Bladder Tumours

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Transitional Cell Carcinoma
  • Bladder cancer is often described as a polyclonal field change defect with frequent recurrences due to a heightened potential for malignant transformation. However, bladder cancer has also been described as a problem with implantation and migration from a previously affected site.
  • more common in whites than in blacks
    • blacks have a worse prognosis than whites.
  • male-to-female ratio is 3:1. 
    • Women generally have a worse prognosis than men.
  • median age at diagnosis is 68 years
    • incidence increases with age.

Types

Almost all bladder cancers are epithelial in origin. 

  • more than 90% are Transitional Cell Carcinoma
  • up to 5% of bladder cancers are squamous cell in origin (US)
    • from chronic irritation - either stone or schistosomiasis (Schistosoma haematobium)
    • 75% of b ladder cancer in underdeveloped nations
  • 2% are adenocarcinomas.
    • from uracus
    • respond poorly to radiation and chemotherapy.
    • radical cystectomy is the treatment of choice
  • Nonurothelial primary bladder tumors are extremely rare and may include 
    • small cell carcinoma, 
      • aggressive tumors associated with a poor prognosis 
      • thought to arise from neuroendocrine stem cells
    • carcinosarcoma, 
      • highly malignant tumours
      • contain both mesenchymal and epithelial elements.
    • primary lymphoma
      • arise in the submucosa of the bladder 
      • treated with radiation therapy
    • sarcoma.
      • Leiomyosarcoma is the most common sarcoma of the bladder.
      • Rhabdomyosarcomas most commonly occur in children and carry a poor prognosis

Staging

  • Ta and T1 tumors and CIS are considered superficial bladder tumors. 
  • T2, T3, and T4 tumors are invasive bladder tumors. 
  • TCC is histologically graded as low grade (formerly graded 1-2) or high grade (formerly graded 3). 
  • CIS is characterized by 
    • full mucosal thickness
    • high-grade dysplasia of the bladder epithelium
    • associated with a poorer prognosis.
  • CIS - Carcinoma in situ, high-grade dysplasia, confined to the epithelium
  • Ta
    • Papillary tumor confined to the epithelium
  • T1
    • Tumor invasion into the lamina propria

    • invasion not deeper than basement membrane

  • T2
    • Tumor invasion into the muscularis propria

    • invasion into muscle but not palpable after resection

  • T3 
    • Tumor involvement of the perivesical fat

    • T3a

      • invasion into muscle, remaining palpable after resection

    • T3b

      • full thickness of bladder wall

  • T4
    •  Tumour involvement of adjacent organs such as prostate, rectum, or pelvic sidewall

    • T4a

      • invasion of prostate, uterus, vagina

    • T4b

      • invasion into other pelvic organs / pelvic wall

  • N+ 
    • Lymph node metastasis
  • M+ 
    • Metastasis 

More than 70% of all newly diagnosed bladder cancers are superficial, approximately 50-70% are Ta, 20-30% are T1, and 10% are CIS. Approximately 5% of patients present with metastatic disease, which commonly involves the lymph nodes, lung, liver, bone, and central nervous system. Approximately 25% of affected patients have muscle-invasive disease at diagnosis.

Classification 

  • The World Health Organization classifies bladder cancers as 
    • low grade (grade 1 and 2) or 
    • high grade (grade 3).
  • classified by growth patterns: 
    • papillary (70%), 
    • sessile
    • mixed (20%)
    • nodular (10%). 
    • Carcinoma in situ (CIS) is a flat, noninvasive, high-grade urothelial carcinoma. 
  • The most significant prognostic factors for bladder cancer are 
    • grade
    • depth of invasion
    • presence of CIS.
  • 55-60% of patients have low-grade superficial disease
    • usually treated conservatively with transurethral resection and periodic cystoscopy. 
  • 40-55% of patients have high-grade disease
    • 50% is muscle invasive and is typically treated with radical cystectomy.

Presentation

  • 80-90% present with painless gross hematuria, 
  • 20-30% of patients with bladder cancer experience irritative bladder symptoms related to more advanced muscle-invasive disease or CIS
    • dysuria, 
    • urgency
    • frequency of urination that are 
  • with advanced disease can present with 
    • pelvic or bony pain, 
    • lower-extremity oedema from iliac vessel compression
    • flank pain from ureteral obstruction. 

Examination

  • rarely found during a physical examination
  • occasionally, an abdominal or pelvic mass may be palpable. 
  • Examine for lymphadenopathy. 

Causes:

  • Up to 80% of bladder cancer cases are associated with environmental exposure
  • Smoking is the most commonly associated risk factor and accounts for approximately 50% of all bladder cancers. 
    • Nitrosamine, 
    • 2-naphthylamine
    • 4-aminobiphenyl 
  • industrial exposure to aromatic amines in dyes, paints, solvents, leather dust, inks, combustion products, rubber, and textiles. 
  • higher-risk occupations associated with bladder cancer include 
    • painting, 
    • driving trucks
    • working with metal
  • medical risk factors
    • prior exposure to radiation treatment of the pelvis 
    • Chemotherapy with cyclophosphamide
      • via exposure to acrolein, a urinary metabolite of cyclophosphamide
    • spinal cord injuries who have long-term indwelling catheters have a 16- to 20-fold increased risk of developing SCC of the bladder.
  • no convincing evidence exists for a hereditary factor
    • familial clusters of bladder cancer have been reported
    • Several genetic mutations have been identified in bladder cancer
    • Mutations of the tumour-suppressor gene p53 associated with high-grade bladder cancer and CIS. 
    • Mutations of the tumour-suppressor genes p15 and p16 associated with low-grade and superficial tumors. 
    • Retinoblastoma (Rb) tumor suppressor gene mutations
    • increased expression of the 
      • epidermal growth factor gene and the 
      • erb-b2 oncogene
    • mutations of the oncogenes 
      • p21 ras
      • c-myc
      • c-jun

Investigations

  • Any patient with gross or microscopic hematuria should be urologically evaluated. 
  • Microscopic hematuria from bladder cancer may be intermittent; therefore, a repeat negative result on urinalysis does not exclude the diagnosis. 
  • Infection may cause hematuria and usually is associated with irritative voiding symptoms (eg, dysuria, frequency, urgency). Irritative voiding symptoms may also be caused by CIS or muscle-invasive bladder cancer. Further evaluate irritative voiding symptoms caused by a urinary tract infection that do not resolve with treatment. 
  • Urinalysis with microscopy
  • Urine culture to rule out infection, if suspected 
  • Voided urinary cytology 
    • may be helpful if results are positive, but a negative cytology result cannot be considered definitive. 
    • Urinary cytology for routine screening is controversial
    •  associated with a significant false-negative rate, especially for low-grade carcinoma (10-50% accuracy rate). The false-positive rate is 1-12%, but it has a 95% accuracy rate for diagnosing high-grade carcinoma and CIS. The sensitivity of urine cytology can be increased by obtaining a bladder barbotage cytology (70%) as opposed to a voided cytology (30%). With a normal finding on cystoscopic examination, further evaluate a positive cytology result on urine study with an upper-tract study and random biopsies of the bladder.
  • Newer molecular and genetic markers in voided urine (high false-positive and false-negative rates)
    • bladder tumor antigen [BTA-Stat, BTA-TRAK], 
    • nuclear matrix protein [NMP-22], 
    • fibrin/fibrinogen degradation products [FDP] 
  • Cystoscopy
    • biopsy samples of suspicious lesions during cystoscopy. 
      • Attempt to include the bladder muscle in the biopsy specimen(allows  pathologist to determine whether the tumour is muscle invasive)
    •  Transitional cell tumors are typically papillary or sessile, and 
    • CIS may appear as an erythematous, velvety lesion
    • attempt to resect the primary tumor completely unless in diverticulum. 
      • bladder diverticulum lacks a surrounding muscle layer, and a deep biopsy of a lesion within a diverticulum risks perforating the bladder and extravesical extravasation of cancer cells.   resection followed by surveillance. Further 
    • investigate efflux of blood from either ureteral orifice with a 
      • retrograde pyelogram, 
      • ureteroscopy
    • Urine cytology  
    • Obtain biopsy samples of the prostatic urethra in men. 
  • Upper-tract imaging
  • CT scan of the abdomen and pelvis with preinfusion and postinfusion phases. This is ideally performed with a CT urogram or followed by a radiograph of the kidneys, ureters, and bladder (KUB) to obtain images similar to those produced with an intravenous pyelogram (IVP)
    • alternatively
      •  IVP + renal ultrasonography.
      • retrograde pyelogram in patients in whom contrast CT cannot be performed because of azotemia or a severe allergy to intravenous contrast. 
  • bone scan
    • unnecessary if 
      • patient is asymptomatic
      • normal calcium and alkaline phosphatase levels

Treatment

Superficial disease (Ta, T1, CIS) 

  • Intravesical immunotherapy (Bacillus Calmette-Guιrin [BCG] immunotherapy (BCG immunotherapy)
    • Consider patients with recurrent CIS for an early cystectomy
      • At 5 and 10 years, approximately 70% and 30% of patients with CIS who are treated with BCG are disease free, respectively. 
      • Recurrent CIS, despite intravesical BCG, is associated with a 63% risk of progression to muscle-invasive bladder cancer. 
      • Recurrence after BCG treatment also may occur in the upper urinary tract or prostatic urethra.
    • Interferon alpha or gamma has been used in the treatment of superficial TCC, either as a single agent therapy or in combination with BCG. Its role has primarily been in post-BCG failure with early promising results. Although BCG with interferon has shown a 42% response with tolerable side effects after BCG failure, no evidence has indicated that re-treating with BCG with interferon is superior to re-treating with BCG alone.
    • Table 1. Recurrence and Progression Rates at 5 Years for Superficial TCC of the Bladder Treated With BCG
    • Stage Recurrence, %
      		 Progression, %
      Ta 55 11
      T1 61 31
      CIS 45 23
      G1 61 7
      G2 56 19
      G3 45 23
  • Intravesical chemotherapy
    • Valrubicin has recently been approved as intravesical chemotherapy for CIS that is refractory to BCG. In patients whose conditions do not respond to BCG, the overall response rate to valrubicin is approximately 20%, and some patients can delay time to cystectomy. Valrubicin is presently not commercially available.
    • Other forms of adjuvant intravesical chemotherapy for superficial bladder cancer include intravesical triethylenethiophosphoramide (thiotepa [Thioplex]), mitomycin-C, doxorubicin, and epirubicin. Although these agents may increase the time to disease recurrence, no evidence indicates that these therapies prevent disease progression.
    • No evidence suggests that these adjuvant therapies are as effective as BCG.
  • Endoscopic treatment
    • Transurethral resection of bladder tumor (TURBT) is the first-line treatment to diagnose, to stage, and to treat visible tumors.
    • Patients with bulky, high-grade, or multifocal tumors should undergo a second procedure to ensure complete resection and accurate staging
    • Approximately 50% of stage T1 tumours are upgraded to muscle-invasive disease.
    • Electrocautery or laser fulguration of the bladder tumor is sufficient for low-grade, small-volume, papillary tumors.
    • No further metastatic workup is needed for obviously superficial tumors.
    • Because bladder cancer is a polyclonal field change defect, continued surveillance is mandatory
  • Radical cystectomy
    • Although typically reserved for muscle-invasive disease, radical surgery is more appropriately used to treat some cases of superficial bladder cancer.
    • Thirty-five to fifty percent of patients who undergo cystectomy for Ta, T1, or CIS are discovered to have muscle-invasive disease, 
      • with 10-15% demonstrating microscopic lymph node metastasis.
      • CIS in upwards of 80% of affected patients progresses to muscle-invasive disease, with 20% of patients found to have muscle-invasive disease at the time of cystectomy.
      • High-grade T1 tumours that recur despite BCG have a 50% likelihood of progressing to muscle-invasive disease
      • Cystectomy performed prior to progression yields a 90% 5-year survival rate
      • The 5-year survival rate drops to 50-60% in muscle-invasive disease.
      • Patients with unresectable large superficial tumors, prostatic urethra involvement, and BCG failure should also undergo radical cystectomy.

Muscle-invasive disease (T2 and greater) 

  • Adjuvant and neoadjuvant chemotherapy
    • Neoadjuvant chemotherapy prior to either radical cystectomy or external beam radiotherapy is controversial.
    • The Southwestern Oncology Group (SWOG) conducted a multicenter randomized prospective study that compared neoadjuvant therapy using a methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) combination with surgery alone. The group concluded that neoadjuvant therapy conferred a treatment benefit compared with surgery alone. However, several criticisms of this study exist. The study was purposely underpowered because of slow recruitment (317 patients over 11 y), because 20% of the patients who were to undergo cystectomy alone never underwent surgery, and because there was no comparison to neoadjuvant therapy. In addition, a recent study re-evaluated the SWOG data and found that surgical factors significantly affected outcomes.
    • In one small series, the T4 tumors of 45% of affected patients responded to chemotherapy, making potentially curative cystectomy possible.
    • Although no definite evidence of benefit exists, patients with P3-P4 or N+ TCC in the United States are typically advised to receive adjuvant chemotherapy. Chemotherapeutic agents for metastatic disease
    • MVAC is the standard treatment of metastatic bladder cancer. MVAC has an objective response rate of 57-70%, a complete response rate of 15-20%, and a 2-year survival rate of 15-20%.
    • Gemcitabine and cisplatin (GC) is a newer regimen and has been shown to be as efficacious as MVAC, but with less toxicity. GC is now considered a first-line treatment agent for bladder cancer.
    • Several novel compounds have shown activity against transitional cell bladder cancer and are now being tested in combination chemotherapy trials. Some of these promising agents are ifosfamide, paclitaxel, docetaxel, and carboplatin.
  • Radical cystoprostatectomy (men)
    • In men, this is the criterion standard for organ-confined, muscle-invasive bladder cancer (eg, T2, T3).
    • Remove the bladder, prostate, and pelvic lymph nodes.
    • Perform a total urethrectomy for anterior urethral involvement, involvement of the prostatic stroma, or diffuse CIS that involves the prostate.
  • Anterior pelvic exenteration (women)
    • Perform this procedure in women diagnosed with muscle-invasive bladder cancer.
    • The procedure involves removal of the bladder, urethra, uterus, ovaries, and anterior vaginal wall.
    • If no tumor involvement of the bladder neck is present, the urethra and anterior vaginal wall may be spared with the construction of an orthotopic neobladder.
  • Radiation Therapy
    • External beam radiation therapy has been shown to be inferior to radical cystectomy for the treatment of bladder cancer. The overall 5-year survival rate after treatment with external beam radiation is 20-40% compared to a 90% 5-year survival after cystectomy for organ-confined disease.
    • Although inferior to radical cystectomy, external beam radiation therapy is used in various countries other than the United States for T2-T3 TCC of the bladder.
    • Neoadjuvant external beam radiation therapy has been attempted for muscle-invasive bladder cancer with no improvement in survival rate.
  • In certain facilities, a bladder-preserving strategy for T2-T3 TCC is applied using a combination of external beam radiation, chemotherapy, and endoscopic resection.
    • Survival rates associated with this approach are comparable to those of cystectomy in selected patients.
    • This combination has a widespread application that is limited by the complexity of the protocol, its toxicity, and a high mortality rate.
    • The mortality rate in the 2 largest US series with the longest follow-up study is 4-5%. In comparison, the mortality rate for most modern cystectomy series is 1-2%.
    • In addition, a significant number of patients ultimately require a salvage cystectomy, which is associated with significantly increased morbidity and decreased options for urinary diversions. In some series, local recurrence of bladder cancer is as high as 50-60% despite the completion of bladder-preserving therapy.

Further Outpatient Care:

  • includes cystoscopy and bladder wash cytologies 
    • every 3 months for 2 years, then 
    • every 6 months for 2 years, then 
    • at least yearly. 

Complications

  • untreated bladder cancer 
    • hematuria, 
    • dysuria, 
    • irritative urinary symptoms, 
    • urinary retention,
    • incontinence, 
    • ureteral obstruction
    • pelvic pain.
  • The perioperative mortality rate is 1-2%. 
  • The local recurrence rate is 5-10%; however, it increases to 15-25% for T3-T4 disease.
  • The 2 most common complications are wound infection and bowel obstruction 
  • Radical cystectomy 
    • The overall early and late complication rate for a radical cystectomy is approximately 25%. 
    • Many patients undergo a radical cystectomy and have multiple comorbid health risk factors (eg, advanced age, cardiovascular disease, pulmonary disease). 
    • Despite these difficulties, this procedure may be performed safely on patients older than 80 years.
    • Following a radical cystectomy, all men are impotent if the parasympathetic nerves from the pelvic plexus (S2-S4) to the corpora cavernosum are not spared at the time of surgery; however, a nerve-sparing approach may reduce the impotency rate to approximately 40-50%. 
  • Orthotopic neobladder 
    • With the recent advances in surgical technique, this procedure is becoming the diversion of choice. Risk factors include daytime and nighttime urinary incontinence of approximately 10% and 15%, respectively. Urinary incontinence may develop from multiple factors, including injury to the external urethral sphincter, increased urine production from solute absorption, and relaxation of the external sphincter, which is greater at night. 

Prognosis

  • Superficial bladder cancer has a good prognosis
    • 5-year survival rates of 82-100%. The 5-year survival rate decreases with increasing stage, as follows:
  • Ta, T1, CIS – 82-100%
  • T2 – 63-83%
  • T3a – 67-71%
  • T3b – 17-57%
  • T4 – 0-22%
  • Prognosis for metastatic transitional cell cancer is dismal, with only 5% of patients living 2 years after diagnosis.
    • As many as 50% of patients with muscle-invasive bladder cancer may have occult metastases that become clinically apparent within 5 years of initial diagnosis. Most patients with overt metastatic disease die within 2 years despite chemotherapy. Approximately 25-30% of patients with only limited regional lymph node metastasis discovered during cystectomy and pelvic lymph node dissection may survive beyond 5 years. 
  • Early diagnosis and improvements in treatment of bladder cancer may be responsible for the improved survival rate of patients with TCC.
  • Further studies of molecular determinants of bladder cancer development and progression aid in prevention, earlier diagnosis, and treatment. Much progress has been made in the treatment of advanced bladder cancer; however, researchers must further elucidate optimal agents and regimens. The underlying genetic changes that result in a bladder tumor occur in the entire urothelium, making the whole lining of the urinary system susceptible to tumor recurrence (ie, 70% within 5 y). Superficial bladder cancer The risk of progression, defined as an increased tumor grade or stage, depends primarily on the tumor grade. The risk of progression increases with tumor grade, as follows:
  • Grade I – 10-15%
  • Grade II – 14-37%
  • Grade III – 33-64%
  • CIS alone, or in association with Ta or T1 papillary tumor, carries a poorer prognosis and a recurrence rate of 63-92%. Diffuse CIS is an especially ominous finding, with 78% progressing to muscle-invasive disease in one study. Other risk factors for recurrence and progression include the tumor size, multifocality, number of tumors, high tumor grade, advanced stage, the presence of CIS, and the time interval to recurrence.
  • Patients with tumor recurrences within 2 years, and especially with recurrences within 3 months, have an aggressive tumour and an increased risk of disease progression.

   

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