Chap93N NMIBC Introduction and diagnosis, risk stratification

  1. Etiology of bladder carcinoma?
    • Tobacco smoking - most important risk factor for BC, contains aromatic amines and polycyclic aromatic hydrocarbons, which are renally excreted.
    • Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons - second most important risk factor (from paint, dye, metal and petroleum products industries)
    • Chlorination of drinking water and subsequent levels of trihalomethanes
    • Arsenic in drinking water
    • Permanent hair dyes
    • Exposure to ionizing radiation. 
    • Cyclophosphamide and pioglitazone
    • Schistosomiasis
  2. What are non muscle invasive bladder carcinoma?
    Malignant urothelial tumors that have not invaded the detrusor are more appropriately termed non–muscle invasive bladder carcinoma.

    The term urothelial cancer (UC) is preferable to theterm transitional cell cancer (TCC).
  3. Histological grading of non-muscle-invasive bladder urothelial carcinomas?
    • 1973 WHO grading
    • Grade 1: well differentiated
    • Grade 2: moderately differentiated
    • Grade 3: poorly differentiated

    • 2004 WHO grading system (papillary lesions)
    • Papillary urothelial neoplasm of low malignant potential (PUNLMP)
    • Low-grade (LG) papillary urothelial carcinoma
    • High-grade (HG) papillary urothelial carcinoma

    Image Upload 1
  4. What is PUNLMP?
    In contrast, essentially benign papillary tumors with orderly cellular arrangement, minimal architectural abnormalities, and minimal nuclear atypia are distinct from those two grades and are designated Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP)
  5. Main histologic layers of urinary bladder?
    • (1) urothelium,
    • (2) suburothelial loose connective tissue called lamina propria, and
    • (3) detrusor or muscularis propria (which is absent beneath the urothelium of diverticulae).
  6. Classification of non muscle invasive bladder carcinoma?
    • Ta - papillary tumor confined to the urothelium.
    • CIS (Tis) - flat, high-grade, non-invasive urothelial carcinoma confined to the urothelium
    • T1 - tumor invading lamina propria, i.e they are invasive (not muscle invasive)
  7. TNM classification?
    • Ta Non-invasive papillary carcinoma
    • Tis Carcinoma in situ: ‘flat tumour’
    • T1 Tumour invades subepithelial connective tissue

    • T2 Tumour invades muscle
    • T2a Tumour invades superficial muscle (inner half)
    • T2b Tumour invades deep muscle (outer half)

    • T3 Tumour invades perivesical tissue
    • T3a Microscopically
    • T3b Macroscopically (extravesical mass)

    • T4 Tumour invades any of the following: prostate stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
    • T4a Tumour invades prostate stroma, seminal vesicles, uterus or vagina
    • T4b Tumour invades pelvic wall or abdominal wall. 

    • N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)
    • N2 Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral)
    • N3 Metastasis in common iliac lymph node(s)
  8. Updates in the American Joint Committee on Cancer staging of urinary bladder cancer - TNM 2018
    Image Upload 2
  9. Recurrance rate and progression rate in low grade and high grade disease?
    Low-grade Ta lesions recur at a rate of 50% to 70% and progress in approximately 5% of cases.

    High grade T1 lesions recur in more than 80% of cases and progress in 50% of patients within 3 years.

    Because of these differing genetic imprints, it has been suggested that papillary pTa tumors could almost be considered benign and might be a completely separate disease entity in contrast to high-grade tumors.
  10. Pathologic Characteristics by Stage?
    2.9% to 18% of Ta tumors are high grade,with an average of 6.9%. 

    Between 40% and 83% of patients with CIS will develop muscle invasion if untreated, especially if associated with papillary tumors

    The most important risk factor for progression is grade, not stage
  11. Role of cytology in UB carcinoma?
    • High sensitivity in G3 and high-grade tumours (84%), but low sensitivity in G1 and low-grade tumours (16%). 
    • The sensitivity in CIS detection is 28-100%.
    • Cytology is useful, particularly as an adjunct to cystoscopy, if G3/CIS malignancy is present.
    • Positive voided urinary cytology can indicate an urothelial tumour anywhere in the urinary tract; negative cytology, however, does not exclude the presence of a tumour.
  12. Cytology in Carcinoma UB?
    • Perform cytology on fresh urine or urine with adequate fixation. Morning urine is not suitable because of the frequent presence of cytolysis. 
    • Use the Paris system for cytology reporting. 
    • Repeat urine cytology in patients with initial cytology results suspicious for high-grade urothelial carcinoma
  13. Urinary molecular marker tests?
    • UroVysion (FISH)
    • Microsatellite analysis 
    • Immunocyt/uCyt 
    • Nuclear matrix Protein 
    • BTA stat
    • BTA TRAK
    • Cytokeratins
  14. Bladder diagram?
    • Image Upload 3
    • 1 = Trigone 6 = Anterior wall
    • 2 = Right ureteral orifice 7 = Posterior wall
    • 3 = Left ureteral orifice 8 = Dome
    • 4 = Right wall 9 = Neck
    • 5 = Left wall 10 = Posterior urethra
  15. Fluorescence Cystoscopy?
    • The imperfect sensitivity of cystoscopy potentially explains the high rate of cancer recurrence soon after complete removal of all visible tumors. 
    • Photoactive porphyrins accumulate preferentially in neoplastic tissue. Under blue light they emit red fluorescence,which can help in the diagnosis of indiscernible malignant lesions.
    • When using this technology, both small papillary tumors and almost one-third more cases of CIS overlooked by cystoscopy are identified
  16. Indication of CT urography in carcinoma UB?
    • Tumours located in the trigone
    • Multiple- or high-risk tumours

    Patients with solitary or limited low-grade Ta lesions do not need imaging, owing to the very low risk of extravesical disease.
  17. Role of TURBT?
    • TURBT under regional or general anesthesia is the initial treatment for visible lesions and is performed to
    • (1) remove all visible tumors and
    • (2) provide specimens for pathologic examination to determine stage and grade.

    Bimanual examination of the bladder should be performed under anesthesia before prepping and draping.

    If a tumor appears to be muscle invasive, biopsies of the borders and base in order to establish invasion maybe performed in lieu of complete resection.
  18. Steps of TURBT?
    • • bimanual palpation under anaesthesia;
    • • insertion of the resectoscope, under visual control with inspection of the whole urethra;
    • • inspection of the whole urothelial lining of the bladder;
    • • biopsy from the prostatic urethra (if indicated);
    • • cold-cup bladder biopsies (if indicated);
    • • resection of the tumour;
    • • recording of findings in the surgery report/record;
    • • precise description of the specimen for pathology evaluation.
  19. Resection of diverticular tumors?
    Significant risk of bladder wall perforation, and accurate staging is difficult to achieve (underlying detrusor is absent). Invasion beyond the lamina propria immediately involves perivesical fat or stage T3a.

    Resection in diverticula almost inevitably leads to perforation.

    High-grade tumors require adequate sampling of the tumor base, often including perivesical fat, despite the near certainty of bladder perforation. 

    Partial or radical cystectomy should be strongly considered for high-grade diverticular lesions
  20. Resection of Anterior wall tumors and tumors at the dome?
    Difficult to reach - minimal bladder filling combined with manual compression of the lower abdominal wall to bring the tumor toward the resectoscope facilitates removal
  21. Resection near the ureteral orifice?
    Pure cutting -  current causes minimal scarring
  22. Methods to reduce the incidence of perforation?
    • Avoiding overdistention of the bladder
    • Using anesthetic paralysis during the resection of significant lateral wall lesions to lessen an obturator reflex response.
    • Large, bulky tumors and those that appear to be muscle invasive are often best resected in a staged manner because it is believed that repeat resection can more safely remove residual tumor if indicated.
  23. Bladder perforation in bladder resection?
    • Majority of perforations are extraperitoneal
    • Resection of dome - intraperitoneal rupture

    • Management - 
    • Extraperitoneal - prolonged urethral catheter drainage
    • Intraperitoneal perforation - less likely to close spontaneously and often requires open or laparoscopic surgical repair.
  24. Indications of Re-TURBT?
    • • after incomplete initial TURB, or in case of doubt about completeness of a TURB);
    • • if there is no muscle in the specimen after initial resection, with the exception of TaLG/G1 tumours and primary CIS;
    • • in T1 tumours

    If indicated, perform a second TURB within two-six weeks after initial resection. This second TURB should include resection of the primary tumour site.
  25. Role of “Random” or Additional Biopsies?
    Biopsies of any suspicious areas are an important part of a complete evaluation.

    The current consensus is that random biopsies are not indicated in low-risk patients (i.e., those with low-grade papillary tumors and negative cytology).

    Prostatic urethral biopsy using the cutting loop may be performed, especially if neobladder creation is anticipated for high-risk disease
  26. Simultaneous TURP and TURBT?
    Low-grade bladder tumor -  may be performed at the same setting

    High-grade bladder tumor - should not be resected coincident to TURP to avoid tumor seeding and possible intravasation of tumor cells likely to metastasize
  27. Predicting disease recurrance and progression?
    • Number of tumors (single, 2-7, >7)
    • Tumor diameter (<3, >3 cm)
    • Prior Recurrance rate (Primary, <=1 recurrance per year, >1) 
    • Ta/T1 
    • CIS (Yes/No)
    • G1/G2/G3

    Total recurrance = For Recurrance 0-17, For progression 0-23
  28. Risk stratification? (EAU 2018)
    • Low-risk tumours
    • Primary
    • Solitary,
    • TaG1 (PUNLMP, LG*),
    • < 3 cm,
    • No CIS.

    Intermediate risk tumours - All tumours not defined in the two adjacent categories (between the category of low and high-risk).

    • High-risk tumours - Any of the following:
    • • T1 tumours;
    • • G3 (HG**) tumour;
    • • CIS;
    • • Multiple, recurrent and large (> 3 cm) TaG1G2/LG tumours (all features must be present)*.
  29. EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta  T1 Bladder Cancer?
    • Number of tumors
    • Tumor size
    • Prior recurrence rate
    • T category
    • Concomitant carcinoma in situ
    • Grade
  30. Adjuvant therapy in TaT1, CIS tumors?  (EAU 2018)
    Low risk/ presumed to be at intermediate risk with previous low recurrence rate (≤ one recurrence per year) and expected EORTC recurrence score < 5, one immediate chemotherapy instillation is recommended. 

    Intermediate-risk tumours (with or without immediate instillation), one-year full-dose bacillus Calmette-Guérin (BCG) treatment (induction plus three-weekly instillations at 3, 6 and 12 months), or instillations of chemotherapy (the optimal schedule is not known) for a maximum of one year is recommended. The final choice should reflect the individual patient’s risk of recurrence and progression as well as the efficacy and side effects of each treatment modality. 

    In patients with high-risk tumours, full-dose intravesical BCG for one to three years (induction plus three-weekly instillationsat 3, 6, 12, 18, 24, 30 and 36 months), is indicated. The additional beneficial effect of the second and third years of maintenance should be weighed against its added costs and inconveniences.
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Chap93N NMIBC Introduction and diagnosis, risk stratification
Non muscle invasive bladder carcinoma