Histology And Etiology Of Bladder Cancer

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From the renal pelvis through the urinary bladder into the urethra, the urinary tract is lined by a specialized 'transitional' epithelium called 'urothelium' (Figure 14.1), whose structure is in several respects different from that of squamous epithelia in the skin and other organs. The urothelium forms a low permeability barrier that prevents the components of the urine, even water, from seeping back into the body. In a transitional epithelium, cells from several layers retain contact with the basement membrane. This allows them to shift across each other depending on the filling state. The top cellular layer forms the actual barrier and consists of terminally differentiated 'umbrella' cells linked by tight junctions. The low permeability in the urothelium is achieved by a dense protein array in their apical membrane composed of uroplakins. These proteins are specific markers of urothelial differentiation. The

Figure 14.1 Histological comparison of a squamous and a transitional epithelium. Epidermis (left) and urothelium (right). Note also the sebacous glands in the left figure.

urothelium normally turns over very slowly, but can proliferate rapidly and extensively in response to injury or to bacterial infections to replace damaged areas.

Bladder cancer is a generic term for carcinomas developing from the urothelium. Indeed, most urothelial cancers grow in this part of the urinary tract, but as those in other segments have similar properties, the designation is often loosely used. Most carcinomas arising from urothelium retain morphological and biochemical markers of its original structure. In particular, they express urothelial differentiation markers such as uroplakins and specific cytokeratins (e.g. CK7). These cancers are accordingly categorized as transitional cell carcinomas (TCC).

Bladder cancer is the «fifth-most frequent cancer and more prevalent in males. Transitional cell carcinoma represents the predominant histological type in industrialized countries. In countries with endemic schistosomiasis, a second type of bladder cancer, designated squamous cell carcinoma, is more prevalent (Figure 14.2). Although originating as well from cells of the urothelium, this carcinoma consists of - sometimes well-organized - layers of cells that resemble a squamous epithelium. Accordingly, the cancer cells express markers of such epithelia, but not of urothelium, e.g. the cytokeratin CK14 or even involucrin. This is a clear instance of metaplasia, since no squamous epithelium exists in the normal urinary tract upwards of the distal part of the urethra.

Urothelium Histology
Figure 14.2 Histology of transitional cell carcinoma (left) and squamous cell carcinoma (right) arising from the urothelium

Transitional cell carcinoma can be induced by chemical carcinogens. This was first realized by the surgeon Ludwig Rehn who at the end of the 19th century treated workers making azo-dyes in a chemical plant in a suburb of Frankfurt in Germany. These people were literally drenched in aniline, benzidine, and the dyes made from them, and developed bladder cancers early in life and at a high rate. Today, in spite of much better precautions, occupational risks for bladder cancer remain in the chemical industry and in other branches where workers are exposed to aromatic amines or their metabolizable derivatives.

Other chemicals such as nitrosamines, nitro-aromates, polyaromates, and the cytostatic drug cyclophosphamide, as well as arsenic are also established or very likely bladder carcinogens. A cocktail of carcinogens is inhaled with tobacco smoke and the risk of bladder cancer is consequentially increased approximately 4-fold in smokers. The rate of bladder cancer is also enhanced in Eastern Europeans who have incorporated radioactive cesium from the Chernobyl accident.

The fact that carcinogenicity by aromatic amines shows such a strong organ preference has facilitated its understanding. To become carcinogenic, aromatic amines must be activated by hydroxylation at the amino group (Figure 14.3). This

Aromatic Drugs

Figure 14.3 Metabolic activation of f-naphtylamine to a carcinogen This is a simplified scheme that ignores a.o. that acetylated arylamines can still be N-hydroxylated, even though less efficiently. Perhaps more importantly, the role of NAT1 is not illustrated, because it is debated. It is suggested that in kidney and urothelial tissue this enzyme promotes carcinogenesis by acetylating glucuronidated N-OH-arylamines.

Figure 14.3 Metabolic activation of f-naphtylamine to a carcinogen This is a simplified scheme that ignores a.o. that acetylated arylamines can still be N-hydroxylated, even though less efficiently. Perhaps more importantly, the role of NAT1 is not illustrated, because it is debated. It is suggested that in kidney and urothelial tissue this enzyme promotes carcinogenesis by acetylating glucuronidated N-OH-arylamines.

reaction is performed by isoenzymes of the P450 monooxygenase family, whose genes are designated CYP. Protonation of this N-hydroxyl group leads to dissociation of a water molecule and formation of a highly reactive arenium ion. Hydroxylation at the amino group is prevented by its acetylation. This is catalyzed by N-acetyltransferases, mostly by NAT2 enzymes. Moreover, the efficiency of excretion of hydroxylated amines into the urine vs. the gut depends on the extent of glucuronylation and sulfatation performed by UDP-glucuronyl transferases and sulfotransferase, respectively.

As many of the enzymes involved in the metabolism of arylamines are polymorphic in humans (Table 14.1), the carcinogenicity of aromatic amines in individual humans depends not only on their level of exposure, but also on their genetic constitution. In chemical workers exposed to aromatic amines, NAT2 appears to constitute the dominant genetic factor. Depending on dozens of combinations of different alleles, humans display two different phenotypes, 'slow' and 'rapid' acetylators, which are also important in the response to a range of medical drugs. Rapid acetylators are much less susceptible to bladder carcinogenesis by aromatic amines, although they may excrete more metabolites into the gut, leading to a somewhat increased risk for colorectal cancer.

Among bladder cancer patients in general, the NAT2 genotype tends to be a less dominant factor because other carcinogens and endogenous processes contribute. However, the risk of smokers to develop bladder cancer is even greater in those who lack the GSTM1 glutathione transferase, which metabolizes chemical carcinogens related to benzopyrene. This lack is caused by homozygosity for the deletion null-allele of the GSTM1 gene (^2.3, cf. Table 14.1).

While transitional cell carcinoma is often induced by chemical carcinogens, squamous cell carcinoma typically arises after chronic inflammation of the bladder. This is most obvious in schistostoma-induced bladder cancer. Schistosoma parasites enter the human body from contaminated water and establish themselves in the lung, liver, and urinary bladder. In the bladder, schistosoma mansoni causes a chronic inflammation (bilharziosis) with permanent tissue damage and regeneration. This prepares the ground for the development of squamous carcinoma. This relationship makes bladder cancer one of the most frequent cancers in warmer countries with endemic bilharziosis caused by this species of trematode parasites.

In industrialized countries of the North, «90% of all bladder cancers display transitional cell carcinoma histology, while most of the rest are squamous cell carcinoma. Transitional cell carcinoma comprises two subtypes with different properties. The most frequent type is a papillary tumor which grows predominantly into the lumen and remains well recognizable as being derived from urothelium. Although they are malignant, only «20% of these tumors actually progress to an invasive stage and further to metastasis. Most, but not all of the tumors that will eventually become invasive are less than well-differentiated initially. Papillary tumors can usually be removed by local resection, but tend to recur at different localizations in the urothelium, sometimes having progressed to a less differentiated or more invasive state.

The reasons for this behavior are not entirely clear. Bladder cancer is often regarded as an example of 'field cancerization' because multiple tumors arise in different places at the same time or successively, i.e. synchronously or metachronously. This could mean that the entire tissue has been transformed towards a kind of preneoplastic stage, perhaps as a consequence of exposure to carcinogens, chronic irritation or inflammation, or as a consequence of factors released by the actual cancer cells.

Table 14.1. Polymorphic genes and enzymes in carcinogen metabolism



Enzyme activity


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