bubble_chart Overview

Bladder tumors are the most common tumors in the genitourinary system, with an increasing incidence in recent years. Among urothelial tumors, transitional cell tumors of the bladder have the highest occurrence rate.

bubble_chart Epidemiology

The incidence in males is 3 to 4 times higher than in females, with the highest incidence rate (58%) occurring in the 51 to 70 age group. Teenagers in their 10s can also develop the disease, which may be related to smoking. Javapour, Benson, Zhang Xiaosi, and Qian Songxi reported 40, 12, 3, and 8 cases of bladder cancer in adolescents, respectively. Among these groups, 26 cases smoked 1 to 1.5 packs per day with a history of 2 to 3 years. Benson (1983) reported that there were only 17 documented cases of the disease (referring to transitional cell carcinoma) in children under 10 years old.

bubble_chart Etiology

The discussion is divided into two main aspects: chemical carcinogens and endogenous tryptophan metabolism abnormalities. ①Chemical carcinogens: Pure amines do not have carcinogenic effects. The carcinogenic substances are intermediates in dyes, such as 1-naphthylamine, 2-naphthylamine, and benzidine. The antioxidant 4-aminobiphenyl used in rubber and plastics also has bladder carcinogenic effects. The latency period for cancer development after human exposure to carcinogens ranges from 5 to 50 years, typically around 20 years. ②The relationship between endogenous tryptophan metabolism abnormalities and bladder tumors: Many bladder cancer patients have no clear history of exposure to chemical carcinogens, which may be related to abnormal tryptophan metabolism in the body. The normal metabolites of tryptophan, such as abdominal mass, are intermediate metabolites belonging to the category of ortho-hydroxyamino phenols and can induce bladder tumors in mice.

Recent studies have found a significant correlation between smoking and bladder tumors. Male smokers have a four times higher incidence of bladder cancer compared to non-smokers. Artificial sweeteners like saccharin also have bladder carcinogenic effects. Additionally, long-term use of the analgesic phenacetin can increase the risk of bladder tumors. Chronic bladder infections and irritation, as well as the drug cyclophosphamide, can also cause bladder cancer.

bubble_chart Pathological Changes

Bladder tumors can be divided into two major categories: those originating from epithelial tissue and those from non-epithelial tissue.

1. Tumors arising from epithelial tissue mainly include transitional epithelial tumors, adenocarcinoma, and squamous cell carcinoma. 98% of bladder tumors originate from epithelial tissue, with transitional epithelial tumors accounting for 95%.

(1) Transitional epithelial tumors: These primarily include carcinoma in situ, papilloma, papillary carcinoma, and solid carcinoma. The latter two may coexist in a single tumor, referred to as papillary solid carcinoma. This classification is convenient for clinical application, but there is considerable debate regarding whether they represent different stages of a continuous progression of the same disease or distinct entities from the outset.

a. Carcinoma in situ is a unique type of transitional epithelial tumor, initially confined to the transitional epithelium, forming slightly raised, velvety red patches that do not invade the basement membrane. However, the cells exhibit poor differentiation and loss of intercellular adhesion, making them prone to shedding and easily detectable in urine. The natural course of carcinoma in situ is unpredictable: some cases remain asymptomatic for long periods without progression to invasion, while others develop rapidly. The transition from carcinoma in situ to invasive carcinoma generally takes 1 to 5 years, though it can extend up to 20 years. Consequently, some researchers propose that carcinoma in situ exists in two forms: one representing a precursor to invasive solid carcinoma, and another, termed paradoxical carcinoma, which lacks invasive potential and is relatively benign.

b. Papilloma is a benign tumor histologically characterized by its origin from normal bladder mucosa, projecting into the bladder like aquatic plants, with a slender stalk containing distinct fibrous tissue and a central vascular core. Papillomas have a tendency to recur, with a 60% recurrence rate within 5 years, of which 48.6% recur more than twice. Regular cystoscopic follow-up is necessary post-surgery.

c. Papillary carcinoma is the most common among transitional epithelial tumors. Pathologically, it features short, thick, and fused papillae, an irregular tumor surface with necrosis or calcium deposits, and a broad base or thick, short stalk. Occasionally, papillary carcinoma may grow as large as a small fist but retains a stalk without infiltrating other areas. Although rare, this form should be noted to avoid unnecessary total bladder resection.

d. Solid carcinoma is the most malignant among transitional epithelial tumors, with an uneven surface, no distinct papillae, ulcerations with raised edges, and a nodular appearance. It invades deeply early on, hence also termed invasive carcinoma.

The development of various transitional epithelial bladder tumors may correlate with different states of the transitional epithelium. Simple epithelial hyperplasia without dysplasia may progress to superficial papilloma; concurrent hyperplasia and dysplasia may lead to highly malignant papillary carcinoma; and isolated dysplasia without hyperplasia may result in flat carcinoma in situ.

Distinguishing between recurrence and new tumor formation in transitional epithelial bladder tumors can be challenging. So-called recurrence may arise from three causes: ① The bladder epithelium continues to be affected by carcinogens in the urine, reflecting its instability and potential widespread epithelial changes; ② Recurrence often occurs at the bladder incision or dome, suggesting implantation of free tumor cells; ③ Residual tumor tissue post-resection or undetected macroscopic tumor remnants.

(2) Adenocarcinoma: Also known as glandular carcinoma, mucinous adenocarcinoma, or signet-ring cell carcinoma, it is a relatively rare bladder tumor. Adenocarcinoma is commonly found in the bladder trigone, lateral walls, and dome. Adenocarcinomas in the bladder trigone often originate from glandular cystitis or cystic cystitis. Both glandular and cystic cystitis are related to cloacal development, as during the embryonic stage, the cloaca divides into the urogenital sinus and rectum. If intestinal mucosa remains on the urogenital sinus side during this division, glandular epithelium may develop later, potentially leading to glandular or cystic cystitis. Chronic irritation can also cause glandular metaplasia of the transitional epithelium. Adenocarcinomas located in the bladder dome frequently arise from urachal remnants and are often concealed, with symptoms typically appearing only at an advanced stage. Metastatic adenocarcinoma can also occur in the bladder, originating from primary adenocarcinomas in the rectum, stomach, endometrium, ovaries, breast, or prostate, though this is extremely rare, accounting for 0.26% in a reported series of 5,000 autopsies.

(3) Squamous cell carcinoma of the bladder: Also relatively uncommon, accounting for 0.58% to 5.55% in 12 recent domestic reports on bladder tumors. The transitional epithelium of the bladder can undergo metaplasia into squamous epithelium under various stimuli. Reports indicate that focal squamous metaplasia can reach 60%, but the primary type remains transitional cell carcinoma. Only when consistent pathological changes are observed throughout the tumor can a diagnosis of squamous cell carcinoma be made. There are numerous domestic reports of bladder stones accompanied by bladder cancer. Generally, squamous cell carcinoma of the bladder is more malignant than transitional epithelial carcinoma, progresses rapidly, invades deeply, and has a poor prognosis.

2. Non-epithelial bladder tumors: These are tumors originating from mesenchymal tissue, accounting for less than 20% of all bladder tumors. They include hemangioma, lymphangioma, cervical malignancy with cachexia, leiomyoma or fleshy tumor, myoblastoma, rhabdomyomatous fleshy tumor, pheochromocytoma, malignant melanoma, polyp, carcinoid, plasmacytoma, fibroma, fibrous fleshy tumor, myxoid lipomatous fleshy tumor, carcinosarcoma, histiocytoma, schwannoma, soft bone tumor, malignant teratoma, and dermoid cyst, among others. The attack of noxious factor lymphoma may be a systemic disease; hemangiomas may occur simultaneously with hemangiomas of adjacent organs and be interconnected, complicating surgery. Rhabdomyomatous fleshy tumors originate from the trigone of the bladder or submucosal tissue, expanding into the submucosal layer while pushing the bladder mucosa inward, forming small lobulated masses resembling a cluster of grapes, hence also called grape-like fleshy tumors. However, a few may form solid masses. Microscopically, rhabdomyoid fibers and immature embryonic mesenchymal cells can be observed.

The malignancy of bladder tumors is classified by "grade." The earliest method was the Broder 4-grade system, but its precise application is challenging, with difficulty distinguishing between grades II and III. Recently, a three-grade system has been more commonly adopted: - Grade I: Well-differentiated tumors with more than seven layers of transitional epithelium, showing slight structural and nuclear atypia compared to normal, with occasional mitoses. - Grade II: In addition to epithelial thickening, cell polarity is lost, moderate nuclear atypia is present, and mitoses are common. - Grade III: Undifferentiated, bearing no resemblance to normal epithelium, with frequent mitoses. This grade corresponds to grades III and II in the Broder system. Some advocate grouping papillomas with grade I papillary carcinomas, while others strictly separate papillomas. We support the latter, as some papillomas may never recur after treatment or recur while remaining papillomas. Generally, grade correlates with invasiveness: the likelihood of invasion is 10% for grade I, 50% for grade II, and 80% for grade III.

The staging of bladder tumors refers to the depth of tumor invasion and helps estimate prognosis. Currently, two main staging methods are used: one is the Jewett-Strong method modified by Marshall (JSM), and the other is the TNM system by the International Union Against Cancer (UICC) (where T refers to the tumor itself, N to lymph nodes, and M to metastasis). A comparison of the two methods is shown in Table 28-1.

The metastatic pathways of bladder tumors include lymphatic spread, hematogenous spread, direct extension, and direct tumor cell implantation. Lymphatic metastasis is the most common route, with bladder cancer potentially spreading to the internal iliac, external iliac, and obturator lymph node groups, or even to the common iliac lymph nodes. Some studies indicate that the internal iliac and obturator lymph nodes are the first stations for bladder cancer metastasis.

Hematogenous metastasis is often seen in advanced-stage cases, most commonly affecting the liver, followed by the lungs and bones. Metastases to the skin, adrenal glands, kidneys, pancreas, heart, testes, salivary glands, ovaries, muscles, and gastrointestinal tract have also been reported, though these are relatively rare.

Direct extension frequently involves the prostate or posterior urethra. Bladder cancer may extend beyond the bladder, forming fixed masses adherent to the pelvis, or spread to the mucosal layer at the dome of the bladder.

Tumor cell direct implantation can occur during surgery, leading to the formation of masses at the bladder incision site or beneath the skin incision postoperatively. The recurrence of tumors within the bladder or the appearance of multiple tumors may also be partly attributed to tumor cell implantation. Additionally, the occurrence of tumors at the urethral stump after total bladder resection may result from surgical implantation.

bubble_chart Clinical Manifestations

More than 3/4 of patients present with hematuria as the first symptom. Most of them exhibit painless hematuria, while a minority show microscopic hematuria. The degree of hematuria and anemia is generally proportional to the size of the tumor, but in rare cases, a small papilloma can repeatedly bleed to the point of anemia.

Secondly, bladder irritation symptoms—urgency, frequency, and dysuria—are late-stage [third-stage] symptoms, indicating invasive bladder cancer and extensive carcinoma in situ. Pedunculated tumors near the bladder neck can cause dysuria or urinary retention. In children, rhabdomyosarcoma is the most common lower urinary tract tumor under the age of 4, with dysuria as the main symptom, accompanied by pyuria and fever; the latter two symptoms often prompt medical attention. Sometimes, rhabdomyosarcoma can prolapse from the urethral orifice in girls, with the prolapsed portion showing necrosis or continued growth. A pelvic mass is often palpable on digital rectal examination.

Other symptoms of bladder cancer include lower limb edema, pelvic mass, bone pain, abdominal pain, or systemic symptoms such as weight loss and weakness, all of which indicate tumor metastasis. When a lower abdominal mass is the initial symptom, primary adenocarcinoma of the bladder neck originating from the ureter should be considered first.

bubble_chart Auxiliary Examination

Currently, cystoscopy remains the primary method for examining bladder tumors. Initially, it can differentiate whether the tumor is benign or malignant. Benign papillomas are easily recognizable, featuring a clear stalk from which numerous finger-like or villous branches extend, floating in the water. The bladder mucosa around the stalk appears normal. If the tumor is sessile, with a broad base, and the surrounding bladder mucosa is irregular, thickened, or edematous and congested, the tumor may present as short, uneven protrusions or a mass resembling a fist, with ulcerated bleeding and gray-white pus-like deposits. A reduced bladder capacity and turbid, bloody irrigation fluid all suggest the presence of a malignant tumor. Some tumors located at the dome or anterior wall are often difficult to detect with standard cystoscopy and may be overlooked by examiners. The use of flexible cystoscopy can compensate for this limitation.

Through cystoscopy, a biopsy can be performed to assess the malignancy grade and depth of the tumor. Samples can also be taken from areas near and distant to the tumor to check for epithelial abnormalities or carcinoma in situ, which is a crucial step in determining treatment plans and prognosis. When taking biopsies, it is important to sample both the base and the apex of the tumor, as the malignancy grade of the apical tissue is generally higher than that of the base.

For carcinoma in situ and smaller tumors that are difficult to detect with standard cystoscopy, microscopic chromocystoscopy (Microscopic-chromocystoscopy) can be used. After staining the bladder cavity Neijing with methylene blue, normal epithelium does not take up the dye, allowing early identification of tumors for biopsy and facilitating early diagnosis. However, this type of cystoscope is expensive and not yet widely available.

Bladder radiography is less commonly used today but can sometimes supplement cystoscopy. For instance, it may be employed when a bladder tumor is too large to be fully visualized by cystoscopy. In cases of large pedunculated papillomas, bladder radiography can reveal the gap between the tumor and the bladder wall and sometimes even the stalk of the tumor. Tin dioxide can be used as a contrast agent along with air for double-contrast radiography, as its particles adhere well to the tumor surface, providing clear imaging. Occasionally, triple-repeat bladder radiography may be performed: 30 mL of 50% sodium diatrizoate is injected into the bladder, followed by injections of 30, 40, and 50 mL of saline, respectively. After each injection, the patient remains in the same position, and a single exposure is taken, with each exposure accounting for one-third of the total exposure. In a normal bladder, the upper edge appears as three symmetrical layers of varying density, merging into a single edge at the upper border of the pubis. In cases of bladder wall infiltration, asymmetric expansion can be observed in addition to filling defects, indicating loss of contractility due to cancerous infiltration.

For estimating the clinical staging of bladder tumors, bimanual examination under anesthesia was previously emphasized, but it is inaccurate in over 50% of cases, often underestimating the stage. A palpable, mobile tumor is usually a pedunculated papilloma, whereas a fixed hard mass or one larger than observed on cystoscopy suggests tumor infiltration into the perivesical tissues (Stage C or T3b).

Currently, CT is considered the most accurate non-invasive method for staging bladder tumors. Shao Hongxun et al. reported a 90.6% concordance rate between CT scans and pathological findings in 32 cases of bladder tumors. CT scans can clearly detect bladder tumors as small as 1 cm, distinguish muscle layer infiltration and perivesical invasion, and also identify enlarged pelvic lymph nodes. However, CT cannot determine whether enlarged lymph nodes are metastatic, which requires comprehensive consideration of other clinical factors. Dorsal foot lymphography can reveal the structure of enlarged lymph nodes and aid in assessing metastasis, but lymphography is sometimes difficult to interpret, with certain false-positive or false-negative rates. The first-station lymph nodes of bladder cancer, such as the internal iliac and obturator lymph nodes, are generally not easily visualized. Additionally, lymphography is a meticulous and time-consuming examination method that has not yet been widely adopted. Transabdominal ultrasound imaging is another non-invasive method for diagnosing bladder tumor staging. According to Wang Wencheng et al. (Chinese Journal of Urology, 1987, 8:152), its accuracy in determining significant muscle layer infiltration reaches 84.8%. Transurethral intravesical ultrasound imaging achieves an accuracy of 93% in assessing bladder tumor infiltration (Na Yanqun et al., Chinese Journal of Urology, 1986, 7:347). However, this method is painful for patients and cannot detect whether pelvic lymph nodes are metastatic.

Intravenous urography is essential in the diagnosis of bladder tumors, with the primary purpose of determining whether the upper urinary tract also has tumors or not. According to reports by Zhang Jilun et al., bladder tumors accompanied by tumors in other organs of the urinary system account for 6.2%. Shinka reported that among 519 cases of bladder tumors, 12 had upper urinary tract transitional epithelial tumors (2.3%). The incidence of transitional epithelial tumors in the renal pelvis and ureter accompanied by bladder tumors is even higher.

Urinary cytology plays a certain role in the diagnosis of bladder tumors, with a general positive rate of 80%. It is equally important as urine red blood cell examination for monitoring tumor recurrence. For workers exposed to carcinogens, cancer cells may appear in the urine before the tumor develops. The positive rate of urinary cytology is also closely related to the malignancy of the tumor. Well-differentiated papillomas may have individual cells resembling normal cells, presenting as sheets of normal epithelial cells or "atypical" cells. The better the differentiation of the tumor cells, the stronger their adhesion, making them less likely to shed. Reports indicate that the positive rate for grade I transitional cell carcinoma is only 10%, grade II 50%, grade III 90%, and carcinoma in situ almost 100%. Inflammation of the urinary system or radiation therapy can cause false-positive reactions.

Flow cytometry (FCM) is another cytological method for diagnosing bladder tumors by measuring abnormal DNA content in cells. Normal urine should not contain aneuploid stem cell lines; hyperdiploid cells should be less than 10%. If aneuploid cells exceed 15%, a diagnosis of cancer can be made. The increase in aneuploid cells is proportional to the malignancy of the tumor. Reports show a positive rate of 31% for papillomas, 86% for non-invasive papillary carcinomas, 92% for invasive carcinomas, and 97% for carcinoma in situ. Among FCM-positive cases, 18 showed tumors on cystoscopy 12 months later. However, some believe FCM does not offer significant advantages over urinary cytology, and the high cost of FCM equipment makes it difficult to widely implement.

Measuring the ABO(H) antigen on the surface of tumor cells helps estimate tumor progression and prognosis. ABO(H) antigens are present on the surface of various epithelial cells in the body, including urinary tract transitional epithelium. The specific red cell adherence test (SRCA) is commonly used, but this method has a low detection rate for "H" antigens in "O" blood type patients and a high false-positive rate. In recent years, the PAP method (double-bridge peroxidase-antiperoxidase method) has been widely adopted, proving significantly superior to SRCA in detecting H antigens. High-grade or advanced-stage bladder cancers often lose cell surface antigens, indicating a poor prognosis. Fan Jie, Liu Shiyi et al. (Chinese Journal of Urology, 1986, 7:139) reported in their study on the double-PAP method that among 44 cases of superficial bladder cancer, 22 were antigen-negative, with 19 recurrences, 12 cases of infiltration or metastasis, and 8 deaths. In contrast, among the 22 antigen-positive cases, only 3 recurred, with 1 case of infiltration and 1 death. This demonstrates the prognostic value of ABO(H) antigen detection on tumor cell surfaces. Another advantage of this method is that it can be performed on preserved tissue wax blocks, facilitating retrospective studies. For patients with preserved antigens, conservative treatments (bladder-preserving surgeries) may be considered, while those who lose antigens should be evaluated for aggressive surgical interventions as early as possible.

bubble_chart Treatment Measures

The treatment of bladder tumors is relatively complex and should be tailored based on different pathological and clinical processes. For superficial bladder tumors, transurethral resection (TURBt) or electrocautery can be employed. Tumors with differentiation above the medulla, staging within T2, and a diameter of less than 2 cm are all indications for TURBt. Multiple tumors can be resected in stages. The TURBt method involves no incision, can be repeated, has minimal impact on the patient, and allows for rapid postoperative recovery. It is widely adopted both domestically and internationally and can almost replace partial bladder resection. Some international reports even suggest that TURBt yields better outcomes than partial bladder resection. The overall 5-year survival rate for TURBt is approximately 70%, with only 10–15% progressing to invasive carcinoma requiring aggressive treatment.

After transurethral tumor resection, two-thirds of cases experience recurrence. Currently, intravesical drug instillation is commonly used to prevent recurrence. Commonly used drugs include Bacillus Calmette-Guérin (BCG), mitomycin, or doxorubicin, with BCG being the most effective. Thiotepa was frequently used in the past but yielded unsatisfactory results and carried the risk of bone marrow suppression, so it is now rarely employed.

(1) Intravesical BCG therapy: Domestically, the current standard involves instilling 120 mg of BCG (produced by the Beijing Institute of Biological Products) and 50 mL of saline into the bladder via a catheter, retaining it for 2 hours. Initially, this is done weekly for 6 doses, followed by monthly instillations for 2 years. Internationally, BCG strains such as Tice, Pasteur, Moreau, and Connaught are used. Differences in strains and dosages may affect efficacy. Yao Qingxiang et al. reported (Chinese Journal of Urology, 1987, 8:158) that among 36 cases using intravesical BCG for recurrence prevention, with an average follow-up of 18.4 months, only 2 cases recurred at 20 and 24 months, respectively. Mei Hua et al. reported (Chinese Journal of Urology, 1987, 8:28) that among 43 cases (using the Danish strain 1 produced by the Guangzhou Institute of Biology), the average follow-up was 23.44 months, with 2 recurrences. Brosman reported 53 cases with an average follow-up of 21 months and 4 recurrences.

Other administration methods, such as skin scarification and direct tumor injection, are no longer used.

Domestically, Meng Jing et al. recommended using low-dose BCG (Pasteur strain 2, containing approximately 2×10 bacteria per mL) at 1 mL or Corynebacterium parvum (Beijing 7627) at 2 mL (Meng Jing et al., Chinese Journal of Urology, 1987, 7:23). Both are administered monthly without interruption, resulting in a low tumor recurrence rate (about 15%). Due to the low dose, complications are also mild, making this approach noteworthy.

Intravesical BCG instillation is also highly effective for treating bladder carcinoma in situ. Zhang Deyuan et al. reported 7 cases (Chinese Journal of Urology, 1987, 8:264), of which 6 showed no tumor upon biopsy after 3 months of instillation. Herr reported 47 cases of flat bladder carcinoma in situ treated with 120 mg of Pasteur strain BCG plus 50 mL of saline weekly for 6 doses (23 cases also received intradermal BCG). Overall, 32 cases (68%) remained tumor-free after 6 years.

Thus, intravesical BCG instillation significantly reduces bladder tumor recurrence rates, sparing some patients from bladder resection or delaying the need for surgery.

According to Lamm's analysis of 1,278 cases of BCG intravesical instillation, complications included bladder inflammation in 91%, fever above 39.4°C in 3.9%, granulomatous prostatitis in 1.3%, BCG pneumonia or hepatitis in 0.9%, arthritis and arthralgia in 0.5%, hematuria requiring catheterization or blood transfusion in 0.5%, rash in 0.2%, hypotension in 0.1%, and cytopenia in 0.1%. Other domestic and international reports have also documented rare complications such as granulomatous renal masses, periurethral granulomas, and abscesses. The latter is often associated with direct BCG injection into the urethra without using a catheter.

The mechanism of action of intravesical BCG instillation is still not conclusively determined. Some believe it may be an inflammatory reaction, as its efficacy is proportional to bladder irritation symptoms, while others suggest it is a nonspecific immune response. Reports indicate that during intravesical BCG perfusion therapy, when the purified protein derivative (PPD) skin test changes from negative to positive or granulomas appear in the bladder, the therapeutic effect is often favorable. Clinical and animal experiments show that after intravesical BCG instillation, round cell infiltrates dominated by lymphoid structures can be observed in the bladder wall, extending from the mucosal layer to the muscular layer. This also explains why BCG treatment is effective for some superficial muscle-invasive bladder tumors. It is now believed that the inflammation induced by BCG can activate the macrophage system and T-cell proliferation. After macrophages phagocytize BCG and tumor cells, they can stimulate BCG-sensitized T lymphocytes to produce interleukin-2 (IL-2), which activates the proliferation of T precursor cells, generating T cells with specific tumor-killing capabilities and inducing tumor-specific immunity. Merguerian reported treating 13 cases of bladder tumors with intravesical instillation of low-dose BCG (60 mL) combined with IL-2 (3500 units), achieving comparable efficacy to high-dose BCG but with less severe bladder reactions due to the reduced BCG dosage. This method leverages exogenous IL-2 to stimulate the proliferation of functionally specialized T cells.

(2) Netto proposed an oral BCG method: Based on the degree of skin reaction (e.g., PPD, PNCB tests), categorized as "none," "grade II," or "significant," patients were administered liquid BCG orally at doses of 800, 400, or 200 mL, respectively. The tumor recurrence rate was only 6.2%. Later, the same method was used to treat 10 cases of muscle-invasive bladder tumors, resulting in tumor disappearance in 7 cases with no toxic reactions. However, this is currently the only report, and the number of cases is still insufficient.

(3) Intravesical mitomycin instillation: The currently recommended dose is 40 mg dissolved in 40 mL of water, administered via catheter into the emptied bladder. The patient changes position every 15 minutes for a total of 2 hours. The treatment is given once weekly for 8 weeks, followed by monthly instillations for one year. Due to its high molecular weight (>200), mitomycin is not absorbed by the bladder mucosa. If the bladder has no wounds or has healed, there are no systemic reactions. The main side effect is contact dermatitis, which can be avoided by rinsing the area after instillation.

(4) Intravesical doxorubicin instillation: 50 mg of doxorubicin dissolved in 50 mL of saline is instilled into the bladder immediately after TURBt and retained for 30 minutes as a single application, with cystoscopy re-evaluation after six months. Alternatively, instillations can begin 1–2 weeks after TURBt, administered weekly for 4 weeks, then monthly for one year. Experiments show that perioperative intravesical doxorubicin instillation results in very low blood concentrations, avoiding systemic reactions. However, its efficacy for both treatment and prevention remains unsatisfactory.

The above intravesical chemotherapy methods can be used to treat tumors, but they are time-consuming and less rapid than TURBt. Therefore, they are primarily used post-TURBt to prevent recurrence. Among the various recurrence prevention methods, intravesical BCG instillation has shown the best efficacy.

(5) Laser Therapy: In addition to TURBt, another method for locally eliminating superficial bladder tumors is laser treatment or laser hematoporphyrin derivative (HPD) phototherapy, which has shown certain efficacy. Jiang Yu et al. reported using YAG laser to treat 50 cases involving 185 tumors, achieving a cure rate of 95.13%, with 7 cases recurring (11.8%). The laser dosage was measured in units of 50 watts for 5 seconds per flash, with each tumor requiring approximately 20–50 units. The tumor sizes ranged from 1.5 cm to 5 cm, and the number of tumors varied from 2 to 8. Tumors located on the anterior wall, neck, and dome of the bladder were difficult to irradiate. Two cases experienced bladder bleeding after laser irradiation, requiring a blood transfusion of 400 ml. Additionally, if the Na:YAG laser power exceeds 50 watts, its penetration increases, and excessive irradiation may lead to bladder perforation.

Laser hematoporphyrin derivative phototherapy has the following characteristics: hematoporphyrin derivative is easily absorbed by malignant cells and stored for a relatively long time. After laser irradiation, tumor cells can be destroyed, but the required laser energy is much less. The method involves intravenous injection of HPD at 5mg/kg body weight. After 24 to 72 hours, a laser fiber is inserted via a bladder mirror to irradiate the tumor. The laser used is an argon-ion dye laser, which emits red light with a maximum power of 910 milliwatts and a terminal power of 100 to 500 milliwatts. Da Yinggeng et al. reported that 18 out of 20 tumors in 9 cases completely disappeared, with follow-up ranging from 9 to 12.5 months, and 3 cases experienced recurrence. Zeng Xiangfu et al. reported similar results in 10 cases. Benson believes this method is most suitable for treating bladder carcinoma in situ, reporting 4 cured cases. One drawback is that patients must avoid light for one month after treatment; otherwise, photosensitive dermatitis or long-term facial pigmentation may occur.

The application of YAG laser or hematoporphyrin derivative laser irradiation therapy is a new attempt, serving as a bloodless resection method that avoids surgical dissemination of tumor cells and reduces the chance of recurrence. However, laser equipment is complex and costly, limiting its widespread adoption.

For bladder tumors with muscle layer infiltration, TURBt alone yields poor results, with the best 5-year survival rate being 40%. Recently, HERBt reported 45 cases deemed suitable for conservative treatment (i.e., TURBt plus intravesical BCG perfusion). Each procedure involves thorough transurethral resection of abnormal bladder sections followed by intravesical drug perfusion, with strict staging for each resection. These patients were followed for 3 to 7 years (average 5.1 years), with 30 cases (67%) retaining bladder function. Among them, 9 cases survived tumor-free, while 21 required repeated TURBt and intravesical drug perfusion. Of the 15 treatment failures, 11 underwent bladder resection, and 4 survived with metastatic tumors. HERBt’s experience suggests that continuous restaging can identify a subgroup without frequent muscle layer infiltration, suitable for conservative therapy to preserve bladder function.

(6) Partial bladder resection: This procedure is relatively simple, preserves bladder function, and is easily accepted by patients. However, its indications are very limited, suitable only for: A) single, large tumors that cannot be resected transurethrally; B) random biopsies of bladder mucosa outside the tumor showing no carcinoma in situ or epithelial dysplasia, with no lesions in the prostatic urethra; C) the ability to resect normal mucosa 2 cm from the tumor. Some also advocate preoperative radiotherapy (10–12 Gy or 1000–1200 rad) to prevent tumor cell implantation in the wound (occurring in about 10–20% of bladder incision surgeries). The overall 5-year survival rate for this surgery is 48%, with 100% for stage A, 67% for stage B₁, and 37.5% for stage B₂. Therefore, this surgery should ideally be limited to stage B₁ or earlier. With the availability of intracavitary equipment, the need for this surgery is reduced.

The above methods all involve bladder-preserving surgeries. After initial treatment, patients should undergo bladder镜检查 every 3 months for the first season, every 6 months after 2 years, and then at appropriately extended intervals based on circumstances. The biological characteristics of transitional cell carcinoma in young adults differ from those in the elderly, with most being low-stage, low-grade non-invasive tumors that rarely recur. Thus, excessive bladder镜检查 is unnecessary, and bladder-preserving surgeries should be prioritized.

Total bladder resection is suitable for rapidly recurring tumors with increasing stage/grade upon each recurrence, or bladder tumors with epithelial dysplasia or carcinoma in situ outside the tumor. The loss of ABO(H) antigens on tumor cell surfaces may also be considered.

Stage B2 bladder cancer and solid carcinomas often have regional lymph node metastases, and radical total cystectomy may be considered. The mortality rates for total cystectomy and radical total cystectomy are approximately 8% and 11%, respectively. Currently, there are two debated points worth noting regarding these two procedures: one is the issue of preoperative radiotherapy. Radiotherapy typically involves pelvic irradiation of 40Gy (4000rad) within 4 weeks before surgery, followed by radical total cystectomy 1–3 weeks later; or 12Gy (1200rad) irradiation over 4 days, with radical surgery performed within 12 days. Preoperative radiotherapy can improve survival rates for two reasons: ① to eliminate residual微量 cancer cells after surgery; ② to reduce the chance of cancer cell dissemination into lymphatic or blood vessels during surgery and to diminish the viability of already disseminated cancer cells. However, over the past decade, the efficacy of preoperative radiotherapy has been debated. Whitmore reported that its main advantage is a lower pelvic recurrence rate, but this has not been confirmed by others (e.g., Prout, Skinner, and Lieskovsky). Some argue that preoperative radiotherapy is a recent development and comparing it to past单纯 total cystectomy or radical resection is unreasonable, as modern surgical techniques and postoperative care have significantly improved. Skinner (1984) reported a comparison of 100 cases with short-course preoperative radiotherapy and 97 cases with单纯 total cystectomy, finding no significant survival advantage in the preoperative radiotherapy group. The 5-year survival rates for P₂ and P_3a stages with单纯 cystectomy were 75%, while for P; a and P_3b stages, it was 40%. The pelvic recurrence rates also showed no significant difference between the two groups, at 9% (preoperative radiotherapy group) and 7% (单纯 cystectomy group). Currently, due to the delay in surgery and higher complication rates associated with preoperative radiotherapy, it has not been widely accepted in urology and appears to be increasingly abandoned.

Another issue is the evaluation of pelvic lymph node dissection. Some believe that during total bladder removal, pelvic lymph node dissection can only serve as a diagnostic method to clarify the staging of bladder cancer and estimate prognosis, because when pelvic lymph node metastasis occurs, distant metastasis or micrometastasis is often present. However, others argue that about 10–20% of patients have only micrometastasis in pelvic lymph nodes and can survive for more than 5 years after pelvic lymph node dissection. Skinner reported that after thorough lymph node dissection, the 5-year survival rate for patients with lymph node metastasis could reach 35%, and the survival rate was related to the number of positive lymph nodes (see Table 28.2). Smith and Whitmore also reported similar findings: among 1,334 cases with regional lymph node metastasis, the overall 5-year tumor-free survival rate was low; of the 104 cases with more than one positive lymph node, only 4 survived. Therefore, pelvic lymph node dissection is still effective for a small subset of cases, particularly for those with only microscopic lymph node metastasis, and may also have some therapeutic effect for those with 1–2 or fewer positive lymph nodes. Selective pelvic lymph node dissection is worth considering.

Table 28-2 Relationship Between Survival Rate and Lymph Node Positivity.

Radiotherapy is less effective than radical total bladder resection and is mostly used only for patients who are not suitable for surgery. However, in the UK, radiotherapy remains the primary treatment for invasive bladder cancer, known as radical radiotherapy or definitive radiation. Typically, cobalt external irradiation or a linear accelerator is used to deliver 7000 cGy in 35 fractions over 7 weeks. According to reports by Goffinet or Caldwell et al., the 5-year survival rate for B2 or C stage bladder cancer ranges between 14% and 37%. However, only 20–25% of tumors are radiosensitive, while the remaining patients either retain their tumors or undergo bladder resection, termed salvage cystectomy, with most ultimately succumbing to the tumor. The survival rate for salvage cystectomy is 12%. For superficial tumors, the survival rate after salvage cystectomy following radiotherapy failure is 60–65%, whereas for invasive tumors, it is 12–25%. Jenkin et al. reported (Brit J Urol, 1988, 62:343) on 182 cases of T2 and T3 stages treated with a linear accelerator delivering 5000–5500 cGy in 20 fractions over 4 weeks. The overall corrected 5-year survival rate was 40%. During follow-up, 75 cases were radiosensitive with no recurrence, achieving a 5-year survival rate of 20%; among these, 11 cases underwent total bladder resection after recurrence, with a 5-year survival rate of 36%. In contrast, all 9 cases that did not undergo bladder resection died within 3 years. For the 87 cases where radiotherapy was ineffective, the 5-year survival rate was 18%, with 22 cases undergoing salvage total bladder resection achieving a 5-year survival rate of 47%, while the remaining 65 cases who did not undergo surgery had a rate of 3%.

One major complication of radiation therapy is radiation-induced cystitis. A small number of patients experience severe bladder bleeding after radiation, necessitating bladder removal. However, pathological examination reveals no remaining tumors in the bladder, indicating a downstaging phenomenon of bladder tumors post-radiation.

The prognosis for metastatic bladder cancer is very poor. In the report by Smith and Whitmore, among 134 cases with lymph node metastasis who underwent radical total cystectomy, only 7% survived for 5 years, while 82% died from cancer. The actual survival time ranged from 7 months for N4 stage to 22 months for N1 stage. For such patients, treatment hopes lie primarily in chemotherapy. Recently, Sternberg reported the M-VAC regimen (Table 28-3) for treating 92 cases of advanced-stage urothelial carcinoma (mainly bladder cancer), which serves as a reference. Analysis of 83 cases with complete data showed that 57 achieved complete remission (CR), with an average survival of 19 months. Among the CR group, 17 cases (30%, ranging from 26 to 49 months) had an average survival of 42 months, and 11 cases survived for over 3 years (13% of the 83 cases, or 35% of the CR group). In the 31 CR cases, 11 were clinical CR, 10 were pathological CR, and 10 achieved CR after surgical resection of residual lesions. The 11 clinical CR cases received an average of 5 cycles of treatment, with 6 experiencing tumor recurrence. Among the 10 pathological CR cases, 3 later developed brain metastasis, 1 had bone metastasis, 1 had liver metastasis, and 1 had local recurrence. From these data, the M-VAC regimen proves effective for metastatic advanced-stage urothelial carcinoma. When used alone or combined with surgical resection of residual lesions, CR and PR rates reached 69–100%. Compared to pre-M-VAC reports, survival time for CR patients significantly increased, with notable regression of metastatic lesions, particularly in lymph nodes and lungs, which responded better than bone or liver metastases.

Sternberg et al. preliminarily applied the M-VAC regimen to 50 cases of bladder cancer (T2–T4) without lymph node or other metastases. After 1–5 cycles, 22% achieved clinical CR and 42% achieved PR. Pathological staging (including total cystectomy, partial cystectomy, exploratory laparotomy, and selective lymph node biopsy) confirmed that 30% of originally T3 lesions and 17% of T4 lesions converted to P0.

Thus, the M-VAC regimen is a noteworthy new chemotherapy approach for bladder cancer (Table 28-3).

The treatment of pediatric bladder grape-like fleshy tumors has shown significant improvement in recent years. Surgery and chemotherapy need to be combined, with chemotherapy playing an increasingly important role. Due to chemotherapy, there is now a trend toward tumor-sparing bladder surgery. Specifically, vincristine is administered 4 to 6 weeks before surgery until the bladder tumor shrinks or stops shrinking (most tumors can shrink by 50%). Then, tumor enucleation and clearance are performed while preserving the bladder. Postoperatively, vincristine is continued for a total of two years. Additionally, actinomycin D, cyclophosphamide, and adriamycin are administered in monthly rotations for two years postoperatively. This regimen can be referred to as the VACA treatment protocol.

It is understood that Beijing Children's Hospital has used this protocol to treat bladder rhabdomyosarcoma. Among the cases, two have nearly completed the two-year postoperative chemotherapy and have been tumor-free for 23 months. The other four cases have been followed for 6 to 10 months postoperatively, with two remaining tumor-free and two developing small bladder tumors. The latter were confirmed as recurrence upon resection and are currently continuing treatment with normal urinary function. In the past, children who underwent total bladder resection with chemotherapy had a survival rate of 5 out of 6 cases for 7 to 11 years. One case, which did not adhere to the chemotherapy schedule after discharge, died due to metastasis.

From the above, it is evident that chemotherapy will become a crucial component in the treatment of bladder tumors.