1 OVERVIEW
Bladder cancer (BC) is one of the most common malignant tumors of the urinary system. Statistically, it is the ninth most common malignant tumor worldwide, the seventh most commonly diagnosed malignant tumor (9.5/100 000) in the male population, and the tenth in females (2.410/100 000). The mortality of BC ranked the thirteenth among other malignancies, 3.2/100 000 for men versus 0.9/100 000 for women.
BC varies by geography, race, and gender. All age groups can be affected, BC is most prevalent in the 50–70 years old age group, and the incidence in men is 3–4 times than that in women.
According to the data released by the National Cancer Registration Center of China in 2019, the BC incidence in China was 5.80/100 000 in 2015, ranked the thirteenth among systemic malignancies. The BC incidence (per 100 000 person-years) was 8.83 for men (ranking the seventh) versus 2.61 for women (ranking the seventeenth). In 2015, the mortality of BC in China was 2.37/100 000, ranking the thirteenth among all malignancies. The BC mortality (per 100 000 person-years) was 3.56 for men (ranking the eleventh) vs. 1.11 for women (ranking the sixteenth).
The morbidity and mortality of BC are higher in urban areas than those in rural areas across all age groups. In 2015, the incidence of BC in urban areas was 6.77/100 000 (10.36/100 000 for men; 3.04/100 000 for women) and 4.55/100 000 for rural areas (6.89/100 000 for men; 2.06/100 000 for women). In 2015, the mortality of BC in urban areas was 2.69/100 000 (4.01/100 000 for men; 1.31/100 000 for women), and that in rural areas was 1.95/100 000 (3.00/100 000 for men; 0.85/100 000 for women). For same-staged BC patients, the prognosis is better in males.
BC poses a serious threat to public health, and standardized diagnosis and treatment are of great significance in improving BC's clinical outcomes in China.
2 SCREENING AND DIAGNOSIS
2.1 Etiology
The pathogenesis of BC is a complex, multifactorial, and multistep pathological process, which has not yet been elucidated. Both genetic and environmental factors play important roles.
2.1.1 Environmental risk factors
Tobacco smoking and long-term exposure to industrial chemicals are currently the most significant risk factors for BC. Smoking accounts for approximately 50% of cases, increasing the risk for BC by 2–3 folds. The risk of BC increases with smoking intensity and duration. Aromatic amines, such as 4-aminobiphenyl, contained in cigarettes are considered carcinogenic. The effect of smoking on a diagnosed case relapse and progression of BC is unclear.
Long-term occupational exposure to aromatic amines, polycyclic aromatic or chlorinated hydrocarbons, β-naphthylamine, and 4-aminobiphenyl is another significant risk factor, accounting for about 20% of all BC cases. This type of occupational exposure mainly occurs in plants that prepare, process, manufacture, or produce textiles, dye, rubber, pharmaceuticals, pesticides, paints, leather, aluminum, or steel.
Other carcinogens of squamous cell carcinoma and adenocarcinoma in the bladder include chronic cystitis (recurrent infection with bacteria, parasitic trematode, or human papillomavirus, etc.) and long-term foreign body contact (by indwelling catheter, stones).
A history of cyclophosphamide chemotherapy, phenacetin abuse, pelvic radiotherapy, and the use of the antidiabetic drug pioglitazone can all increase the risk for BC. High dietary intake of fat or cholesterol, long-term consumption of water with a high arsenic content or chlorinated drinking water, coffee, or artificial sweeteners may dispose one to increased risk for BC. The use of hair dye is also associated with BC.
2.1.2 Genetic predisposition
The carcinogenesis and progression of BC are related to hereditary and genetic abnormalities. Those with a family history of BC are at doubled risk, the specific mechanism of which awaits further investigation.
Malignant changes in urothelium start first at the DNA level, driven by chemical carcinogens. Tobacco smoke and various other chemical products contain aromatic amines, such as 2-naphthylamine and 4-aminobiphenyl, which are renally excreted, driving the malignant transformation of urothelial cells.
Oncogenes related to BC include HER-2, HRAS, BCL-2, FGFR3, C-myc, MDM2, MSH2, and so on. Another molecular mechanism is the inactivation of genes encoding proteins that regulate cell growth, DNA repair, or apoptosis, so that cells with damaged DNA do not undergo apoptosis, resulting in uncontrolled cell growth. For example, deletion or loss of heterozygosity of tumor suppressor genes such as P53, RB, and P21 on chromosomes 17, 13, and 9 is related to the oncogenesis of BC.
Urothelial neoplasms are temporally and spatially multicentric. A history of upper urinary tract urothelial carcinoma increases the risk for BC by 15%–50%.
2.2 Clinical presentation
Clinical diagnosis is made based on the patient's medical history, signs and symptoms, combined with laboratory tests, imaging, urinary cytology and tumor markers, and cystoscopy. Cystoscopy is the most important examination method, and the gold standard for the diagnosis of BC depends on the histological evaluation of biopsied tissue. Imaging of the upper urinary tract excludes the possibility of renal pelvic and/or ureteral tumors.
2.2.1 Symptoms caused by the primary tumor
Hematuria is the most common finding in BC. About 80%–90% of BC patients have an onset symptom of painless intermittent gross hematuria. The color of urine can range from a tinge of red to dark brown, and blood clots can form occasionally. Some patients only experience hematuria at the beginning of micturition, which indicates bladder neck lesions, or terminal hematuria indicating lesions in the trigone, neck of the bladder, or posterior urethra. A small number of patients only have microscopic hematuria.
The severity, duration, and degree of hematuria are not consistent with the stage, size, number, and shape of the lesion. BC is accidentally discovered in some patients during routine physical examination or examination for other diseases.
About 10% of BC patients manifest with symptoms of bladder irritation, that is dysuria, frequency, and urgency to urinate. Carcinoma in situ (CIS), muscle-invasive urothelial carcinoma, squamous cell carcinoma, or adenocarcinoma might be suspected in patients with the aforementioned irritative voiding symptoms.
2.2.2 Symptoms caused by localized invasion
Other symptoms include lower back pain caused by ureteral obstruction, lower extremity edema, bone pain, urinary retention, and weight loss, all of which are late-stage symptoms.
2.3 Physical examination
Patients with BC generally have no indicative signs, and the diagnostic value of a focused urological examination for early-stage BC (e.g., Ta, T1) is limited. A palpable pelvic mass suggests a locally advanced tumor.
2.4 Diagnostic tests
2.4.1 Laboratory tests
(1) General laboratory test: Before treatment, patients need to undergo routine blood work. ① Complete blood count; ② liver and kidney function tests, plus other tests when necessary; ③ prothrombin time and activated prothrombin time.
(2) Urine cytology and urinary molecular marker tests: Urine examination includes an examination of voided urine or bladder washing specimens for exfoliated cancer cells and urinary tumor marker detection.
① Urinary cytology: Urinary cytology is one of the important methods for the diagnosis and follow-up of BC. The detection of cancer cells in the urine is one of the qualitative diagnoses of pelvic ureteral carcinoma and BC. Fresh urine or urine with adequate fixation is the preferred specimen for cytology or bladder washing specimen to improve the diagnostic rate. It is recommended to collect urine for 3 consecutive days, and then centrifuge the specimen for fixation. The sensitivity of urinary cytology is 13%–75%, and the specificity is 85%–100%. Cytology has high sensitivity in high-grade tumors, including CIS (84%), but low sensitivity in G1 and low-grade tumors (16%).
The result of cytology is affected by factors such as not enough exfoliated cells, urinary tract infection, stones, or bladder infusion therapy. Its specificity exceeds 90%. Exfoliated cells in the urine suspected of malignancy need to be checked multiple times to avoid false-positive results. Besides, cystoscopy and imaging must be done in adjunct to reduce the chance of missed diagnosis.
Flow cytometry is also used to examine voided urine or bladder-washing specimens. The principle is to stain the chromatin of exfoliated cells with DNA-specific fluorescent agents and analyze the DNA ploidy, reflecting the state of cell division, by installed software. The tumor cells often found vigorously proliferating tend to be polyploid. Generally, diploid represents low-grade malignancy, and triploid to tetraploid represents high-grade malignancy. The sensitivity and specificity of flow cytometry in the diagnosis of BC are related to the stage and degree of tumor differentiation. However, flow cytometry is not a substitute for routine urinary cytology.
② Urinary tumor marker tests: There are a variety of relatively mature urinary molecular marker tests, including nuclear matrix protein 22, bladder tumor antigen tests (BTAstat and BTAtrak), immunoassay urinalysis, fibrinogen degradation products, and UroVysion (fluorescence in situ hybridization [FISH]), and so forth.
Other tests include: telomerase reverse transcriptase, survivin, microsatellite analysis, measurements of soluble fragments of cytokeratin, and so on. These tests are highly sensitive, but their specificity is lower than that of urinary cytology.
UroVysion (FISH) has both high sensitivity and high specificity, even though its specificity is lower than that of urinary cytology. Further, bladder inflammation, stones, and radiotherapy can lower its specificity. FISH technique has a high positive predictive value for urothelial carcinoma in the Chinese population.
Because of the low specificity of urinary tumor marker tests, none of these markers have been accepted as a routine practice by any clinical guidelines, making it obvious that no urinary tumor marker can replace cystoscopy and urinary cytology in the diagnosis or follow-up of BC.
2.4.2 Imaging
Ultrasonography, computed tomography (CT), CT urography (CTU), magnetic resonance imaging (MRI) and MR urography (MRU), intravenous urography (IVU), chest X-ray or CT of the chest, and so on are all imaging modalities employed to visualize the size and scope of bladder lesions, determine whether retroperitoneal and pelvic lymph nodes are enlarged, and detect the presence of distant metastasis. Imaging is helpful in determining the clinical stage of BC.
(1) Ultrasound: Ultrasound is the most used imaging modality to diagnose BC. Kidneys, ureters, prostate, and pelvic or retroperitoneal lymph nodes can all be visualized during ultrasonography.
Ultrasound can be performed transabdominal, transrectal, or transurethral.
Transabdominal ultrasonography has a sensitivity of 63%–98% and a specificity of 99% for the diagnosis of BC. Kidneys, ureters, and other abdominal organs can be examined at the same time.
Transrectal ultrasonography can clearly visualize the trigone, bladder neck, and prostate. The transducer can be placed in close proximity to the tumor base to better evaluate the depth of tumor infiltration, which gives a clearer image than transabdominal ultrasonography. It is suitable for patients with poor bladder filling.
Transurethral ultrasonography needs to be performed under local anesthesia of the urethra. Although the image is clear with relatively high accuracy of tumor staging, this procedure is rather invasive and has not been widely used.
Color Doppler ultrasonography can display the direction and speed of blood flow in vessels feeding the neoplasm at its base, but with limited value in tumor staging.
Contrast-enhanced ultrasonography can improve the detection of BC and evaluate the depth of invasion. Ultrasound cannot accurately diagnose CIS of the bladder.
Ultrasonographic findings: Abnormal localized protrusions in the bladder wall that do not move with shift of position; irregular surfaces; interrupted or loss of the hierarchical structure within the bladder wall; hyperechoic or mixed masses that are papillary or cauliflower-shaped, either pedunculated or sessile; tumors may be solitary or multiple. Color Doppler examination can visualize the blood flow in and out of the tumor.
(2) CT: CT (plain + enhanced scan) is valuable in BC diagnosis and evaluating the extent of tumor infiltration. CT can detect small tumors (1–5 mm). If cystoscopy shows a broad-based sessile lesion that is likely to be high-grade malignancy with myometrial invasion, a following CT is recommended to determine the extent of tumor infiltration, and whether there is a local invasion or distant metastasis.
It is difficult for CT to visualize bladder CIS and ureter, or to accurately distinguish nonmuscle-invasive BC (NMIBC) (Ta, T1) from T2–T3a BC, nor is it easy to determine the nature of enlarged lymph nodes.
The accuracy of CT examination in patients with MIBC was 54.9%, among which about 39% were staged lower than the actual pathological staging, and 6.1% were overstaged. A history of abdominal surgery or local inflammatory response can lead to higher staging.
CTU: CTU is recommended for patients with multiple bladder tumors, high-risk tumors, and tumors in the trigone. CTU can provide information on the status of the upper urinary tract, surrounding lymph nodes, and adjacent organs, and has basically replaced traditional IVU.
CT images typically show local thickening of the bladder wall or a mass protruding into the bladder. Lumps vary in shape, often papillary, cauliflower-shaped, or irregular. The outer edge is often smooth, and when the tumor invades the bladder wall, its outer edge can be rough. Sand-like calcifications are common at the core of large masses, and the contour of the bladder may be deformed in large and superficial tumors. The mass has a value of 30–40 HU in a plain CT scan, with heterogeneous enhancement. When the tumor evades outside the bladder wall, the outline of the bladder becomes blurry, and the surrounding fat disappears. Adjacent tissues and organs may be involved, and there might be enlarged lymph nodes in the pelvic cavity or retroperitoneum.
(3) Multiparametric MRI: MRI has good soft tissue resolution and can diagnose and stage tumors. MRI shows whether the tumor invades the peribladder fat, or metastasizes to the pelvic lymph nodes, adjacent organs, or the bone, and so on.
T1-weighted images of bladder tumors have low to moderate signal intensity, similar to that of the bladder wall, which is higher than the low signal intensity of urine and lower than the high signal intensity of peribladder fat. Urine has a high signal intensity in T2-weighted images. Detrusor muscle normally has low signal intensity, and most bladder tumors have medium signal intensity. Low signal intensity creeping into the detrusor muscle suggests muscular invasion. Diffusion-weighted imaging (DWI) can better assess whether the tumor has invaded the surrounding tissue.
Dynamic contrast-enhanced MRI is more accurate than CT or plain MRI in visualizing muscle invasion. It is more accurate than CT in diagnosing BC of T3a or less. Multiparametric MRI examination is of great value in evaluating whether there is muscular invasion, with a sensitivity of 90%–94% and a specificity of 87%–95%. High field strength (3.0 T) and DWI can improve its sensitivity and specificity. The sensitivity of MRI to bone metastases is higher than that of CT, even better than that of radionuclide bone scan.
MRU examination: MRU shows the entire urinary tract, not only identifying the site of upper urinary tract obstruction but also visualizing intraluminal masses causing hydronephrosis if there are any. MRU is especially suitable for patients with contrast-associated allergy or renal insufficiency, patients whose kidneys cannot be visualized by IVU, and patients with hydronephrosis.
(4) IVU: IVU can detect tumors in the upper urinary tract. Due to IVU's low sensitivity to upper urinary tract tumors, the risk of missed diagnosis is high, especially when the tumors are small or hydronephrosis has not yet set in. With clearer imaging, CTU and MRU have now replaced IVU examinations.
(5) X-ray or chest CT: Preoperative and postoperative anteroposterior and lateral chest X-ray is done routinely on patients to screen for metastasis.
Chest CT is more sensitive in detecting lung metastases. Preoperative chest CT is recommended for patients with pulmonary nodules or MIBC patients who are planning to undergo total cystectomy to exclude lung metastases.
Lung metastases appear as single or numerous diffusely distributed round nodules on X-ray or chest CT.
(6) Radionuclide bone imaging: Radionuclide bone imaging is mostly used to detect bone metastases. It is highly sensitive to bone metastases, thus assisting in tumor staging. Bone metastases can be detected 3–6 months earlier by radionuclide bone imaging than X-ray.
Radionuclide bone imaging is not a routine examination for patients with BC. It is recommended when the patient experiences bone pain or has an elevated serum alkaline phosphatase level that suggests bone metastasis.
Metastatic BC induces osteolytic changes to the bone, most of which manifest as abnormally increased concentrations of radioactive material. Seldomly, a sparseness of radioactive material is on site of the metastasis. The spine is the most common site of bone metastasis, followed by the pelvis, ribs, skull, femur, and proximal humerus. Radionuclide bone imaging is not specific for bone metastases, especially for a sole lesion, the nature of which needed to be confirmed by CT or MRI.
(7) Positron emission tomography-CT (PET-CT): The tracer fluorodeoxyglucose is excreted by the kidneys into the bladder, which hampers the visualization of the regional lymph nodes and small tumors in the bladder. PET-CT is rather costly and is generally not used as a routine examination.
Commonly used tracers include choline, methionine, acetic acid, and so on. Carbon-11 (11C)-choline and 11C-acetic acid are not excreted by the kidney, and PET-CT with these tracers can concurrently visualize the site of BC and its metastatic lymph nodes. The accuracy of PET-CT in diagnosing lymph node metastasis is better than that of CT and MRI, and it is used for preoperative staging in MIBC patients, evaluation of terminal-stage patients, and assessment of treatment efficacy. PET-CT cannot yet completely replace MRI and radionuclide bone imaging in the diagnosis of bone metastases.
2.4.3 Cystoscopy and other examinations
(1) Cystoscopy: Cystoscopy is the most reliable method for BC diagnosis and one of the main methods to monitor for recurrence.
Cystoscopy uses either a rigid or a flexible instrument, and routine painless cystoscopy is recommended. A flexible instrument with topical intraurethral anesthetic lubricant instillation is recommended if possible. Compared with a rigid instrument, a flexible one produces less damage and better compliance in male patients, with no blind spots.
Cystoscopy can directly visualize the number, size, shape (papillary or broad-based), location, and growth pattern of bladder tumors, and if there are any abnormalities in the surrounding mucosa. Histological evaluation is done on sampled tissue.
When the urinary cytology is positive for tumor cells or the bladder mucosa appears abnormal, a selective biopsy is recommended to confirm the diagnosis. Random biopsy should be considered on the appear-to-be normal bladder mucosa with a positive urinary cytology, or when CIS is suspected.
The risk of concomitant urethral prostate cancer increases when tumors are in the trigone or bladder neck. It is recommended to perform a biopsy on the prostate urethra to confirm the diagnosis. When the urinary cytology is positive or mucosa of the prostate urethra appears abnormal, this site should be biopsied.
Routine random or selective biopsy of normal bladder mucosa is not recommended for NMIBC (< 2% chance of finding CIS).
Cystoscopy may cause complications such as urinary tract infection, bleeding, urethral injury and stricture.
① Fluorescence cystoscopy: Fluorescence cystoscopy is performed by intravesical instillation of a photosensitizing agent, such as 5-aminolevulinic acid, hexyl aminolevulinate, pyroxetine, and so on. The photosensitive dye is preferentially absorbed by hypermetabolic tissue such as malignant or dysplastic urothelium. Activation of the photosensitizer by exposure to light of the appropriate wavelength causes the hypermetabolic tissue to appear intensely red, which is in stark contrast with the blue of the normal bladder mucosa. Fluorescence cystoscopy results in better detection (by 14%–25%) and visualization of both papillary bladder tumors and CIS lesions compared to standard white light cystoscopy.
Fluorescence cystoscopy is recommended when bladder CIS is suspected, or when urine cytology is positive, but the mucosa appears normal under standard white light ordinary cystoscopy.
Meta-analysis of 12 randomized controlled studies, a total of 2258 cases of NMIBC cystoscopic resection under fluorescent light illumination showed that, compared with conventional white light cystoscopy, this method improved the rate of tumor detection, significantly reduced the postoperative recurrence, and prolonged the recurrence-free interval, with a clear recurrence-free survival benefit, but it failed to translate into reduced risk of progression to MIBC.
Fluorescence cystoscopy's specificity for diagnosing BC is 63%, which is lower than that of conventional white light cystoscopy (81%). Relatively low specificity might be attributed to inflammation, recent cystoscopic resection or intravesical chemotherapy.
② Narrow band imaging NBI cystoscopy: NBI is an optic enhancement technique that filters the white light into two different bandwidths, including blue (415 nm) and green (540 nm) spectrum. As the light is strongly absorbed by hemoglobin and only penetrates the tissue superficially, NBI is better at identifying small capillaries and superficial structures on mucosal surfaces than the conventional white light cystoscopy. Since BC has abundant vasculature, NBI cystoscopy is superior in the early detection of small lesions, improves the detection rate of CIS, and reduces postoperative recurrence.
The sensitivity, specificity, and accuracy of NBI cystoscopy in diagnosing CIS are superior to those of white light cystoscopy. Tumors that could only be detected by NBI cystoscopy but not by conventional cystoscopy accounted for 17.1% of all BC. Bladder tumors were found by NBI cystoscopy in 42% of patients with positive urine cytology, but no significant findings by white light cystoscopy.
Compared with cystoscopic resection under white light illumination, NBI-guided resection of bladder tumors can reduce postoperative recurrence in NMIBC patients.
(2) Diagnostic transurethral resection of bladder tumors (TURBt): If imaging confirms tumor-like lesions in the bladder, diagnostic TURBt can be performed directly. The purpose is to remove the tumor and send the specimen for histological evaluation to confirm the diagnosis, and to assess its grade and stage. To ensure the adequacy of the resection, the bladder wall muscle should be visualized at the resection base.
(3) Ureteroscopy: For patients suspected of upper urinary tract lesions, ureteroscopy can help confirm the diagnosis, when CTU or MRU are inconclusive.
2.4.4 Recommendations for the clinical diagnostic approach of bladder cancer (Table 1)
2.5 Differential diagnosis
Hematuria is one of the common clinical symptoms of urinary system diseases. Hematuria caused by BC needs to be differentiated from hematuria from stones, infection, tuberculosis, congenital malformation, blunt trauma, prostatic hyperplasia, and glomerular diseases. Differential diagnosis must be made from other tumors such as urachal cancer, prostate cancer, or pelvic, cervical cancer, colorectal cancer invading the bladder, and benign bladder lesions such as cystitis glandularis.
2.5.1 Urachal cancer
Tumors on top of the bladder need to be differentiated from urachal carcinoma. Urachal carcinoma arises in the remnants of the urachus, the bulk of which is located mostly outside or in the bladder wall. If the tumor penetrates the bladder wall, some affected individuals will have mucinuria as urachal cancer produces mucus.
Cystoscopy and imaging in the pelvic region can aid in differential diagnosis. Urachal tumors most commonly present as a midline, broad-based cystic mass near the dome of the bladder, and the bladder mucosa can be intact or ruptured. Imaging studies suggest that the bulk of the tumor is located outside the bladder wall.
2.5.2 Bladder-invading prostate cancer or benign prostatic hyperplasia
Most patients have symptoms of dysuria. Prostate cancer may be mistaken for tumors in the trigone during ultrasonography, MRI, or CT scans. Serum prostate-specific antigen, digital rectal examination, and MRI are helpful for differential diagnosis, and cystoscopy can pinpoint the origin of the tumor.
2.5.3 Tumors of other pelvic organs that invade the bladder
Cervical cancer and colorectal carcinoma are more common in the bladder. Patients have symptoms or signs suggestive of the primary diseases. Past medical history, imaging, or colonoscopy can help make the differential diagnosis.
2.5.4 Cystitis glandularis
The presenting symptoms include dysuria, frequency, urgency, or painless hematuria. Imaging shows a large mass near the neck of the bladder. The lesions are most often found in the trigone area and bladder neck, and the ureteral orifice cannot be seen clearly during cystoscopy. Lesions usually present as small multicentric microscopic foci; however, occasionally they can form raised intramucosal or polypoid lesions. It is avascular and nearly transparent; a biopsy is required to confirm the diagnosis.
2.5.5 Inverted papilloma of the bladder (IPB)
Most of them are solitary tumors in the trigone area. On cystoscopy, IPB presents primarily as a pedunculated, such as papillary, polypoid, seaweed-like, or sessile mass with a smooth surface.
3 HISTOPATHOLOGY AND STAGING
3.1 Histology
Currently, the 2004 World Health Organization (WHO) classification of urinary tract tumors is adapted. BC includes urothelial (transitional cell) carcinoma, squamous cell carcinoma, adenocarcinoma, urachal carcinoma, tumors of Müllerian type, neuroendocrine tumors (e.g., small cell neuroendocrine carcinoma), mesenchymal tumors, mixed carcinomas, sarcomatoid carcinoma, and metastatic carcinoma. Among them, urothelial carcinoma is the most common, accounting for more than 90% of BC. Squamous cell carcinoma amounts to about 3%–7%, and adenocarcinoma accounts for less than 2%. This guideline mainly discusses the diagnosis and treatment of urothelial carcinoma of the bladder.
In 2016, WHO updated a histological classification system for urothelial carcinomas including two main categories, invasive urothelial lesions and noninvasive urothelial lesions. Invasive urothelial lesions are divided into different subtypes, which are closely related to their prognoses. In addition to making the main pathological diagnosis, pathologists also need to determine whether there are mixed subtypes (Table 2).
3.1.1 CIS
CIS of the bladder is a flat, high-grade, noninvasive urothelial carcinoma that is often multifocal. It can be missed or misinterpreted as an inflammatory lesion during cystoscopy, and a biopsy is required to confirm the diagnosis.
3.1.2 Other pathological manifestations of BC
The presence of lymphovascular invasion in cancer tissue specimens is associated with an increased risk of pathological upstaging and a worse prognosis. Micropapillary, sarcomatoid, and plasmacytoid subtypes had poorer prognoses.
3.2 Histological grading
The malignancy of BC is expressed by grade (G), which predicts the risk of recurrence and progression. The WHO classification system is currently used. The 2004 histological classification system for urothelial carcinomas was also taken into the updated 2016 WHO classification.
The 1973 WHO classification distinguished between grade 1 (G1/GI), grade 2 (G2/GII), and grade 3 (G3/GIII) categories of well-differentiated, moderately differentiated, and poorly differentiated tumor cells.
The 2004/2016 WHO classification system includes papillary urothelial neoplasms of low malignant potential, noninvasive papillary carcinoma low grade, and high grade. The WHO 2004 is recommended (see Table 3).
There is a significant shift of patients between the categories of the WHO 1973 and the WHO 2004/2016 systems. There is no evidence that the 2004/2016 classification outperforms the 1973 classification in the prediction of recurrence and progression. The 2004 WHO classification is currently adapted.
3.3 Pathology report
It is very important to standardize the procedures during specimen collection, handling, and evaluation.
3.3.1 Pathology report of a specimen from TURBt
The pathological report should specify the location (whether there is muscular invasion), grade and stage of the tumor, lymphovascular invasion, histological variants, and presence of CIS and detrusor muscle.
3.3.2 Pathology report of the specimen from total cystectomy
Morphological subtypes and stages of the tumor should be included in the report. It is compulsory to check the urethra, ureters, and prostate in men, and the uterus and vaginal vault in women for a clear margin, all lymph node specimens should be provided in their totality, clearly labeled by their regions.
3.3.3 Immunohistochemistry
Immunohistochemical analysis is helpful to determine the expression of specific urothelial carcinoma-associated molecules, to distinguish reactive hyperplasia from CIS, and to diagnose spindle cell tumors or metastatic lesions. 2013 ISUP recommendation: Cells of the urothelial origin stain positively for GATA3, CK7, CK20, P63, HMWCK, and CK5/6; CD44, CK20, P53, and so on. Stains can differentiate reactive hyperplasia from CIS; ALK1, SMA, desmin, P63, HMWCK, and CK5/6 are helpful for the diagnosis of spindle cell tumor and metastatic cancer.
Immunohistochemistry is valuable for the diagnosis, staging, and prognosis of BC, but further research is needed.
3.4 Staging
Staging is mainly based on the extent of the primary tumor, regional lymph invasion, and distant metastasis. For staging, the Union for International Cancer Control Tumor, Node, Metastasis (TNM) Classification (2017, 8th edition) is recommended. The pathological staging is shown in Table 4, and the clinical staging is shown in Table 5.
NMIBC and MIBC are classified according to whether the tumor invades the muscle. NMIBC accounts for about 75% of BC, including Tis (CIS, 5%–10%), Ta (70%–75%), and T1 (20%–25%). Intra-epithelial CIS (Tis) confined to the mucosa is poorly differentiated and is considered high-grade due to its high risk of muscular invasion. MIBC refers to stage T2 and above.
3.5 Molecular markers
Studies have shown that the mechanisms of tumorigenesis and the development of NMIBC and MIBC are different on the molecular level. Various molecular subtypes of BC based on transcriptomic profiles become useful in clinical practice. In 2019, a consensus on molecular subtype classification was reported, which identified six MIBC molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%).
The molecular classification of MIBC can be used in clinical trials in search of novel treatments. Currently, the most clinically relevant biomarkers include: CDKN2A (34%); FGFR3 (21%); PIK3CA (20%); ERBB2 (17%); PD1/PD-L1, and so on. The aforementioned genetic abnormalities may affect the outcomes of specific treatments. For example, alterations in FGFR3 including both mutations and gene fusions have been shown to be associated with response to the FGFR inhibitor erdafitinib. The efficacy of immune checkpoint inhibitors, atezolizumab or pembrolizumab, is related to the level of PD-L1 expression.
The histopathology, clinical and pathological stages, and grades are of great prognostic value. Studies have found that several biomarkers can predict the prognosis of patients: serum vascular endothelial growth factor and circulating tumor cells, as well as defects in DNA damage repair genes including ERCC2, ATM, RB1, and FANCC, may predict response to cisplatin-based neoadjuvant chemotherapy. More recently, alterations in FGFR3 including both mutations and gene fusions have been associated with response to fibroblast growth factor receptor (FGFR) inhibitors.
Molecular subtypes, immune gene cell signatures, and stromal signaling may play important roles in predicting response to immunotherapy. Although PD-L1 immunohistochemistry and tumor mutational burden have been associated with response to immune checkpoint blockade in some cases, further studies are needed. Prospective studies of predictive molecular biomarkers provide valuable clinical and pathological data, but it still awaits to be verified by a phase III randomized controlled trial.
The molecular markers are now mainly used to predict prognosis and response to various therapeutic regimens, especially the response to neoadjuvant chemotherapy and immune checkpoint inhibitors. Although promising, there are currently no validated predictive molecular markers routinely used in clinical practice. Further validation studies are awaited.
3.6 Recommendations for histopathological assessment of tumor specimens
The recommendations are shown in Table 6.
This English version was translated from the Chinese version—“Guidelines for Diagnosis and Treatment of Tumor and Blood Related Diseases (version 2022)” released by the General Office of the National Health Commission of the People's Republic of China. The copyright of the English version has been obtained. If there is any conflict in the information, the Chinese version shall prevail. See the Chinese version at the website of the National Health Commission of the People's Republic of China.
2023 The Authors. UroPrecision published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.
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