JM, Gallicchio L, Burke AE, Hoffman SC, Diener-West M, Helzlsouer KJ, Comstock GW. A prospective cohort study of bladder cancer risk in relation to active cigarette smoking and household exposure to secondhand cigarette smoke. Am J Epidemiol. 2007 Mar; 165(6):660-6. PMID: 17204516 DOI: 10.1093/aje/kwk047

18.  Tripathi A, Folsom AR, Anderson KE; Iowa Women's Health Study. Risk factors for urinary bladder carcinoma in postmenopausal women. The Iowa Women's Health Study. Cancer. 2002 Dec; 95(11):2316-23. PMID: 12436437 DOI: 10.1002/cncr.10975

19.  Sturgeon SR, Hartge P, Silverman DT, Kantor AF, Linehan WM, Lynch C, Hoover RN. Associations between bladder cancer risk factors and tumor stage and grade at diagnosis. Epidemiology. 1994 Mar; 5(2):218-25. PMID: 8172997