BLADDER TUMOR introduction and management

Bladder tumors, specifically bladder cancer, occur when abnormal cells grow uncontrollably in the bladder lining, forming a tumor. These tumors can be non-muscle invasive (staying within the bladder lining) or muscle-invasive (penetrating into the bladder muscle). The most common type of bladder cancer is urothelial carcinoma.
Key Points:
Types of Bladder Tumors:
The most common type is urothelial carcinoma, followed by squamous cell carcinoma and adenocarcinoma

1. BASICS IN BLADDER TUMOR Dr LAKSHMI KANDHAN

2. EPIDEMIOLOGY Bladder cancer (BC) is the seventh most commonly diagnosed cancer in the male population worldwide, while it drops to tenth when both genders are considered. Recurrence and routine surveillance/treatment make bladder cancer most expensive malignancy to treat from diagnosis to death. M:F = 3:1 (survival better in men). Peak incidence ages 60-70 years. Majority (~93%) are urothelial cancer (transitional cell carcinoma).

3. RISK FACTORS GENETICS N -acetyltransferase 2 (NAT2) and a deletion of glutathione S-transferase μ ( GSTM1). Both of these genes are associated with the ability to metabolize aromatic amines. Lynch syndrome. SMOKING Tobacco is the main known cause of bladder cancer and accounts for 30% to 40% of all urothelial carcinoma. BODY MASS INDEX The mechanism of excess weight contributing to cancer risk includes insulin resistance, chronic hyperinsulinemia, increased bioavailability of steroid hormones, and localized inflammation.

4. RISK FACTORS OCCUPATIONAL RISK Occupational exposures account for between 5% and 10% of all bladder cancer . T obacco, dye, and rubber workers, hairdressers, painters, and leather workers. SCHISTOSOMIASIS S. haematobium is the one linked to squamous cell bladder cancer. S. haematobium live in the venules of the human urinary bladder, where they lay eggs, producing irritation and tissue fibrosis.

5. RISK FACTORS RADIATION DRUGS – Pioglitazone, Cyclophosphamide MEDICAL CONDITIONS – Neurogenic bladder and spinal cord injuries with long term catheters. Bladder calculi , Urinary outflow obstruction. Recurrent UTI.

6. SIGNS AND SYMPTOMS Gross haematuria most common Most commonly intermittent Gross 68-97% Microhaematuria- 11% Irritative voiding symptoms (especially in absence of UTI)

7. IMAGING CT urogram – Detect papillary tumour in the urinary tract IV urography – Alternate for CT Urogram Ultrasound - M oderate sensitivity to a wide range of abnormalities in the upper- and lower urinary tract. It cannot rule out all potential causes of haematuria.

8. CYSTOSCOPY Gold standard All adult patients with gross haematuria and 35 years and older with microscopic haematuria White light cystoscopy Blue light cystoscopy

9. WHITE LIGHT CYSTOSCOPY White light cystoscopy (WLC) is the cornerstone detection method for NMIBC, and transurethral resection of bladder tumour (TURBT) is the gold standard treatment procedure performed during WLC.

10. BLUE LIGHT CYSTOSCOPY

11. WHITE VS BLUE

12. BLUE LIGHT CYSTOSCOPY DISADVANTAGES H ydrophilicity at physiological pH L ow solubility in fats leading - rapid disappearance R educed residual tumour rates and increased 3-year recurrence free rates compared with WLC C ONTRAINDICATION G ross hematuria BCG or intravesical chemotherapy - false fluorescence

13. NARROW BAND IMAGING Optical image enhancement - improve the visibility of blood vessels inherent to neoplastic processes. 2 specific wavelengths that are absorbed by haemoglobin; 415-nm - superficial mucosal layers 540-nm - penetrates more deeply.

14. NARROW BAND IMAGING 415 nm – superficial – brownish 540 nm – deeper - cyan

15. OPTICAL COHERENCE TOMOGRAPHY R eal-time imaging technology using near-infrared light (890–1300 nm) to provide cross-sectional images of biologic tissues. Early experience suggests more than 90% sensitivity, specificity.

16. OPTICAL COHERENCE TOMOGRAPHY A small probe - cystoscope into bladder - real-time examination of bladder tumours. Normal urothelium - thin horizontal layer of uniform low signal intensity LP - scattering and thus appears as a brighter horizontal underlying layer with OCT. Between these two layers , the basement membrane Distinguish layers of urothelium and lamina propria as well as muscularis propria

17. OPTICAL COHERENCE TOMOGRAPHY BC - irregular, thickened layer of heterogeneous signal intensity in OCT images. The visualization of CIS – difficult. CIS and inflammation - heterogeneous signal intensity of the unbroadened urothelium, causing a reduced contrast with the untouched LP NMIBC - sensitivity of 75–90% and a specificity of 89% with OCT

18. CONFOCAL LASER ENDOMICROSCOPY CLE - confocal microscopy - high-resolution cellular and subcellular imaging. M icro-architectural and cellular level to distinguish between normal urothelium, benign inflammatory lesions, and low vs high-grade tumours A 488 nm low-power laser scans a tissue section of interest below the surface. Using fluorescein - intravenously or topically. CLE images are acquired as video sequences at a rate of 12 frames per second via direct contact of the probe with tissues of interest.

19. a)Normal urothelium surrounding the papillary tumour highlighting organized, monomorphic cells. b) High- grade, papillary tumour with papillary structures and distorted microvasculature. c) High-grade, carcinoma-in-situ featuring pleomorphic cells and disorganized microarchitecture.

20. URINE CYTOLOGY It has high sensitivity in HG and G3 tumours (84%), but low sensitivity in LG/G1 tumours (16%). The sensitivity in CIS detection is 28–100% . Cytology is useful, particularly as an adjunct to cystoscopy, in patients with HG/G3 tumours. Positive voided urinary cytology can indicate an urothelial carcinoma anywhere in the urinary tract; negative cytology, however, does not exclude its presence.

21. The Paris System published in 2016 redefined urinary cytology diagnostic categories as follows: No adequate diagnosis possible (No diagnosis); Negative for urothelial carcinoma (Negative); Atypical urothelial cells (Atypia); Suspicious for HG urothelial carcinoma (Suspicious); High-grade/G3 urothelial carcinoma (Malignant). The principle of the system and its terminology underlines the role of urinary cytology in detection of G3 and HG tumours.

22. URINARY MOLECULAR MARKERS UroVysion assay(FISH) Nuclear Matrix Protein (NMP)22 Fibroblast Growth Factor Receptor (FGFR)3/Telomerase Reverse Transcriptase (TERT) M icrosatellite analysis

23. BLADDER TUMOR ANTIGEN BTA assay detects two basement membrane antigens – Human complement factor H related protein and complement factor H using monoclonal antibodies. Two forms of BTA test : BTA STAT test BTA TRAK test

24. IMMUNOCYT Cell based adjunct to urine cytology. Fluorescent labelled antibodies are directed against three antigens expressed by exfoliated urothelial cells - Glycosylated form of CEA and two mucins. Operator dependent , interobserver variability.

25. CxBladder Cell based urine assay that comprises five m RNA fragments. Currently available urinary biomarkers miss many patients with bladder cancer and yield false positives in others. Biomarkers are currently used in combination with cystoscopy as a surveillance strategy for patients with a known history of NMIBC.

26. PATHOLOGY Epithelial Metaplasia. Papilloma and Inverted Papilloma. Nephrogenic adenoma. Leucoplakia. Cystitis Cystica and Glandularis . Precursor malignant lesions. Malignant lesions.

27. EPITHELIAL METAPLASIA Focal area of transformed urothelium, with otherwise normal nuclear and cellular morphology. Located on the trigone. Biopsy is unnecessary. No treatment required.

28. PAPILLOMA & INVERTED PAPILLOMA Papilloma is characterised by benign proliferative growth of delicate stalks lined by normal appearing urothelium. An inverted papilloma is a benign proliferative lesion that is associated with chronic inflammation or bladder outlet obstruction and can be located throughout the bladder but most commonly on the trigone, accounting for less than 1% of all bladder tumors . Painless gross hematuria . Lack of cytologic atypia.

29. NEPHROGENIC ADENOMA R are tumor caused by chronic irritation of the urothelium and can arise from trauma, prior surgery, renal transplantation, intravesical chemotherapy, stones, catheters, and infection. Composed of glandular appearing tubules similar to renal tubules that involve mucosa and submucosa of the bladder. Cystoscopically, it may appear like a papillary neoplasm and may be hard to distinguish from more aggressive bladder neoplasms. Lesions may cause dysuria, hematuria, prompting cystoscopic investigation. Recurrence does occur but is uncommon and can be safely managed with repeat resection.

30. LEUKOPLAKIA W hite, flaky plaques floating in the bladder. F requent, recurrent infections with urinary urgency and frequency. B ladder mucosa is chronically inflamed, displaying diffuse squamous metaplasia of keratinizing type leukoplakia . M ore recently a connection between leukoplakia as an independent risk factor for bladder cancer has been disproven. Staack et al. (2006) performed cytogenic studies of bladder leukoplakia in 77 cases using DNA analysis for tumor suppressor gene TP52 and found no evidence to suggest that this condition was premalignant; therefore cystoscopy, biopsy, and further treatment were unnecessary.

31. CYSTITIS CYSTICA & GLANDULARIS Cystitis cystica and/or glandularis is a common finding in normal bladders, typically associated with inflammation or chronic obstruction. These benign lesions represent cystic nests that are lined by columnar or cuboidal cells and are generally associated with proliferation of Von Brunn nests. Although cystitis glandularis can transform into adenocarcinoma , the risk is low , regular endoscopic evaluation of these entities is recommended. Treatment is transurethral resection.

32. PRECURSOR MALIGNANT LESIONS The 2004 World Health Organization classification system for urothelial neoplasia classifies pre-malignan t lesions as U rothelial hyperplasia (flat and papillary) Reactive atypia U rothelial atypia of unknown significance (AUS) U rothelial dysplasia L ow-grade intraurothelial neoplasia

33. MALIGNANT LESIONS Urothelial carcinoma is the most common malignancy of the urinary tract and is the second most common cause of death among all genitourinary tumors . Non–muscle-invasive bladder cancer, comprising low- and high-grade noninvasive papillary neoplasms, CIS, and urothelial carcinoma with invasion into the lamina propria (T1) , make up approximately 70% of all bladder urothelial carcinoma.

34. CIS CIS is characterized by noninvasive, flat high-grade tumors. There is severe nuclear atypia, loss of cellular polarity. The genetic abnormalities of CIS are more similar to high-grade, invasive tumors of the urinary tract, furthering the concept that CIS is a precursor to high-grade invasive carcinoma. RB, TP53, and PTEN. Clinically, CIS in association with invasive tumors carries a worse prognosis, with a 45% to 65% 5-year mortality rate.

35. PUNLMP PUNLMP is a papillary growth with minimal cytologic atypia that is more than seven cells thick, generally solitary, and typically located on the trigone. Cell polarity is maintained, and nuclei are mildly enlarged. Five-year recurrence rates after PUNLMP are estimated to be 20.1% Progression to MIBC among patients with PUNLMP is less than 1%.

36. STAGING

37. MOLECULAR BIOLOGY

38. MOLECULAR BIOLOGY

39. HISTOLOGICAL VARIANTS UROTHELIAL MALIGNANCIES NON UROTHELIAL MALIGNANCIES MICROPAPILLARY VARIANT SMALL CELL CARCINOMA SARCOMATOID VARIANT SQUAMOUS CELL CARCINOMA PLASMACYTOID VARIANT ADENOCARCINOMA NESTED VARIANT URACHAL ADENOCARCINOMA UROTHELIAL CARCINOMA WITH DIVERGENT DIFFERENTIATION

40. SMALL CELL CARCINOMA Small cell carcinoma is a rare, poorly differentiated neuroendocrine neoplasm that primarily arises in the lung but can occur in extrapulmonary sites, including the prostate and bladder. Although patients typically are seen with hematuria, there have been reports of paraneoplastic syndromes associated with small cell carcinoma including hypercalcemia, Cushing syndrome, and sensory neuropathy. C linically aggressive and chemosensitive .

41. SQUAMOUS CELL CARCINOMA Chronic infection with S. haematobium or other bacteria leads to SCC of the bladder. The central factor contributing to the development of SCC is chronic inflammation of the urinary tract. Historically patients with spinal cord injury requiring chronic catheterization had an incidence of SCC of 2.3%; however, this incidence rate has declined to 0.39% because of the trend toward intermittent self-catheterization. Radical cystectomy is the mainstay treatment for SCC, and there is no clear consensus regarding the use of neoadjuvant chemotherapy before surgery.

42. ADENOCARCINOMA Adenocarcinoma may be a primary cancer arising from the bladder urothelium with a pure glandular phenotype, or may be a secondary cancer from a distant metastasis, or more commonly from direct extension from the colon, prostate, endometrium, or cervix. Although the urachus is not an anatomic component of the urinary bladder, urachal adenocarcinomas share similar pathologic and clinical features to bladder adenocarcinoma. Risk factors for adenocarcinoma are a history of bladder exstrophy, schistosomiasis, and chronic irritation or obstruction.

43. URACHAL ADENOCARCINOMA Urachal adenocarcinoma is a rare cancer, accounting for approximately one-third of all bladder adenocarcinomas, that arises from the allantoic remnant that connects the bladder to the umbilical cord during embryogenesis. Although urachal remnants are typically lined by urothelial cells, urachal cancer is almost always adenocarcinoma in origin.

44. URACHAL ADENOCARCINOMA The 2016 WHO classification introduced criteria for the diagnosis of urachal adenocarcinoma : T umor should be located in the bladder dome or anterior abdominal wall, with the epicenter of the tumor occurring in the bladder wall. 2. T umor could not have widespread cystitis cystica, and there should be a thorough investigation for a secondary source for the adenocarcinoma. The standard treatment for urachal adenocarcinoma is en bloc resection of the bladder dome, urachal ligament and umbilicus.

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