Transitional cell carcinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [2]

Overview

Genes involved in the pathogenesis of transitional cell carcinoma of bladder include HRAS, Rb1, PTEN/MMAC1, NAT2, and GSTM1. On gross pathology, flat lesions or papillary lesions are characteristic findings of non-invasive transitional cell carcinomas; a large infiltrative mass or a multifocal, flat to papillary lesion with delicate fronds are characteristic findings of invasive transitional cell carcinomas. On microscopic histopathological analysis, loss of cell polarity, nuclear crowding, and cytologic atypia are characteristic findings of flat lesion; fibrovascular stalks, umbrella cells, and eosinophilic cytoplasm are characteristic findings of papillary lesion; invasion beyond the basement membrane is the characteristic finding of invasive transitional cell carcinomas.

Pathogenesis

• The surface epithelium (urothelium) that lines the mucosal surfaces of the entire urinary tract is exposed to potential carcinogens that are either excreted in the urine or activated from precursors in the urine by hydrolyzing enzymes.
• This "field cancerization" effect is one hypothesis to explain the multifocal occurrence that is a characteristic feature of urothelial carcinomas of both the urinary bladder and the upper urinary tract.
• In the majority of cases, multifocal urothelial carcinomas are monoclonal which supports their presumed origin from a single genetically altered cell,referred to as the monoclonality hypothesis.
• Under normal conditions, the bladder, the lower part of the kidneys, the ureters, and the proximal urethra are lined with a specialized mucous membrane referred to as transitional epithelium (also called urothelium).
• Most cancers that form in the bladder, the lower part of the kidneys, the ureters, and the proximal urethra are transitional cell carcinomas (also called urothelial carcinomas) that derive from transitional epithelium.

Genetics

• Genetic mutations involved in the pathogenesis of bladder cancer include:

• HRAS mutation
• Rb1 mutation
• PTEN/MMAC1 mutation
• NAT2 slow acetylator phenotype
• GSTM1 null phenotype

Pathology

Gross Pathology

The following table illustrates the findings on gross pathology for the subtypes of transitional cell carcinoma:

Type	Description
Non-invasive urothelial carcinoma	Flat lesions or papillary lesions
Invasive urothelial carcinoma	Large infiltrative mass or a multifocal, flat to papillary lesion with delicate fronds

Microscopic Pathology

Non-invasive urothelial carcinoma

• Flat lesions

• On microscopic histopathological analysis, loss of cell polarity, nuclear crowding, and cytologic atypia are characteristic findings.

• Papillary lesions

• On microscopic histopathological analysis, fibrovascular stalks, umbrella cells, and eosinophilic cytoplasm are characteristic findings.

Invasive urothelial carcinoma

• Invasive urothelial carcinomas grow from the lining of the renal pelvis or ureter into the deeper layers of the renal pelvis or ureter wall, such as lamina propria and muscularis.
• Transitional cell carcinomas with mixed epithelial features are invasive tumors that have different types of cells mixed with the cancer cells.
• They occur less often than typical invasive transitional cell carcinomas and are generally considered to be more aggressive.
• The following table illustrates the findings on microscopic analysis for invasive transitional cell carcinomas with mixed epithelial features:

Subtype	Features on Histopathological Microscopic Analysis
Urothelial carcinomas with squamous differentiation	Presence of urothelial and squamous cells Observed in 44% of renal pelvis tumors
Urothelial carcinomas with glandular differentiation	Presence of gland cells and true glandular spaces Mucin production Floating signet ring cells within the mucinous material
Micropapillary urothelial carcinomas	Presence of micropapillae High grade neoplasm
Sarcomatoid urothelial carcinomas	Presence of cells that look like sarcoma This aggressive carcinoma has often spread to lymph nodes and organs other than the renal pelvis or ureter when it is diagnosed
Nested variant of urothelial carcinomas	Irregular and confluent small nests and abortive tubules are composed of urothelial cells Very rare but aggressive
Microcystic urothelial carcinomas	Cysts in them that can range in size from microscopic to 2 mm Very rare
Lymphoepithelioma-like urothelial carcinomas	Lymphatic tissue mixed with urothelial cells, or transitional cells Very rare carcinoma More common in men than women
Plasmacytoid and lymphoma-like urothelial carcinomas	Tumor cells that look like lymphoma or plasmacytoma
Giant cell urothelial carcinomas	Abnormally large cells with more than one nucleus
Clear cell urothelial carcinomas	Clear cells (cells with clear cytoplasm and a large nucleus)
Lipid cell variant of urothelial carcinomas	Cells that are filled with fat
Undifferentiated variant of urothelial carcinomas	Cells that don’t have any clear features and don’t look like any other type of cell (they are undifferentiated).
Urothelial carcinomas with trophoblastic differentiation	Presence of cells that look like trophoblasts Human chorionic gonadotropin production within the cells

Grading

According to the WHO grading criteria, there are two grades of transitional cell carcinoma based on the degree of cellular differentiation:

Grade	Description
Low grade	Tumors with the least degree of cellular anaplasia Rarely invades the muscular wall of the bladder or spreads to other parts of the body Often recurs after treatment
High grade	Tumors with the most severe degrees of cellular anaplasia Commonly recurs and also has a st rong tendency to invade the muscular wall of the bladder and spread to other parts of the body. High grade transitional cell carcinoma is much more likely to result in death

Associated Conditions

Following table illustrates the cancers that may be associated with transitional cell carcinoma of urinary tract:

Association	Percentage of cases
Bladder cancer after the diagnosis of upper urinary tract transitional cell cancer	20 - 50%
Upper urinary tract transitional cell cancer after the diagnosis of bladder cancer	0.74 - 4%
Upper urinary tract transitional cell cancer after cystectomy	2 - 9%

References