Urological neoplasia

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188 CHAPTER 6 Urological neoplasia

Pathology and molecular biology

Neoplasia may be benign or malignant. Malignant neoplasms, characterized by local invasion of normal tissue or distant spread (metastasis) via lymphatic or vascular channels, may be primary or secondary.

Primary urological neoplasms most commonly arise from the lining epithelium of the genitourinary tract—benign (less commonly) or malignant. Neoplasms are considered to arise from a single abnormal cell, through successive aberrant divisions. This is called clonal expansion.

Malignant epithelial neoplasms are termed carcinomas; carcinomas may be further characterized histologically by prefixing either adenoif the neoplasm is glandular, or squamous cell or urothelial cell (formerly transitional cell) according to the epithelium from which it has arisen.

Benign epithelial neoplasms from glandular or transitional epithelium are respectively termed adenoma or papillary neoplasm of low malignant potential (PNLMP) (formerly papilloma).

Connective tissue neoplasms are described according to their components, adding benign (-oma) or malignant (-sarcoma) suffixes. For example, a benign neoplasm composed of blood vessels, fat, and smooth muscle is an angiomyolipoma; a malignant neoplasm composed of smooth muscle is a leiomyosarcoma. Sarcomas are rare in urological organs, constituting 1% of all neoplasms.

In the early stages of tumorigenesis, an identifiable precursor lesion may exist. Several invasive carcinomas are considered to arise from non-inva- sive epithelial lesions. As an example in the bladder it is known as carcinoma in situ (CIS) may progress and become muscle invasive and metastatic bladder cancer.

There are exceptions and rarities. The most common primary testicular neoplasms arise from testicular tubules and are collectively described as germ cell tumors. Rarely, primary malignant lymphoma can arise in the testis.

In the kidney, the childhood Wilms tumor arises from the embryonic mesenchyme of the metanephric blastema, while the relatively common benign oncocytoma is thought to arise from cells of the collecting ducts.

Secondary neoplasms within urological tissues are uncommon; they may arise by direct invasion from adjacent tissues (e.g., adenocarcinoma of the sigmoid colon may invade the bladder) or hematogenous spread from another site in the genitourinary (GU) system or more remote site such as breast cancer involving the kidney.

Like all neoplasia, urological neoplasia is a result of molecular genetic alterations. It may be hereditary or sporadic, depending on whether the genetic abnormalities are partly constitutional (germ-line) or wholly somatic (acquired).

Hereditary tumors tend to appear at a younger age than their sporadic counterparts and are often multifocal, due to an underlying constitutional genetic abnormality such as von Hipple–Lindau syndrome and renal cell carcinoma. Tumor formation results from loss of the balance between cell division and withdrawal from the cell cycle by differentiation or programmed cell death (apoptosis). Signals regulating cell proliferation and

PATHOLOGY AND MOLECULAR BIOLOGY 189

interactions come from proteins, encoded by messenger RNA that is in turn transcribed from genomic DNA.

Genetic abnormalities may promote tumor development or growth in a number of ways:

•Activation (overexpression) of oncogenes encoding transcription factors (e.g., c-myc)

•Inactivation (reduced expression) of tumor suppressor genes (e.g., pp. 190, 246, 279)

•Overexpression of peptide growth factors (e.g., insulin-like growth factor 1 [IGF-1])

•Overexpression of angiogenic factors (e.g., vascular endothelial growth factor [VEGF])

The diverse proteins encoded by tumor suppressor genes stabilize the cell, ensuring differentiation and a finite lifespan in which the cell performs its function. Inactivation of such genes by deletion or mutation may result in loss of this negative growth control.

For example, the gene for phosphatase and tensin homologue (PTEN) is a prostate tumor suppressor gene encoding a phosphatase that is active against protein and lipid substrates. It is present in normal epithelium but is commonly reduced in prostate cancer. It inhibits one of the intracellular signaling pathways, PI3 kinase-Akt, that is essential for cell cycle progression and cell survival. Inactivation of PTEN would therefore promote cell immortalization and proliferation.

Interest in the molecular genetics of urological neoplasia will lead to improved screening tests for hereditary diseases, enhanced diagnostic testing, and expanded choice for “targeted” treatment strategies. As an example, the newer multikinase receptor inhibitors such as sunitinib, sorafenib and temsirolimus are based on the latest understanding of the molecular biology of renal cell carcinoma.