Stages, Grades and Types of  Bladder Cancer: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Christopher Lucchesi.

The bladder is a hollow organ located in the lower abdominal region. The bladder is contiguous with the ureters above, through which urine flows from the kidneys, and the urethra below, which dispels urine from the body. There are four parts to the bladder, the apex or dome, body, fundus, and neck. The apex is the anterosuperior part of the bladder that points towards the abdominal wall. The fundus, or base, is the posteroinferior part of the bladder. The fundus lies on the inferior aspect of the proximal wall while the apex lies on the anterior aspect of the wall, extending towards the pubic symphysis. The body of the bladder is the large area situated between the apex and the fundus. The neck of the bladder is the constricted part of the bladder that leads to the urethra. The upper part of the bladder consists of the apex and body which are above the ureteric orifices. The lower part consists of the fundus, neck, and trigone. The trigone is an inverted triangular-shaped area of space that is made entirely of smooth muscle. Its superolateral angles are formed by the ureteric orifices. The neck lies at the base of the trigone and it is the most inferior point of the bladder.

  • bladder cancer
  • urothelial carcinoma
  • squamous differentiation
  • glandular differentiation
  • squamous cell carcinoma

1. Introduction

In the United States, approximately 82,290 people will be diagnosed with bladder cancer (BlCa) in 2023 [1]. California, which has the largest agricultural workforce, will see the greatest increase in BlCa cases of all the states (8.8% of all BlCa in USA) [2]. Of these patients, almost three quarters will have non-muscle invasive BlCa (NMIBC). Statistically, more than half of NMIBC will recur within 1 year after the first treatment and one third of cases will progress to muscle invasive BlCa (MIBC) [3]. Low-grade NMIBC is commonly managed with transurethral resection (TUR) with 5-year overall survival of 90% [4]. The 5-year survival for non-metastatic MIBC is 70%, which is in stark contrast to metastatic-MIBC, which has a precipitous decrease in survival to 38% when regional and 6% when distant metastases are present. These data ultimately highlight the necessity to better understand BlCa progression [5].
In the developed world, BlCa is the 10th and 11th most common cancer in men and women, respectively [6]. Multiple risk factors have been associated with BlCa; for example, tobacco users are nearly three times as likely to get BlCa [1]. The leading risk factors for BlCa include cigarette smoking and occupational exposures [7]. Multiple aromatic amine compounds, such as 4-aminobiphenyl, benzidine, 2-naphthylamine, and ortho-toluidine have been associated with BlCa prevalence in the occupational setting [8]. Additionally, the American Cancer Society also lists certain medications (e.g., pioglitazone, a drug used in the management of type 2 diabetes mellitus) and herbal supplements (mainly herbs from the Aristolochia family), arsenic in drinking water, and lack of fluids as risk factors for BlCa [9]. Non-hispanic Caucasians are about twice as likely to develop BlCa as African Americans (AA) and Hispanic individuals; however, AAs develop more advanced disease and have a worse prognosis [10][11]. The risk of BlCa also increases with age and is much more common in men than in women [12]. BlCa has been associated with an inflammatory/immune response to irritants [13]. Urinary infections, kidney and bladder stones, and other irritants, such as catheters left in the bladder for prolonged periods, have been linked to the development of squamous cell carcinoma (SCC) of the bladder [14]. Schistosomiasis, a parasite, has also been known to cause bladder SCC, mostly in Africa and the Middle East [15]. Birth defects, such as exstrophy, greatly increase the risk of BlCa (likely due to mucosal metaplasia), as do chemo- and radiotherapy for other cancers, such as prostate cancer, where the treatment affects the bladder [16][17][18][19].

2. Stages of Bladder Cancer

Urothelial carcinomas (UC) can be divided into two categories: NMIBC and MIBC. Approximately 75% of UC are NMIBC [20]. According to WHO classification systems, NMIBC are further divided into three stages: Carcinoma in situ (CIS), Ta (non-invasive papillary), and T1 [21]. These can be further sub-graded as either low or high-grade. Both Ta and CIS are considered non-invasive (Figure 1). Stage CIS is characterized by a flat lesion tumor which remains in the tissue layer from which it originates without spreading into the hollow space of the bladder. Ta, a papillary tumor, grows into the hollow area of the bladder with finger-like projections but does not spread to the connective tissue or muscle tissue of the bladder wall [22]. Cancers in the Ta and CIS stages account for 70% and 20% of all NMIBC, respectively [23]. Tumors in stage T1 spread into the connective tissue layer (lamina propria) under the lining layer of the bladder, but do not spread into the muscle layer. In general, NMIBC is characterized by high recurrence of tumors and a high survival rate after therapeutic mechanisms are employed [24].
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Figure 1. Visual schematic of the bladder, stages of bladder cancer, and mode of metastasis.
MIBC, as the name indicates, indicates tumors that have invaded into the muscularis propria (DSM). This type of BlCa is divided into three distinct stages, T2, T3, and T4, with each stage becoming progressively worse and indicating a more serious prognosis. T2 is characterized by the spreading of the cancer into the inner layer (T2a) or outer layer (T2b) of the muscle of the bladder wall, but the cancer has yet to spread beyond the muscle layer into the fatty tissue layer that surrounds the bladder. Once it moves into the perivisceral tissue, the tumor can be characterized as T3a if it can be seen microscopically, or T3b if it can be visualized macroscopically during imaging and/or can be physically palpated by the physician. When the tumor has spread to the surrounding organs including the prostate and seminal vesicles in males, or the uterus and vagina in females, it is considered T4a. T4b is when the cancer has not only invaded the organs mentioned above but also the pelvic and abdominal wall [22]. Further, MIBCs can be grouped into basal and luminal subtypes—basal MIBCs are associated with shorter disease-specific and overall survival, while luminal MIBCs were enriched with FOXA1, GATA3, ERBB2 and ERBB3, and responded to neo-adjuvant chemotherapy [25].

3. Grades of Bladder Cancer

Grading of bladder cancer is differentiated by a pathologist based on histological diagnosis. Low-grade NMIBC is characterized by high recurrence rates, but rare propensity (10–15%) to progress into high-grade BlCa, invade, or metastasize [26]. High-grade NMIBC comprises the tumors that are characterized by a quick progression into invasive tumors, those of the MIBC category [27]. Ta often recurs after surgical resection, but rarely progress to high-grade T1 tumors or to MIBC (seen in <10% of cases). In contrast, CIS tumors progress in about 50% of cases to T1 and then to MIBC. About 80% of MIBC are thought to arise from CIS tumors. Studies have shown that the ability for low-grade BlCa to progress into high-grade BlCa is likely due to acquired TP53 mutations, whereas TP53 mutations are more frequent in high-grade BlCa, and FGFR3 mutations are more frequent in low-grade tumors [28]. Almost all mortality from BlCa results from high-grade disease. It may be noted that the low vs. high grade designation is typically used only for transitional cell carcinoma. For squamous cell carcinoma or adenocarcinoma, a gradation system of well, moderate, or poorly differentiated cancers is used.

4. Types of Bladder Cancer

BlCa is a heterogeneous disease with multiple subtypes and variants. The most common histology of BlCa is urothelial carcinoma (UC) (also known as transitional cell carcinoma, TCC) that originates in the urothelial cells of the bladder. UC accounts for up to 90% of all BlCa diagnoses [29]. Certain variants of UC elucidated by the World Health Organization (WHO) are rare and hard to diagnose. UC with squamous differentiation (UCSD) is the most common histological variant, found in T1 tumors 8–15% of the time and 20–60% of the time in MIBC. It presents with a significantly higher pathologic stage than pure UC and is defined as high-grade [30]. UCSD is defined by the presence of clear-cut intercellular bridges, intracellular keratinization, or both [31]. As other works have reported, squamous differentiation is significantly correlated with multiple severe prognostic factors including progression to grade 3, lymphovascular invasion, advanced tumor stage, and lymph node metastasis [32]. UC with glandular differentiation (UCGD) is the second most common histological variant and is found in around 10% of all UC cases. This kind of differentiation is more often visualized as urothelial carcinoma with gland-like lumina [31]. Glandular differentiation can exist either in the form of pure adenocarcinoma (rarer and largely associated with schistosomiasis as well as bladder exstrophy) or UCGD [33]. Secondary to UC is squamous cell carcinoma (SCC) of the bladder. SCC accounts for the remaining 10% of BlCa cases and is more common in Africa where it is associated with the protozoan infection schistosomiasis [12][15]. SCC is largely characterized by keratin deposits [34]. It is of important clinical significance to distinguish SCC from UCSD as the latter is treated similarly to pure UC while the former is resistant to chemotherapy requiring radical cystectomy (RC) without neoadjuvant chemotherapy (NAC) [33]. Chronic irritation of the bladder due to bladder stones, multiple urinary tract infections, or long-term indwelling catheters can lead to SCC and can initiate metaplasia from transitional cells to squamous cells [35][36]. SCC has a significantly worse prognosis than UC [37]. Other, rarer forms of BlCa include adenocarcinoma which is only found in 0.5–2% of all cases and small cell carcinoma which is found in less than 1% of all BlCa cases [38]. Small cell carcinoma is poorly differentiated, and highly metastatic with a poorer prognosis than pure UC [39].

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