NEOPLASM OF BLADDER

Dr.P.Viswakumar,M.SAssistant professor,Dept of General Surgery,PSGIMSR

Anatomy of Bladder

The bladder is the most anterior element of the pelvic viscera.

The empty bladder is shaped like a three-sided pyramid .

It has an apex, a base, a superior surface, and two inferolateral surfaces.

Apex: The apex of the bladder is directed toward the top of the pubic symphysis.

Base: The base of the bladder is shaped like an inverted triangle and faces posteroinferiorly.

The inferolateral surfaces of the bladder are cradled between the levator ani muscles of the pelvic diaphragm and the adjacent obturator internus muscles above the attachment of the pelvic diaphragm.

Normal Histology

The mucosal surface of the renal pelvis, ureters, urinary bladder, and urethra is lined by a multilayered epithelium.

The most superficial of which consists of “umbrella cells”.

This epithelial lining has historically been called “transitional epithelium,” it is currently preferentially referred to as urothelium.

The wall of the urinary bladder is formed of four layers: (a) epithelium (urothelium), (b) lamina propria, (c) muscularis propria, and (d) adventitia or serosa.

Urothelial neoplasm

The urothelium of the bladder is traditionally considered to be lined by transitional cells, can transform into a variety of benign and malignant tumors.

Therefore the list of bladder tumors is long and includes those derived from the urothelium and mesenchyme

Benign Tumors of the Bladder

There are numerous benign tumors of Bladder

Common ones :

1) Epithelial metaplasia,

2) Leukoplakia

3) Inverted papilloma

4) Nephrogenic adenoma

5) Leiomyoma

6) Cystitis cystica

7) Cystitis glandularis.

Epithelial metaplasia:

Focal areas of transformed urothelium with normal nuclear and cellular architecture.

Located in trigone either squamous or glandular metaplasia.

As white flaky knobby appearance in case of Squamous metaplasia and raised red areas in case of Glandular ones.

Appx 40% of women and 5% of men had squamous metaplasia.

Usually related to trauma,Infection and surgery.

No treatment necessary.

Leukoplakia

Similar to squamous metaplasia but addition to keratin deposition

Appears as a white flaky substance floating in the bladder.

Benign lesion, and no treatment is necessary

Inverted Papilloma

Associated with chronic inflammation or bladder outlet obstruction and can be located throughout the bladder but most commonly on the trigone.

Inverted papillomas behave in a benign fashion with only a 1% incidence of tumor recurrence.

FISH to differentiate it from Urothelialmalignancy.

TRUP treatment of choice.

Papilloma

Benign proliferative growth in the bladder that is composed of delicate stalks lined by normal-appearing urothelium.

Papillomas had previously been categorized as grade 1 Ta tumors of the bladder which latter classified as non invasive malignancy of bladder.

Papillomas may recur, but they do not progress or invade.

Nephrogenic Adenoma

Rare tumor caused by chronic irritation of the urothelium.

Trauma, previous surgery, renal transplantation, intravesical chemotherapy, stones, catheters, and infections predispose to it.

The lesion may be vascular, which explains the presence of gross hematuria in most cases.

The most frequent presenting symptom is gross hematuria, often in conjunction with a urinary tract infection.

Transurethral resection and elimination of the chronic irritation.

Cystitis Cystica and Glandularis

Common finding in normal bladders, usually associated with inflammation or chronic obstruction.

Represent cystic nests that are lined by columnar or cuboidal cells.

Cystitis glandularis may develop into or coexist with intestinal metaplasia, which are benign tumors characterized by goblet cells that are histologically similar to colonic epithelium.

The most common presenting feature of cystitis cystica or glandularis is irritative voiding symptoms and hematuria.

Treatment is transurethral resection and relief of the obstruction or inflammatory condition.

Leiomyoma

Most common nonepithelial benign tumor of the bladder composed of benign smooth muscle.

Most commonly in women of childbearing age and are histologically similar to leiomyomas of the uterus.

Leiomyomas appear as smooth indentations of the bladder.

Imaging, especially with magnetic resonance imaging (MRI), can confirm the diagnosis.

Surgical resection is required if the leiomyoma is large or painful.

Cancer of Bladder

Topic of discussion for any malignancy

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Cancer of bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Urothelial cancer

Why urothelial cancer is important ?

Urothelial cancer is a cancer of the environment and age.

The incidence and prevalence rates increase with age, peaking in the 8th decade of life.

There is a strong association between environmental toxins and urothelial cancer formation.

Unfortunately, the incidence rate is rising the fastest in underdeveloped countries where industrialization has led to carcinogenic exposure.

7% of all cancers.

Bladder cancer is the 9th most common cancer worldwide, with 357,000 cases recorded in 2002.

Bladder cancer is the 13th most common cause of death, accounting for 145,000 deaths worldwide.

The incidence rate of bladder cancer has been rising in Asia and Russia because of an increased prevalence of smoking.

Cancer of bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Etiology/Risk factorsGenetic - N-acetyl transferase (NAT) detoxifies nitrosamines, a known bladder carcinogen. Specifically, NAT-2 regulates the rate of acetylation of

compounds such as caffeine, which are related to bladder cancer formation.

The slow NAT-2 polymorphism is related to bladder cancer with an odds ratio of 1.4 compared with the fast polymorphism.

Glutathione-S-transferase (GSTM1) conjugates several reactive chemicals, including arylamines and nitrosamines.

The null GSTM1 polymorphism is associated with an increased bladder risk with a relative risk of 1.5.

The null GSTM1 and slow NAT-2 lead to high levels of 3-aminobiphenyl and higher risk of bladder cancer.

External risk factors

The bladder is the main internal organ affected by occupational carcinogens after skin and Lung.

The primary culprits are the aromatic amines that bind to DNA.

Among the first chemical agents implicated in the formation of bladder cancer in dye and rubber workers were benzidine and β-naphthylamine.

Other industrial agents implicated in bladder cancer formation include polycyclic aromatic hydrocarbons (PAH), diesel exhaust, and paint substances.

Smoking - Accounts for 60% and 30% of all urothelial cancers in males and females, respectively.

Nutritional factors - moderately higher in coffee and tea drinkers, but this may be compounded by smoking or other dietary factors associated with people who drink coffee or tea.

Less fluid intake. Alcohol : No association has been proved. Acetaminopen : Commonly used analgesic-

increased risk of renal and bladder cancer.

Inflammation/ Infection:

1) Schistosoma hematobium – Squamous cell ca of bladder.

2) HPV.

3) Bacterial – Chronic infection esp with E.Coliand Pseudomonas.

Radiation exposure : Urothelial cancer formation after radiation is not age related, but the latency period is 15 to 30 years.

Chemotherapy – Only agent Cyclophosphamide.

Hereditary

Cancer of bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Pathology

90% of bladder cancers are of urothelialorigin, 5% are squamous cell carcinomas, and less than 2% are adenocarcinoma or other variants.

At initial presentation, 80% of urothelialtumors are non–muscle invasive.

WHO grading of Non invasive tumors

Hyperplasia (flat and papillary)

Reactive atypia

Atypia of unknown significance

Urothelial dysplasia (low-grade intraurothelial neoplasia)

Urothelial carcinoma in situ (high-grade intraurothelialneoplasia)

Urothelial papilloma

Urothelial papilloma, inverted type

Papillary urothelial neoplasm of low malignant potential

Noninvasive low-grade papillary urothelial carcinoma

Noninvasive high-grade papillary urothelial carcinoma

WHO grading of Invasive tumors Lamina propria invasion

Muscularis propria (detrusor muscle) invasion

Precusor lesions

Hyperplasia (flat and papillary)

Reactive atypia

Atypia of unknown significance

Urothelial dysplasia

Urothelial carcinoma in situ

Urothelial papilloma

Urothelial papilloma, inverted type

Papillary urothelial neoplasm of low malignant potential

Noninvasive low-grade papillary urothelial carcinoma

Noninvasive high-grade papillary urothelial carcinoma

Papilloma Carcinoma in situ

Low grade papillary tumor High grade papillary tumor

Cancer of Bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Clinical features

Often vague

Gross or microscopic hematuria.(Most common).

Increased urinary frequency due to irritation of bladder. (20-30%)

Less commonly UTI or upper urinary tract obstruction symptoms in advanced cases.

Pelvic or bony pain, lower-extremity edema, or flank pain - In patients with advanced disease.

Palpable mass on physical examination - Rare in superficial bladder cancer.

Cancer of Bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Investigation and Diagnosis

Urine studies include the following: Urinalysis with microscopy Urine culture to rule out infection, if suspected Voided urinary cytology Urinary tumor marker testingUrinary cytology: Standard noninvasive diagnostic method Low sensitivity for low-grade and early stage

cancers Fluorescence in situ hybridization (FISH) may

improve the accuracy of cytology

Investigation and Diagnosis

Cystoscopy The primary modality for the diagnosis of bladder

carcinoma Permits biopsy and resection of papillary tumors

Upper urinary tract imaging Necessary for the hematuria workup American Urologic Association Best Practice Policy

recommends computed tomography (CT) scanning of the abdomen and pelvis with contrast, with preinfusion and postinfusion phases

Imaging is ideally performed with CT urography, using multidetector CT

Ultrasonography is commonly used, but it may miss urothelial tumors of the upper tract and small stones

Urinary tumor markers

More than 30 urinary biomarkers have been reported for use in bladder cancer diagnosis.

Only few available for commercial use others still in experimental phase.

They are urine cytology,

fluorescence in-situ hybridization (FISH),

nuclear matrix protein (NMP-22),

BTA STAT, (Bladder tumor Antigen)

BTA TRAK,

ImmunoCyt/uCyt+,

CertNDx, and

CxBladder.( Uses 5 mRNA markers)

Cystoscopy

Interpretation of Results

The diagnostic strategy for patients with negative cystoscopy is as follows:

Negative urine cytology and FISH - Routine follow-up

Negative urine cytology, positive FISH -Increased frequency of surveillance

Positive urine cytology, positive or negative FISH - Cancer until proven otherwise

Cancer of bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

TNM Staging Primary Tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Ta Noninvasive papillary carcinoma

Tis Carcinoma in situ: “flat tumor”

T1 Tumor invades subepithelial connective tissue

T2 Tumor invades muscularis propria

pT2a Tumor invades superficial muscularis propria

(inner half)

pT2b Tumor invades deep muscularis propria (outer half)

T3 Tumor invades perivesical tissue

pT3a Microscopically

pT3b Macroscopically (extravesical mass)

T4 Tumor invades any of the following: prostatic

stroma, seminal vesicles, uterus, vagina, pelvic wall,

abdominal wall

T4a Tumor invades prostatic stroma, uterus, vagina

T4b Tumor invades pelvic wall, abdominal wall

Regional Lymph Nodes (N)

Regional lymph nodes include both primary and secondary

drainage regions. All other nodes above the aortic

bifurcation are considered distant lymph nodes.

NX Lymph nodes cannot be assessed

No lymph node metastasis

N1 Single regional lymph node metastasis in the true

pelvis (hypogastric, obturator, external iliac, or

presacral lymph node)

N2 Multiple regional lymph node metastasis in the

true pelvis (hypogastric, obturator, external iliac,

or presacral lymph node metastasis)

N3 Lymph node metastasis to the common iliac

lymph nodes

Distant Metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

Treatment Protocol

Treatment protocols for bladder cancer includes those of

1) Surgery

2)Chemotherapy,

3)Immunotherapy,

4)Systemic neoadjuvant

5)Adjuvant therapy.

Non-muscle invasive bladder cancer (Ta, Tis, T1) Non-muscle invasive bladder cancers are divided

into 3 groups: Ta, Tis, and T1 Ta are noninvasive papillary lesions confined to the

urothelium and have not penetrated the basement membrane.

Standard treatment for non-muscle invasive bladder cancer is a complete transurethral resection of the bladder tumor (TURBT).

Intravesical chemotherapy is generally used as prophylactic or adjuvant therapy after complete endoscopic resection

It is rarely used as therapy to eradicate residual disease that could not be completely resected.

Postoperataive adjuvant intravesical chemotherapy for non-muscle invasive bladder cancer[1, 2] :

One postoperative intravesical dose (within 24h, but usually immediately after resection) has been shown to reduce recurrence, but not progression, of disease

Mitomycin 40 mg in 20 mL sterile water or

Epirubicin 80 mg in 40 mL sterile water or

Thiotepa 30 mg in 15 mL sterile water or

Doxorubicin 50 mg in 20 mL sterile water

High grade or T1 disease: Management of T1 tumors with TURBT is generally

not adequate enough; use of intravesical bacillus Calmette-Guerin (BCG) after TURBT is recommended

Intravesical adjuvant immunotherapy for non-muscle invasive bladder cancer[1, 3, 2] : BCG 81 mg (TheraCys) or 50 mg (TICE BCG) in 50

mL sterile saline instilled into the bladder through a catheter and held for 2h; it is instilled into the bladder weekly for 6wk

Maintenance therapy: 81 mg intravesically given on Days 1, 8, and 15 of Months 3, 6, 12, 18, 24, and 36 after initiation

Muscle invasive bladder cancer

The treatment of muscle-invasive bladder cancer is as follows:

Radical cystoprostatectomy in men

Anterior pelvic exenteration in women

Bilateral pelvic lymphadenectomy (PLND), standard or extended

Creation of a urinary diversion

Neoadjuvant chemotherapy - May improve cancer-specific survival

Chemotherapeutic regimens for metastatic bladder cancer include the following:

Methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC)

Gemcitabine and cisplatin (GC)

Cancer of bladder

1) Incidence and prevalence.

2) Etiology/ Risk factors.

3) Pathology.

4) Clinical features.

5) Investigation and diagnosis.

6) Staging and Management.

7) Prognosis

Prognosis

The recurrence rate for superficial TCC of the bladder is high. As many as 80% of patients have at least 1 recurrence.

The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of CIS.

In patients undergoing radical cystectomy for muscle-invasive bladder cancer, the presence of nodal involvement is the most important prognostic factor.

Prognosis

Non–muscle invasive bladder cancer has a good prognosis, with 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 patients with metastatic urothelial

cancer is poor, with only 5-10% of patients living 2 years after diagnosis.

Other types of Bladder CancerSquamous Cell Ca:

The second most common cell type associated with bladder cancer in industrialized countries.

However, SCC is the most common form of bladder cancer, accounting for 75% of cases in developing nations.

In developing nations, SCC is often associated with bladder infection by Schistosoma haematobium.

The overall 5-year survival rate was 56% for pT1 and 68% for pT2 tumors. However, the 5-year survival rate for pT3 and pT4 tumors was only 19%

Other types of Bladder Cancer Approximately 2% of bladder cancers are

adenocarcinomas.

Nonurothelial primary bladder tumors are extremely rare and may include small cell carcinoma, carcinosarcoma, primary lymphoma, and sarcoma.

Small cell carcinoma of the urinary bladder accounts for only 0.3-0.7% of all bladder tumors.

Conclusion

Urinary tract is lined by multilayered epithelium called ‘Urothelium’

Urothelium can transform into wide variety benign and malignant neoplasms.

Most common malignancy of bladder is Urothelial carcinoma followed by squamous cell carcinoma.

It is a common malignancy due to occupation hazard for those working in chemical esp., Dyeing industry.

Genetic factors such NAT and Glutathione deficiency states and smokers are more prone for urothelial cancer.

Schistasomiasis leading cause of SCC in developing world.

80% cases at presentation are non muscle invasive

Hematuria is the most common presenting complaint

Conclusion

Cystoscopy, urine tumor markers,USG and CT abdomen are the investigations used in diagnosis and staging of the tumor.

Muscle non invasive cancers include Ta,Tis and T1 stage tumors.

Such cases treated with TURBT and intravesiclechemotherapy depending on grade

Others are treated with radical surgery and follow up adjuvant chemotherapy.

Prognosis of superfiscial bladder cancer is good touching 80-100% 5 yr survival rate and prognosis worsens with increasing depth of invasion.