Bladder transitional cell carcinoma

　　1. Causes of disease

　　The occurrence of bladder tumors has two aspects: intrinsic genetic factors and extrinsic environmental factors. The occurrence of tumors is the result of the complex interaction of multiple factors.

　　1. Genetic susceptibility The incidence of bladder cancer varies by up to 10 times between countries in the world, with Western Europe and North America being the highest, and Eastern Europe and some Asian countries being relatively low. Interestingly, the genetic similarity of the British, Australians, and New Zealanders is also reflected in their similar incidence of bladder tumors. Schistosomiasis in Egypt accounts for 18% of all cancers. The transitional cell carcinoma in the Taiwan region may be related to the surrounding vascular 'black foot disease'. Bladder tumors are closely related to gender and age. The incidence in men is 2 to 10 times higher than in women; the incidence is high after 60 years old, which may be because environmental carcinogenic factors need to wait for a relatively long time. Bladder cancer rarely occurs before the age of 40, and young people with bladder cancer often have well-differentiated papillary transitional cell carcinoma, which is rarely recurrent after treatment.

　　2. Risk factors Bladder cancer is related to environmental factors, occupation, smoking, infection, chronic inflammation, calculi, foreign bodies, pelvic irradiation, and cytotoxic chemotherapy drugs. It is now believed that 25% to 27% of bladder cancers are related to occupation, with half of the men and one-third of the women being related to smoking.

　　(1) The incidence of bladder cancer among industrial workers in the dye and textile industry is relatively high. It is now widely recognized that 2-naphthylamine, 1-naphthylamine, diphenyl, and 4-nitro-diphenyl are carcinogens in the chemical industry. These substances are metabolized by the liver, reduced to alpha-aminonaphthalic acid, and act on the urothelium to cause occupational bladder cancer. Since urine stays in the bladder for the longest time, the incidence of bladder cancer in the urinary system is the highest.

　　(2) The relative risk of bladder cancer due to smoking is 2-10, and it is related to the amount of smoking. About one-third of bladder cancer patients have a long history of smoking. The carcinogenic effect of smoking may be related to many chemical carcinogens present in cigarettes. The level of tryptophan metabolites in the urine of smokers increases by 50%, and the tryptophan metabolism level can return to normal after smoking cessation. It has been confirmed that tryptophan metabolites have potential carcinogenicity.

　　(3) Bladder tumors caused by bladder infection are squamous cell carcinomas, which are more common than transitional cell carcinomas. Chronic cystitis caused by Schistosoma haematobium, calculi, and bladder diverticula often leads to squamous cell carcinoma. 80% of paraplegic patients have squamous metaplasia in the bladder, and 5% develop squamous cell carcinoma. Urinary retention may also be a cause of bladder cancer.

　　(4) Certain drugs can cause urothelial tumors. It has been confirmed that the analgesic drug phenacetin can cause renal pelvis and bladder transitional cell carcinoma due to its similar chemical structure to aniline, and excessive dosage. Another drug, cyclophosphamide, can also increase the risk of bladder cancer. For patients with tumors and those without tumors, such as systemic lupus erythematosus and rheumatoid arthritis, the risk of bladder cancer can be increased by a factor of 9.

　　(5) High-dose pelvic radiation therapy for cervical cancer increases the risk of bladder cancer by a factor of 4, which is related to the dose and duration of radiation.

　　3. Studies on the biological characteristics of bladder cancer indicate that the occurrence of bladder cancer is a multi-step process, involving various gene mutations, which can be further divided into early and late stages. Early mutations lead to the initial transformation of urothelial cells, while late mutations enable the deteriorated cells to become invasive and metastatic. Great progress has been made in the identification of bladder cancer gene mutations, but no single (or several) chromosomal or gene changes are present in all bladder tumors. Moreover, different genetic factors seem to be capable of leading to the same tumor morphology, which illustrates the diversity of carcinogenic factors and their DNA target sites. To date, no decisive mutations affecting the occurrence of bladder cancer have been found, but this does not negate the significant role played by various mutations in the development of tumors. Some hypotheses suggest that there are two pathways for the occurrence of bladder cancer: one involves the transformation of不死干细胞 (immortal stem cells), and the other involves the transformation of basal cells into不死 due to viral infection. Both pathways include the development process from superficial to invasive and finally to metastasis, with different gene mutations playing a role at different stages of development. In the first pathway, the deletion of the 9q chromosome leads to the transformation of stem cells into superficial cancer, while the inactivation of the tumor suppressor genes P53 and Rb and the activation of H-ras further promote the progression of the lesion. In the second pathway, the initial change is the inactivation of the tumor suppressor genes P53 and Rb by viral carcinogens, followed by other gene mutations leading to the occurrence and development of tumors. While studying oncogenes and tumor suppressor genes, tumor experts have also begun to focus on the process of information transmission from the cell surface to the nucleus of cancer cells, attempting to reveal the occurrence and development of tumors.

　　Second, pathogenesis

　　1. The normal bladder urothelium is a transitional epithelium, about 3 to 7 layers thick. The surface of normal epithelial cells is covered with large umbrella cells overlying some small cells below, and the surface umbrella cells are often binucleated or multinucleated. The size and shape of the cells change with the degree of bladder expansion. In the deep mucosa, the cells are round, elliptical, elongated, or columnar, embedded in the fibrous basement membrane, which allows the cells to slide between each other. When the urothelial cells of the urinary tract react to inflammation, chronic irritation, or carcinogens, proliferative changes (hyperplasia and metaplasia) can occur.

　　More than 90% of bladder cancers are transitional cell carcinomas, which have diverse growth patterns, including papillary, sessile infiltration, nodular, and intracellular growth. It has a large potential for anaplasia; therefore, transitional cell carcinomas can contain spindle cells, squamous epithelial cells, and glandular epithelial cells. One-third of bladder cancers may have the above components. Transitional cell carcinomas are more common in the base and lateral wall of the bladder trigone. However, transitional cell carcinomas can occur at any part of the bladder. About 70% of bladder cancers are papillary, 10% are nodular, and 20% are mixed. According to the degree of tumor cell differentiation, tumors are divided into grade I, grade II, and grade III. Grade I cancer refers to well-differentiated tumor cells, with more than 7 layers of transitional epithelium, cells showing mild anaplasia and polymorphism, increased nuclear-cytoplasmic ratio, mild disorder of cell maturation from basal to superficial cells, and mitotic figures are occasionally seen. Grade II cancer shows a highly disordered maturation from the basal layer to the superficial layer, loss of polarity, a significantly increased nuclear-cytoplasmic ratio with nuclear polymorphism, large nucleoli, and mitotic figures are more common. Grade III cancer is a poorly differentiated type, with significant nuclear polymorphism, frequent mitotic figures, and tumor cells have almost no similarity with normal transitional epithelium.

　　2. Spread of the tumor The spread of bladder cancer includes the direct infiltration and spread at the primary site, or the metastasis to other sites through lymphatic, hematogenous, and implantation.

　　(1) Direct spread: The invasive growth of bladder cancer can penetrate the entire bladder wall, extend to the surrounding fat around the bladder, adhere to the pelvic wall to form a fixed mass, or spread to the peritoneum at the top, or directly spread to adjacent organs.

　　(2) Lymph node metastasis and hematogenous metastasis: Lymph node metastasis of bladder cancer is relatively common, mostly pelvic lymph node metastasis (78%), among which the obturator lymph node is the most common, accounting for 74%, followed by the iliac external lymph node accounting for 65%, the iliac common lymph node 20%, and the paravesical lymph node is rare, accounting for 16%. Distant metastasis is more common in advanced bladder cancer, and common sites of metastasis include liver (38%), lung (36%), bone (27%), adrenal gland (21%), colorectal (13%) and other sites.

　　3. Metastasis by implantation can occur at abdominal wall incisions after open surgery, at the bladder neck, prostate, and urethra damaged after transurethral resection, but it is extremely rare.

　　4. TNM staging

　　Bladder tumor TNM staging:

　　Tx: The primary tumor is unassessable.

　　To: No primary tumor found.

　　Tls: Primary cancer.

　　Ta: Papilloma, non-invasive papillary carcinoma.

　　T1: Tumor invades the submucosal layer (proper layer).

　　T2: Tumor invades the superficial muscular layer.

　　T3a: Tumor invades the deep muscular layer.

　　T3b: Tumor invades the surrounding fat of the bladder.

　　T4: Tumor invades adjacent organs, such as prostate/uterus/vagina/pelvic cavity or abdominal wall.

　　Nx: Lymph node metastasis cannot be estimated.

　　N0: No lymph node metastasis found.

　　N1: Single lymph node metastasis, diameter

　　N2: Single or multiple lymph node metastases, diameter 2-5cm.

　　N3: Single or multiple lymph node metastases, diameter > 5cm.

　　Mx: Distant metastasis cannot be estimated.

　　M0: No distant metastasis found.

　　M1: Metastasis to distant sites.

　　If the tumor involves the ureteral orifice, it can cause occlusion of the ureteral orifice, leading to hydronephrosis of the renal pelvis at the occlusion site. In severe cases, due to significantly increased intracystic pressure, it can cause a decrease in glomerular filtration rate, impeding the excretion of creatinine and urea nitrogen, and even leading to renal insufficiency. If infection is present, it can cause more severe hematuria and symptoms such as frequent urination, urgency, and fever. Patients with persistent hematuria can also develop anemia due to blood loss.

　　1. The main symptom of bladder cancer is hematuria, and almost all patients have hematuria. Among them, about 85% are the first symptom, and most are gross hematuria. However, microscopic hematuria often appears before gross hematuria, in the early stage of the disease. Carson et al. (1979) conducted further examinations on 200 patients with microscopic hematuria and found that 22 cases were bladder cancer, accounting for 11%; 38 cases that were initially not found to have a cause were followed up for 2 years, and 6 cases were found to have lesions.

　　2. The characteristics of gross hematuria are painless, mostly complete hematuria, which can also be manifested as initial or terminal hematuria during urination, showing intermittent occurrence, which can also persist. The interval time ranges from several days to several months. Generally, the interval time is longer in the early stage, and it gradually shortens as the condition progresses. The degree of hematuria depends on the amount of bleeding, manifested as water-like meat, accompanied by irregular or patchy blood clots, or even large blood clots filling the bladder. Generally, the size of the tumor is proportional to the degree of hematuria. Severe bleeding can lead to anemia due to blood loss. There are also cases where the tumor is not large, but repeated bleeding causes anemia.

　　3. Bladder irritation symptoms, such as frequent urination, urgency, and dysuria, are another main symptom of bladder cancer, accounting for about 10% of the initial symptoms of bladder cancer. The tumor damages the bladder's defense against infection, and the tumor is similar to a foreign body in the bladder, hindering the elimination of infection. Therefore, 40% of bladder cancers are accompanied by urinary tract infections. Extensive in situ cancer or invasive cancer can first appear with obvious bladder irritation symptoms, even leading to urgent urinary incontinence, pain in the supra-pubic area, penis, and perineum. If the tumor is located at the bladder neck or invades the neck, large necrotic tissue shedding from the tumor or a large tumor can cause a decrease in bladder capacity or be accompanied by stones, all of which can cause bladder irritation symptoms. Bladder cancers with bladder irritation symptoms or those that have excreted 'putrid flesh' are often in the late stage or invasive, with poor prognosis.

　　4. Cancers involving the bladder neck or the prostate, pedunculated cancers near the neck, and large necrotic and shed cancer tissues can all block the neck orifice, causing difficulty in urination. In the late stage, symptoms such as lower limb edema, pelvic mass, cough, chest pain, and metastatic symptoms such as cachexia and anemia may occur.

　　1. Primary prevention involves establishing good living habits, quitting smoking, and maintaining a healthy mental state. Vigorously strengthen environmental, labor health legislation, supervision, and management, and those who may be exposed to dyes, rubber, plastics, and other industrial materials should be regularly examined and take certain protective measures. Taking vitamin B6 is expected to block the abnormal metabolism of tryptophan. Active treatment should be given to chronic cystitis, mucosal leukoplakia, calculi, and schistosomiasis haematobium.

　　2. Secondary prevention through mass screening can detect bladder cancer at an early stage. Generally, simple urine routine and urine detached cell examinations are performed. Hematuria is the first and most common clinical manifestation of bladder cancer, often presenting as painless intermittent symptoms. Further urine cytology, cystoscopy, and X-ray imaging should be performed. Once diagnosed, surgery should be performed as soon as possible, and the method can be chosen according to the tumor location, size, number, and depth of invasion, such as transurethral tumor resection, partial cystectomy, or total cystectomy. The treatment of superficial bladder tumors with hot saline irrigation and pressure perfusion has certain efficacy, as the tumor is subjected to the dual effects of ischemia and heat, leading to necrosis and shedding. Radiotherapy can be used simultaneously with surgery or alone for patients with surgical contraindications. Chemotherapy is generally used for intravesical instillation of chemotherapy drugs, the main purpose of which is to prevent postoperative recurrence. Intravesical instillation of freeze-dried BCG (Bacillus Calmette-Guérin) is effective for treating bladder in situ carcinoma and can also be used for postoperative prevention of recurrence. Laser therapy or photodynamic therapy using laser blood porphyrin derivatives is effective for superficial bladder tumors. To prevent recurrence after surgery, cystoscopy should be performed regularly, once every 3 months for 2 years, then once every 6 months for another 2 years, and finally once a year to maintain throughout life. To exclude upper urinary tract urothelial tumors, intravenous pyelography may be performed if necessary.

　　3. For advanced bladder cancer where the patient cannot tolerate a total cystectomy, a simple ureterosigmoidostomy can be performed. In cases where the patient's condition is poor and renal insufficiency makes it difficult to tolerate urinary diversion or reconstruction surgery, a ureteroskin fistula can be performed. For patients with advanced disease who experience pain and cachexia, symptomatic and supportive treatment should be provided.

　　1. The examination of detached cells is convenient and easy to perform, and can be repeated multiple times, but the positive rate of early tumors is relatively low. ①Flow cytometry: This method can determine the tumor DNA content, aneuploid cell count, and has a high diagnostic accuracy for in situ carcinoma and high-grade, advanced tumors, up to 90%. ②Acridine orange test: The tumor cells are stained with acridine orange fluorescent dye, observed under a fluorescence microscope, and can display the image of the amount of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) in the cell nucleus, as well as the morphological structure of the cell, which is helpful in judging the tumor cells and their vitality status.

　　2. Tumor markers are not only helpful for tumor diagnosis but also have predictive significance for the judgment of tumor biological behavior. ① Bladder tumor antigen (BTA): A bladder tumor-secreted protease that degrades the bladder basement membrane into type IV collagen, fibronectin, and laminin, etc., basic components. These degradation products are excreted into the adjacent urine, forming basement membrane complexes, known as bladder tumor antigen (BTA). The components are specific polypeptides with a relative molecular mass of 16,000 to 165,000. The BTA reagent is a method for detecting bladder tumor membrane antigen, with high sensitivity and specificity for transitional cell carcinoma. Currently, there are two types of BTA reagents: BTAstat and BTAtest. The status of the two BTA reagents in diagnosis is parallel. In the study of sensitivity and specificity, it was found that the sensitivity and specificity of BTAstat and BTAtest were 65.90% and 63.63% and 82.89% and 81.57%, respectively, without significant differences. If the two reagents are used in combination, the specificity of diagnosis can be significantly improved without reducing the sensitivity, which indicates that the combined use can reduce the false-positive rate and avoid further examinations or treatments caused by false-positive results. BTA is a kit that medical personnel can master without time, place, or equipment constraints and without special training, with results available in 5 minutes. The examination is non-invasive, only requiring the collection of 20ml of urine, and the examination within 48 hours will not affect the results. BTA detection has certain false positives and false negatives and cannot be used independently to diagnose bladder cancer. In addition, the BTA reagent is expensive, and it is currently difficult to promote its comprehensive use. ② LewisX antigen detection: LewisX is an ABO blood type-related antigen that does not exist in normal urinary tract epithelium, while 5% to 89% of transitional cell carcinomas can detect LewisX, and it is unrelated to the tumor grade. ③ Nuclear matrix protein 22 (nuclear matrix protein 22, NMP22): NMP22 is a nuclear mitotic apparatus protein. The NMP22 in bladder tumor cells is more than 25 times that of normal cells. The sensitivity for diagnosing bladder cancer is 48% to 90%, and the specificity is 70% to 92%. NMP22 has high sensitivity for advanced and high-stage bladder cancer and can be used for follow-up monitoring in the absence of stones, inflammation, etc. ④ Fibrin/fibrin degradation products (fibrin degradation products, FDP): The sensitivity of diagnosing bladder cancer with a rapid immunodetection method for urinary FDP is 68%, and the sensitivity for T2 to T4 stage bladder cancer is even as high as 100%. ⑤ Hyaluronidase detection hyaluronidase, HAase: Hyaluronidase is an endogenous glycosidase that degrades extracellular matrix hyaluronic acid and plays an important role in tumor progression. The sensitivity of detecting hyaluronidase activity in the urine of G2, G3 grade bladder cancer using gel technology reaches 92% to 100%. ⑥ Telomerase activity (telomerase): Telomeres are protective structures located at the ends of chromosomes.As the cell divides and gradually shortens, until the cell dies, the role of telomerase is to elongate the telomere. It has now been found that the activity of telomerase is enhanced in various tumor cells. This method can diagnose bladder cancer including low-grade, low-stage tumors, with a sensitivity of up to 91%.

　　3. Imaging examination

　　(1) Ultrasound: ① Abdominal approach is the most commonly used, which can obtain the basic images of tumor size, number, location, and base width and narrowness, providing a basis for the differentiation between stage A and C, with the advantages of simple operation, no pain, and can be repeated. However, due to the limitation of the pelvis on the conduction of sound wave pulses, and the influence of factors such as abdominal wall thickness, scars, intestinal gas, and bleeding from cancer, the diagnostic rate is relatively low. ② Transrectal cross-sectional examination can accurately display the anterior wall, lateral walls, and base of the bladder tumor, but the top and neck display is not satisfactory. Longitudinal section examination can clearly display the base, trigone, and neck tumors of the bladder, accurately measure the size, and to some extent understand the depth of tumor infiltration. ③ Transurethral approach can clearly show the location, size, and accurate determination of the depth of tumor infiltration of the bladder tumor, and can also display the images of the lower segment of both ureters, the intramural segment of the bladder wall, both seminal vesicles, and the prostate. This examination has a high coincidence rate of 90% to 94% between preoperative clinical staging of bladder cancer and postoperative pathological examination results, but the disadvantage is that it is insufficient to display the infiltration of the tumor and the condition of the surrounding pelvic organs of the bladder.

　　(2) IVU: It can also clarify the condition of the upper urinary tract, and in patients with larger tumors, there may be a filling defect in the bladder area.

　　(3) CT, MRI: CT is currently the most accurate non-invasive examination for diagnosing bladder cancer and clinical staging. In addition to determining the size of the tumor and the depth of its infiltration into the bladder wall, it can also provide information about the presence of metastasis in pelvic and retroperitoneal lymph nodes, and whether there is metastasis in the liver or adrenal glands. It has special significance for the diagnosis of intravesical cancer and intramural cancer. Enhanced CT and spiral CT scans can increase the accuracy of staging, while MRI can provide multiple cross-sectional images, thus providing a better understanding of local anatomical structure relationships. However, it does not have a stronger advantage over CT in clinical staging.

　　4. Cystoscopy is the most important method for diagnosing bladder tumors, which can clearly determine whether there is a tumor and its number, size, shape, and the location of the pedicle, and can also perform biopsies.

　　1. Increase water intake. Because the amount of water intake directly affects the concentration of urine in the bladder, which has an important impact on the occurrence of bladder tumors. For those with less water intake, the urine in the bladder must be reduced, and the concentration of carcinogens from the kidneys excreted into the bladder is also correspondingly higher. These highly concentrated carcinogens can cause strong irritation to the bladder mucosa. Those with less water intake will inevitably extend the interval between urination, which creates favorable conditions for the reproduction of bacteria (such as Escherichia coli) in the bladder. Most people who frequently develop bladder cancer do not like to drink water or tea.

　　2. Everyone should adhere to a scientific diet, eat more fresh vegetables and fruits. Because fresh vegetables and fruits contain abundant vitamins and trace elements, which can decompose the carcinogens in the body such as nitrosamines. It is best to eat less meat, as meat can produce substances with similar structures to aniline and benzidine during the metabolic process in the body. There have been investigations that workers in factories using aniline and benzidine chemical raw materials have a higher incidence of bladder cancer.

　　For patients with tumors who smoke frequently, they should quit smoking immediately. Studies have shown that cigarettes contain various toxic carcinogens such as nicotine, tar, and tobacco, and heavy smokers have a higher concentration of carcinogens in their urine. If the daily smoking index reaches 600 (number of cigarettes smoked per day × number of smoking years), it reaches a dangerous level for bladder cancer.

　　1. Treatment

　　The biological characteristics of bladder tumors vary greatly, and there are many treatment methods, but the basic treatment method is still surgery, with radiotherapy, chemotherapy, and immunotherapy in an auxiliary position. In principle, superficial bladder tumors are treated with bladder-preserving surgery, while invasive cancer is treated with total cystectomy with urinary diversion or in situ neobladder surgery.

　　1. The treatment of superficial bladder tumors mainly refers to bladder cancer at stages Ta to T1. Currently, the treatment opinion for superficial bladder cancer is basically consistent, that is, to clean the visible tumor as much as possible through the urethra, and then supplemented with intravesical instillation therapy. Superficial bladder cancer rarely requires total cystectomy, unless there are diffuse, inoperable papillary tumors or in situ cancer that is ineffective to treat with intravesical therapy.

　　(1) Transurethral resection of bladder tumor (TURBT): Most superficial bladder cancer patients can receive effective treatment through TURBT. The superficial part of the tumor is first resected, and the specimen is removed for pathological examination. Then, the deep part of the tissue is resected, and the resected tissue is sent for pathological examination. This allows for the complete resection of the tumor and provides valuable information for determining the grade and stage of the tumor. Tumors invading the orifice of the ureter should be resected at the same time, but the wound should not be electrocauterized after tumor resection to prevent stenosis of the orifice. Tumors in bladder diverticula are not suitable for transurethral resection of bladder tumor.

　　(2) Laser resection of bladder tumor via urethra: Lasers have the basic characteristics of strong directionality, high intensity, good monochromaticity, and good coherence, which have a good effect on the treatment of bladder cancer. There are many types of lasers, including solid-state lasers and gas lasers, among which the neodymium-yttrium-aluminum-garnet laser (Nd∶YAG laser) is the most widely used and has the best effect. The laser is introduced into the bladder through an endoscope via a fiber optic cable, and treatment is performed under direct vision. This treatment is non-contact, with consistent treatment depth and controllable, causing minimal trauma and few complications. Special advantages include: ① Blocking lymphatic vessels during laser irradiation can prevent the spread of cancer; ② Non-contact treatment avoids or reduces the release of viable cancer cells; ③ Simple, safe operation with less bleeding and low recurrence rate.

　　(3) Photodynamic Therapy (PDT): Also known as photosensitization therapy, the principle of photodynamic therapy is the toxic effect of photosensitizers, light, and oxygen on cells. Photosensitizers with strong affinity for cancer tissue are injected into the body, allowing them to accumulate and bind, and then activate them with light to produce intracellular toxicity, rendering cancer cells inactive. The commonly used photosensitizers are hemin and its derivative HPD. The general dose of HPD is 2.5 to 5 mg/kg body weight, followed by laser irradiation 48 to 72 hours after intravenous injection. Generally, argon ion laser is used as the light source, introduced by a quartz light guide fiber. It is mainly suitable for the treatment of in situ cancer and superficial bladder cancer, as well as precancerous mucosal lesions. The therapeutic effects of this method for in situ cancer and superficial bladder cancer are above 90% and reach 95% respectively. This method has the advantages of high selectivity for cancer tissue, no damage to normal tissue, and mild systemic reactions, and can be treated repeatedly. The side effects of photodynamic therapy are skin photosensitivity reactions caused by the absorption of a small amount of HPD and its derivatives, which may result in mild edema and hyperpigmentation after exposure to light. The main preventive measure is to avoid light for at least one week. Some patients may experience frequent urination, urgency, and reduced bladder capacity. In recent years, 5-aminolevulinic acid (ALA) has been used as a new photosensitizer, overcoming the shortcomings of HPD, with the advantages of strong fluorescence, no allergic reactions, and no need to avoid light.

　　(4) Partial Cystectomy: Partial cystectomy is a relatively simple surgical procedure. In hospitals that do not have intracavitary urological surgical instruments, partial cystectomy is the main method of treating bladder tumors. As long as the lesion tissue can be completely removed during surgery and the possibility of tumor tissue falling off and contaminating the wound can be minimized, the efficacy is relatively definite.

　　(5) Bladder Instillation Chemotherapy: Bladder instillation chemotherapy is a method of injecting a certain dose of one or more chemotherapy drugs into the bladder and retaining them for a period of time to achieve therapeutic or preventive effects against tumor recurrence. This method has the following advantages: ① Anticancer drugs can act directly on the tumor for a relatively long time at a high concentration in the bladder; ② It can kill the residual tumor cells left in the bladder after surgery, prevent tumor cell implantation, and reduce the possibility of recurrence; ③ It can reduce the toxic and side effects of systemic medication; ④ It can preserve the bladder, making life convenient and retaining sexual function. The ideal bladder instillation chemotherapy drug should have a direct antimalignant transitional cell action and a relatively low systemic toxicity when no special drug action is present. The drugs available for selection include hydroxycamptothecin 6-12mg, mitomycin (mitomycin C) 40mg, doxorubicin 40mg, mitoxantrone 12mg, cisplatin 40mg, and pirarubicin 40mg dissolved in 40-60ml of normal saline, instilled once a week, and changed to once a month after 2 months, lasting for 1-2 years.

　　(6) Bladder Immune Therapy: ① Freeze-dried BCG (Bacillus Calmette-Guerin, BCG): Freeze-dried BCG is an attenuated strain of Mycobacterium bovis tuberculosis. The bladder instillation of freeze-dried BCG is currently the most effective method for preventing tumor recurrence. In addition, freeze-dried BCG can also be used to treat in situ carcinoma. The method is to dilute 120-150mg of freeze-dried BCG in 50ml of normal saline, administered once a week, and after 6 sessions, changed to once a month, lasting for 1-2 years. ② Interferon (IFN): IFN has antiproliferative and immunostimulatory properties and is widely used as an antitumor drug. IFN can be effective in 1/3 of in situ carcinomas. A prospective study shows that the application of recombinant IFN 100×10^7u, once a week for a total of 12 times; followed by once a month for a total of 1 year, with a complete remission rate of 43%. ③ Adalimumab (Interleukin-2, IL-2): The function of IL-2 is to promote the proliferation of T lymphocytes, leading to the proliferation and differentiation of cytotoxic T lymphocytes, activation of natural killer cells NK cells, induction of lymphokine-activated killer cells LAK cells and tumor infiltrating lymphocytes TIL cells, and promotion of the production of various lymphokines by peripheral blood lymphocytes, playing an important role in immune regulation. The commonly used dose for bladder instillation is 3500U, once a week for a total of 6 times; thereafter, once a month for a total of 1 year.

　　(7) Cystoscopy follow-up and urinary tract造影 examination: Postoperative follow-up examinations for superficial bladder cancer patients include: In the first 2 years, a cystoscopy should be performed every 3 months; in the following 2 years, every 6 months; and then once a year. An excretory urography examination should be performed once a year or every two years.

　　2. Treatment of invasive bladder cancer: In recent years, there has been significant progress in the treatment of invasive bladder cancer, from a single surgical treatment to a comprehensive treatment including surgical treatment, chemotherapy, radiotherapy, and biological therapy, with a significant improvement in treatment efficacy. However, surgical treatment remains the most important treatment method. For localized lesions, partial cystectomy can be performed, otherwise, radical cystectomy should be considered with urinary diversion or neobladder surgery, and radiotherapy and chemotherapy may be needed if necessary.

　　(1) Partial cystectomy: Indications include solitary localized cancer, more than 3 cm from the bladder neck, tumors that are difficult to resect by TUR, and cancer in diverticula. Preoperative bladderoscopy mucosal biopsy should be performed to determine that there is no tumor or carcinoma in situ in other parts of the bladder and in the prostatic urethra, and the resection range should include 2 cm of bladder mucosa around the tumor. If the tumor is close to the ureteral orifice, a ureteral reimplantation should be performed.

　　(2) Cystectomy: ①Indications: Multiple bladder cancer, large infiltrative cancer located at the neck and trigone of the bladder, tumors without clear boundaries, recurrent bladder cancer, and patients with large tumor volume who have a small bladder capacity after partial resection. ②Cystectomy combined with preoperative radiotherapy: Radiotherapy can kill tumor cells, avoid systemic and local spread during surgery, and thus improve the survival rate of surgery. ③Cystectomy combined with preoperative arterial chemotherapy: Preoperative iliac internal artery chemotherapy and embolization, but it may cause adhesions and increase the difficulty of bladder resection.

　　(3) Radical cystectomy: In males, it includes the bladder, prostate, seminal vesicle, surrounding adipose tissue, and the peritoneum covering it; in females, it includes the bladder, urethra, and surrounding adipose tissue, and often involves the simultaneous removal of the uterus, fallopian tubes, ovaries, and part of the anterior vaginal wall.

　　(4) Radical cystoprostatectomy with preservation of the erectile nerve: Walsh first reported a modified radical cystoprostatectomy with preservation of the erectile nerve in 1987, which can preserve the erectile function in most patients after surgery. The key points of the operation are to transect the bladder artery and pedicle close to the seminal vesicle and vas deferens when dealing with the lateral ligament of the prostate, in order to avoid injury to the distal part of the vascular nerve bundle.

　　(5) Radiotherapy: Radiotherapy can be used when it is difficult to perform radical cystectomy for bladder cancer or the patient refuses surgery, which can help the patient retain urinary and sexual functions.

　　(6) Chemotherapy: Chemotherapy is the main treatment for bladder cancer with metastasis. Currently, it is believed that cisplatin, doxorubicin, methotrexate, vincristine, fluorouracil, and other drugs are relatively effective.

　　Second, Prognosis

　　Prognosis depends on the type of tumor cells, pathological stage, grade, and the patient's own immunity. For Ta, T1 stage transitional epithelial cancer cells with grade I differentiation, the 5-year survival rate is over 80%; for T1 stage cells with grade II and III differentiation, the 5-year survival rate is 40%, but half of those who retain the bladder have recurrence. Partial cystectomy: 5-year survival rate of 45% for T2 stage, 23% for T3 stage. Total cystectomy: 5-year survival rate of 16% to 48% for T2 and T3 stages. Radical total cystectomy significantly improves the 5-year survival rate for T2 and T3 stages, reaching 30% to 70%, and all patients with T4 stage die within one year without treatment, with reports of 5-year survival rates of 6% to 10% after radiotherapy. With the improvement of chemotherapy and surgical techniques, the recurrence rate of bladder cancer has significantly decreased, and the long-term survival rate has also been continuously improved. Many drugs are used for postoperative bladder irrigation, and it is recently believed that strong anticancer drugs (such as doxorubicin) should be used for irrigation in the short term after surgery to kill residual tumor cells; long-term irrigation can use macromolecular anticancer drugs such as doxorubicin or immunostimulants (lyophilized BCG) to enhance the local tissue immunity to prevent recurrence. However, some scholars even suggest that long-term bladder irrigation may not be necessary. Now, tumor dormancy therapy (tumordormancy therapy) has been proposed, which is to block the tumor angiogenesis to block the way of nutrient supplementation for cancer cells, inhibit the proliferation of tumor cells, and lead to the ultimate regression of tumors. Since vascular endothelial growth factor (VEGF) is a key factor in angiogenesis, it is now possible to effectively inhibit tumor growth by injecting VEGF monoclonal antibodies, making it enter a resting phase. In addition, sucralfate can bind to VEGF, thereby inhibiting the proliferation and migration of vascular endothelial cells induced by VEGF. Postoperative cystoscopy and urine sediment cell examination are very important. It is necessary to avoid risk factors that may induce bladder cancer, such as aniline, dyes, smoking, and actively treat glandular cystitis, bladder calculi, urinary retention, and other conditions.