bladder%20cancer
BLADDER CANCER

Bladder cancer is a heterogenous neoplasm that ranges from non-life-threatening, low-grade, superficial papillary lesions to high-grade invasive tumors that often metastasizes at the presentation.

It is the most common cancer involving the urinary system and it is the 11th most commonly diagnosed in the world.

Microscopic or gross painless hematuria is the most common presenting complaint.

Bladder%20cancer Diagnosis

Diagnosis

  • Non-invasive-muscle disease may be diagnosed by initial cytoscopy and cytology
    • Once suspected, imaging of upper tract collecting system is required
  • Carcinoma in situ (CIS) is diagnosed by a combination of cystoscopy, urine cytology and histological evaluation of multiple bladder biopsies
  • Patients should be assessed for the presence of regional or distant metastases
    • Tests include cystoscopy, chest radiograph/CT scan, bone scan in patients with symptoms or high alkaline phosphatase, imaging of the upper tracts with a CT/MRI scan of abdomen and pelvis

Staging

Pathologic Staging

  • TNM staging system by the American Joint Committee on Cancer (AJCC) (8th edition) is the most commonly used staging system
  • Grading the tumor is an important prognostic indicator with regard to the potential for disease recurrence and progression
  • After stage and grade have been identified, treatment decisions are based on the depth of invasion and extent of disease

Primary Tumor

Tx Tumor size cannot be assessed
T0 No primary tumor present
Ta Non-invasive papillary carcinoma
Tis "Flat tumor"/urothelial carcinoma in situ
T1 Papillary tumor invading the lamina propria/subepithelial connective tissue
T2 Tumor is in the muscularis propria/muscles
  pT2a Tumor is in the inner half/superficial muscularis propria
  pT2b Tumor is in the outer half/deep muscularis propria
T3 Tumor is in the perivesical tissue
  pT3a Microscopically
  pT3b Macroscopically (extravesical mass)
T4 Extravesical tumor is in any of the following: Prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
  T4a Extravesical tumor is in the prostatic stroma, seminal vesicles, uterus, vagina
  T4b iExtravesical tumor s in the pelvic wall, abdominal wall

Regional Lymph Node (LN) Evaluation

  • Consists of both primary and secondary drainage regions
  • Distant lymph nodes are all other nodes that are above the bifurcation
  • More than 9 lymph nodes should be investigated to reflect N0 appropriately
Nx Regional lymph nodes cannot be assessed
N0 Absence of regional lymph nodes
N1 Presence of a single regional LN metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral LN)
N2 Several regional LN metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral LN metastasis)
N3 LN metastasis to the common iliac LN

Metastatic Disease (M)

M0 Distant metastasis is not present
M1 Presence of distant metastasis
M1a Distant metastasis present is limited to lymph nodes beyond the common iliacs
M1b Non-lymph node distant metastasis

AJCC Pathologic Staging

 Stage 0a Ta  N0  M0
 Stage 0is Tis  N0  M0
 Stage I T1  N0  M0
 Stage II T2a  N0  M0

T2b  N0  M0
 Stage IIIA T3a  N0  M0
  T3b  N0  M0
  T4a  N0  M0
  T1-T4a  N1  M0
 Stage IIIB T1-T4a  N2, N3  M0
 Stage IVA T4b  Any N  M0
  Any T   Any N  M1a
 Stage IVB Any T   Any N  M1b

Patient’s Stratification into Risk Groups

  • Essential in facilitating treatment recommendations
  • Low-risk tumors are characterized by any of the following:
    • Primary, solitary, low-grade, Ta, G1, ≤3 cm, no CIS
    • Papillary urothelial neoplasm of low malignant potential
  • Features of intermediate-risk tumors include:
    • Recurrence of low-grade Ta tumor within 1 year
    • Solitary low-grade Ta tumor >3 cm
    • Low-grade multifocal Ta tumor
    • High-grade Ta tumor ≤3 cm
    • Low-grade T1 tumor
  • High-risk tumors can be any of the following:
    • High-grade T1 tumor
    • G3 or high-grade tumor
    • Recurrent high-grade Ta tumor
    • High-grade Ta >3 cm or multifocal tumor
    • Carcinoma in situ
    • All of the following: Multiple, recurrent and large (>3 cm) Ta G1G2 tumors
    • High-grade tumor with BCG treatment failure
    • Any variant histology, lymphovascular invasion or high-grade prostatic urethral involvement

WHO Grading

  • The 1973 WHO classification is the widely used classification for grading of non-muscle-invasive urothelial neoplasms
    • In 2004 members of WHO and International Society of Urological Pathology (ISUP) published and recommended a revised consensus classification for papillary neoplasms
    • The 2004 WHO classification is yet to be validated by clinical trials therefore, tumors are graded using both the 1973 and 2004 WHO classifications, though the vast majority of clinicians now use the 2004 classification
  • 1973 WHO Classification
    • Grade 1 (G1): Well-differentiated urothelial papilloma
    • Grade 2 (G2): Moderately-differentiated urothelial papilloma
    • Grade 3 (G3): Poorly-differentiated urothelial papilloma
  • 2004/2016 WHO Classification (papillary lesions)
    • Urothelial papilloma (completely benign lesion)
    • Papillary urothelial neoplasm of low malignant potential (PUNLMP)
    • Low-grade papillary urothelial carcinoma
    • High-grade papillary urothelial carcinoma

Evaluation

  • Tumor specimen should be evaluated as follows:
    • Depth of invasion (categories pT2 vs pT3a, pT3b, or pT4)
    • Margins with special attention paid to the radial margin, prostate, ureter, urethra and peritoneal fat and uterus and vaginal top
    • Histological subtype, if it has clinical implications
    • Extensive lymph node representation (>9)
    • Bladder wall blood vessel invasion (optional evaluation)
    • Pattern of muscle invasion (optional evaluation)
Transurethral Resection of Bladder Tumor (TURBT)
  • TURBT with a bimanual examination under anesthesia is performed to resect visible tumor and to sample muscle within the area of the tumor to assess whether invasion has occurred
    • May omit specimen collection in patients with documented low-grade Ta disease
  • Main goal is to make the right histopathological diagnosis and staging as it is essential in the diagnosis and management decision-making process
  • Specimen collection adjacent to a papillary tumor or prostate urethral biopsy may be considered for suspected or known carcinoma in situ
  • Repeat TURBT may be done in patients with suspected papillary lesions if with incomplete initial resection, absence of muscle in collected specimen (for high-grade disease), presence of large (≥3 cm) or multifocal lesions or any T1 lesions
  • Repeat TURBT may be done in patients with suspected sessile or muscle-invasive tumor if with absence of muscle in collected specimen (for high-grade disease), any T1 lesions, resection done restricted further evaluation for staging, incomplete resection and considering trimodality bladder preservation therapy

Physical Examination

  • Rectal and vaginal bimanual palpation should be done
    • In patients with locally advanced tumors, a palpable pelvic mass can be found
    • To assess whether there is a palpable mass or if the tumor is fixed to the pelvic wall, a bimanual examination under anesthesia should be done before and after transurethral resection of the bladder tumor (TURBT)

Laboratory Tests

Lab Tests

  • Lab studies (eg CBC, chemistry profile that includes alkaline phosphatase) must be performed before treatment to accurately determine clinical staging
    • Bone scan is performed if elevated alkaline phosphatase is present
Urinary Cytology
  • Examination of voided urine or bladder washings for exfoliated cancer cells have a high sensitivity in high-grade tumors and is a useful indicator in cases of high-grade malignancy or CIS, but low sensitivity in G1 tumors
  • Useful as an adjunct to cystoscopy when a G3 malignancy or CIS is present
  • Positive voided urinary cytology may indicate an urothelial tumor anywhere in the urinary tract; negative cytology, however, does not exclude the presence of a tumor

Imaging

  • Chest imaging is indicated if invasive disease is suspected
  • CT or MRI is recommended if:
    • Tumor after cystoscopy appeared to be solid, high-grade or suggests muscle invasion
    • Radical treatment is being considered for locally advanced or metastatic disease
    • Pelvic MRI with or without contrast: For staging of sessile or high-grade non-muscle invasive tumors in addition to CT urography

Computer Tomography (CT) 

  • 1st first choice for the workup of non-muscle-invasive bladder cancer in many Asian countries
  • CT with or without contrast is the preferred imaging study for staging of patients with muscle invasive bladder cancer
  • FDG-PET/CT may be used in select patients with T2 muscle-invasive disease and in patients with ≥cT3 disease 
    • May also be used to evaluate suspected or previously documented extraosseous metastasis 
  • 4-phase renal CT using multidetector CT (MDCT) machine has been used for detection and staging of bladder tumors
    • Includes pre-contrast phase, corticomedullary phase, nephrographic phase, and excretory phase
  • CT urography is used for disease staging and to detect papillary tumors in the urinary tract, which can be seen as filling defects or indicated by hydronephrosis
    • In patients who can safely receive intravenous agents this is the preferred procedure
  • Plain CT together with retrograde ureteropyelography is an option for patients with contraindications for iodinated or gadolinium-based contrast agents
  • Brain CT with contrast may only be used if MRI is contraindicated

Magnetic Resonance Imaging (MRI)

  • Pelvic MRI with or without contrast: For staging of sessile or high-grade non-muscle invasive tumors and muscle invasive tumors in addition to CT urography
  • MR urography is an imaging option for patients with poor renal status or iodinated contrast allergy but with GFR>30 without acute renal failure
  • Brain MRI may help identify symptomatic or high-risk patients with brain metastasis

Ultrasound 

  • Renal ultrasound is another imaging option for patients with contraindications for iodinated or gadolinium-based contrast agents 
  • Transabdominal ultrasound permits characterization of renal masses, detection of hydronephrosis, and visualization of intraluminal masses in the bladder
    • Useful tool for detection of obstruction in patients with hematuria

Other Imaging Techniques

  • Intravenous urography can be an alternative if CT is not available

Cystoscopy

  • Should be done in patients presenting with symptoms of bladder cancer to determine if a lesion is present
    • If a lesion is present, the patient should undergo transurethral resection of the bladder (TURBT) to confirm the diagnosis and to determine the extent of disease within the bladder
    • Urine cytology may also be obtained around the time of cystoscopy
  • Current standard in the evaluation and staging of bladder cancer is white light cystoscopy
  • In non-muscle-invasive bladder cancer detection particularly CIS, it was found that blue-light cystoscopy is more effective than white-light cystoscopy
  • Diagnosis of papillary bladder cancer ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue
Photodynamic Diagnosis (Fluorescence Cystoscopy)
  • Performed using violet light after intravesical installation of 5-aminolevulinic acid (ALA) or hexaminolevulinic acid (HAL)
  • Fluorescence-guided biopsy and resection are more sensitive than conventional procedures for detection of malignant tumors, particularly for CIS
  • Photodynamic diagnosis had lower specificity than white-light endoscopy
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