Bladder cancer:Presentation two recently treated cases with review of the literature

A 23 –year old gentleman presented with gross total hematuria since 1 month. He was a non-smoker and non- alcoholic. He did not have any comorbidities. The patient was investigated with imaging(ultrasonography) and blood biochemistry and hematological tests. The ultrasonography revealed 3 cm papillary growth in right lateral wall of the bladder and the urine cytology confirmed malignancy. He was taken up for endoscopy which confirmed the clinical diagnosis. With the help of resectoscope; the growth was resected .At the end of the procedure a deep cut was taken to include the muscularis propria to aid in staging of the disease and the further treatment. The final histology came as Ta Grade 2 The patient has been kept on 3 monthly follow-up with check cystoscopy. Case 2: A 69 year old lady presented with difficulty in passing urine and a very weak stream. She had also complaints of dysuria. She was treated outside by urethral dilatation. As she was not benefitted she presented to us; ours being referral centre. On investigations there was a bladder mass on ultrasonography with corresponding urine cytology confirming the malignancy. The patient was taken up for pan- cystourethroscopy which revealed large growth on right lateral wall, posterior wall occupying whole trigone. The biopsy was taken from one of the edges taking care to include deep muscle. The growth as such was not amenable for endoscopic treatment(Trans Urethral Resection of Bladder Tumour). The final histopathology report came as High Grade Papillary Urothelial Carcinoma with lamina propria invasion and deep muscle invasion could not be commented upon. As the lesion was grade 3 with large size;a decision was taken up for radical cystectomy. All types of diversion were discussed with the patient and ileal conduit –the traditional diversion was opted for. The patient was successfully taken up for Radical cystectomy and ileal conduit and presently she is recuperating from the surgery. case 1: Radical cystectomy:excised bladder specimen showing mass in the bladder and the urethra held with the clamp We have discussed about these two cases as the bladder cancer can present in various stages and the treatment is also tailored upon the staging, the grading and the patients wellbeing (and sometimes choice - especially as far intestinal diversion is concerned ;if it doesnot compromise the oncological safety). Anatomy of the bladder The bladder is a hollow organ in the lower abdomen. It stores urine, the urine produced by the kidneys. Urine passes from each kidney into the bladder through a long cylindrical tube called a ureter. Urine leaves the bladder through another tube, the urethra. Understanding bladder cancer The wall of the bladder is lined with cells called transitional cells and squamous cells. More than 90 percent of bladder cancers begin in the transitional cells. This type of bladder cancer is called transitional cell carcinoma. Cancer that is only in cells in the lining of the bladder is called superficial bladder cancer. Cancer that begins as a superficial tumor may grow through the lining and into the muscular wall of the bladder. This is known as invasive cancer. Invasive cancer may extend through the bladder wall. It may grow into a nearby organ such as the uterus or vagina (in women) or the prostate gland (in men). It also may invade the wall of the abdomen. When bladder cancer spreads outside the bladder, cancer cells are often found in nearby lymph nodes. If the cancer has reached these nodes, cancer cells may have spread to other lymph nodes or other organs, such as the lungs, liver, or bones.Some of the lymphnode spread like para-aortic lymphnodes or nodes at the aortic bifurcation may denote the metastatic disease precluding surgery and indicating the need of chemotherapy rather than a curative option. When cancer spreads from its original place to another part of the body, the disease is metastatic bladder cancer. Less than 10% of the carcinomas are squamous cell carcinoma or adenocarcinoma. In underdeveloped nations, SCC is associated with bladder infection by Schistosoma haematobium(In india, this infection is found at the coastal belt of Maharashtra region) . Adenocarcinomas account for less than 2% of primary bladder tumors. These tumors are observed most commonly in exstrophic bladders and respond poorly to radiation and chemotherapy. Radical cystectomy is the treatment of choice. Small cell carcinomas are extremely aggressive tumors associated with a poor prognosis and are thought to arise from neuroendocrine stem cells. Pathophysiology The World Health Organization classifies bladder cancers as low grade (grade 1 and 2) or high grade (grade 3). Tumors are also classified by growth patterns: papillary (70%), sessile or mixed (20%), and 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, and the presence of CIS. Upon presentation, 55-60% of patients have low-grade superficial disease, which is usually treated conservatively with transurethral resection and periodic cystoscopy. Forty to forty-five percent of patients have high-grade disease, of which 50% is muscle invasive and is typically treated with radical cystectomy. Bladder cancer: Who's at risk? No one knows the exact causes of bladder cancer. However, it is clear that this disease is not contagious. People who get bladder cancer are more likely than other people to have certain risk factors. Still, most people with known risk factors do not get bladder cancer, and many who do get this disease have none of these factors( so a clear cut cause and effect relationship may not be obtained in all cases). Doctors always find themselves in dilemma when a patient asks why he got the disease and ends up in answering a multifactorial cause for the cancer. Studies have found the following risk factors for bladder cancer: 1. Age. The chance of getting bladder cancer goes up as people get older. People under 40 rarely get this disease. 2. Sex: Men are likelier to get the disease than the females(3-4:1) 3. Tobacco. The use of tobacco is a major risk factor. Cigarette smokers are two to three times more likely than nonsmokers to get bladder cancer. Pipe and cigar smokers are also at increased risk. 4. Occupation. Some workers have a higher risk of getting bladder cancer because of carcinogens in the workplace. Workers in the rubber, chemical, and leather industries are at risk. So are hairdressers, machinists, metal workers, printers, painters, textile workers, and truck drivers. 5. Infections. Being infected with certain parasites(like scistosomiasis) increases the risk of bladder cancer. 6. Treatment with cyclophosphamide or arsenic. These drugs are used to treat cancer and some other conditions. They raise the risk of bladder cancer. 7. Race. Whites get bladder cancer twice as often as African Americans and Hispanics. The lowest rates are among Asians. 8. Family history. People with family members who have bladder cancer are more likely to get the disease. Certain genes have been identified as the cause for the development or progress of the disease. Symptoms of bladder cancer Common symptoms of bladder cancer include: • Blood in the urine (making the urine slightly rusty to deep red), • Pain during urination • Frequency, or urgency. • Dysuria- especially if Carcinoma in Situ has been the cause • Weak stream: especially if bladder neck region is affected as in our second case. • Flank pain: In case of bladder tumor blocking one of the orifices the kidney can get swelled up(Hydro-ureteronephrosis) and the patient can have the flank pain because of that reason. These symptoms are not sure signs of bladder cancer. Infections, benign tumors, bladder stones, also can cause these symptoms. Anyone with these symptoms should see a doctor so that the doctor can diagnose and treat any problem as early as possible. Diagnosis of bladder cancer • Physical exam -- The doctor feels the abdomen and pelvis for tumors. The physical exam may include a rectal or vaginal exam; this is useful in advanced disease spreading to the pelvic wall precluding probably a complete resection(so called R0 resection). • Urine tests -- The laboratory checks the urine for blood, cytology. • Intravenous pyelogram/ CT UROGRAPHY: The radiologist injects the dye(radio-contrast one) to delieneate the kidneys and bladder region mainly for assessing the upper tracts. As the bladder cancer has a tendency for a field change (it may affect many regions of the genitourinary tract simultaneously or metachronously) the imaging can detect such changes. The CT urography/MRI is now-a-days more and more resorted to for its reliability in staging the local disease.It also vaguely indicates the lymphnode status • Cystoscopy – An endoscope is inserted into the bladder through the urethra to examine the lining of the bladder. The patient may need anesthesia for this procedure as the same sitting can be utilized for diagnosis/biopsy/complete resection of a superficial tumor. Staging The following is the TNM staging system for bladder cancer: • 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 • T2 - Tumor invasion into the muscularis propria • T3 - Tumor involvement of the perivesical fat • T4 - Tumor involvement of adjacent organs such as prostate, rectum, or pelvic sidewall • N+ - Lymph node metastasis • M+ - Metastasis More than 70% of all newly diagnosed bladder cancers are non–muscle invasive, 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. Treatment • Ta, T1, and CIS 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 tumors are upgraded to muscle-invasive disease.This procedure is called as Relook TURBT and is usually undertaken after a period of 4 weeks to restage the disease  Because bladder cancer is a polyclonal field change defect, continued surveillance is mandatory with IVP/CT Urography for upper tract affections. Radical cystectomy Muscle-invasive disease (T2 and greater) Radical cystoprostatectomy (men)  Removes the bladder, prostate, and pelvic lymph nodes.  a total urethrectomy involvement of the prostatic stroma  High-grade T1 tumors 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 not amenable for large superficial tumors( in our second case), prostatic urethra involvement, and BCG failure( these people have aggressive tumour) should also undergo radical cystectomy. 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, anterior vaginal wall, and pelvic lymph nodes.  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. • In our second case as the bladder neck was involved and the anterior vaginal wall was appearing adherent the bladder neck, the proximal urethra with anterior vaginal wall was removed. The vagina was reconstructed using the posterior vaginal wall folding onto itself anteriorly making a vaginal stump. Pelvic lymphadenectomy  Approximately 25% of patients undergoing radical cystectomy have lymph node metastases at the time of surgery.  Bilateral pelvic lymphadenectomy (PLND) should be performed in conjunction with radical cystoprostatectomy and anterior pelvic exenteration.  PLND adds prognostic information by appropriately staging the patient and may confer a therapeutic benefit.  The boundaries of a standard PLND include the bifurcation of the common iliac artery and vein superiorly, the genitofemoral nerve laterally, the obturator fossa posteriorly, and the circumflex iliac vein (or node of Cloquet) inferiorly. Some surgeons routinely do extended lymphadenectomy till aortic bifurcation. There is some evidence(although no randomized controlled studies to show the benefit) that it gives the survival benefit After performing a cystectomy, a urinary diversion must be created from an intestinal segment. The various types of urinary diversions can be separated into the following continent and incontinent diversions:  Conduit (incontinent diversion;): Conduits can be constructed from either ileum or colon. The ileal conduit is the most common incontinent diversion performed and has been used for more than 40 years with excellent reliability and minimal morbidity. A small segment of ileum (at least 15 cm proximal to the ileocecal valve) is taken out of gastrointestinal continuity but maintained on its mesentery, with care to preserve its blood supply. The gastrointestinal tract is restored with a small-bowel anastomosis. The ureters are anastomosed to an end or side of this intestinal segment and the other end is brought out as a stoma to the abdominal wall. Urine continuously collects in an external collection device worn over the stoma.  We usually follow the Wallace technique where the ureters are anastomosed to the end of the ileal conduit.  Indiana pouch (continent diversion): This is a continent urinary reservoir created from a detubularized right colon and an efferent limb of terminal ileum. The terminal ileum is plicated and brought to the abdominal wall. The ileocecal valve acts as a continence mechanism. The Indiana pouch is emptied with a clean intermittent catheterization 4-6 times per day.  Neobladder (continent diversion; see image below): Various segments of intestine including ileum, ileum and colon, and sigmoid colon can be used to construct a reservoir. The ureters are implanted to the reservoir, and the reservoir is anastomosed to the urethra. This operation has been performed successfully in men for more than 20 years and, more recently, in women(Our experience with women has not been exactly good so we continue to offer traditional Ileal conduit for women.). The orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder. Patients have volitional control of urination and void by Credes maneuver- pressing anterior abdominal wall/Valsalva. Contraindications to performing continent urinary diversions include renal and liver dysfunction,comorbidities,impaired dexterity(in case if a man/woman needs self catheterization to empty the bladder then it will be problematic for such patients with handicap) Laparoscopic and robotic surgery  Recently, laparoscopic and robotic-assisted radical cystectomies have been performed in small numbers at select academic (PRIVATE HOSPITALS cannot afford ) centers.  The urinary diversion is almost universally performed extracorporeally through a miniature laparotomy incision. 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.  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 selective cases of urothelial carcinoma(small focal T2 disease away from ureteric orifices with good perforamce scale so as to tolerate the combination of radiotherapy and chemotherapy) is applied using a combination of external beam radiation, chemotherapy, and endoscopic resection.  Survival rates associated with this approach are comparable with 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 advantage is bladder is preserved with similar survival rates but few patients ultimately require salvage cystectomy, which is associated with significantly increased morbidity and decreased options for urinary diversions.As the post-chemotherapy radical cystectomy is difficult surgery to perform for want of surgical planes and lot of post-chemotherapy/radiotherapy fibrosis •Segmental cystectomy: In some patients where the bladder growth is at the apex enblock segmental cystectomy can be done with pelvic lymphnode dissection.A very few patients qualify for the such surgery.Anyhow this surgery gives similar results like radical cystectomy. Post –TUR the patient may have blood in urine for few days or burning micturition which usually subsides on itself. Bladder cancer surgery may affect a person's sexual function. Because the surgeon removes the uterus and ovaries in a radical cystectomy, women are not able to get pregnant. Also, menopause occurs at once. Hot flashes and other symptoms of menopause caused by surgery may be more severe than those caused by natural menopause. Many women take hormone replacement therapy (HRT) to relieve these problems. If the surgeon removes part of the vagina during a radical cystectomy, sexual intercourse may be difficult because of short vaginal stump. In the past, nearly all men were impotent after radical cystectomy, but improvements in surgery have made it possible for some men to avoid this problem. The introduction of nerve sparing radical cystectomy tries to preserve the potency. Men who have had their prostate gland and seminal vesicles removed no longer produce semen, so they have dry orgasms. Men who wish to father children may consider sperm banking before surgery or sperm retrieval later on. Radiation therapy uses high-energy rays to kill cancer cells. Like surgery, radiation therapy is local therapy. It affects cancer cells only in the treated area. • External radiation:. Most people receiving external radiation are treated 5 days a week for 5 to 7 weeks as an outpatient. This schedule helps protect healthy cells and tissues by spreading out the total dose of radiation. • external radiation may permanently darken or "bronze" the skin in the treated area. Patients usually lose hair in the treated area and their skin may become erythematous, dry, tender, and itchy. • Radiation therapy to the abdomen may cause nausea, vomiting, diarrhea, or urinary discomfort. • Radiation therapy also may cause a decrease in the number of white blood cells (neutropenia), cells that help protect the body against infection. If the blood counts are low, the radiation oncologist may start Granulocyte Stimulating Factor and withhold the radiation therapy till the neutropenis recovers. • For both men and women, radiation treatment for bladder cancer can affect sexuality. Women may experience vaginal dryness, and men may have difficulty with erections. Medical Care The treatment of non–muscle-invasive (Ta, T1, CIS) and muscle-invasive bladder cancer should be differentiated. Treatments within each category include both surgical and medical approaches. • Non–muscle-invasive disease (Ta, T1, CIS) o Intravesical immunotherapy (Bacillus Calmette-Guérin [BCG] immunotherapy)  BCG immunotherapy is used in the treatment of Ta(high grade), T1(all grades), and CIS urothelial carcinoma of the bladder and may help to decrease the rate of recurrence and progression.  BCG immunotherapy is the most effective intravesical therapy and involves a live attenuated strain of Mycobacterium bovis. BCG induces a nonspecific, cytokine-mediated immune response to foreign protein.  Because BCG is a live attenuated organism, it can cause an acute disseminated tuberculosis like illness if it enters the bloodstream (BCG sepsis), possibly resulting in death. Therefore, the use of BCG is contraindicated in patients with gross hematuria.The patient should be under surveillance after the BCG instillation.The procedure should be avoided if during the catheter introduction during the instillation causes bleeding  BCG typically causes mild systemic symptoms that resolve within 24-48 hours after intravesical instillation. BCG can also cause granulomatous cystitis or prostatitis with bladder contraction.  Typically, BCG is administered weekly for 6 weeks. Another 6-week course may be administered if a repeat cystoscopy reveals tumor persistence or recurrence.  Interferon alpha or gamma has been used in the treatment of stages Ta, T1 and CIS urothelial carcinoma, 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. oIntravesical 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. Other forms of adjuvant intravesical chemotherapy for bladder cancer mitomycin-C, doxorubicin, and epirubicin. There has been evidence to suggest that immediate peri-operative instillation of the mitomicin may prevent recurrence upto 40% of the cases. •Muscle-invasive disease (T2 and greater) o 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. oChemotherapeutic 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. Prognosis: • 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. Surveillance: Several reviews have been performed to assess the myriad urine markers proposed for bladder cancer surveillance. While FISH and NMP-22 are promising, the clinical evidence is insufficient to warrant the substitution of the cystoscopic follow-up scheme with any of the currently available urine marker tests.NMP-22 may have a role in low grade bladder cancers where cytology sometimes shows nothing.