Bladder wall thickening due to cancer Bladder tumor in FDG PET due to the high physiological FDG-concentration in the bladder, furosemide was supplied together with 200 MBq FDG. The uptake cranial to the lesion is a physiological uptake in the colon. Currently, the best diagnosis of the state of the bladder is by way of cystoscopy, which is a procedure in which a flexible or rigid tube (called a cystoscope) bearing a camera and various instruments are inserted into the bladder through the urethra. The flexible procedure allows for a visual inspection of the bladder, for minor remedial work to be undertaken and for samples of suspicious lesions to be taken for a biopsy. A rigid cystoscope is used under general anesthesia in the operating room and can support remedial work and biopsies as well as more extensive tumor removal. Unlike papillary lesion, which grow into the bladder cavity and are readily visible, carcinoma in situ lesion are flat and obscure. Detection of carcinoma in situ lesions requires multiple biopsies from different areas of interior bladder wall. Photodynamic detection (blue light cystoscopy) can aid in the detection of carcinoma in situ. In photodynamic detection, a dye is instilled into the bladder with the help of a catheter. Cancer cells take up this dye and are visible under blue light, providing visual clues on areas to biopsied or resected. However, visual detection in any form listed above, is not sufficient for establishing pathological classification, cell type or the stage of the present tumor. A so-called cold cup biopsy during an ordinary cystoscopy (rigid or flexible) will not be sufficient for pathological staging either. Hence, a visual detection needs to be followed by transurethral surgery. The procedure is called transurethral resection of bladder tumor (TURBT). Further, a rectal and vaginal bimanual examination should be carried out before and after the TURBT to assess whether there is a palpable mass or if the tumour is fixed ("tethered") to the pelvic wall. The pathological classification and staging information obtained by the TURBT-procedure, is of fundamental importance for making the appropriate choice of ensuing treatment and/or follow-up routines. If invasive or high grade (includes carcinoma in situ) cancer is detected on TURBT, an MRI and/or CT scan of the abdomen and pelvis or urogram and CT chest or x-ray chest should be conducted for disease staging and to look for cancer spread (metastasis). Increase in alkaline phosphatase levels without evidence of liver disease should be evaluated for bone metastasis by a bone scan. Although 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT has been explored as a viable method for staging, there is no consensus to support its role in routine clinical evaluations. Urine cytology can be obtained in voided urine or at the time of the cystoscopy ("bladder washing"). Cytology is not very sensitive for low-grade or grade 1 tumors (a negative result cannot reliably exclude bladder cancer) but has a high specificity (a positive result reliably detects bladder cancer). There are newer non-invasive urine bound markers available as aids in the diagnosis of bladder cancer, including human complement factor H-related protein, high-molecular-weight carcinoembryonic antigen, and nuclear matrix protein 22 (NMP22). In United States the FDA has approved NMP22, NMP22 BladderChek, and UroVysion tests for detection and surveillance of bladder cancer and ImmunoCyt, BTA-TRAK, and BTA-STAT tests have been approved for surveillance only. BTA-STAT and BladderChek can be performed in the clinic and others are done in the laboratory. Other non-invasive urine based tests include the CertNDx Bladder Cancer Assay, which detects FGFR3 mutation and Urine Bladder Cancer test (UBC), which is a sandwich ELISA for Cytokeratin 8/18 fragment. Likewise, NMP22 is a sandwich ELISA and NMP22 BladderChek is a dipstick immunoassay, both of them detect nuclear 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 Type Relative incidence Subtypes Transitional cell carcinoma 95% Papillary (70%) Non-papillary (30%) Non-transitional cell carcinoma 5% 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. Variant Histology Percentage of non-papillary cases Implications Squamous differentiation Presence of intercellular bridges or keratinization 60% Outcomes similar to conventional transitional cell carcinoma Glandular differentiation Presence of true glandular spaces 10% Sarcomatoid foci Presence of both epithelial and mesenchymal differentiation 7% Clinically aggressive Micropapillary variant Resembles papillary serous carcinoma of the ovary or resembling micropapillary carcinoma of breast or lung 3.7% Clinically aggressive, early cystectomy recommended Urothelial carcinoma with small tubules and microcystic form Presence of cysts with a size range of microscopic to 1-2mm Rare Lymphoepithelioma-like carcinoma Resembles lymphoepithelioma of the nasopharynx Lymphoma-like and plasmacytoid variants Malignant cells resemble cells of malignant lymphoma or plasmacytoma Nested variant Histologically look similar to von Brunn's nests Can be misdiagnosed as benign von Brunn's nests or non-invasive low-grade papillary urothelial carcinoma Urothelial carcinoma with giant cells Presence of epithelial tumour giant cells and looks similar to giant cell carcinoma of the lung Trophoblastic differentiation Presence of syncytiotrophoblastic giant cells or choriocarcinomatous differentiation, may express HCG Clear cell variant Clear cell pattern with glycogen-rich cytoplasm Plasmacytoid Cells with abundant lipid content, mimic signet ring cell adenocarcinoma of stomach/ lobular breast cancer Clinically aggressive, propensity for peritoneal spread Unusual stromal reactions Presence of following; pseudosarcomatous stroma, stromal osseous or cartilaginous metaplasia, osteoclast-type giant cells, lymphoid infiltrate Staging 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 treatments and estimate outcomes. Staging usually follows the first transurethral resection of bladder tumor (TURBT). Papillary tumors confined to the mucosa or which invade the lamina propria are classified as Ta or T1. Flat lesion are classified as Tis. Both are grouped together as non-muscle invasive disease for therapeutic purposes. 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
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