mitotic apparatus protein (numa) tumor marker (a type of nuclear matrix protein). urovysion is a fluorescence in situ hybridization which detects aneuploidy in chromosomes 3, 7, 17 and loss of the 9p21 locus. immunocyt is an immunofluorescence test which detects glycosylated cea and mucin-like antigens (m344, ldq10, 19a11). bta-stat is a dipstick immunoassay for detection of human complement factor h-related protein. bta-trak is a sandwich elisa which also detects human complement factor h-related protein. sensitivities across biomarkers ranged from 0.57 to 0.82 and specificities from 0.74 to 0.88. biomarkers fared better when used in combination with urine cytology than when used alone. however, detection accuracy is poor for low grade cancers and 10% cancers are still missed. current guidelines do not recommended using urinary biomarkers for detection and surveillance. classification histopathology of urothelial carcinoma of the urinary bladder. transurethral biopsy. h&e stain typerelative incidencesubtypes transitional cell carcinoma95%papillary (70%) non-papillary (30%) non-transitional cell carcinoma5% squamous cell carcinomas, adenocarcinomas, sarcomas, small cell carcinomas, and secondary deposits from cancers elsewhere in the body. non-papillary carcinoma includes carcinoma in situ (cis), microinvasive carcinoma and frankly invasive carcinoma. carcinoma in situ (cis) invariably consists of cytologically high-grade tumour cells. transitional cell carcinoma can undergo differentiation (25%) into its variants. when seen under a microscope, papillary transitional cell carcinoma can present in its typical form or as one of its variations (squamous, glandular differentiation or micropapillary variant). different variations of non-papillary transitional cell carcinoma are listed below. varianthistologypercentage of non-papillary casesimplications squamous differentiationpresence of intercellular bridges or keratinization60%outcomes similar to conventional transitional cell carcinoma glandular differentiationpresence of true glandular spaces10% sarcomatoid focipresence of both epithelial and mesenchymal differentiation7%clinically aggressive micropapillary variantresembles papillary serous carcinoma of the ovary or resembling micropapillary carcinoma of breast or lung3.7%clinically aggressive, early cystectomy recommended urothelial carcinoma with small tubules and microcystic formpresence of cysts with a size range of microscopic to 1-2mmrare lymphoepithelioma-like carcinomaresembles lymphoepithelioma of the nasopharynx lymphoma-like and plasmacytoid variantsmalignant cells resemble cells of malignant lymphoma or plasmacytoma nested varianthistologically look similar to von brunn's nestscan be misdiagnosed as benign von brunn's nests or non-invasive low-grade papillary urothelial carcinoma urothelial carcinoma with giant cellspresence of epithelial tumour giant cells and looks similar to giant cell carcinoma of the lung trophoblastic differentiationpresence of syncytiotrophoblastic giant cells or choriocarcinomatous differentiation, may express hcg clear cell variantclear cell pattern with glycogen-rich cytoplasm plasmacytoidcells with abundant lipid content, mimic signet ring cell adenocarcinoma of stomach/ lobular breast cancerclinically aggressive, propensity for peritoneal spread unusual stromal reactionspresence of following; pseudosarcomatous stroma, stromal osseous or cartilaginous metaplasia, osteoclast-type giant cells, lymphoid infiltrate staging diagram showing the t stages of bladder cancer stage n1 bladder cancer advanced bladder cancer (m1b) lymph nodes in the pelvis. bladder cancer commonly spreads to obturator and internal iliac (not labelled) lymphatic drainage of the bladder (lateral view).tumors on the superolateral bladder wall spread to external iliac lymph nodes bladder cancer is staged (classified by the extent of spread of the cancer) and graded (how abnormal and aggressive the cells appear under the microscope) to determine treatment and predict outcomes. staging is usually performed with transurethral resection of bladder tumor (turbt) and radiologic imaging (ct and mri). papillary tumors confined to the mucosa or which invade the lamina propria are classified as ta or t1. flat lesions that do not invade the basement membrane of the bladder mucosa are termed tis (in situ). all three categories (tis, ta and t1) are grouped together as non-muscle invasive disease for therapeutic purposes and in most cases they are offered cystoscopic resection with turbt without the need for radical resection of the entire urinary bladder. tumors in the remaining categories (t2, t3 and t4) are termed muscle-invasive disease and are associated with less favorable prognosis. in the tnm staging system (8th edn. 2017) for bladder cancer: t (primary tumour) tx primary tumour cannot be assessed t0 no evidence of primary tumour ta non-invasive papillary carcinoma tis carcinoma in situ ('flat tumour') t1 tumour invades subepithelial connective tissue t2a tumour invades superficial muscle (inner half of the detrusor muscle) t2b tumour invades deep muscle (outer half of the detrusor muscle) t3 tumour invades perivesical tissue: t3a microscopically t3b macroscopically (extravesical mass) t4a tumour invades prostate, uterus or vagina t4b tumour invades pelvic wall or abdominal wall n (lymph nodes) nx regional lymph nodes cannot be assessed n0 no regional lymph node metastasis n1 metastasis in a single lymph node in true pelvis (hypogastric, obturator, external iliac, or presacral nodes) n2 metastasis in multiple lymph nodes in true pelvis (hypogastric, obturator, external iliac, or presacral nodes) n3 metastasis in common iliac lymph nodes m (distant metastasis) mx distant metastasis cannot be assessed m0 no distant metastasis m1 distant metastasis. m1a: the cancer has spread only to lymph nodes outside of the pelvis. m1b: the cancer has spread other parts of the body. the most common sites for bladder cancer metastases are the lymph nodes, bones, lung, liver, and peritoneum. the most common sentinel lymph nodes draining bladder cancer are obturator and internal iliac lymph nodes. the location of lymphatic spread depends on the location of the tumors. tumors on the superolateral bladder wall spread to external iliac lymph nodes. tumors on the neck, anterior wall and fundus spread commonly to the internal iliac lymph nodes. from the regional lymph nodes (i.e. obturator, internal and external lymph nodes) the cancer spreads to distant sites like the common iliac lymph nodes and paraaortic lymph nodes. skipped lymph node lesions are not seen in bladder cancer. numerical the stages above can be integrated into a numerical staging (with roman numerals) as follows: stagetumornodesmetastasis5-year survival in the us stage 0a tan0m098% stage 0is tisn0m095% stage i t1n0m063% stage ii t2an0m0 t2b stage iiia t3an0m035% t3b t4a t1-4an1 stage iiib t1-4an2m0 n3 stage iva t4bany nm0 any tm1a stage ivb any tany nm1b5% grading according to who classification (1973) bladder cancers are histologically graded into: g1 – well differentiated, g2 – moderately differentiated g3 – poorly differentiated who classification (2004/2016) papillary lesions urothelial papilloma papillary urothelial neoplasm of low malignant potential (punlmp) low grade high grade flat lesions urothelial proliferation of uncertain malignant potential reactive atypia atypia of unknown significance urothelial dysplasia urothelial cis (always high grade) primary secondary concurrent risk stratification people with non-muscle invasive bladder cancer (nmibc), are risk-stratified based on clinical and pathological factors so that they are treated appropriately depending on their probability of having progression and/or recurrence. people with non-muscle invasive tumors are categorized into low-risk, intermediate-risk and high-risk or provided with a numerical risk score. risk-stratification framework is provided by american urology association/society of urological oncology (aua/suo stratification), european association of urology (eau) guidelines, european organization for research and treatment of cancer (eortc) risk tables and club urológico español de tratamiento oncológico (cueto) scoring model. aua risk stratification for non-muscle invasive bladder cancer low riskintermediate riskhigh risk low grade solitary ta tumor, smaller than 3 cmrecurrence within 1 year, low grade ta tumorhigh grade t1 papillary urothelial neoplasm of low malignant potentialsolitary low grade ta tumor, bigger than 3 cmany recurrent tumor or any high grade ta low grade ta, multifocal tumorshigh grade ta, bigger than 3 cm (or multifocal) high grade ta, smaller than 3 cmany carcinoma in situ low grade t1any bcg failure in high grade tumors any variant histology any lymphovascular invasion any high grade prostatic urethral involvement the eortc and cueto model use a cumulative score obtained from individual prognostic factors, which are then converted into risk of progression and recurrence. the six prognostic factors included in the eortc model are number of tumors, recurrence rate, t-stage, presence of carcinoma-in-situ and grade of the tumor. scoring for recurrence in the cueto model incorporates 6 variables; age, gender, grade, tumor status, number of tumors and presence of tis. for progression scoring the previous 6 variables plus t stage is used. eortc/cueto risk of recurrence depending on the cumulative score modelcumulative score for recurrencerecurrence at 1-year (%)recurrence at 5-year (%) eortc01531 1-42446 5-93862 10-176178 cueto0-48.221 5-61236 7-92548 10-164268 eortc/cueto risk of progression depending on the cumulative score modelcumulative score for progressionprogression at 1-year (%)progression at 5-year (%) eortc00.20.8 2-616 7-13517 12-231745 cueto0-41.23.7 5-6312 7-95.521 10-161434 prevention diet as of 2019, there is limited high level evidence to suggest that eating vegetable and fruits decreases the risk of bladder cancer. fruit and yellow-orange vegetables, particularly carrots and those containing selenium, citrus fruits and cruciferous vegetables have been identified as having a possibly protective effect. while it is suggested that the polyphenol compounds in tea may have an inhibitory effect on bladder tumor formation and growth, there is limited evidence to suggesting drinking tea decreases bladder cancer risk. a 2022 review found that a mediterranean diet has a protective effect on bladder cancer risk. higher consumption of monounsaturated fat and plant-based oils decrease bladder cancer risk in women. higher consumption of total dietary fiber and whole grains is associated with a reduced risk of bladder cancer. screening as of 2019 there is insufficient evidence to determine if screening for bladder cancer in people without symptoms is effective or not. treatment flow chart of treatment the treatment of bladder cancer depends on how deeply the tumor invades into the bladder wall. treatment strategies for bladder cancer include: non-muscle invasive: transurethral resection of bladder tumor (turbt) with or without intravesical chemotherapy or immunotherapy muscle invasive stage ii/stage iiia: radical cystectomy plus neoadjuvant chemotherapy (multimodal therapy, preferred) or transurethral resection with chemoradiation (trimodal therapy, highly selected people) or partial cystectomy plus neoadjuvant chemotherapy (in highly selected people) stage iiib/iva: cisplatin-based chemotherapy followed by radical cystectomy or chemoradiation or observation depending on treatment response stage ivb (locally advanced; unresectable tumors): palliative radiotherapy metastatic disease: cisplatin-based chemotherapy metastatic disease but unfit for cisplatin-based chemotherapy: carboplatin-based chemotherapy metastatic disease with contraindication for chemotherapy: checkpoint inhibitors if programmed death ligand 1 (pd l1) positive squamous cell carcinoma or adenocarcinoma of bladder: radical cystectomy transurethral resection non-muscle invasive bladder cancer (those not entering the muscle layer of the bladder) can be "shaved off" using an electrocautery device attached to a cystoscope, which in that case is called a resectoscope. the procedure is called transurethral resection of bladder tumor (turbt) and serves primarily for pathological staging. in case of non-muscle invasive bladder cancer the turbt is in itself the treatment, but in case of muscle invasive cancer, the procedure is insufficient for final treatment. additionally, blue light cystoscopy with optical-imaging agent hexaminolevulinate (hal) is recommended at initial turbt to increase lesion detection (especially carcinoma in situ) and improve resection quality thereby reducing recurrence. it is important to assess the quality of the resection: if there is evidence of incomplete resection, or if there is no muscle in the specimen (without which muscle invasiveness cannot be determined), then a second turbt is strongly recommended. moreover, nearly half of the people with high-grade noninvasive disease have residual tumor after primary turbt; in such cases a second turbt is important for avoiding under-staging. at this point classifying people into risk groups is recommended. treatment and surveillance for different risk groups is indicated in the table below. another method for reducing recurrence of tumors is medication after turbt surgery. the two most common medicines used for this purpose are bacillus calmette–guérin (bcg) and mitomycin. for people who have already had a turbt procedure, bcg may lead to similar risk of death and may reduce the risk of tumor recurrence. however, this medication may increase the risk of serious unwanted side effects. more research is needed to confirm these results. chemotherapy drug treatment (chemotherapy) into the bladder(intravesical) a single instillation of chemotherapy into the bladder after primary turbt has shown benefit in deceasing recurrence by 35% in non-muscle invasive disease. medications which can used for this purpose are mitomycin c (mmc), epirubicin, pirarubicin and gemcitabine. instillation of post-operative chemotherapy should be conducted within first few hours after turbt. as time progress residual tumor cells are known to adhere firmly and are covered by extracellular matrix which decrease the efficacy of the instillation. the most common side effect is chemical cystitis and skin irritation. if there is a suspicion of bladder perforation during turbt, chemotherapy should not be instilled into the bladder as serious adverse events are known to occur due to drug extravasation. studies have shown that