Материал: Oxford American Handbook of Urology ( PDFDrive )

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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

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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.

190 CHAPTER 6 Urological neoplasia

Prostate cancer: epidemiology and etiology

Hormonal influence

Growth of prostate cancer (PC), like benign prostatic epithelium, is under the influence of testosterone and its potent metabolite, dihydrotestosterone. Removal of these androgens by castration largely results in programmed cell death (apoptosis) and involution of the prostate. PC is not seen in eunuchs or people with congenital deficiency of 5-A-reductase (5AR), which converts testosterone to dihydrotestosterone (DHT).

Estrogens, including phytoestrogens found in foodstuffs used in Asian and Oriental cuisine, have a similar negative growth effect on PC. This is one explanation why individuals in this part of the world are less likely to develop clinical disease and have lower death rates from prostate cancer.

Other proposed dietary inhibitors of PC growth include vitamins E and D, and the antioxidants lycopene (present in cooked tomatoes) and the trace element selenium (see also p. 244). A very large U.S. trial (SELECT Trial) failed to demonstrate that formulations of vitamin E and selenium, used alone or in combination, could reduce the risk of PC.

Genetics

The multifocal and heterogeneous nature of PC makes clinical genetic studies difficult, as this cancer exhibits numerous genetic abnormalities, increasing with more advanced stage and grade.

Identified genetic changes include inactivation of tumor suppressor genes PTEN (chromosome 10q) and p53 (chromosome 17p), activation of c-myc and bcl-2 proto-oncogenes, and PC susceptibility genes such as ELAC2/HPC2, SR-A/MSR1, CHEK2, BRCA2, and others. Shortened CAG repeat length in the androgen receptor gene is associated with an increased risk of the disease.

Risk factors

Age

This is an important risk factor for development of histological PC. Less than 10% of cases are diagnosed in men <54 years of age, with 64% of cases diagnosed between 55 and 74 years of age. Autopsy prevalence of PC rises from 31% for men in their 30’s to 83% in their 80’s.

This rise is paralleled several years earlier by a premalignant lesion— high-grade prostatic intraepithelial neoplasia (HGPIN). However, most prostate cancer does not achieve a clinically recognizable and aggressive state.

Geographic variation

The disease appears to be more common in Western nations, particularly Scandinavian countries and the United States. The clinical diagnosis of the disease is less common in Asia and the Far East, but immigrants to the United States from Asia and Japan have a 20-fold increased risk. This suggests an environmental etiology, such as the Western diet (higher levels of meat, dairy, and saturated fat), may be important.

PROSTATE CANCER: EPIDEMIOLOGY AND ETIOLOGY 191

Race

Black men are at greater risk than Caucasians; Asians and Oriental races have a low risk of prostate cancer unless they migrate to the West. The world’s highest incidence is among U.S. and Jamaican Blacks, although there are few reliable data available regarding African and European Blacks.

Family history

From 5% to 10% of prostate cancer cases are thought to be inherited. Hereditary PC tends to occur in younger (<55 years) men who have a family history of multiple relatives afflicted; genetic abnormalities on chromosomes 1q, 8p, Xp and mutations of the BRCA2 gene are reported.

The risk of a man developing PC is doubled if there is one affected first-degree relative and can be further increased if there are two. A familial association between breast cancer and prostate cancer has also been suggested.

HPC-1 gene on chromosome 1 is strongly associated with familial PC; HPC-1 mutation results in defective RNase L and accumulation of genetic defects, and eventually prostate cancer.

Familial PC tends to follow a similar clinical course to sporadic PC.

Other factors

Some controversy surrounds the possible increased risk of developing PC conferred by sexual overactivity, viral infections, and vasectomy. The balance of data and opinion currently go against these putative risk factors. Exposure to cadmium has been suggested to raise the risk of PC, but convincing contemporary data are lacking.