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Ovid: Oxford Handbook of Urology

Authors: Reynard, John; Brewster, Simon; Biers, Suzanne Title: Oxford Handbook of Urology, 1st Edition Copyright ©2006 Oxford University Press > Table of Contents > Chapter 7 – Urological neoplasia Chapter 7 Urological neoplasia P.188
Molecular biology and pathology 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 adeno if the neoplasm is glandular, or squamous cell or transitional cell according to the epithelium from which it has arisen. Benign epithelial neoplasms from glandular or transitional epithelium are respectively termed adenoma or transitional cell 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 tumourigenesis, an identifiable precursor lesion may exist. Several carcinomas are considered to arise from non-invasive epithelial lesions. In the bladder it is known as carcinoma in situ (CIS), while in the prostate there are two such lesions—prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP). There are exceptions and rarities. The most common primary testicular neoplasms arise from testicular tubules and are collectively described as germ cell tumours. Rarely, primary malignant lymphoma can arise in the testis. In the kidney, the childhood Wilm’s tumour 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 haematogenous spread from a distant site such as the lung. Like all neoplasia, urological neoplasia is a genetic disease. It may be hereditary or sporadic, depending on whether the genetic abnormalities are partly constitutional (germ-line) or wholly somatic (acquired). Hereditary tumours tend to appear at a younger age than their sporadic counterparts and are often multifocal, due to an underlying constitutional genetic abnormality. Tumour 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 interactions come from proteins, encoded by messenger RNA that is in turn transcribed from genomic DNA. Genetic abnormalities may promote tumour development or growth in a number of ways:

  • Activation (overexpression) of oncogenes encoding transcription factors (e.g. c-myc)
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  • Inactivation (reduced expression) of tumour suppressor genes (e.g. p.53)
  • Overexpression of peptide growth factors (e.g. insulin-like growth factor 1)
  • Overexpression of angiogenic factors (e.g. vascular endothelial growth factor)

The diverse proteins encoded by tumour suppressor genes stabilize the cell, ensuring differentiation and a finite lifespan in which it 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 tumour 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 signalling 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 may lead to the development of screening tests for hereditary diseases, prognostic data, and ultimately new strategies for treatment. P.192
Prostate cancer: epidemiology and aetiology Hormonal influence Growth of prostate cancer (PC), like benign prostatic epithelium, is under the promotional 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 5α-reductase, which converts testosterone to dihydrotestosterone. Oestrogens, including phyto-oestrogens found in foodstuffs used in Asian and Oriental cuisine, have a similar negative growth effect on PC. This helps explain why these races rarely develop the clinical disease (or die) of prostate cancer, as discussed below. Other dietary inhibitors of PC growth include vitamins E and D, and the antioxidants lycopene (present in tomatoes) and trace element selenium (see also p.242). Risk factors Age is an important risk factor for development of histological PC, the disease being rare below 40 years and becoming increasingly common with rising age, according to postmortem studies. Prevalence of PC rises from 29% in the 6th decade to 67% in the 9th decade. This rise is paralleled several years earlier by an identified premalignant lesion—prostatic intraepithelial neoplasia (PIN). However, most prostate cancer does not achieve a clinically recognizable and aggressive state. 75% of prostate cancers are diagnosed in men >65 years, though the incidence amongst men aged 50–59 has trebled since the 1970s. Geographic variation: the disease is more common in Western nations, particularly Scandinavian countries and the United States. The disease is rare in Asia and the Far East, but US migrants from Asia and Japan have a 20-fold increased risk. This suggests an environmental aetiology, such as the Western diet, may be important. Race: Black men are at greater risk than Caucasians; Asians and Oriental races rarely develop prostate cancer unless they migrate to the West. The world’s highest incidence is among US and Jamaican Blacks, although there is little data available regarding African and European Blacks. Jamaica has the highest mortality rate in the world. Family history: 5–10% of prostate cancers are believed to be inherited. Hereditary prostate cancer tends to occur in younger (<60 years) men who have a family history; genetic abnormalities on chromosomes 1q, 8p, Xp and mutations of the BRCA2 gene are reported. The risk of a man developing prostate cancer is doubled if there is one affected first-degree relative, and is 4-fold if there are two. Some controversy surrounds the possible increased risk of developing PC conferred by sexual overactivity, viral infections, and vasectomy. The balance of data and opinion go against these putative risk factors at present. Exposure to cadmium has been suggested to raise the risk of PC, but no new data have been forthcoming since the 1960s. P.193
Prostate cancer: incidence, prevalence, and mortality Incidence The diagnosis of prostate cancer is on the increase, probably as a result of increasing use of serum prostatic specific antigen (PSA) testing for both symptomatic and asymptomatic men, and the use of more extensive prostatic biopsy protocols. In 1999, 24,714 men were diagnosed with prostate cancer in the UK, mean age 72 years. This exceeds the number of men diagnosed with lung cancer (23,456), placing prostate cancer as the most commonly diagnosed male cancer (excluding skin). Prevalence Currently, it is estimated that a man has a 1 in 12 lifetime risk of being diagnosed with prostate cancer as a result of clinical symptoms, signs, or PSA testing. However, the true prevalence of the disease is hinted at by postmortem studies carried out on men who have died of other causes. These have demonstrated histological evidence of prostate cancer in 10% of men in their 3rd decade, 34% in their 5th decade, to 67% in their 9th. This leads to the concept of ‘latent’ prostate cancer—a biologically non-aggressive and slow-growing form of the disease, which may be unnecessarily detected by PSA screening (p.197). Mortality It is estimated that 3% of men die of prostate cancer. Mortality increased slowly in the UK and USA during the 1970s and 80s, peaking in 1990 at 3% per yr. However, in 1991, mortality started to decrease in the USA by 2% per yr. In the UK, there are also signs of reduction in mortality, though smaller. In 2001, 9887 deaths were attributed to prostate cancer in the UK, the second most common form of male cancer death (12% of all). This compares with 8524 deaths due to colorectal cancer and 20,384 due to lung cancer. This recent trend toward a reduction in prostate cancer mortality appears to be due to treatment, perhaps early use of hormone therapy for advanced disease, and increased aggressive treatment of localized disease. It is perhaps too early to hail this reduction as a triumph of PSA screening programmes, as some in the USA have suggested. P.195
Prostate cancer pathology: adenocarcinoma By far the most common (>95%) prostatic malignancy is adenocarcinoma—carcinoma of the acinar or ductal epithelium. The basal cell layer is absent and the basement membrane is breached by the malignant cells which invade into the prostatic fibromuscular stroma. Macroscopically, they tend to be hard and white, though a soft mucin-producing variety exists. The prostatic urethra, ducts, or stroma may be invaded by transitional cell carcinoma of the bladder (see Fig. 7.6 and p.262). Prostatic sarcomas, most common of which is the rhabdomyosarcoma, are rare but may be seen in childhood. Secondary deposits (metastases) from other sites are rare. Adenocarcinoma of the prostate Most (75%) of adenocarcinomas occur in the peripheral zone of the prostate and most (85%) are multifocal. 20% appear to arise from the transition zones and 5% from the embryologically distinct central zone. The tumour spreads locally through the poorly formed prostatic capsule (this is absent at the apex and base of the gland) into surrounding tissue, at which time it is termed ‘locally advanced’. Hence, the disease may involve the urethral sphincter, corpora of the penis, seminal vesicles, and trigone of the bladder including the distal ureters. Local spread is often along the course of autonomic nerves (perineural invasion). The most frequent sites of metastasis are lymph nodes and bone, although lung, liver, testis, and brain are not uncommon. Bone metastases are characteristically sclerotic, rarely lytic. The axial skeleton (spine and pelvis) are most commonly affected, followed by the proximal long bones, ribs, clavicles, and the skull. Prostate cancer is a complex disease, exhibiting numerous genetic abnormalities, increasing with stage and grade. Frequent changes include:

  • somatic loss of alleles on chromosomes 8, 16, and 18
  • inactivation of tumour suppressor genes PTEN (chromosome 10q) and p53 (chromosome 17p)
  • activation of c-myc and bcl-2 protooncogenes.

Prostate cancer pathology: possible premalignant lesions Two histological lesions are currently regarded as either premalignant or perimalignant—prostatic intraepithelial neoplasia and atypical small acinar proliferation. Prostatic intraepithelial neoplasia (PIN) PIN consists of architecturally benign prostatic acini and ducts lined by cytologically atypical cells. The basal cell layer is present, although the basement membrane may be fragmented. PIN was formerly known as ductal dysplasia or reported by pathologists as ‘suspicious for cancer’. PIN was classified into low-grade (mild) and high-grade (moderate to severe) forms, based on the presence of prominent nucleoli. Subsequently, pathologists have agreed to report only high-grade PIN, since low-grade PIN reporting is very subjective and has no prognostic value. On the other hand, high-grade PIN is believed to be a precursor for intermediate or high-grade prostate cancer and its finding in sextant peripheral zone prostate biopsies carries a 30–40% prediction of prostate cancer at subsequent biopsy. However, with the widespread use of more extensive biopsy protocols, the significance of isolated high-grade PIN has become less clear. High-grade PIN is reported in 5–10% of prostate needle biopsies. It does not appear to affect the serum PSA value. The site of the PIN is not indicative of the site of subsequently diagnosed cancer, nor is PIN always present in a prostate containing cancer. Currently, it is recommended that repeat systematic biopsies should be performed if isolated high-grade PIN is reported on needle biopsy or TURP. Atypical small acinar proliferation (ASAP) This is another histopathological prostatic lesion that pathologists report on needle biopsies as ‘suspicious for cancer’. The acini are small, lined with cytologically abnormal epithelial cells. The columnar cells have prominent nuclei containing nucleoli, while the basal layer may be focally absent. The basement membrane is intact. As with PIN, studies have shown ASAP in needle biopsy predicts cancer at subsequent biopsy in over 40% of cases. Currently, it is recommended that repeat systematic biopsies should be performed if isolated ASAP is reported on needle biopsy or TURP. P.197
Prostatic specific antigen (PSA) and prostate cancer screening Screening men aged 50–70 years with PSA and DRE, and subsequent early detection and treatment, may reduce the significant mortality and morbidity caused by prostate cancer. Supporters of screening say these acceptable and relatively inexpensive tests will detect clinically significant disease before it leaves the prostate. The lead-time, estimated at 6–12 years, between the screened diagnosis and the clinical diagnosis, should enable more organ-confined cancers to be diagnosed and cured. However, because of the low specificity of PSA (40%) and the high prevalence of latent prostate cancer, opponents argue that many men would suffer unnecessary anxiety, biopsies, over-diagnosis (25–50%), and over-treatment. Mathematical models suggest fewer men screened in their 6th decade would be over-diagnosed compared to those in their 7th or 8th decade. Added to this, the treatments have morbidity and cost. From an academic point of view, prostate cancer fails to fulfil most of the criteria set out by Wilson and Jungner, including a clear understanding of the natural history of the disease and adequate resources and facilities to screen the population. UK population screening studies have picked up prostate cancer in 3% of those tested, the vast majority diagnosed with localized disease. A large, non-randomized study over a 6-year period from Tyrol, Austria, demonstrated an 80% reduction in the diagnosis of metastatic disease and a 30% reduction in the expected mortality due to prostate cancer. Conversely, a cohort comparison between biopsy and treatment rates in Seattle and Connecticut showed that diagnosis and interventions were more prevalent in Seattle and yet the mortality rates were similar in the two states. The results of pivotal European and North American randomized trials are awaited, due in 2008. Survival and quality of life are the key outcome measures. Currently, there is little support for a prostate cancer screening programme in the UK, although the Department of Health advocates that counselling should be provided to inform asymptomatic men requesting screening prior to being screened—the so-called ‘risk management programme’ (see p.203). P.198
Prostate cancer: clinical presentation Since the widespread use of serum PSA testing, the majority of patients have non-metastatic disease at presentation. Shown below are the possible presentations, grouped by disease stage. Localized prostate cancer (T1–2)

  • Asymptomatic, with screening serum PSA or incidental digital rectal examination (DRE)
  • Lower urinary tract symptoms (probably due to coexisting benign hyperplasia causing bladder outflow obstruction)
  • Haematospermia
  • Haematuria (probably due to coexisting benign hyperplasia)
  • Perineal discomfort (probably due to coexisting prostatitis)

Locally advanced cancer (T3–4)

  • Asymptomatic, with screening serum PSA or incidental DRE
  • Lower urinary tract symptoms
  • Haematospermia
  • Haematuria
  • Perineal discomfort
  • Symptoms of renal failure/anuria due to ureteric obstruction
  • Malignant priapism (rare)
  • Rectal obstruction (rare)

Metastatic disease (N+, M+)

  • Asymptomatic (‘occult disease’), with screening serum PSA or incidental DRE
  • Swelling of lower limb due to lymphatic obstruction
  • Anorexia, weight loss
  • Bone pain, pathological fracture
  • Neurological symptoms/signs in lower limbs (spinal cord compression)
  • Anaemia
  • Dyspnoea, jaundice, bleeding tendency (coagulopathy)

A note about the DRE Since most prostate cancers arise in the peripheral, posterior part of the prostate, they should be palpable on DRE. An abnormal DRE is defined by asymmetry, a nodule, or a fixed craggy mass. ~50% of abnormal DREs are associated with prostate cancer, the remainder being benign hyperplasia, prostatic calculi, chronic prostatitis, or post-radiotherapy change. Only 40% of cancers diagnosed by DRE will be organ-confined. The fact that an abnormal DRE in the presence of a normal PSA (2.5–4.0ng/ml) carries a 30% chance of predicting prostate cancer rules out any suggestion that the DRE could be abandoned. P.200
PSA and prostate cancer See p.44 for an introduction to the serum PSA test. Until the development of commercial serum PSA assays in the late 1980s, the only serum marker for prostate cancer was acid phosphatase. This was highly specific for prostate cancer metastatic to bone, but lacked sensitivity in detecting less advanced disease and was even normal in >20% patients with bone metastases. Prior to the PSA era, most men with newly diagnosed prostate cancer had advanced incurable disease. PSA has revolutionized the diagnosis and management of prostate cancer, although its use in screening and early detection remains controversial. The predictive values of PSA and digital rectal examination (DRE) for diagnosing prostate cancer in biopsies are shown in Table 7.1. In addition to its use as a serum marker for the diagnosis of prostate cancer, PSA elevations may help in staging, counselling, and monitoring prostate cancer patients. Here are some examples:

  • PSA generally increases with advancing stage and tumour volume, although a small proportion of poorly differentiated tumours fail to express PSA.
  • PSA is used, along with clinical (DRE) T stage and Gleason score, to predict pathological tumour staging and outcome after radical treatments using statistically derived nomograms and artificial neural networks.
  • >50% of patients have extra-prostatic disease if PSA >10ng/ml.
  • <5% of patients have lymph node metastases and only 1% have bone metastases if PSA <20ng/ml.
  • 66% of patients have lymphatic involvement and 90% have seminal vesicle involvement if PSA >50ng/ml.
  • PSA should be virtually undetectable following radical prostatectomy for gland-confined disease.
  • PSA rise after radical prostatectomy precedes the development of clinical metastatic disease by a mean time of 8 years.
  • PSA falls to within the normal range in 80% of patients with metastatic disease on hormone therapy within 4 months; the PSA rises in a mean time of 18 months after starting hormone therapy, signalling progressing disease.

PSA is prostate-specific, but sadly not prostate cancer-specific. Other causes of elevated serum PSA are shown in Table 7.2, the most common of which is benign prostatic hyperplasia. In the presence of infection or instrumentation, PSA should not be requested until at least 28 days after the event, to avoid a false +ve result causing unnecessary concern to doctor and patient. Ideally, PSA should not be requested within 2 days of ejaculation or DRE, but in practice it makes negligible difference to the result.

Table 7.1 The predictive value of PSA and DRE for biopsy diagnosis of prostate cancer
PSA (ng/ml) ≤0.5 0.6–1.0 1.1–2.0 2.1–3.0 3.1–4.0 4.1–10 >10.0
DRE normal 6.6% 10% 17% 24% 27% 27% >50%
DRE abnormal — 15% 15% 30% 30% 45% >75%
Table 7.2 Conditions, excluding prostate cancer, which cause elevated PSA
Cause of elevated PSA Minor elevation <10ng/ml Intermediate elevation 10–20ng/ml Major elevation20–100ng/ml
Benign hyperplasia √ √  
Urinary tract infection   √ √
Acute prostatitis   √ √
Chronic prostatitis √ √  
Retention/catheterization   √  
Biopsy, TURP   √ √
Ejaculation, DRE √    

PSA derivatives: free-to-total ratio, density, and velocity Measurement of the free-to-total (F:T) PSA ratio increases the specificity of total PSA because the ratio is lower in men with prostate cancer than in men with benign hyperplasia. This may be helpful in deciding whether to re-biopsy a patient with previous benign biopsies. While, overall, a man with a normal DRE and a PSA of 4–10ng/ml has a 27% risk of prostate cancer (see Table 7.1, p. 201), this risk rises to 60% if the F:T ratio is 10% and falls to 10% if his ratio is >25%. The F:T ratio may also be useful in the total PSA range 2.5–4ng/ml. Chronic prostatitis may also cause a reduced F:T ratio. An important limitation of this investigation is the instability of free PSA. The serum must be assayed within 3h or frozen at -20°C, otherwise the free component reduces and a low ratio will be reported. There is considerable interest in the more stable complexed PSA concentration, although it cannot yet be used alone. Consideration may be given to the prostate volume, since large benign prostates are the most common cause of mildly elevated PSA. Serum PSA/prostate volume = PSA density, and serum PSA/prostate transition-zone volume = PSA-TZ density. Various cut-off densities have been proposed to raise the specificity of total PSA, possibly to reduce the need for prostatic biopsy, but the issue remains controversial. Short-term variations in serum PSA occur in the presence or absence of cancer, the cause of which may be technical or physiological. Longer term, the PSA tends to rise slowly due to BPH and faster due to prostate cancer—PSA velocity. A PSA velocity >0.75ng/ml per year over at least 18 months in total PSA range 4–10ng/ml is suggestive of the presence of PC, given that only 5% of men without cancer exhibit such a velocity. A PSA velocity >20% per year should also prompt the recommendation of a biopsy, although a slower velocity does not exclude the presence of cancer. The use of PSA velocity is an option for the patient who wishes to avoid an initial or repeat prostatic biopsy. P.203
Counselling before PSA testing Counselling is mandatory before offering a PSA and DRE to asymptomatic men, particularly to highlight the potential disadvantages of having an abnormal result, since the case for benefit to screening is not currently proven (see p.197). This forms the basis of the UK Department of Health NHS Prostate Cancer Risk Management Programme (2002), whereby only men requesting the investigations and who have been appropriately counselled should be tested. Such counselling is less fundamental when investigating a symptomatic patient, because a diagnosis of prostate cancer could alter the management. However, all patients should be informed when PSA testing is being considered. The following points should be used in counselling asymptomatic men:

  • Cancer will be identified in <5% men screened.
  • Sensitivity is 80%: a false -ve result is possible.
  • Specificity is 40–50%: a false +ve result is possible.
  • Prostatic biopsy is uncomfortable and carries a 1% risk of sepsis or significant bleeding.
  • Repeat biopsy may be recommended (PIN, ASAP, or rising PSA).
  • Treatment may not be necessary, or may not be curative.
  • Treatment-related morbidity could lead to a reduction in quality of life.

Prostate cancer: transrectal ultrasonography and biopsies The most common diagnostic modality for prostate cancer is currently transrectal ultrasonography (TRUS) with guided biopsies (Fig. 7.1). TRUS provides imaging of the prostate and seminal vesicles using a 7.5mHz biplane intra-rectal probe measuring approximately 1.5cm in diameter. Most patients find the procedure uncomfortable, some painful. It takes 5min and is undertaken on an outpatient basis with or without some form of anaesthetic. Various anaesthetic techniques are available, including the ultrasound-guided peri-prostatic injection of local anaesthetic, peri-anal GTN paste, or inhalation of nitrous oxide/air (Entonox). A DRE precedes insertion of the probe. If biopsies are planned, an antiseptic rectal wall cleansing is also undertaken. Broad-spectrum antimicrobials are given before and after the procedure. Transrectal ultrasonography can image the outline of the prostate, cysts, abscesses, and calcifications within the prostate. Hypoechoic and hyperechoic lesions in the peripheral zone may be due to prostate cancer or inflammatory conditions, although most prostate cancers are isoechoic and are not ‘seen’. Indications for transrectal ultrasonography alone

  • Accurate measurement of prostate volume.
  • Male infertility with azospermia, to look for seminal vesicle and ejaculatory duct obstruction due to calculus or Müllerian cyst.
  • Suspected prostatic abscess (can be drained by needle aspiration).
  • Investigation of chronic pelvic pain, looking for prostatic cyst or calculi.

Indications for transrectal ultrasonography with biopsies

  • An abnormal DRE and/or an elevated PSA (exceptions include very elderly men with massively elevated PSA and abnormal DRE, or those in whom a TURP is indicated for BOO with severe LUTS/retention where histology will be obtained). See Table 3.1.
  • Previous biopsies showing isolated PIN or ASAP.
  • Previous biopsies normal, but PSA rising or DRE abnormal.
  • To confirm viable prostate cancer following treatment if further treatment is being considered.
Fig. 7.1 Transrectal ultrasound scanning (TRUS). An ultrasound probe is inserted into the rectum to guide the biopsy needle into the correct position so that several core biopsies can be taken from different areas of the prostate

Biopsy protocol 6–12 18FG trucut needle biopsies are taken in a systematic fashion, to include any palpable or sonographic target lesion. The traditional sextant protocol (a parasagittal base, mid-gland, and apex from each side) has been superseded by 8, 10, or 12 biopsies, adding samples from the far lateral peripheral zones (Fig. 7.2). Studies have demonstrated these extra biopsies detect up to 15% more cancers. Additional biopsies of each transition zone may be taken if a transition zone cancer is suspected, or if a patient is undergoing repeat biopsies due to a rising PSA. Seminal vesicles biopsies occasionally add staging information if they appear abnormal on DRE, TRUS, or MRI. Complications of prostatic biopsy

  • Occasional vaso-vagal ‘fainting’ immediately after the procedure.
  • 0.5% risk of septicaemia, which may be life-threatening.
  • 0.5% risk of significant rectal bleeding.
  • Likely, mild haemospermia or haematuria, for up to three weeks.

It is not safe to biopsy a warfarinised patient; biopsying patients on low-dose aspirin remains controversial, but is not at present considered unsafe. Other anti-platelet drugs (e.g. clopidogrel) are usually stopped for 10 days prior. It is important too that the patient appreciates that -ve biopsies do not exclude the possibility of prostate cancer, and that a +ve result will not necessarily result in the recommendation of immediate treatment. Prostate cancer may also be diagnosed by TURP histology or clinically (without histology) in certain circumstances. For example, it could be viewed as unnecessarily invasive to biopsy a frail symptomatic patient with a craggy hard prostate and a PSA of >100ng/ml prior to commencing hormone therapy.

Fig. 7.2 Biopsy protocols

Prostate cancer staging Tumour staging uses the TNM classification (see Table 7.3 and Fig. 7.3). As with all cancer, prostate cancer staging may be considered clinical (prefixed with ‘c’) or pathological (prefixed with ‘p’), dependent on available data. T stage is assessed by digital rectal examination (see Fig. 7.3) and imaging (TRUS, MRI). Current imaging resolution limits reliability in detection of focal and microscopic extraprostatic extension of disease. Recent prostatic biopsy may also confuse the interpretation of MRI images, particularly regarding the seminal vesicles. N stage is assessed by imaging (MRI) or biopsy as necessary. Pelvic lymph node dissection is the gold-standard assessment of N stage. MRI or CT scanning may image enlarged nodes and most radiologists report nodes of >8mm in maximal diameter. However, nodes larger than this often contain no cancer, while micrometastases may be present in normal-sized nodes. M stage is assessed by physical examination, imaging (MRI or isotope bone scan, chest radiology) and biochemical investigations (including creatinine and alkaline phosphatase). Partin’s nomograms based on several thousand radical prostatectomies, are used widely to predict pathological T and N stage by combining clinical T stage, PSA, and biopsy Gleason score (see Table 7.4; reproduced with permission from Partin et al. 2001).1 Higher pathological stage (i.e. pT3 disease) found at radical prostatectomy may also be predicted by:

  • higher percentages (>66%) of positive biopsies
  • cancer invading adipose in the biopsies (there is no fat in the prostate)
  • possibly the presence of perineural cancer invasion within the prostate.
Table 7.3 TNM (1992) staging of adenocarcinoma of the prostate
T0 No tumour (pT0 if no cancer found by histological examination)
Tx T stage uncertain
T1a Cancer non-palpable on digital rectal examination (DRE), present in <5% of TURP specimens (in up to 18% of TURPs)
T1b Cancer non-palpable on DRE, present in >5% of TURP specimens
T1c Cancer non-palpable on DRE, present in needle biopsy taken because of elevated PSA
T2a Palpable tumour, feels confined, in <half of one ‘lobe’ on DRE
T2b Palpable tumour, feels confined, in >half of one ‘lobe’ on DRE
T2c Palpable tumour, feels confined, in both ‘lobes’ on DRE
T3a Palpable tumour, locally advanced into periprostatic fat, uni- or bi-lateral and mobile on DRE
T3b Palpable tumour, locally advanced into seminal vesicle(s) on DRE
T4a Palpable tumour, locally advanced into adjacent structures, feels fixed on DRE
T4b Palpable tumour, locally advanced into pelvic side-wall, feels fixed on DRE
Nx Regional lymph not assessed
N0 No regional lymph node metastasis
N1 Tumour involves regional (pelvic) lymph nodes
Mx Distant metastases not assessed
M0 No distant metastasis
M1a Non-regional lymph node metastasis
M1b Tumour metastasis in bone
M1c Tumour metastasis in other sites
Fig. 7.3 The T stages of prostate cancer
Table 7.4 Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. (Reproduced with permission from Elsevier1.)
Clinical stage T1c (nonpalpable, PSA elevated)
PSA range (ng/ml) Pathologic stage Gleason score
2–4 5–6 3+4=7 4+3=7 8–10
0–2.5 Organ confined 95 (89–99) 90 (88–93) 79 (74–85) 71 (62–79) 66 (54–76)
Extraprostatic extension 5 (1–11) 9 (7–12) 17 (13–23) 25 (18–34) 28 (20–38)
Seminal vesicle (+) — 0 (0–1) 2 (1–5) 2 (1–5) 4 (1–10)
Lymph node (+) — — 1 (0–2) 1 (0–4) 1 (0–4)
2.6–4.0 Organ confined 92 (82–98) 84 (81–86) 68 (62–74) 58 (48–67) 52 (41–63)
Extraprostatic extension 8 (2–18) 15 (13–18) 27(22–33) 37 (29–46) 40 (31–50)
Seminal vesicle (+) — 1 (0–1) 4 (2–7) 4 (1–7) 6 (3–12)
Lymph node (+) — — 1 (0–2) 1 (0–3) 1 (0–4)
4.1–6.0 Organ confined 90 (78–98) 80 (78–83) 63 (58–68) 52 (43–60) 46 (36–56)
Extraprostatic extension 10 (2–22) 19 (16–21) 32 (27–36) 42 (35–50) 45 (36–54)
Seminal vesicle (+) — 1 (0–1) 3 (2–5) 3 (1–6) 5 (3–9)
Lymph node (+) — 0 (0–1) 2 (1–3) 3 (1–5) 3 (1–6)
6.1–10.0 Organ confined 87 (73–97) 75 (72–77) 54 (49–59) 43 (35–51) 37 (28–46)
Extraprostatic extension 13 (3–27) 23 (21–25) 36 (32–40) 47 (40–54) 48 (39–57)
Seminal vesicle (+) — 2 (2–3) 8 (6–11) 8 (4–12) 13 (8–19)
Lymph node (+) — 0 (0–1) 2 (1–3) 2 (1–4) 3 (1–5)
>10.0 Organ confined 80 (61–95) 62 (58–64) 37 (32–42) 27 (21–34) 22 (16–30)
Extraprostatic extension 20 (5–39) 33 (30–36) 43 (38–48) 51 (44–59) 50 (42–59)
Seminal vesicle (+) — 4 (3–5) 12 (9–17) 11 (6–17) 17 (10–25)
Lymph node (+) — 2 (1–3) 8 (5–11) 10 (5–17) 11 (5–18)
Clinical stage T2a (palpable <½ of one lobe)
PSA range (ng/ml) Pathologic stage Gleason score
2–4 5–6 3+4=7 4+3=7 8–10
0–2.5 Organ confined 91 (79–98) 81 (77–85) 64 (56–71) 53 (43–63) 47 (35–59)
Extraprostatic extension 9 (2–21) 17 (13–21) 29 (23–36) 40 (30–49) 42 (32–53)
Seminal vesicle (+) — 1 (0–2) 5 (1–9) 4 (1–9) 7 (2–16)
Lymph node (+) — 0 (0–1) 2 (0–5) 3 (0–8) 3 (0–9)
2.6–4.0 Organ confined 85 (69–96) 71 (66–75) 50 (43–57) 39 (30–48) 33 (24–44)
Extraprostatic extension 15 (4–31) 27 (23–31) 41 (35–48) 52 (43–61) 53 (44–63)
Seminal vesicle (+) — 2 (1–3) 7 (3–12) 6 (2–12) 10 (4–18)
Lymph node (+) — 0 (0–1) 2 (0–4) 2 (0–6) 3 (0–8)
4.1–6.0 Organ confined 81 (63–95) 66 (62–70) 44 (39–50) 33 (25–41) 28 (20–37)
Extraprostatic extension 19 (5–37) 32 (28–36) 46 (40–52) 56 (48–64) 58 (49–66)
Seminal vesicle (+) — 1 (1–2) 5 (3–8) 5 (2–8) 8 (4–13)
Lymph node (+) — 1 (0–2) 4 (2–7) 6 (3–11) 6 (2–12)
6.1–10.0 Organ confined 76 (56–94) 58 (54–61) 35 (30–40) 25 (19–32) 21 (15–28)
Extraprostatic extension 24 (6–44) 37 (34–41) 49 (43–54) 58 (51–66) 57 (48–65)
Seminal vesicle (+) — 4 (3–5) 13 (9–18) 11 (6–17) 17 (11–26)
Lymph node (+) — 1 (0–2) 3 (2–6) 5 (2–8) 5 (2–10)
>10.0 Organ confined 65 (43–89) 42 (38–46) 20 (17–24) 14 (10–18) 11 (7–15)
Extraprostatic extension 35 (11–57) 47 (43–52) 49 (43–55) 55 (46–64) 52 (41–62)
Seminal vesicle (+) — 6 (4–8) 16 (11–22) 13 (7–20) 19 (12–29)
Lymph node (+) — 4 (3–7) 14 (9–21) 18 (10–27) 17 (9–29)
Clinical stage T2b (palpable >½ of one lobe, not on both lobes)
PSA range (ng/ml) Pathologic stage Gleason score
2–4 5–6 3+4=7 4+3=7 8–10
0–2.5 Organ confined 88 (73–97) 75 (69–81) 54 (46–63) 43 (33–54) 37 (26–49)
Extraprostatic extension 12 (3–27) 22 (17–28) 35 (28–43) 45 (35–56) 46 (35–58)
Seminal vesicle (+) — 2 (0–3) 6 (2–12) 5 (1–11) 9 (2–20)
Lymph node (+) — 1 (0–2) 4 (0–10) 6 (0–14) 6 (0–16)
2.6–4.0 Organ confined 80 (61–95) 63 (57–69) 41 (33–48) 30 (22–39) 25 (17–34)
Extraprostatic extension 20 (5–39) 34 (28–40) 47 (40–55) 57 (47–67) 57 (46–68)
Seminal vesicle (+) — 2 (1–4) 9 (4–15) 7 (3–14) 12 (5–22)
Lymph node (+) — 1 (0–2) 3 (0–8) 4 (0–12) 5 (0–14)
4.1–6.0 Organ confined 75 (55–93) 57 (52–63) 35 (29–40) 25 (18–32) 21 (14–29)
Extraprostatic extension 25 (7–45) 39 (33–44) 51 (44–57) 60 (50–68) 59 (49–69)
Seminal vesicle (+) — 2 (1–3) 7 (4–11) 5 (3–9) 9 (4–16)
Lymph node (+) — 2 (1–3) 7 (4–13) 10 (5–18) 10 (4–20)
6.1–10.0 Organ confined 69 (47–91) 49 (43–54) 26 (22–31) 19 (14–25) 15 (10–21)
Extraprostatic extension 31 (9–53) 44 (39–49) 52 (46–58) 60 (52–68) 57 (48–67)
Seminal vesicle (+) — 5 (3–8) 16 (10–22) 13 (7–20) 19 (11–29)
Lymph node (+) — 2 (1–3) 6 (4–10) 8 (5–14) 8 (4–16)
>10.0 Organ confined 57 (35–86) 33 (28–38) 14 (11–17) 9 (6–13) 7 (4–10)
Extraprostatic extension 43 (14–65) 52 (46–56) 47 (40–53) 50 (40–60) 46 (36–59)
Seminal vesicle (+) — 8 (5–11) 17 (12–24) 13 (8–21) 19 (12–29)
Lymph node (+) — 8 (5–12) 22 (15–30) 27 (16–39) 27 (14–40)
Clinical stage T2c (palpable on both lobes)
PSA range (ng/ml) Pathologic stage Gleason score
2–4 5–6 3+4=7 4+3=7 8–10
0–2.5 Organ confined 86 (71–97) 73 (63–81) 51 (38–63) 39 (26–54) 34 (21–48)
Extraprostatic extension 14 (3–29) 24 (17–33) 36 (26–48) 45 (32–59) 47 (33–61)
Seminal vesicle (+) — 1 (0–4) 5 (1–13) 5 (1–12) 8 (2–19)
Lymph node (+) — 1 (0–4) 6 (0–18) 9 (0–26) 10 (0–27)
2.6–4.0 Organ confined 78 (58–94) 61 (50–70) 38 (27–50) 27 (18–40) 23 (14–34)
Extraprostatic extension 22 (6–42) 36 (27–45) 48 (37–59) 57 (44–70) 57 (44–70)
Seminal vesicle (+) — 2 (1–5) 8 (2–17) 6 (2–16) 10 (3–22)
Lymph node (+) — 1 (0–4) 5 (0–15) 7 (0–21) 8 (0–22)
4.1–6.0 Organ confined 73 (52–93) 55 (44–64) 31 (23–41) 21 (14–31) 18 (11–28)
Extraprostatic extension 27 (7–48) 40 (32–50) 50 (40–60) 57 (43–68) 57 (43–70)
Seminal vesicle (+) — 2 (1–4) 6 (2–11) 4 (1–10) 7 (2–15)
Lymph node (+) — 3 (1–7) 12 (5–23) 16 (6–32) 16 (6–33)
6.1–10.0 Organ confined 67 (45–91) 46 (36–56) 24 (17–32) 16 (10–24) 13 (8–20)
Extraprostatic extension 33 (9–55) 46 (37–55) 52 (42–61) 58 (46–69) 56 (43–69)
Seminal vesicle (+) — 5 (2–9) 13 (6–23) 11 (4–21) 16 (6–29)
Lymph node (+) — 3 (1–6) 10 (5–18) 13 (6–25) 13 (5–26)
>10.0 Organ confined 54 (32–85) 30 (21–38) 11 (7–17) 7 (4–12) 6 (3–10)
Extraprostatic extension 46 (15–68) 51 (42–60) 42 (30–55) 43 (29–59) 41 (27–57)
Seminal vesicle (+) — 6 (2–12) 13 (6–24) 10 (3–20) 15 (5–28)
Lymph node (+) — 13 (6–22) 33 (18–49) 38 (20–58) 38 (20–59)
Key: PSA = prostate-specific antigen.

Prostate cancer grading Adenocarcinoma of the prostate is graded using the Gleason system (see Fig. 7.4). Microscopically, adenocarcinoma is graded 1 to 5 according to its gland-forming differentiation at relatively low magnification. Cytological features play no part in this grading system. Since most are multifocal, an allowance is made by adding the two dominant grades to give a sum score between 2 and 10. If only one pattern is observed, the grade is simply doubled. The system is used with needle biopsies, TURP, and radical prostatectomy specimens. Gleason scores 2–4 are considered well differentiated; 5–7 are moderately differentiated; and 8–10 are poorly differentiated. In practice, 75% of PCs are graded 5, 6, or 7; 10% are graded 2–4; and, fortunately, only 15% are graded 8–10. Among expert pathologists there is good inter-observer reproducibility with Gleason scoring. However, scores assigned to needle biopsies are lower than those assigned to the subsequent radical prostatectomy specimen in 30–40% of cases, while overgrading on needle biopsy is uncommon. The importance of the Gleason score is that it correlates well with prognosis, stage for stage, however the patient is managed. For example, a Gleason 3+3 = 6 adenocarcinoma carries a worse prognosis than a 3+2 = 5 cancer of equivalent stage. Moreover, cancers of the same Gleason score have a worse prognosis if the predominant grade is higher (for example, 4+3 = 7 is worse than 3+4 = 7). Some men with low-grade tumours develop high-grade tumours after several years. This is probably due to clonal expansion of high-grade cells rather than de-differentiation of low-grade tumour cells. In general, large-volume tumours are more likely to be high-grade than low-volume tumours, but occasionally exceptions are seen. Finally, caution must be taken when Gleason-scoring prostate tissue that has been subjected to certain interventions, most notably hormone therapy. It is well recognized that prostate cancer treated with androgen ablation exhibits changes very similar to those seen in Gleason scores 8–10. It is possible that even treatment of BPH with 5-α-reductase inhibitors could adversely affect the Gleason score of cancer present in the gland. Pathologists are therefore keen to know relevant clinical details and are reluctant to provide Gleason scores for such patients.

Fig. 7.4 A diagrammatic representation of the Gleason grading system for prostate cancer. The grade depends on the structure of the prostatic glands and their relationship to the stromal smooth muscle

Management of localized prostate cancer: watchful waiting It can be seen from incidence and mortality data that the statement ‘more men die with prostate cancer than because of it’ is correct. This is because most prostate cancers are slow-growing and the majority of men diagnosed are >70 years, often with competing morbidities. This forms the basis for ‘watchful waiting’ (WW)—offering some men diagnosed with non-metastatic prostate cancer no initial treatment. The risks of developing metastatic disease and of death due to prostate cancer after 10–15 years of WW can be considered using published data, according to biopsy grade. Table 7.5 summarizes these data. Selection of patients for watchful waiting Watchful waiting is the best option for patients with localized prostate cancer and:

  • Gleason score 2–4 disease (in which the results of the more aggressive treatments described below are no better); any age
  • Gleason score 5 and 6 disease; >75 years old
  • Significant comorbidity; life expectancy considered to be <10 years
  • Stage T1a disease with normal PSA (only 17% T1a will progress, compared to 68% with T1b)

However, WW should be considered and discussed with all who have Gleason score <7, when small-volume disease is predicted by DRE and the biopsy report. Watchful waiting protocols Most men with localized prostate cancer on WW are seen every 6 months for clinical history, examination (including a DRE), and a serum PSA test (before or after DRE). If the disease progresses during follow-up, palliative treatment (e.g. androgen ablation therapy) is recommended. The threshold for treatment was traditionally when symptoms and signs of advanced disease appeared (e.g. back pain and metastases on the bone scan). However, use of PSA, evidence of benefit with earlier use of hormone therapy, and involvement of patient choice have driven earlier thresholds for treatment. Hence, an asymptomatic patient with a rising PSA may choose whether to treat his disease and accept the side-effects, or whether to maintain his current quality of life while leaving the disease untreated. A more intensive form of WW—‘active surveillance’—is advocated by some. This is aimed at younger men with low-volume moderate-grade disease who might be considered for, but wish to avoid, curative treatment. These men are seen with PSA every 3 months and may undergo annual repeat biopsy to look for upgrading. Evidence of progression may prompt aggressive treatment. The risk with this strategy is that the disease may progress beyond the possibility of cure during the period of observation; it is also demanding on health care resources and is the subject of ongoing research.

Table 7.5 Natural history of localized prostate cancer managed with no initial treatment
Biopsy grade % risk of metastsis (10 years) % risk of prostate2 cancer death (15 years) Estimated lost years of life
2–4 19 4–7 <1 year
5 42 6–11 4
6 42 18–30 4
7 42 42–70 5
8–10 74 56–87 6–8

Management of localized prostate cancer: radical prostatectomy Radical (total) prostatectomy (RP) is excision of the entire prostate, including the prostatic urethra, with the seminal vesicles. It may be performed by open retropubic, perineal, or laparoscopic approaches. The perineal approach does not allow a simultaneous pelvic lymph node dissection. Following excision of the prostate, reconstruction of the bladder neck and vesico-urethral anastomosis completes the procedure. RP is indicated for the treatment of fit men with localized prostate cancer whose life expectancy exceeds 10 years, with curative intent. It is not considered to be an appropriate treatment for locally advanced disease. Patients with Gleason score 2–4 disease appear to do as well with WW as with any other treatment. The patient should consider all available treatment options and the complications of RP prior to proceeding. The surgeon should take part in multidisciplinary team discussion of each case; there may be local guidelines on age and upper PSA cut-off for offering RP, perhaps 70 years and 20ng/ml respectively. Stages in the open retropubic procedure

  • The patient is under anaesthetic, catheterized, and positioned supine with the middle of the table ‘broken’ to open up the entry to the pelvis.
  • Through a lower midline incision, staying extraperitoneal, the retropubic space is opened.
  • Obturator fossa lymphadenectomy is undertaken if the PSA >10 or the Gleason score ≥7.
  • Incisions in the endopelvic fascia on either side allow access to the prostatic apex and membranous urethra.
  • Division and haemostatic control of the dorsal vein complex passing under the pubic arch allows access to the membranous urethra, which is divided at the prostatic apex.
  • The prostate is mobilized retrogradely from apex to base, taking Denonvilliers fascia on its posterior surface.
  • If cavernous nerve sparing is undertaken, the apical and posterior dissection is modified.
  • Denonvilliers fascia is incised at the prostatic base, allowing access to the vasa (divided) and seminal vesicles (excised).
  • The bladder neck is divided, thereby freeing the prostate.
  • The bladder neck is reconstructed to the approximate diameter of the membranous urethra.
  • A sutured vesico-urethral anastomosis is stented by a urethral catheter, typically for 2 weeks.
  • The wound is closed leaving pelvic drains, typically for 48h.

The nerve-sparing modification aims to reduce the risk of post-operative erectile dysfunction. The surgeon seeks to minimize injury to the cavernosal nerves passing from the autonomic pelvic plexus on either side in the groove between prostate and rectum, during mobilization of the prostate. This should not be attempted in the presence of palpable disease as it may compromise cancer control. The tips of the seminal vesicles may also be spared in cases with low risk of cancer involvement, potentially reducing bleeding and cavernosal nerve injury. P.222
Post-operative course after radical prostatectomy: complications

  • Day 1: mobilize; check FBC; C&E; transfuse if required; antimicrobials; physiotherapy if required.
  • Day 2: free fluids and diet; remove drains if possible; teach catheter care; encourage bowel.
  • Day 3–4: home with catheter and instructions.

Catheter time varies between 7 and 21 days; a cystogram is required only if there has been a documented urine leak or other catheter problem. Complications of radical prostatectomy General complications (rare) Those of any major surgery: bleeding requiring re-operation and/or transfusion, infection, thromboembolism, and cardiac disturbance. These are minimized by attention to haemostasis, prophylactic antimicrobials, pneumatic calf compression, low-dose heparin post-operatively, and early mobilization. Chest infection may be prevented by physiotherapy and encouragement of deep breathing, especially in smokers. Post-operative death is estimated to occur in 1 in 500 cases. Specific complications—early

  • Per-operative obturator nerve, ureteric, or rectal injury (all rare): these should be managed immediately if recognized—end-to-end nerve anastomosis; ureteric re-implantation; primary rectal closure with or without a loop colostomy.
  • Post-operative catheter displacement (rare): managed with careful replacement if within 48h, while later urethrography may reveal no anastomotic leak.
  • Post-operative urine or lymphatic leak (distinguished by dipstick glycosuria or creatinine concentration) through drains (occasional): managed by prolonged catheter and wound drainage; lymphatic leaks may require sclerotherapy with tetracycline.

Specific complications—late

  • Erectile dysfunction (ED) affects 70–90% of patients; spontaneous erections may return up to 3 years post-operatively. Men >65 years or with pre-existing ED are more likely to suffer long term. 40–70% respond to oral PDE5 inhibitors at 6 months, while others require intraurethral or intracavernosal prostaglandin E1 treatments, a vacuum device, or (rarely) a prosthesis.
  • Incontinence (stress-type) requiring >1 pad/day affects 5% of patients beyond 6 months; this is due to injury of the external urethral sphincter during division and haemostatic control of the dorsal vein complex. Predisposing factors include age >65 years and excessive bleeding. Pre-operative teaching of pelvic floor exercises helps to regain continence; periurethral bulking injections or implantation of an artificial urinary sphincter are occasionally necessary. Incontinence may also develop secondary to bladder neck stenosis or detrusor instability; P.223
    flow rates, post-void residual measurement, urodynamics, and cystoscopy may help.
  • Bladder neck stenosis affects 5–8% of patients; typically occurs 2–6 months post-operatively, rarely becoming a recurrent problem. Predisposing factors include heavy bleeding, post-operative urinary leak, and previous TURP. Patients complain of new voiding difficulties and treatment is by endoscopic bladder neck incision.

Prostate cancer control with radical prostatectomy While no randomized studies exist comparing RP outcomes to those of radiotherapy, a randomized study comparing RP to WW has demonstrated a 50% reduction in death due to prostate cancer and a 66% reduction in metastatic progression in the RP group with a mean follow-up of only 6 years.3 High-grade cancers were excluded from this trial, though non-randomized data suggest more patients with Gleason 7–10 localized disease survive 10 years following RP than with WW or radiotherapy. Excellent long-term results are seen in well-selected patients following RP, particularly those with organ-confined disease and prior lower urinary tract symptoms due to bladder outflow obstruction. Serum PSA is measured a few days after RP, then 6-monthly; it should fall to <0.1ng/ml. The 10-year PSA progression rate following RP (usually defined as a serum PSA >0.2 ng/ml) is about 30%. Of these, 80% will fail within 3 years of RP. Without additional treatment, the time to development of clinical disease after PSA progression averages 8 years.4 A 20-year clinical disease-free survival of 60% is reported.5 Outcome correlates with: Gleason score; pre-operative PSA; pathological T stage; and surgical margin status. Various tissue markers, none yet used routinely, may also predict PSA progression, including aberrant immunohistochemical expression of the p53 tumour suppressor gene in the biopsy or RP specimen.6 Progression-free probabilities are shown in Table 7.6. Neoadjuvant hormone therapy (hormone therapy given 3 months prior to RP) does not alter the PSA progression rate, despite apparently reducing the incidence of positive surgical margins. Management of biochemical relapse post-RP The definition of rising PSA is controversial, though most agree >0.2ng/ml. DRE should be performed in case there is a nodule. Biopsy of the vesicourethral anastomosis is not widely practised unless there is a palpable abnormality. Studies have shown that MRI and bone scans are rarely helpful in searching for metastatic disease unless the PSA is >7ng/ml. Current management options include observation, pelvic radiotherapy, or hormone therapy. A good response to pelvic radiotherapy is likely if:

  • the PSA rise is delayed >1 year
  • the PSA doubles in >10 months
  • the PSA is <1ng/ml
  • the disease was low-grade and low-stage
  • the radiation dose exceeds 64Gy

If the PSA never falls below 0.2, or it rises in the first year with a doubling time of less than 10 months, the response to pelvic radiotherapy is disappointing. It is likely in these circumstances that metastatic disease is present, and some form of hormone therapy is usually recommended. The choice is between non-steroidal anti-androgen monotherapy P.225
(e.g. bicalutamide 150mg daily) or androgen deprivation by bilateral orchidectomy or LH-RH analogues. There are no comparative outcomes data, so discussion focuses on the side-effects. Most patients choose the anti-androgen, wishing to preserve physical and sexual capabilities.

Table 7.6 Progression-free and metastasis-free survival after RP Probability (%)
  Progression-free, 5 years Progression-free, 10 years Disease-specific, 10 years Metastasis-free, 10 years
Gleason 2–4 90 88 94 87
Gleason 5–6 84 79 80 68
Gleason 7 60* 56* 80 68
Gleason 8–10 49 – 77 52
PSA <4 91
PSA 4–9.9 87
PSA 10–19.9 70
PSA 20–50 50
PT1–2 93
PT3a 76
PT3b 37
N+ 7
Margin clear 81
Margin positive 36+
* 3+4 = 7 fares better than 4+3 = 7
+ Only 40–50% of patients with a positive surgical margin after RP develop a rising PSA

Management of localized prostate cancer: radical external beam radiotherapy (EBRT) Since the early 1980s advances in radiotherapy for localized prostate cancer have included the advent of linear accelerators—conformal and intensity-modulated techniques to minimize toxicity to the rectum and bladder. EBRT is administered with curative intent, often accompanied by 3 months of neoadjuvant hormone therapy in high-risk cases. A small, randomized study has demonstrated benefit in terms of progression and survival for patients treated with 6 months’ (2 months each of neoadjuvant, concurrent, and adjuvant) androgen ablation, in addition to radiotherapy, compared with radiotherapy alone.7 Indication clinically localized prostate cancer, life expectancy >5 years. Patients with Gleason score 2–4 disease appear to do as well with WW as with any other treatment with 15-year follow-up. Contraindications

  • Severe lower urinary tract symptoms
  • Inflammatory bowel disease
  • Previous pelvic irradiation

Protocol a 6-week course of daily treatments amounting to a dose of 60–72Gy. Side-effects

  • Transient moderate/severe filling-type LUTS (common, rarely permanent)
  • Haematuria, contracted bladder: 4–23%
  • Moderate to severe gastrointestinal symptoms, bloody diarrhoea, pain, rectal stenosis: 3–32%
  • Erectile dysfunction (ED) gradually develops in 30–50%
  • The risk of a second solid pelvic malignancy is estimated to be 1 in 300, falling to 1 in 70 long-term survivors.

Outcomes of EBRT Definition of treatment failure: the ASTRO (American Society of Therapeutic Radiation Oncologists) definition is 3 consecutive PSA increases measured 4 months apart for 2 years, thereafter 6-monthly. Time to failure is midway through the 3 PSA measurements. Pre-treatment prognostic factors: PSA, Gleason score, clinical stage, percentage of positive biopsies. 5-year PSA failure-free survival is

  • 85% for low risk (T1–2a or PSA <10ng/ml or Gleason <7)
  • 50% for intermediate risk (T2b or PSA 10–20 or Gleason 7)
  • 33% for high risk (T2c or PSA >20ng/ml or Gleason 8–10)

Treatment of PSA relapse post-EBRT Hormone therapy, either with anti-androgens or androgen deprivation, is currently the mainstay of treatment in this setting. However, local salvage treatment appears attractive, potentially offering another chance of cure if metastases cannot be demonstrated at repeat staging. Salvage radical prostatectomy is seldom undertaken because it is technically demanding, highly morbid, and outcomes are poor. Other local salvage treatments include cryotherapy and high-intensity focused ultrasound (HIFU), but outcomes data and access to these treatments are currently limited (see p.230). If salvage local treatment is under consideration, repeat prostatic biopsies should be taken to demonstrate viable tumour cells. This should be at least 30 months post-EBRT, because fatally damaged cells may survive a few cell divisions. P.228
Management of localized prostate cancer: brachytherapy (BT) This is ultrasound-guided transperineal implantation of radioactive seeds, usually I125, into the prostate. It is currently popular, having failed in the 1970s, prior to transrectal ultrasonography. BT is minimally invasive, requires general anaesthesia, and is completed in one or two stages. Either way, approximately 150Gy is delivered, and this may be augmented by an EBRT boost. Another approach is to use Iridium192 wires, left for several hours in situ in a series of applications, either before or after EBRT. The treatment is expensive due to the cost of the consumables. Indications for BT localized T1–2, Gleason <7, PSA <10ng/ml prostate cancer; life expectancy >5 years. Patients with Gleason score 2–4 disease appear to do as well with WW as with any other treatment. Indications for BT with EBRT T1–3, Gleason <8, PSA <20ng/ml prostate cancer. Contraindications to BT previous TURP (risk of incontinence); large volume prostate (>60ml) causes difficulty with seed placement; moderate to severe lower urinary tract symptoms (risk of retention). Complications

  • Perineal haematoma (occasional)
  • Lower urinary tract symptoms (common), due to prostatic oedema post implant
  • Urinary retention (5–20%)
  • Incontinence (5%), if TURP is required to treat urinary retention
  • ED affects up to 50% of patients; gradual onset

LH-RH analogues are often used to reduce prostatic volume prior to treatment. Alpha-blockers are often used to treat LUTS and to improve the chance of successful trial without catheter in patients with urinary retention. Outcomes of BT PSA rises in the first 3 months post implant; it subsequently declines. As with EBRT, the ASTRO definition (see p.226) is used to define progression:

  • 5-year progression-free survival for T1 + 2a, Gleason <7, PSA <10ng/ml is 80–90%
  • 5-year progression-free survival for T2c, Gleason >6, PSA >10ng/ml is 30–50%
  • 8-year progression-free survival for T1 + 2a, Gleason <7, PSA <10 ng/ml is 79%
  • 12-year progression-free survival for T1 + 2a, Gleason <7, PSA <10 ng/ml is 66%9

It is noteworthy that 50% of the patients in these published series had a normal PSA and Gleason score <5; these patients would have done well P.229
with WW. Patients with Gleason 8–10 do poorly after BT. Finally, PSA progression continues steadily several years after treatment. Outcomes of BT plus EBRT 5-year progression-free survival for T1–3, Gleason <8, PSA 10–20ng/ml is 75–95%. Comparisons of BT or BT plus EBRT with RP and EBRT alone

  • There are no randomized studies.
  • In non-randomized comparisons, an age and tumour-matched radical prostatectomy series at 8 years yielded a progression-free survival of 98% (compared to 79% with BT).
  • Outcome of BT appears inferior to EBRT and RP in men with PSA >10 and Gleason score 7–10.

Rising PSA post BT Salvage EBRT, cryotherapy, or HIFU are options if local recurrence is suspected; repeat staging and biopsy are indicated. Salvage prostatectomy is seldom undertaken. If metastatic disease is suspected or proven, hormone therapy is appropriate. P.230
Management of localized and radio-recurrent prostate cancer: cryotherapy and HIFU Two minimally invasive treatments for localized prostate cancer are in development. Proponents claim they are viable alternatives to radical surgery or radiotherapy, and that they are the only current options for ‘salvage’ treatment of organ-confined recurrent disease following radical radiotherapy. Cryotherapy Transperineal ultrasound-guided cryoprobes delivering argon or liquid nitrogen at a temperature of -20°C to -40°C. When applied in two cycles of freeze–thaw, cellular necrosis occurs. The diameter of the ice-ball is monitored using ultrasound; precautions must be taken to protect the urethra, external sphincter, and rectal wall, such as warming devices. An anaesthetic is required; this is a day-case procedure which can be repeated. Results: PSA nadir is usually achieved within 3 months. 25–48% of men with localized disease achieve a PSA nadir of <0.1ng/ml in 3 months, and 96% of men achieve PSA <0.2ng/ml within 6 months. Positive biopsies are observed in 8–25% of patients after cryotherapy. Long-term results are awaited. Complications: ED (40–80%); incontinence (4–27%); LUTS due to urethral sloughing; pelvic pain; transient penile numbness; recto-urethral fistula (rare). In the salvage setting, good short-term PSA responses are reported in 66% of men, at the expense of significant morbidity, including incontinence and urinary retention (70% each). High-intensity focused ultrasound (HIFU) HIFU allows the selective destruction of tissues at depth without damaging intervening structures. Tissue is heated to the point of coagulative necrosis by high-energy ultrasound transmitted to the prostate using a transrectal device. The tissue temperature is raised locally at this point (over 85°C). With each firing of the probe a ‘cigar shaped’ volume of damage is produced (a lesion). After one lesion is created, the focus is repositioned in order to create the next lesion with the same heating process. Lesions are placed side by side to create a continuous volume in which the tissue is necrosed. The rectal wall and the surrounding tissues are undamaged. An anaesthetic is required; this is a day-case procedure which can be repeated. Over 2000 patients have been treated to date in clinical trials of HIFU for the treatment of primary prostate cancer. The likelihood of morbidity is increased in the salvage treatment setting. Long-term results are awaited. Complications: ED; urinary retention; stress incontinence; recto-urethral fistula (rare). P.231
Management of locally advanced non-metastatic prostate cancer (T3–4 N0M0) EBRT in combination with hormone therapy has consistently demonstrated better outcomes compared to EBRT alone, which is associated with a 15–30% 10-year survival. In a European randomized study9 the hormone therapy group received LH-RH analogues for 3 years starting at time of EBRT. Their 5-year overall survival was 79% compared to 62% in the group treated with EBRT alone; the 5-year disease-free survival was 85% compared to 48%. There are potential advantages in starting hormone therapy prior to EBRT; the optimal timing and duration of hormone therapy in this setting remains unclear. Hormone therapy alone is another option in elderly patients or those unwilling to consider radiotherapy. In this setting, a non-steroidal anti-androgen (e.g. bicalutamide 150mg) has equivalent efficacy to androgen deprivation by orchidectomy or LH-RH analogue, with potential advantages in terms of side-effects. However, discussion should include the point that hormone therapy is not a treatment offered with curative intent. A randomized trial of hormone therapy alone versus EBRT plus hormone therapy is underway. Watchful waiting is also an option for non-metastatic T3 disease in an elderly asymptomatic man who may wish to avoid side-effects of treatment. Palliative treatment of locally advanced disease Palliative TURP or medical therapy for LUTS or retention may be necessary. Incontinence can be due to sphincter involvement, though bladder outflow obstruction and instability should be considered: a urinary convene sheath or catheter may be required. Percutaneous nephrostomies or ureteric stents are occasionally necessary for ureteric obstruction. Rarely, a colostomy is necessary to bypass a rectal stenosis. P.232
Management of advanced prostate cancer: hormone therapy I Metastatic disease is the cause of nearly all prostate cancer-related death. Currently incurable, 5-year survival is 25%; 10% survive <6 months, while <10% survive >10 years. The mainstay of treatment is hormone therapy, with cytotoxic chemotherapy in reserve and novel treatments such as growth factor inhibitors, angiogenesis inhibitors, immunotherapy, and gene therapy in development. The concept of hormone therapy was realized in 1941 when Huggins and Hodges reported favourable acid and alkaline phosphatase responses in prostate cancer patients castrated or given oestrogens. Hormone dependence of prostate cancer 95% of circulating androgen, mainly testosterone, is produced by the Leydig cells of the testes under the influence of luteinizing hormone (LH). The anterior pituitary synthesises LH, stimulated by LH-releasing hormone (LH-RH) produced by the hypothalamus. The remaining 5% of circulating androgen is synthesized by the adrenal cortex from cholesterol, under the influence of pituitary ACTH. Testosterone is metabolized to the more potent dihydrotestosterone (DHT), by types 1 and 2 5-α reductase (5AR) enzymes. DHT binds to the androgen receptor, travels to the cell nucleus, and exerts its positive effect on cell growth and division. All prostate epithelial cells are dependent on androgens and fail to grow or undergo programmed cell death in their absence. Similarly, most previously untreated prostate cancer cells are dependent on androgens. Androgen deprivation results in a reduction in PSA and clinical improvement in >70% of patients. However, most will still die within 5 years due to the development of androgen-independent growth. This is considered to be due to growth of androgen-independent cell clones rather than a de-differentiation of previously androgen-dependent cells. The mean time to disease progression after androgen deprivation is 14 months in men with metastatic disease. Prognostic factors Predictors of poor hormone therapy response include:

  • ≥5 metastatic lesions at presentation
  • Elevated alkaline phosphatase at presentation
  • Anaemia at presentation
  • Poor performance status (level of activity) at presentation
  • Low serum testosterone at presentation
  • Failure of bone pain to improve within 3 months of treatment
  • Failure of PSA to normalize within 6 months of treatment (conversely a PSA nadir (= lowest value) of <0.1ng/ml predicts a long-term response)

Management of advanced prostate cancer: hormone therapy II Mechanisms of androgen deprivation

  • Surgical castration: bilateral orchidectomy
  • Medical castration: luteinizing hormone-releasing hormone (LH-RH) agonists, oestrogens; also termed androgen ablation or androgen deprivation
  • Anti-androgens (steroidal or non-steroidal): androgen receptor blockade at target cell
  • Maximal androgen blockade (MAB): medical or surgical castration plus anti-androgen
  • 5-α reductase inhibition (5ARI) with finasteride or dutasteride

Both forms of castration have equivalent efficacy, so patients should be given the choice. Oestrogens are no longer used first-line, due to the significant cardiovascular morbidity observed when they were the only alternative to orchidectomy. Anti-androgens alone are less effective in treating metastatic disease, but equivalent for non-metastatic disease. MAB has a theoretical advantage over castration in blocking the effects of the adrenal androgens, but significant clinical advantages have not been demonstrated in trial meta-analyses. 5ARIs are not licenced for the treatment of prostate cancer, but appear to have a role in prevention. Bilateral orchidectomy A simple procedure, usually carried out under general anaesthesia. Through a midline scrotal incision, both testes may be accessed. The tunica albuginea of each testis is incised and the soft tissue content is removed, after which the capsule is closed. The epidiymes and testicular appendages are preserved. Post-operative complications include scrotal haematoma or infection (both rare). Serum testosterone falls within 8h to <0.2nmol/l. LH-RH agonists Developed in the 1980s, giving patients an alternative to bilateral orchidectomy, with which they are clinically equivalent. They are given by subcutaneous or intramuscular injection, as monthly or 3-monthly depots. Examples include goserelin, triptorelin, and leuprorelin acetates. If the anterior pituitary is overwhelmed with an analogue of LH-releasing hormone (LH-RH), it switches off LH production, although serum testosterone rises in the first 14 days due to a surge of LH. This can result in ‘tumour flare’, manifest in 20% patients with increased symptoms, including catastrophic spinal cord compression. To prevent this, cover with anti-androgens is recommended for a week before and two weeks after the first dose of LH-RH agonist. An LH-RH antagonist is in development which should rapidly reduce serum testosterone. P.235
Side-effects of bilateral orchidectomy and LH-RH agonists

  • Loss of sexual interest (libido) and ED
  • Hot flushes and sweats can be frequent and troublesome during work or social activity
  • Weight gain
  • Gynaecomastia
  • Anaemia
  • Cognitive (mood) changes
  • Osteoporosis and pathological fracture secondary to osteoporosis may occur in patients on long-term (>5 years) treatment

Anti-androgens These are administered as tablets. Examples include bicalutamide (150mg daily as monotherapy; 50mg daily for MAB, in combination with LH-RH analogues or orchidectomy), flutamide, and cyproterone acetate. The first two raise the serum testosterone slightly, so sexual interest and performance should be maintained, although many such patients have pre-existing ED due to the advancing disease. Side-effects include frequent gynaecomastia, breast tenderness, and occasional liver dysfunction; flutamide also causes frequent GI upset. At its full dose of 100mg tds cyproterone acetate may cause reversible dyspnoea; it may be used at 50mg bd for treatment of castration-induced hot flushes. P.236
Management of advanced prostate cancer: hormone therapy III Monitoring treatment Typically, patients will have baseline PSA, full blood count, renal and liver function tests, a renal ultrasound, and a bone scan. The PSA is repeated after 3 months, 6 months, and 6-monthly thereafter until it rises. Liver function is checked 3-monthly if anti-androgen monotherapy is used. Renal function should be checked on disease progression, and bone imaging if clinically indicated. While PSA is very useful as a marker for response and progression, 15% of patients show clinical progression without PSA rise. This may occur in anaplastic tumours that fail to express PSA. Advice on exercise, diet, and treatment of erectile dysfunction is often sought by patients during treatment. Early versus delayed hormone therapy Traditionally, hormone therapy was reserved for patients with symptomatic metastatic disease. Arguments against early hormone therapy revolve around its side-effects and cost. However, studies of patients with locally advanced and metastatic disease have demonstrated slower disease progression and reduced morbidity when treated with androgen deprivation early (i.e. before the onset of symptoms). Improved survival has also been reported in patients without bone metastases but including node-positive disease, when treated immediately. Trials have also demonstrated slower disease progression in patients given bicalutamide 150mg daily (compared with placebo) for 2 years after treatment of high-risk, clinically localized prostate cancer with RP or RT. This benefit is not seen in patients managed by watchful waiting. Intermittent hormone therapy The potential advantages of stopping hormone therapy when the disease has remitted, then re-starting it when the PSA has risen again are the reduced side-effects and cost. However, there are no randomized trials yet demonstrating survival equivalence or advantage. None of the LH-RH analogues or anti-androgens are licensed for intermittent therapy. Moreover, it can take up to 6 months after stopping treatment for the serum testosterone to recover, hence side-effects may persist into the off-treatment periods. P.237
Management of advanced prostate cancer: androgen-independent disease Second-line hormone therapy When the PSA rises from its lowest (nadir) value, or if symptomatic progression occurs despite a favourable biochemical response to first-line hormone therapy, the disease has entered its androgen-independent phase. In these circumstances, further treatment is usually considered. Most patients receiving anti-androgen monotherapy respond after switching to androgen ablation (orchidectomy or LH-RH analogue). If there is relapse during androgen ablation, 25% respond by adding an anti-androgen (e.g. bicalutamide 50mg daily) to establish maximal androgen blockade (MAB). If MAB was used from initiation of hormone therapy, withdrawal of the anti-androgen paradoxically elicits a favourable response in 25% of patients. A further rise in PSA may require third-line hormonal therapy such as the addition of oestrogens or corticosteroids. For example, diethylstilboestrol 1mg daily with 75mg aspirin for thromboembolic prophylaxis elicits a response in up to 60% of these patients. The mean duration of response is 4 months. The prognostic factors for survival with androgen-independent disease are identical to the factors predicting response to hormone therapy (see p.232), plus time from initiation of hormone therapy to initiation of chemotherapy and visceral metastasis status. Cytotoxic chemotherapy Systemic chemotherapy is offered to appropriate patients with androgen-independent metastatic disease, by the medical oncologist. Men with low-volume disease who have failed radical local treatment and hormone therapy are also candidates for chemotherapy. Elderly, frail, and infirm patients with significant bone disease, renal impairment, haematological and clotting abnormalities are unsuitable. Correction of renal and bone marrow dysfunction is necessary prior to treatment. Symptom palliation Symptom improvements are reported with cytotoxic chemotherapy. In a randomized trial of mitoxantrone plus prednisolone versus prednisolone alone, 29% in the combination group experienced a reduction in pain and analgesic use compared with 12% in the prednisolone alone group. PSA response did not predict palliative response. In another study, docetaxel plus prednisolone produced a pain reduction in 35% compared to 22% of patients given mitoxantrone and prednisolone, resulting in improved quality of life scores. Cancer control There are several reports of single-agent chemotherapy in the PSA era, most defining response as >50% decrease in PSA. Responses are reported in 20–40% of patients with haematological toxicity (especially P.239
neutropenia) for most agents. Better responses (up to 75%) reported with newer combination regimes (e.g. estramustine phosphate plus docetaxel) but with greater toxicity. The median survival following chemotherapy ranges from 24 to 44 weeks. Results of two randomized studies comparing docetaxel with mitoxantrone plus prednisolone have shown a 2.4–3 months’ median survival advantage in favour of docetaxel.10 P.240
Palliative management of prostate cancer The involvement of the acute pain team, palliative care physicians, and nurses is often necessary in the terminal phase of the illness, to optimize quality of life. Pain is undoubtedly the most debilitating symptom of advanced prostate cancer. The pathogenesis of this pain is poorly understood, but there is known to be increased osteoclastic and osteoblastic activity. Table 7.7 categorizes the pain syndromes and their management. Spinal cord compression (see p.457) Lower urinary tract symptoms/urinary retention A TURP may be required for bladder outflow obstruction (BOO) or retention. Instrumentation can be difficult if there is a bulky fixed prostate cancer. The bladder may be contracted due to disease involvement, causing misery even after relief of BOO. This may perhaps respond to anticholinergic therapy. A long-term urethral or suprapubic catheter may be required for difficult voiding symptoms or recurrent retention. Ureteric obstruction (see p.456) This is a uro-oncological emergency. Locally advanced prostate cancer and bladder cancer may cause bilateral ureteric obstruction. The patient presents either with symptoms and signs of renal failure, or anuric without a palpable bladder. Renal ultrasound will demonstrate bilateral hydronephrosis and an empty bladder. After treating any life-threatening hyperkalaemia, the treatment options include bilateral percutaneous nephrostomies or ureteric stents. A clotting screen is required prior to nephrostomy insertion. Insertion of retrograde ureteric stents in this scenario is usually unsuccessful because tumour on the trigone obscures the location of the ureteric orifices. Antegrade ureteric stenting following placement of nephrostomies is usually successful. Hormone therapy should be commenced if not previously used; even in patients with androgen-independent disease, there are reports of high-dose intravenous oestrogens (Honvan) unobstructing ureters. Unilateral ureteric obstruction is occasionally observed at presentation or on progression. If asymptomatic, this may be managed conservatively provided there is a normal contralateral kidney. Anaemia, thrombocytopaenia, and coagulopathy For some patients, their haemoglobin levels drop rapidly and they become symptomatic on a regular basis. This tends to be normochromic and normocytic, and often occurs without other symptoms and with normal renal function. Such patients require regular transfusions. Platelet transfusions are rarely required for bleeding. Terminal patients may develop a clinical picture similar to disseminated intravascular coagulation (DIC) leading to problematic haematuria.

Table 7.7 Pain syndromes and their management
Pain type Initial management Other options
Focal bone pain Medical: simple, NSAIDs, opiates
Single-shot radiotherapy, 800cGy (75% respond up to 6 months)
Surgical fixation of pathological fracture or extensive lytic metastasis
Diffuse bone pain Medical: NSAIDs, opiates
Multi-shot radiotherapy or radiopharmaceutical (e.g. Strontium89)
Steroids; bisphosphonates; chemotherapy
Epidural metastasis and cord compression See p.457  
Plexopathies (rare—caused by direct tumour extension) Medical: NSAIDs, opiates
Radiotherapy; nerve blocks
Tricyclics; anticonvulsants
Other pain syndromes: skull/cranial nerve, liver, rectum/perineum Radiotherapy
Medical: NSAIDs, opiates, steroids
Intrathecal chemotherapy for meningeal involvement

Prostate cancer: prevention; complementary and alternative therapies The fact that as many as 27% of men in their 3rd decade have histological prostate cancer, even though the disease is rarely detected clinically <50 years, suggests that there are years of opportunity for preventative strategies. Dietary intervention There are many epidemiological and laboratory data supporting dietary interventions, though randomized prospective trials are awaited.

  • High fat diets, particularly those rich in saturated fat and omega-6 fatty acids, are linked to increased risk of prostate cancer diagnosis.
  • Soy products contain phyto-oestrogens including the isoflavone, genistein. Genistein is a natural inhibitor of tyrosine kinase receptors and inhibits prostate cancer cell lines. Chinese Americans have a 24-fold risk of developing prostate cancer compared to native Chinese, perhaps due to a difference in their respective diets.
  • Lycopene, present in cooked tomatoes and tomato products, is considered to reduce risk of prostate cancer progression and inhibits cell lines.
  • Selenium supplementation (0.2mg/day) was shown to reduce the risk of developing prostate cancer in a melanoma prevention trial. Selenium is a trace element required as an antioxidant. It is present in brazil nuts, found in relatively low concentration in European soil, and can be assayed using toe-nail clippings.
  • Vitamin E supplementation was shown to reduce the incidence of prostate cancer in Finnish smokers. It is an antioxidant.
  • Vitamins A (retinoids) and D both inhibit growth of prostate cell lines, and vitamin D receptor polymorphisms appear to predispose certain individuals to prostate cancer.
  • In a pan-European study, large consumers of vegetables (e.g. vegetarians) did not exhibit a reduced incidence of prostate cancer
  • Studies from UK, Europe, and the USA have shown that 25–40% of prostate cancer patients are taking some form of complementary therapy, most without informing their doctor. These can occasionally be harmful: for example, a ‘Chinese herb’ mixture called PC-SPES, now withdrawn, frequently caused thromboembolism.

Smoking has recently been shown in population studies to be significantly associated not with prostate cancer diagnosis, but fatal prostate cancer. No definite link exists between alcohol consumption, vasectomy, or sexual activity with prostate cancer. Studies have suggested an increased risk associated with early sexual activity and a reduced risk associated with frequent masturbation, but these require substantiation. P.243
Chemoprevention with antiandrogens Given that prostate cancer starts, in the main, as an androgen-dependent disease, interest in its prevention has also focused on antiandrogens. While non-steroidal antiandrogens would have unacceptable side-effects and cost, the 5-? reductase inhibitors could be feasible chemoprevention agents. The Prostate Cancer Prevention Trial recruited 18,000 men who had no clinical or biochemical evidence of prostate cancer. They were randomized to placebo or finasteride 5mg daily for up to 7 years. The men were offered biopsy if they developed a rising PSA, an abnormality on DRE, or at end of study. Prostate cancer was detected in 24% and 18% of participants in placebo and finasteride arms respectively, suggesting that finasteride reduces the risk of developing prostate cancer by 25%. However, Gleason 7+ cancers were significantly more frequent in the finasteride arm. While this could be due to the effect of the 5-α reductase inhibitors on tissue architecture, nobody is rushing to recommend this to their patients without full discussion of the implications.11 P.244
Bladder cancer: epidemiology and aetiology Bladder cancer is the second most common urological malignancy, accounting for 4973 deaths in the UK in 2001. This represents 3% of all cancer deaths. Incidence is ~13,000 per year, indicating that the majority of patients have curable or controllable disease. Risk factors

  • Men are 2.5 times more likely to develop the disease than women, the reasons for which are unclear but may be associated with greater urine residuals in the bladder.
  • Age increases risk, most commonly diagnosed in the 8th decade and rare <50 years.
  • Racially, Black people have a lower incidence than White people, but inexplicably they appear to carry a poorer prognosis.
  • Environmental carcinogens, found in urine, are the major cause of bladder cancer.
  • Chronic inflammation of bladder mucosa: bladder stones, long-term catheters, and, notoriously, the ova of Schistosoma haematobium (bilharziasis) are implicated in the development of squamous cell carcinoma of the bladder.
  • Smoking is the major cause of bladder cancer in the developed world. Cigarette smoke contains the carcinogens 4-aminobiphenyl (4-ABP) and 2-naphthylamine (see Fig. 7.5). Slow hepatic acetylation (detoxification) of 4-ABP by N-acetyltransferase and glutathione S-transferase M1 (GST M1), or induction of the cytochrome p-450 1A2 demethylating enzyme, appear to increase urinary carcinogenic exposure of the urothelium. Smokers have a 2–5-fold risk compared to non-smokers, with respect to development of bladder cancer and subsequent recurrences. Estimates suggest that 30–50% of bladder cancer is caused by smoking. There is a slow (20-year) reduction in risk following cessation of smoking.
  • Occupational exposure to carcinogens, in particular aromatic hydrocarbons like aniline (see Fig. 7.5), is a recognized cause of bladder cancer. See the box for examples of ‘at risk’ occupations. A latent period of 25–45 years exists between exposure and carcinogenesis.
  • Drugs: phenacitin and cyclophosphamide.
  • Pelvic radiotherapy.

No evidence for a hereditary genetic aetiology exists, though many somatic genetic abnormalities have been identified. The most common cytogenetic abnormality is loss of chromosomes 9p, 9q, 11p 13q, and 17q. Activation/ amplification of oncogenes (p21 ras, c-myc, c-jun, erbB-2), inactivation of tumour suppressor genes (p53 mutations appear to worsen survival after treatment, retinoblastoma, p16 cyclin-dependent kinse inhibitor), and increased expression of angiogenic factors (e.g. vascular endothelial growth factor, VEGF) are reported in transitional cell carcinomas.

Fig. 7.5 Carcinogens known to increase risk of bladder cancer

Occupations associated with transitional cell carcinomas

  • Rubber manufacture (e.g. tyres or electric cable)
  • Dye manufacture
  • Fine chemical manufacture (e.g. auramine)
  • Retort houses of gas works
  • Rope and textile manufacture
  • Hairdressers
  • Leather workers
  • Plumbers
  • Painters
  • Drivers exposed to diesel exhaust

Bladder cancer: pathology and staging Benign tumours of the bladder, including inverted papilloma and nephrogenic adenoma, are uncommon. The vast majority of primary bladder cancers are malignant and epithelial in origin:

  • >90% are transitional cell carcinoma (TCC)
  • 1–7% are squamous cell carcinoma (SCC)
  • 75% are SCC in areas where schistosomiasis is endemic
  • 2% are adenocarcinoma
  • Rarities include phaeochromocytoma, melanoma, lymphoma, and sarcoma arising within the bladder muscle
  • Secondary bladder cancers are mostly metastatic adenocarcinoma from gut, prostate, kidney, or ovary

Tumour spread

  • Direct tumour growth to involve the detrusor, the ureteric orifices, prostate, urethra, uterus, vagina, perivesical fat, bowel, or pelvic side walls.
  • Implantation into wounds/percutaneous catheter tracts.
  • Lymphatic infiltration of the iliac and para-aortic nodes.
  • Haematogenous, most commonly to liver (38%), lung (36%), adrenal gland (21%), and bone (27%). Any other organ may be involved.

Histological grading is divided into: well, moderately, and poorly differentiated (abbreviated to G1, G2, and G3 respectively). Staging is by the TNM (1997) classification (see Fig. 7.6 and Table 7.8). All rely upon physical examination and imaging, the pathological classification (prefixed ‘p’) corresponding to the TNM categories. Transitional cell carcinoma TCC may be single or multifocal. Because 5% of patients will have a synchronous upper tract TCC and metachronous recurrences may develop after several years—the urothelial ‘field-change’ theory of polyclonality is favoured over the theory of tumour monoclonality with transcoelomic implantation (seeding). Primary TCC is considered clinically as superficial or muscle-invasive:

  • 70% of tumours are papillary, usually G1 or G2, exhibiting at least 7 transitional cell layers covering a fibro-vascular core (normal transitional epithelium has ~5 cell layers). Papillary TCC is usually superficial, confined to the bladder mucosa (Ta) or submucosa (T1). 10% of patients subsequently develop muscle-invasive or metastatic disease. However, a subset of superficial TCC, G3T1 tumours, are more aggressive, with 40% subsequently upstaging.
  • 10% of TCC have mixed papillary and solid morphology and 10% are solid. These are usually G3, half of which are muscle-invasive at presentation.
Fig. 7.6 A diagrammatic representation of the T staging of bladder TCC. (Reproduced with permission from Brewster et al. 2001)12


  • 10% of TCC is flat carcinoma in situ (CIS). This is poorly differentiated carcinoma, but confined to the epithelium and associated with an intact basement membrane. 50% of CIS lesions occur in isolation; the remainder occur in association with muscle-invasive TCC. CIS usually appears as a flat, red, velvety patch on the bladder mucosa; 15–40% of such lesions are CIS, the remainder being focal cystitis of varying aetiology. The cells are poorly cohesive, up to 100% of patients with CIS exhibiting positive urine cytology, in contrast to much lower yields (17–72%) with G1/2 papillary TCC. 40–83% of untreated CIS lesions will progress to muscle-invasive TCC, making CIS the most aggressive form of superficial TCC.

5% of patients with G1/2 TCC and at least 20% with G3 TCC (including CIS) have vascular or lymphatic spread. Metastatic node disease is found in: 0% Tis, 6% Ta, 10% T1, 18% T2 and T3a, 25–33% T3b and T4 TCC. Squamous cell carcinoma SCC is usually solid or ulcerative and muscle-invasive at presentation. SCC accounts for only 1% of UK bladder cancers. SCC in the bladder is associated with chronic inflammation and urothelial squamous metaplasia, rather than CIS. In Egypt, 80% of SCC is induced by the ova of Schistosoma haematobium. 5% of paraplegics with long-term catheters develop SCC. Smoking is also a risk factor for SCC. The prognosis is better for bilharzial SCC than for non-bilharzial disease, probably because it tends to be lower-grade and metastases are less common in these patients. Adenocarcinoma Adenocarcinoma is rare, usually solid/ulcerative, G3, and carries a poor prognosis. One third originate in the urachus, the remnant of the allantois, located deep to the bladder mucosa in the dome of the bladder. Adenocarcinoma is a long-term (10–20+ year) complication of bladder exstrophy and bowel implantation into the urinary tract, particularly bladder substitutions and ileal conduits after cystectomy. There is association with cystitis glandularis, rather than CIS. Secondary adenocarcinoma of the bladder may arise as discussed above.

Table 7.8 TNM staging of bladder carcinoma
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscularis propria (detrusor): T2a inner half; T2b outer half
T3 Tumour invades beyond muscularis propria into perivesical fat: T3a = microscopic; T3b = macroscopic
T4a Tumour invades any of: prostate, uterus, vagina, bowel
T4b Tumour invades pelvic or abdominal wall
Nx Regional (iliac and para-aortic) lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node <2cm in greatest dimension
N2 Metastasis in a single lymph node 2–5cm or multiple nodes <5cm
N3 Metastasis in a single lymph node or multiple nodes >5cm in greatest dimension
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis present

Bladder cancer: presentation Symptoms

  • The most common presenting symptom (85% of cases) is painless total haematuria. This may be initial or terminal if the lesion is at the bladder neck or in the prostatic urethra. 34% of patients >50 years and 10% <50 years with macroscopic haematuria have bladder cancer. History of smoking or occupational exposure is relevant.
  • Asymptomatic microscopic haematuria, found on routine urine stick-testing. Up to 16% of females and 4% of males have stick-test haematuria: less than 5% of those <50 years, while 7–13% of those >50 years will have a malignancy.
  • Pain is unusual, even if the patient has obstructed upper tracts, since the obstruction and renal deterioration arise gradually.
  • Filling-type lower urinary tract symptoms, such as urgency or suprapubic pain. There is almost always microscopic or macroscopic haematuria. This so-called ‘malignant cystitis’ is typical in patients with CIS.
  • Recurrent urinary tract infections and pneumaturia due to malignant colovesical fistula, though less common than benign causes (diverticular and Crohn’s disease).
  • More advanced cases may present with lower-limb swelling due to lymphatic/venous obstruction, bone pain, weight loss, anorexia, confusion, and anuria (renal failure due to bilateral ureteric obstruction).
  • Urachal adenocarcinomas may present with a blood or mucus umbilical discharge or a deep subumbilical mass (rare).


  • General examination may reveal pallor, indicating anaemia due to chronic renal impairment or blood loss.
  • Abdominal examination may reveal a suprapubic mass in the case of locally advanced disease. Digital rectal examination may reveal a mass above or involving the prostate.

Although the likelihood of diagnosing bladder cancer in patients <50 years is low, all patients with these presenting features should be investigated. P.251
Bladder cancer: diagnosis and staging After a urinary tract infection has been excluded or treated, all patients with microscopic or macroscopic haematuria require investigation of their upper tracts, bladder, and urethra. Usually, renal ultrasound and flexible cystoscopy, performed under local anaesthetic, are first-line investigations. If these fail to find a cause, an IVU or CTU and urine cytology are justified second-line investigations. Patients with predominantly filling-type LUTS, suprapubic pain, or recurrent UTI/pneumaturia should also have urine cytology and cystoscopy. CTU before and after IV contrast is becoming the first-line radiological investigation of haematuria. It is faster and more sensitive than ultrasound or IVU in the detection of renal (parenchymal and urothelial) and ureteric tumours. However, it carries a higher radiation dose and is more expensive. CTU also detects some bladder tumours, but may overcall bladder wall hypertrophy as tumour and will miss flat CIS and urethral pathology. Thus it cannot replace cystoscopy. If there is hydronephrosis in association with a bladder tumour, it is likely that the tumour is causing the obstruction to the distal ureter. This tends to be caused by muscle-invasive disease rather than superficial TCC. False -ve cytology is frequent (40–70%) in patients with papillary TCC, but more sensitive (90–100%) in patients with high-grade TCC and CIS. False +ve cytology can arise due to infection, inflammation, instrumentation, and chemotherapy. If all investigations are normal, consideration should be given to nephrological disorders that may cause haematuria, such as glomerulonephritis. Cross-referral to a renal physician is advised in patients with persisting microscopic haematuria, especially those with associated proteinuria or hypertension. Transurethral resection of bladder tumour (TURBT) usually provides definitive histological diagnosis (see p.246). This is usually undertaken under general or spinal anaesthesia; bimanual examination is mandatory before and after bladder tumour resection, to assess size, position, and mobility. The pathologist should report on the tumour type, grade, and stage; in particular, the presence or absence of muscularis propria should be noted, since its absence will preclude reliable T staging. Red patches are biopsied separately; the prostatic urethra is biopsied if radical reconstructive surgery is under consideration. Care is taken in resecting tumours at the dome, since intraperitoneal bladder perforation may occur, especially in women with thin-walled bladders. P.253
Staging investigations are usually reserved for patients with biopsy-proven muscle-invasive bladder cancer unless clinically indicated, since superficial TCC and CIS disease are rarely associated with metastases.

  • Pelvic CT or MRI may demonstrate extra-vesical tumour extension or iliac lymphadenopathy, reported if >8mm in maximal diameter.
  • Chest X-ray
  • Isotope bone scan (positive in 5–15% of patients with muscle-invasive TCC) is obtained in cases being considered for radical treatment.
  • Staging lymphadenectomy (open or laparoscopic) may be indicated in the presence of CT-detected pelvic lymphadenopathy if radical treatment is under consideration.

Management of superficial TCC: transurethral resection of bladder tumour (TURBT) The diagnostic role of TURBT is discussed on p.252. Therapeutically, a visually complete tumour resection is adequate treatment for 70% of newly presenting patients with Ta/T1 superficial disease. The remaining 30% of patients experience early recurrence, 15% with upstaging. Because of this, it is proposed that all new patients receive adjuvant treatment (see below). Complications are uncommon, including bleeding, sepsis, bladder perforation, incomplete resection, and urethral stricture. Alternatively, transurethral laser ablation is less likely to cause bleeding but histological sampling would be inadequate. Follow-up after TURBT Most urologists perform review cystoscopy at 3 months. If this demonstrates recurrence, 70% will further recur. If not, only 20% will further recur. If the bladder is clear at follow-up, further cystoscopies are performed at 6 months and thereafter annually until the patient is no longer fit to undergo treatment. There is no accepted protocol for upper tract surveillance in patients with a history of bladder TCC, although some urologists recommend 2-yearly IVU. Transurethral cystodiathermy or laser are accepted quicker and less morbid procedures for ablating small, superficial recurrences. Patients with G3T1 TCC and CIS are at significantly higher risk of recurrence and 40% upstage. Also, some patients experience persistent symptomatic multifocal G1/2, Ta/1 recurrent TCC, demanding frequent follow-up procedures. In these circumstances, adjuvant treatment is indicated (see p.256). Patients with solid G3 disease whose biopsy material does not contain muscularis propria should be re-resected early (within a few weeks) since the possibility of muscle invasion has not been excluded. Table 7.9 summarizes the management of bladder cancer, stage by stage.

Table 7.9 A summary of the management of bladder cancer
Histology Risk of recurrence post-TURBT Risk of stage progression Further treatment Urological follow-up
G1/2, Ta/1 TCC 30% 10–15% Single-dose intravesical chemotherapy Review cystoscopies, commencing 3 months
Persistent multifocal recurrent G1/2, Ta/1 70%+ 10–15% Intravesical chemotherapy ×6 weekly doses Review cystoscopies, commencing 3 months
G3, T1 TCC 80% 40% Intravesical BCG ×6 weekly doses Review cystoscopies, commencing 6–12 weeks
CIS (carcinoma in situ, severe intraepithelial dysplasia) 80% 40% Intravesical BCG ×6 weekly doses ± maintenance Cystoscopies + biopsy and cytology, commencing 3 months
pT2/3, N0, M0 TCC, SCC, or adenocarcinoma Usually TUR is incomplete N/a Radical cystectomy, radiotherapy, or palliative TURBT (unfit) Cystoscopies if bladder is preserved; urethral washings for cytology
T4 or metastatic TCC, SCC, or adenocarcinoma Usually TUR is incomplete N/a Systemic chemotherapy; multidisciplinary team symptom palliation Palliative treatment for local bladder symptoms

Management of superficial TCC: adjuvant intravesical chemotherapy and BCG Adjuvant intravesical chemotherapy Intravesical chemotherapy (e.g. mitomycin C (MMC) 40mg in 50ml saline) is used for G1–2, Ta or T1 tumours, and recurrent multifocal TCC. MMC is an antibiotic chemotherapeutic agent that inhibits DNA synthesis. In experimental studies, it may cause regression of small papillary TCC, so should be cytotoxic for microscopic residual disease post TURBT. It significantly (40%+) reduces the likelihood of tumour recurrence compared to TURBT alone, but has never been shown to prevent progression to muscle invasion and has no impact upon survival. It is used either as a single dose within 24h of first TURBT, or weekly for 6 weeks commencing up to 2 weeks post TURBT. It is administered via a urethral catheter and held in the bladder for 1h. Other agents include doxorubicin and epirubicin. Toxicity of MMC: 15% patients report transient filling-type LUTS; occasionally a rash develops on the genitals or palms of the hands, so treatment must be stopped. Systemic toxicity is rare with MMC. Adjuvant intravesical BCG Bacille Calmette–Guérin (BCG) is an attenuated strain of Mycobacterium bovis. Commercially available strains include Pasteur, Connaught, and Tice. It acts as an immune stimulant, upregulating cytokines such as IL-6 and IL-8 in the bladder wall. BCG is given as a 6-week course for G3T1 TCC and for CIS, starting at least 2 weeks post TURBT. It is administered via a urethral catheter, 80mg in 50ml saline, and retained in the bladder for 1h. BCG produces complete responses in 60–70% of patients, compared to TURBT alone. 30% do not respond, and 30% of responders relapse within 5 years. It is more effective than MMC for adjuvant treatment of G1/2,Ta/1 TCC, but is not often used (except as second-line occasionally) because of the additional toxicity. Two studies have suggested that BCG may delay tumour progression to muscle invasion. Though less expensive and more effective, BCG is more toxic than intravesical chemotherapy, causing irritative symptoms in nearly all patients and low-grade fever with myalgia in 25%. Up to 6% of patients develop a high persistent fever, requiring anti-tuberculous therapy for up to 6 months with isoniazid and pyridoxine, or standard triple therapy (rifampicin, isoniazid, and ethambutol) in critically ill patients. Granulomatous prostatitis and epididymo-orchitis are rare complications. Contraindications include

  • Immunosuppressed patients
  • Pregnant or lactating women
  • Patients with haematological malignancy
  • After a traumatic catheterization

Cystoscopy too early after BCG can look alarming, due to generalized inflammatory response. Review cystoscopy and biopsy 3 months after BCG may still reveal chronic granulomatous inflammation. The value of maintenance BCG (e.g. 6-monthly treatments for 3 years after the initial 6-week course) is uncertain, although one study demonstrated a benefit for superficial TCC, excluding CIS, compared with a single 6-week course. Recurrent G3T1 TCC or CIS A second course of BCG could be offered; 50% will respond. Otherwise proceed without delay to radical cystectomy. The latter has a cure rate of 90%. P.258
Muscle-invasive bladder cancer: surgical management of localized (pT2/3a) disease This is a dangerous disease; untreated 5-year survival is 3%. In the absence of prospective randomized trials comparing the surgical and non-surgical treatments, the options for a patient with newly diagnosed confined muscle-invasive bladder cancer are: Bladder preserving

  • Radical transurethral resection of bladder tumour (TURBT) plus systemic chemotherapy: little data, not mainstream
  • Palliative TURBT ± palliative radiotherapy (RT): for elderly/unfit patients
  • Partial cystectomy ± neoadjuvant systemic chemotherapy
  • TURBT plus definitive RT (see p.260): poor options for SCC and adenocarcinoma as they are seldom radiosensitive

Radical cystectomy with

  • Ileal conduit urinary diversion
  • Ureterosigmoidostomy urinary diversion
  • Continent urinary diversion
  • ± Neoadjuvant chemotherapy: some evidence of benefit (see p.262)
  • ± Neoadjuvant RT: no evidence of benefit

Partial cystectomy A good option for well-selected patients with small solitary disease located near the dome, and for urachal carcinoma. Morbidity is less than with radical cystectomy. The surgical specimen should be covered with perivesical fat, with a 1.5cm margin of macroscopically normal bladder around the tumour. There should be no biopsy evidence of CIS elsewhere in the bladder. The bladder must be closed without tension and catheterized for 7–10 days to allow healing. Subsequent review cystoscopies ensure no tumour recurrence. Radical cystectomy with urinary diversion This is the most effective primary treatment for muscle-invasive TCC, SCC, and adenocarcinoma, and can be used as salvage treatment if RT has failed. It is also a treatment for G3T1 TCC and CIS, refractory to BCG. However, this is a major undertaking for the patient and surgeon, requiring support from cancer specialist nurse, stomatherapist, or continence advisor. The procedure Through a midline abdominal transperitoneal approach, the entire bladder is excised along with perivesical vascular pedicles, fat, and urachus, plus the prostate or anterior vaginal wall. The anterior urethra is not excised unless there is prior biopsy evidence of tumour at the female bladder neck or prostatic urethra (when recurrence occurs in 37%). The ureters are divided close to the bladder, ensuring their disease-free status P.259
by frozen-section histology if necessary, and anastamosed into the chosen urinary diversion (see pp.264–6). A bilateral pelvic lymphadenectomy is undertaken at the time. Some centres are pioneering laparoscopic cystectomy, though long operating times and technical considerations will probably limit this approach. Major complications Affect 25% of cystectomy patients. These include peri-operative death (1%), re-operation (10%), bleeding, thromboembolism, sepsis, wound infection/dehiscence (10%), intestinal obstruction or prolonged ileus (10%), cardio-pulmonary morbidity, and rectal injury (4%). Erectile dysfunction is likely after cystectomy due to cavernosal nerve injury. The complications of urinary diversion are discussed on pp.264–6. Post-operative care

  • Many patients will spend the first 24h in the high-dependency unit or ITU.
  • Daily clinical evaluation, including inspection of the wound (and stoma if present), plus monitoring of blood count and creatinine/electrolytes, is mandatory.
  • Broad-spectrum antimicrobial prophylaxis and thromboembolic prophylaxis with TED stockings, pneumatic calf compression, and subcutaneous heparin are standard.
  • Mobilization after 24h is ideal.
  • Chest physiotherapy and adequate analgesia is especially important in smokers and patients with chest comorbidity.
  • Oral intake is restricted until bowel sounds are present; some patients may require parenteral nutrition in the presence of gastrointestinal complications.
  • Drains are usually sited in the pelvis and near the uretero-diversion anastomosis, plus ureteric catheters passing from the renal pelves through the diversion and exiting percutaneously, plus a catheter draining the diversion (except in the case of ileal conduit) exiting urethrally or suprapubically.
  • Most patients stay in hospital 10–14 days.

Salvage radical cystectomy is technically a more difficult and slightly more morbid procedure. Relatively few patients who have failed primary RT are suitable for this second chance of a cure; fit patients with clinically localized disease. Efficacy of radical cystectomy 5-year survival rates are as follows:

• Stage T1/CIS 90+%
• Stages T2, T3a 63–88%
• Stage T3b 37–61%
• Stage T4a (into prostate) 10%
• Stage T×N1–2 30%
• Salvage T0 70%
• Salvage T1 50%
• Salvage T2, 3a 25%

Muscle-invasive bladder cancer: radical and palliative radiotherapy Radical external beam radiotherapy (RT) A good option for treating muscle-invasive (pT2/3/4) TCC in patients who are unfit or unwilling to undergo cystectomy, but who still wish to have the chance of cure. The 5-year survival rates are inferior to those of surgery, but the bladder is preserved and the complications are less significant. Typically, a total dose of 70Gy is administered in 30 fractions over 6 weeks. Higher-grade tumours tend to do less well, perhaps because of the undetected presence of disease outside the field of irradiation. Beyond this, prediction of radiotherapy response remains difficult, relying on follow-up cystoscopy and biopsy. CIS, SCC, and adenocarcinoma are poorly sensitive to radiotherapy. There may be a small benefit in the use of neoadjuvant or adjuvant cisplatin-based combination chemotherapy with RT in locally advanced (pT3b/4) disease (see p.262). Complications Occur in 70% of patients; self-limiting in 90% of cases. These include radiation cystitis (filling LUTS and dysuria) and proctitis (diarrhoea and rectal bleeding). These effects usually last only a few months. Refractory radiation cystitis and haematuria may rarely require desperate measures such as intravesical alum, formalin, hyperbaric oxygen, iliac artery embolization, or even palliative cystectomy. Efficacy of RT 5-year survival rates are as follows:

• Stage T1 35%
• Stage T2 40%
• Stage T3a 35%
• Stage T3b, T4 20%
• Stage T×N1–2 7%

If disease persists or recurs, salvage cystectomy may still be successful in appropriately selected patients; 5-year survival rates 30–50%. Otherwise, cytotoxic chemotherapy (see p.263) and palliative measures may be considered. Palliative treatment Includes radiotherapy for metastatic bone pain (30Gy) or to palliate symptomatic local tumour (40–50Gy). Intractable haematuria may be controlled by intravesical formalin or alum, hyperbaric oxygen, bilateral internal iliac artery embolization or ligation, or palliative cystectomy. Ureteric obstruction may be relieved by percutaneous nephrostomy and antegrade stenting (see p.456). Involvement of a palliative care team can be very helpful to the patient and family. P.261
Muscle-invasive bladder cancer: management of locally advanced and metastatic disease Locally advanced bladder cancer (pT3b/4) Many patients treated with primary cystectomy or radiotherapy (RT) with curative intent succumb to metastatic disease due to incomplete tumour excision or micrometastases. At this stage, 5-year survival is only 5–10%. There is interest in augmenting primary treatment in an effort to improve outcomes. Neoadjuvant RT Randomized studies have suggested improvements in local control using RT prior to cystectomy, but no survival benefit has been demonstrated. Adjuvant RT The rationale for post-cystectomy RT is that patients with proven residual or nodal disease may benefit from loco-regional treatment. However, it leads to unacceptably high morbidity and has no demonstrable advantages. Post-treatment bowel obstruction occurs 4.5 times more commonly in RT patients. Adjuvant cystectomy Two studies have demonstrated an improvement in local control and a survival advantage when treating locally advanced disease with cystectomy after RT, compared to RT alone. However, this treatment strategy does not happen in current UK practice, probably due to the increased morbidity of surgery in this setting. Neoadjuvant chemotherapy Preoperative chemotherapy could theoretically downstage the disease and treat micrometastases before the patient was debilitated by surgery. A recent meta-analysis has suggested a 5% survival advantage with the use of cisplatin-based combination chemotherapy prior to cystectomy compared with cystectomy alone. This may be offered to patients suspected of having locally advanced disease after clinical examination and staging imaging. Adjuvant chemotherapy The rationale for post-cystectomy chemotherapy is that patients with proven residual or nodal disease may benefit from systemic treatment. Trials have been hampered by protocol problems, surgical complications interfering with treatment, and difficulty in assessing response in the absence of measurable disease. However, 2 of 4 studies have shown a survival benefit of almost 2 years in the treated groups, using cisplatin-based regimes. Neoadjuvant or adjuvant chemotherapy with RT The recent meta-analysis also showed a 5% survival advantage with the use of cisplatin-based combination chemotherapy when RT was used as P.263
definitive treatment. This may be offered to patients suspected of having locally advanced disease after clinical examination and staging imaging. Metastatic bladder cancer Systemic chemotherapy This modality is routine for patients with unresectable, diffusely metastatic measurable disease. Combination therapy is more effective than single-agent treatment.

  • A complete response is seen in 20% of patients given methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), though 20% of patients develop neutropaenia and 3% die of sepsis. Long-term disease-free survival is rare. Most UK centres are using cisplatin, methotrexate, and vinblastin (CMV).
  • Gemcitobine, a relatively new antimetabolite agent, has been used alone and in combination with cisplatin, with complete responses reported in 25–40% of patients.
  • Another new class of agents, taxanes paclitaxel and docetaxel, are microtubule disassembly inhibitors. Responses range from 25–80% using these agents alone or in combination. The cost of these agents currently prohibits their use in the UK National Health Service.

Radiotherapy Roles for RT include palliation of metastatic pain, spinal cord compression. Surgery There is no surgical role in treatment of extravesical metastatic disease. P.264
Bladder cancer: urinary diversion after cystectomy Ureterosigmoidostomy The oldest form of urinary diversion, whereby the ureters drain into the sigmoid colon, either in its native form or following its detubularization and reconstruction into a pouch (Mainz II). This diversion requires no appliance (stoma bag, catheter), so remains popular in developing countries. In recreating a ‘cloaca’, the patient may be prone to upper UTI with the risk of long-term renal deterioration, metabolic hyperchloraemic acidosis, and loose, frequent stools. The low-pressure and capacious Mainz II pouch reduces these complications. Ileal conduit This was developed in 1950 and remains the most popular form of urinary diversion in the UK. 15cm of subterminal ileum is isolated on its mesentery, the ureters are anastomosed to the proximal end, the distal end is brought out in the right iliac fossa as a stoma. The ileum is anastomosed to gain enteral continuity. Complications

  • Prolonged ileus
  • Urinary leak
  • Enteral leak
  • Pyelonephriris
  • Uretero-ileal stricture
  • Stoma problems—skin irritation, stenosis, and parastomal hernia

Patients require stomatherapy support and some find difficulty in adjusting their lifestyle to cope with a stoma-bag. Metabolic complications are uncommon. In post-RT salvage patients, a jejunal or colonic conduit is used because of concerns about the healing of radiation-damaged ileum. The conduit may be brought out in the upper abdomen and patients require careful electrolyte monitoring due to sodium loss and hyperkalaemia. Continent diversion The advantage of such a diversion is the absence of an external collection device. A neobladder (pouch) is fashioned from 60cm of detubularized ileum or right hemicolon. The ureters drain into the neobladder, usually through an anti-reflux submucosal tunnel. This may be drained by the patient via a catheterizable stoma, such as the appendix or uterine tube (the ‘Mitrofanoff principle’) brought out in the right iliac fossa. Alternatively, the neobladder may be anastomosed to the patient’s urethra so that natural voiding can be established. Patients void by relaxing their external sphincter and performing a Valsalva. This orthotopic neobladder should require no catheter, unless the pouch is too large and fails to empty adequately. In this case, the patient must be prepared to perform intermittent self-catheterization.

Fig. 7.7 (a) The distal 40–44cm of resected ileum opened along the antimesenteric border with scissors. Spatulated ureters are anastomosed end to side with 4-0 running suture on either side of proximal end of afferent tubular ileal limb. Ureters are stented. (b) The two medial borders of the U-shaped, opened, distal ileal segment are oversewn with a single-layer seromuscular continuous suture. The bottom of the U is folded between the two ends of the U. (c) Before complete closure of the reservoir, a 8–10mm hole is cut into the most caudal part of the reservoir (left). Six sutures are placed between the seromuscular layer of the anastomotic area of the reservoir and the membranous urethra (right). An 18F urethral catheter is inserted. (d) Before complete closure of the pouch, a cystostomy tube is inserted and brought out suprapubically adjacent to the wound (Reproduced with permission from Studer et al. 1996)13

Popular ileal pouches include those of Studer (Fig. 7.7), Camey II, and Kock; ileo-caecal pouches include the Indiana and Mainz I. Which one is chosen often comes down to the surgeon’s preference; they carry similar complication risks. Previously irradiated bowel can safely be used to form pouches, though complications are more likely. Complications relating to neobladders include

  • Urinary leakage and peritonitis
  • Pelvic abscess
  • Stone formation
  • Catheterizing difficulties and stomal stenosis
  • Urinary incontinence and nocturnal enuresis
  • Pouch-ureteric reflux and UTI
  • Uretero-pouch anastomotic stricture
  • Late neobladder rupture

Metabolic abnormalities include early fluid and electrolyte imbalances; later, urinary electrolyte absorption may cause hyperchloraemic acidosis, and loss of small bowel may result in vitamin B12 deficiency. Metabolic acidosis is less likely in patients with normal renal function; treatment is with sodium bicarbonate and potassium citrate. Annual B12 monitoring should be undertaken, with supplementation if necessary. Adenocarcinoma may develop (5%) in intestinal conduit, neobladder, or sigmoid colon mucosa in the long term, due to the carcinogenic bacterial metabolism of urinary nitrosamines. This tends to occur near to the inflow of urine. It is therefore advisable to perform annual visual surveillance of urinary diversions after 10 years. If the urethra is in situ, annual urethroscopy and cytology is important. P.267
Transitional cell carcinoma (TCC) of the renal pelvis and ureter TCC accounts for 90% of upper urinary tract tumours, the remainder being benign inverted papilloma, fibroepithelial polyp, squamous cell carcinoma (associated with longstanding staghorn calculus disease), adenocarcimona (rare), and various rare non-urothelial tumours including sarcoma.

  • Renal pelvic TCC is uncommon, accounting for 10% of renal tumours and 4% of all TCC.
  • Ureteric TCC is rare, accounting for only 1% of all newly presenting TCC. Half are multifocal; 75% located distally; while only 3% are located in the proximal ureter.

Risk factors are similar to those of TCC in the bladder (see pp.244–5).

  • Males are affected three times as commonly as females.
  • Incidence increases with age.
  • Smoking confers a two-fold risk, and there are various occupational causes.
  • TCC does not have a genetic hereditary form, although there is a high incidence of upper tract TCC in families from some villages in Balkan countries (‘Balkan nephropathy’) that remains unexplained.

Pathology and staging The tumour usually has a papillary structure, but occasionally solid. It is bilateral in 2–4%. It arises within the renal pelvis, less frequently in one of the calyces or ureter. Histologically, features of TCC are present, described below. Staging is by the TNM classification. Spread is by:

  • Direct extension, including into the renal vein and vena cava.
  • Lymphatic spread to para-aortic, para-caval, and pelvic nodes.
  • Blood-borne spread most commonly to liver, lung, and bone.


  • Painless total haematuria (80%).
  • Loin pain (30%), often caused by clots passing down the ureter (‘clot colic’).
  • Asymptomatic when detected, associated with synchronous bladder TCC (4%).

At follow-up, ~50% of patients will develop a metachronous bladder TCC and 2% will develop contralateral upper tract TCC. Investigations Ultrasound is excellent for detecting the more common renal parenchymal tumours, but not sensitive in detecting tumours of the renal pelvis or ureter. Diagnosis is usually made on urine cytology and IVU or CTU, respectively revealing malignant cells and a filling defect in the renal pelvis or ureter. If doubt exists, selective ureteric urine cytology, retrograde pyelo-ureterography or flexible uretero-renoscopy are indicated. P.269
If ultrasound and cystoscopy are normal during the investigation of haematuria, an IVU or CT is recommended. Staging imaging is obtained by contrast-enhanced abdominal CT, chest X-ray, and, occasionally, isotope bone scan. Staging is by the TNM (1997) classification (see Table 7.10) following histological confirmation of the diagnosis. All rely upon physical examination and imaging, the pathological classification corresponding to the TNM categories. Treatment and prognosis Nephroureterectomy If staging indicates non-metastatic disease in the presence of a normal contralateral kidney, the gold standard treatment with curative intent is nephroureterectomy, open or laparoscopic. The open approach uses either a long transperitoneal midline incision or separate loin and iliac fossa incisions. The entire ureter is taken with a cuff of bladder, because of the 50% incidence of subsequent ureteric stump recurrence. Follow-up should include annual cystoscopy and IVU or CTU to detect metachronous TCC development. Percutaneous/ureterorenoscopic resection/ablation For patients with a single functioning kidney, bilateral disease, or those who are unfit, percutaneous or ureterorenoscopic resection or ablation of the tumour are the minimally invasive options. Topical chemotherapy (e.g. mitomycin C) may subsequently be instilled through the nephrostomy or ureteric catheters. This nephron-sparing approach is less likely to be curative than definitive surgery. Systemic combination chemotherapy for unresectable or metastatic disease using cyclophosphamide, methtrexate, and vincristine is associated with a 30% total or partial response at the expense of moderate toxicity. Palliative surgery or arterial embolization may be necessary for troublesome haematuria. Radiotherapy is generally ineffective. 5-year survival

• Organ-confined T1,2 60–100%
• Locally advanced T3,4 20–50%
• Node-positive N+ 15%
Pulmonary, bone metastases M+ 10%
Table 7.10 TNM staging of carcinomas of the renal pelvis and ureter
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades muscularis propria
T3 Tumour invades beyond muscularis propria into perinephric or periureteric fat or renal parenchyma
T4 Tumour invades adjacent organs or through kidney into perinephric fat
Nx Regional (para-aortic) lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node <2cm
N2 Metastasis in a single lymph node 2–5cm or multiple nodes <5cm
N3 Metastasis in a single lymph or multiple nodes >5cm
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis present

Radiological assessment of renal masses Abdominal ultrasound The first-line investigation for a patient with loin pain or a suspected renal mass. The size resolution for renal masses is 1.5cm, exhibiting variable echo patterns. Ultrasound may also detect renal cysts, most of which are simple: smooth-walled, round or oval, without internal echoes and complete transmission with a strong acoustic shadow posteriorly. If the cyst has a solid intracystic element, septations, an irregular or calcified wall, further imaging with CT is indicated. CT scan If a renal mass is detected, a thin slice CT scan before and after contrast is the most important investigation. In general, any solid enhancing renal mass is considered a renal carcinoma until proven otherwise. Even relatively avascular renal carcinomas enhance by 10–25 Hounsfield units.1 Occasionally, an isodense but enhancing area of kidney is demonstrated (‘pseudotumour’) and may correspond to a harmless hypertrophied cortical column (of Bertin) or dysmorphic segment. CT may mislead with respect to liver invasion (rare) due to ‘partial volume effect’; real-time ultrasound is more accurate. Lymphadenopathy >2cm is invariably indicative of metastases. Bosniak developed the following radiological classification of renal cysts:

  • Uncomplicated, simple (see above criteria); benign; no follow-up if asymptomatic
  • Minimally complicated; septa, calcification, hyperdense (contain blood); benign but require radiological follow-up
  • Complicated; irregular margin, thickened septa, thick irregular calcification; indeterminate, surgical exploration indicated unless there is history of trauma or infection
  • Large, irregular cyst margins with solid components internally; cystic renal carcinoma until proved otherwise; surgery required

MRI with gadolinium contrast may be used for imaging the inferior vena cava, locally advanced disease, renal insufficiency, or for patients allergic to iodinated contrast. Renal arteriography is seldom used in the diagnostic setting, but may be helpful to delineate the number and position of renal arteries in preparation for nephron-sparing surgery or surgery for horseshoe kidneys. Fine needle aspiration/needle biopsy Ultrasound or CT-guided fine needle aspiration (FNA) or needle biopsy in the investigation of renal masses is of limited value because of the accuracy of modern cross-sectional imaging, false -ve biopsy results (5–15%), plus risks of haemorrhage (5%) and tumour spillage (rare). FNA is useful for aspiration of renal abscess or infected cyst, or to diagnose suspected lymphoma or metastatic lesions. Table 7.11 provides a practical radiological classification of renal masses.

Table 7.11 Classification of renal masses by radiographic appearance
Simple cyst Complex cyst Fatty mass Others (excluding rarities)
Cyst Renal carcinoma Angiomyolipoma Renal cell carcinoma
Multiple cysts Cystic nephroma Lipoma Metastasis
Parapelvic cyst Haeorrhagic cyst Liposarcoma Lymphoma
Calyceal diverticulum Metastasis Wilms’ tumour Sarcoma Abscess
Infected cyst Tuberculosis
Lymphoma Oncocytoma
Tuberculosis Xanthogranulomatous pyelonephritis
Renal artery aneurysm Phaeochromocytoma (adrenal)
Arterio-venous malformation Wilms’ tumour (p.322)
Hydrocalyx Transitional cell carcinoma

Footnote 1 Hounsfield units are a measure of X-ray atenuation applied to CT scanning: -1000 units equates with air, 0 units equates with water, and +1000 equates with bone. P.273
Benign renal masses The most common (70%) are simple cysts, present in >50% of >50-year-olds. Rarely symptomatic, treatment by aspiration or laparoscopic de-roofing is seldom considered. Most benign renal tumours are rare; the two most clinically important are oncocytoma and angiomyolipoma. Oncocytoma This is uncommon, accounting for 3–7% of renal tumours. Males are twice as commonly affected as females. They occur simultaneously with renal cell carcinoma in 7–32% of cases. Pathology Oncocytomas are spherical, capsulated, brown/tan colour, mean size 4–6cm. Half contain a central scar. They may be multifocal and bilateral (4–13%) and 10–20% extend into perinephric fat. Histologically, they comprise aggregates of eosinophillic cells, packed with mitochondria. Mitoses are rare and they are considered benign, not known to metastasize. There is often loss of the Y chromosome. Presentation Oncocytomas often (83%) present as an incidental finding, or with loin pain or haematuria. Investigations Oncocytoma cannot often be distinguished radiologically from RCCs; may coexist with RCC. Rarely, they exhibit a ‘spoke-wheel’ pattern on CT scanning, caused by stellate central scar. Percutaneous biopsy is not recommended since it often leads to continuing uncertainty about the diagnosis. Treatment Radical or partial nephrectomy is indicated, as for renal carcinoma. No follow-up is necessary. Angiomyolipoma (AML) 80% of these benign clonal neoplasms (hamartomas) occur sporadically; mostly middle-aged females. 20% are in association with tuberous sclerosis (TS)—an autosomal dominant syndrome characterized by mental retardation, epilepsy, adenoma sebaceum, and other hamartomas. 50% of TS patients develop AMLs; mean age 30 years; 66% female; frequently multifocal and bilateral. Pathology AML is composed of blood vessels, smooth muscle, and fat. They are always considered benign, although extrarenal AMLs have been reported in venous system and hilar lymph nodes. Macroscopically, it looks like a well-circumscribed lump of fat. Solitary AMLs are more frequently found in the right kidney. P.275
Presentation AMLs frequently present as incidental findings (>50%) on ultrasound or CT scans. They may present with flank pain, palpable mass, or painless haematuria. Massive and life-threatening retroperitoneal bleeding occurs in up to 10% of cases (Wunderlich’s syndrome). Investigations Ultrasound reflects from fat, hence a characteristic bright echo pattern. This does not cast an ‘acoustic shadow’ beyond, helping to distinguish an AML from a calculus. CT shows fatty tumour as low-density (Hounsfield units <10) in 86% of AMLs. If the proportion of fat is low, a definite diagnosis cannot be made. Measurement of the diameter is relevant to treatment. Treatment In studies, 52–82% of patients with AML >4cm are symptomatic compared with only 23% with smaller tumours. Therefore, asymptomatic AMLs can be followed with serial ultrasound if <4cm, while those bleeding or >4cm should be treated surgically or by embolization. Emergency nephrectomy or selective renal artery embolization may be life-saving. In patients with TS, in whom multiple bilateral lesions are present, conservative treatment should be attempted. P.276
Renal cell carcinoma: epidemiology and aetiology Renal cell carcinoma—also known as hypernephroma (since it was erroneously believed to originate in the adrenal gland), clear cell carcinoma, and Grawitz’s tumour—is an adenocarcinoma. It is the most common of renal tumours, accounting for 85% of renal malignancies and 2% of all cancer deaths. In the UK, 3676 patients were diagnosed (1999) and just over 2000 patients died of renal cell carcinoma (RCC) (2001). RCC is the most lethal of all urological tumours, approximately 40% of patients dying of the condition. Incidence has increased since the 1980s when ultrasound was introduced to investigate non-specific abdominal symptoms. It occurs in sporadic (common) and hereditary (rare) forms. Aetiology Males are affected twice as commonly as females; peak incidence of sporadic RCC is 6th–8th decade. Environmental Studies have shown associations with:

  • urban dwelling
  • low socio-economic status
  • tobacco chewing
  • smoking cigarettes, pipe, or cigars (1.4–2.3-fold risk)
  • renal failure and dialysis (30-fold risk)
  • obesity
  • hypertension (1.4–2-fold risk)
  • asbestos exposure
  • the analgesic phenacitin
  • thorium dioxide

Nutrition is considered important: Asian migrants to Western countries are at increased risk of RCC; vitamins A, C, E, and fruit/vegetable consumption are protective. Anatomical risk factors include polycystic and horseshoe kidneys. Genetic von Hippel Lindau (VHL) syndrome 50% of individuals with this autosomal dominant syndrome, characterized by phaeochromocytoma, renal and pancreatic cysts, and cerebellar haemangioblastoma, develop RCC, often bilateral and multifocal. Patients typically present in 3rd, 4th, or 5th decades. VHL syndrome occurs due to loss of both copies of a tumour suppressor gene at chromosome 3p25–26; this and other genes on 3p are also implicated in causing the common sporadic form of RCC. Inactivation of the VHL gene leads to effects on gene transcription, including dysregulation of hypoxia inducible factor 1 (HIF-1), an intracellular protein that plays an important role in the cellular response to hypoxia and starvation. This results in upregulation of vascular endothelial growth factor (VEGF), the most prominent angiogenic factor in RCC, explaining why some RCCs are highly vascular. P.277
A papillary variant of RCC also has an autosomal dominant familial component, characterized by trisomy 7 and 17, with activation of the c-MET proto-oncogene. c-MET encodes the receptor tyrosone kinase for hepatocyte growth factor, which regulates epithelial proliferation and differentiation in a wide variety of organs, including the normal kidney. P.278
Renal cell carcinoma: pathology, staging, and prognosis RCC is adenocarcinoma of the renal cortex, believed to arise from proximal convoluted tubule. Usually tan coloured and solid, 7–20% are multifocal, 10–20% contain calcification, and 10–25% contain cysts or are predominantly cystic. Rarely grossly infiltrative, they are usually circumscribed by a pseudocapsule of compressed tissue. Spread

  • By direct extension to adrenal gland (7.5% in tumours >5cm), through the renal capsule, into renal vein (5% at presentation), inferior vena cava (IVC), right atrium
  • By lymphatics to hilar and para-aortic lymph nodes
  • Haematogenous to lung (75%), bone (20%), liver (18%), and brain (8%).

Histological classification of RCC

  • Conventional (70–80%): arise from the proximal tubule; highly vascular; cells clear (glycogen, cholesterol) or granular (eosinophillic cytoplasm, mitochondria)
  • Papillary (10–15%): papillary, tubular, and solid variants; 40% multifocal; small incidental tumours could equate with Bell’s legendary ‘benign adenoma’
  • Chromophobe (5%): arises from the cortical portion of the collecting duct; possess a perinuclear halo of microvesicles
  • Collecting duct (Bellini): rare; young patients; poor prognosis
  • Medullary cell: rare; arises from calyceal epithelium; young, black, sickle-cell sufferers; poor prognosis.

The term ‘sarcomatoid’ is used to describe an infiltrative, poorly differentiated variant of any type. Genetic changes associated with RCC are described on p.276. RCC is an unusually immunogenic tumour, expressing numerous antigens (e.g. RAGE-1, MN-9). Reports of spontaneous regression, prolonged stabilization, and complete responses to immunotherapy support this. Tumour-infiltrating lymphocytes are readily obtained from RCCs including T-helper, dendritic, natural killer, and cytotoxic T cells. Efforts are ongoing to refine immunotherapy for RCC (see p.288). RCC is also unusually vascular, overexpressing angiogenic factors, principally VEGF but also basic FGF and TGF-β. Grading is by the Fuhrman system (1 = well-differentiated; 2 = moderately differentiated; 3 and 4 = poorly differentiated) based on nuclear size, outline, and nucleoli. Staging is by the TNM (1997) classification following histological confirmation of the diagnosis (see Fig. 7.8 and Table 7.12). All rely upon physical examination and imaging; the pathological classification (prefixed ‘p’) corresponds to the TNM categories. Staging is the most important prognostic indicator for RCC.

Fig. 7.8 Renal cell carcinoma staging. (a) Primary tumour limited to kidney (T1/T2). (b) Primary tumour invading perinephric fascia or adrenal gland (T3a). (c) Primary tumour extends into renal veins or IVC below diaphragm (T3b); above diaphragm/into right atrium (T3c); outside perinephric fascia (e.g. into liver, bowel, or posterior abdominal wall) (T4). (d) N and M staging: multiple para-aortic/para-caval nodes; pulmonary, bone, or brain metastases (T1–4N2M1)

Prognosis—5-year survival

• Organ-confined T1 90–100%
T2 60–95%
• Capsular transgression/adrenal T3a 60–70%
• Renal vein or IVC thrombus T3b/c 50–80% (25% with IVC wall invasion)
• Visceral/lymph node involvment T4 or N+ 5–30%
• Distant metastasis M+ 5–30%
Table 7.12 TNM staging of RCC
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour <7cm, limited to the kidney
T2 Tumour >7cm, limited to the kidney
T3 Tumour extends outside the kidney, but not beyond Gerota’s (perinephric) fascia
T3a: tumour invades adrenal gland or perinephric fat
T3b: tumour grossly extends into renal vein or sub-diaphragmatic IVC
T3c: tumour grossly extends into supra-diaphragmatic IVC or heart
T4 Tumour invades beyond Gerota’s fascia
Nx Regional (para-aortic) lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single node
N2 Metastasis in 2 or more nodes
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis present

Renal cell carcinoma: presentation and investigations More than 50% of RCCs are now detected incidentally on abdominal imaging carried out to investigate vague or unrelated symptoms. Thus, the stage at diagnosis of RCC is lower than it was in the pre-ultrasound era. Presentation Of the symptomatic RCCs diagnosed, 50% of patients present with haematuria, 40% with loin pain, 30% of patients notice a mass, and 25% have symptoms or signs of metastatic disease (night sweats, fever, fatigue, weight loss, haemoptysis). Less than 10% patients exhibit the classic triad of haematuria, pain, and mass. Less common presenting features include acute varicocoele due to obstruction of the testicular vein by tumour within the left renal vein (5%), and lower limb oedema due to venous obstruction. Paraneoplastic syndromes due to ectopic hormone secretion by the tumour occur in 10–40% of patients; these may be associated with any disease stage (Table 7.13). Investigations

  • Radiological evaluation of haematuria, loin pain, and renal masses is described on p.272.
  • Needle biopsy of renal masses is not recommended, since the result may be misleading and complications include haemorrhage and seeding of the biopsy tract.
  • Urine cytology and culture should be normal.
  • Full blood count may reveal polycythaemia or anaemia.
  • Serum creatinine and electrolytes, calcium and liver function tests are essential.

When RCC is diagnosed radiologically, staging chest CT and bone scan (if clinically indicated) will follow. Any suggestion of renal vein or IVC involvement on CT may be further investigated with MRI. Angiography may be helpful in planning partial nephrectomy or surgery for horseshoe kidneys. Contralateral kidney function is assessed by uptake and excretion of CT contrast and the serum creatinine. If doubt persists, an isotope renogram is obtained.

Table 7.13 Paraneoplastic syndromes
Syndrome associated with RCC Cause
Anaemia Haematuria, chronic disease
Polycythaemia Ectopic secretion of erythropoeitin
Hypertension (25%) Ectopic secretion of renin, renal artery compression, or A-V fistula
Hypoglycaemia Ectopic secretion of insulin
Cushing’s Ectopic secretion of ACTH
Hypercalcaemia (10–20%) Ectopic secretion of parathyroid hormone-like substance
Gynaecomastia, amenorrhoea, reduced libido, baldness Ectopic secretion of gonadotrophins
Stauffer’s syndrome: hepatic dysfunction, fever, anorexia Unknown; resolves in 60–70% of patients post-nephrectomy

Renal cell carcinoma: surgical treatment I Surgery is the mainstay of treatment for RCC. Increases in diagnosis of smaller early-stage RCC and the concept of cytoreductive surgery for advanced disease has impacted on surgical treatment strategies of the disease, while reduction in mortality remains elusive. Localized disease—radical nephrectomy Open approach Though undergoing critical review due to the success of the newer approaches below, this remains the gold standard curative treatment of localized RCC. The aim is to excise the kidney with Gerota’s fascia, perhaps with ipsilateral adrenal gland (tumours >5cm) and regional nodes (controversial), removing all tumour with adequate surgical margins. Surgical approach is transperitoneal (good access to hilar vessels) or thoraco-abdominal (for very large or T3c tumours). Following renal mobilization, the ureter is divided; ligation and division of the renal artery or arteries should ideally take place prior to ligation and division of the renal vein to prevent vascular swelling of the kidney. If present, excision of hilar or para-aortic/para-caval lymph nodes will improve pathological tumour staging. Complications include mortality up to 2% from bleeding or embolism of tumour thrombus; bowel, pancreatic, splenic, or pleural injury. Laparoscopic approach Well accepted for treating benign disease, this approach appears suitable for T1 (<7cm) RCCs. Approaches are either transperitoneal or retroperitoneal. The specimen is removed whole or morselated in a bag through an iliac incision. Advantages over open surgery include less pain, reduced hospital stay, and quicker return to normal activity. Morbidity is reported in 8–38% of cases, including pulmonary embolism and poorly understood effects on renal function. Long-term (10-year) results are not yet available, but reports of 5-year disease-specific survival >90% for T1 tumours are respectable. Localized disease—partial nephrectomy Nephron-sparing surgery is the best option for multifocal, bilateral tumours, particularly if the patient has VHL syndrome or single functioning kidney when the prospect of renal replacement therapy looms; it has become acceptable to treat small (<4cm) tumours, even with a normal contralateral kidney, unless the tumour is close to the pelvicalyceal system. Arteriography or 3-dimensional CT reconstructions are helpful to the surgeon. Open transperitoneal or loin approaches are used; laparoscopic partial nephrectomy is difficult in the best of hands. The renal artery is clamped and the kidney packed with crushed ice. Generally, results are comparable with open surgery. Specific complications include failure of complete excision of the tumour(s) leading to local recurrence in up to 10% of cases, and urinary P.285
leak from the collecting system. Some patients develop hyperfiltration renal injury, eventually require renal replacement therapy: proteinuria is a prognostic sign. Laparoscopic partial nephrectomy is under evaluation at time of writing. Post-operative follow-up aims to detect local or distant recurrence (incidence 7% for T1N0M0, 20% for T2N0M0, and 40% for T3N0M0) to permit additional treatment if indicated. After partial nephrectomy, concern will also focus on recurrence in the remnant kidney. There is no consensus regarding the optimal regime: typically, stage-dependent 6-monthly clinical assessment and annual CT imaging of chest and abdomen for 3–10 years. P.286
Renal cell carcinoma: surgical treatment II Localized RCC—lymphadenectomy Lymph node involvement in RCC is a poor prognostic factor. Incidence ranges from 6% in T1–2 tumours, to 46% in T3a, to 62–66% in higher stage disease. Lymphadectomy at time of nephrectomy may add prognostic information, especially if there is obvious lymphadenopathy, but therapeutic benefit remains unclear. Formal lymphadenectomy adds time and increases blood loss, while nodes are clear in about 95% of cases. Localized RCC—treatment of local recurrence Though uncommon, if there is local recurrence in the renal bed after radical nephrectomy, surgical excision remains the preferred treatment choice, provided there are no signs of distant disease. Local recurrence is more common after partial nephrectomy, where it can be treated by a further partial or total nephrectomy. Localized RCC—alternatives to surgery

  • Observation: small (<3cm) solid, well-marginated renal masses may be safely followed with repeat scans in elderly or unfit individuals; growth is slow and metastasis rare.
  • Cryosurgery: performed using intra-operative ultrasound by open, percutaneous, or laparoscopic routes; this is an emerging nephron-sparing treatment option.
  • High-intensity focused ultrasound: this extra-corporeal minimallyinvasive yet highly accurate treatment is under evaluation.

Locally advanced RCC Disease involving the IVC right atrium, liver, bowel, or posterior abdominal wall demands special surgical skills. In appropriate patients, an aggressive surgical approach involving a multidisciplinary surgical team to achieve negative margins appears to provide survival benefit. Adjuvant treatment

  • Radiotherapy: early studies suggested a role for pre-operative RT, though recent studies have failed to show a survival benefit for either pre- or post-operative RT. It may retard growth of residual tumour after nephrectomy.
  • Immunotherapy: randomized trials of adjuvant immunotherapy versus observation alone are ongoing for patients with positive nodes, surgical margins, and venous invasion.

Metastatic RCC Nephrectomy has long been indicated for palliation of symptoms (pain, haematuria) in patients with metastatic RCC (if inoperable, arterial embolization can be helpful). There appeared to be no other tangible benefit to surgery. But recently, a median survival benefit of 10 months for patients with good performance status treated with cytoreductive P.287
nephrectomy prior to immunotherapy (interferon-α) was reported. This has further expanded the indications for surgery in RCC. Resection of solitary metastases is an option for a few patients, usually a few months after nephrectomy, thereby ensuring the lesion remains solitary. P.288
Renal cell carcinoma: management of metastatic disease Surgery ~25% of patients with RCC exhibit metastatic disease at presentation; 20–30% progress subsequently to this stage following nephrectomy. The prognosis is poor, so despite the rare possibility of spontaneous metastatic regression following nephrectomy, it was not usually undertaken except to relieve local symptoms of pain or haematuria. The case for nephrectomy in metastatic RCC has re-opened, as discussed on p.286. Metastasectomy may be of benefit to the 1.5–3% of patients who develop a solitary metastasis (particularly in lung, adrenal, or brain) following nephrectomy. Hormone therapy and chemotherapy little role in RCC. Radiotherapy useful for palliation of metastatic lesions in bone and brain, and in combination with surgery for spinal cord compression. Immunotherapy The immunogenicity of RCC is discussed on p.278. The first cytokines to be used therapeutically, to activate anti-tumour immune response, were interferons and, subsequently, interleukin-2 (IL-2). Randomized studies in the 1990s demonstrated modest response rates (10–20%) after systemic immunotherapy using these cytokines alone and in combination; toxicity could be severe. Responses were more likely in patients with good performance status, prior nephrectomy, and small-volume metastatic burden. An MRC trial of interferon-? versus medroxyprogesterone demonstrated a 2.5- month survival advantage in the immunotherapy group. The current first-line treatment of metastatic RCC is single-agent immunotherapy (interferon-? or interleukin-2) preceded by nephrectomy in selected patients. Under investigation:

  • Combination immunotherapy in early trials suggests a higher response rate with significant but manageable toxicity.
  • Adoptive immunotherapy lymphocytes or dendritic cells (the most efficient of the antigen-presenting cells) obtained from the tumour are expanded ex vivo in the presence of cytokines and tumour antigens, then returned to the patient as an autologous vaccine.
  • Gene therapy using tumour cell lines or autologous tumour cells, transfected ex vivo with cytokines, subsequently irradiated, and administered as a vaccine.
  • Anti-angiogenic therapy. As discussed on p.276, most RCCs are highly angiogenic, so should be a good therapeutic target for angiogenesis inhibitors currently in development (e.g. Thalidomide) in combination with immunotherapy or used alone as third-line treatment.

Palliative care Steroids (e.g. dexamethazone 4mg qds) improve appetite and mental state, but are unlikely to impact on tumour growth. The involvement of multidisciplinary uro-oncology, palliative, and primary care teams is essential to support these patients and their relatives. P.290
Testicular cancer: epidemiology and aetiology Incidence and mortality Primary testicular cancer (TC) is the most common solid cancer in men aged 20–45; rare below 15 years and above 60 years. Constituting 1–2% of all male cancers, the lifetime risk of developing testicular cancer is 1 in 500. It is also considered the most curable cancer, with 1990 new cases but only 68 deaths in the UK (2001). It is increasing in incidence; reported to affect 7 per 100,000 men. Public health campaigns encouraging testicular self-examination (TSE) for young men are ongoing. Epidemiology and aetiology

  • Age: the most common affected age group is 20–45 years, with germ cell tumours; teratomas are more common at ages 20–35; while seminoma is more common at ages 35–45 years. Rarely, infants and boys below 10 years develop yolk sac tumours and 50% men >60 years with TC have lymphoma.
  • Race: white people are three times more likely to develop TC than black people in the USA.
  • Cryptorchidism: 10% of TC occur in undescended testes: the risk increases by 3–14 times compared to men with normally descended testes. Ultrastructural changes are present in these testes by age 3 years, although earlier orchidopexy does not completely eliminate the risk of developing TC. 5–10% of patients with a cryptorchid testis develop malignancy in the normally descended contralateral testis.
  • Intratubular germ cell neoplasia (IGCN): synonymous with carcinoma in situ, although the disease arises from malignant change in spermatogonia. 50% of cases develop invasive germ cell TC within 5 years. The population incidence is 0.8%. Risk factors include cryptorchidism, extra-gonadal germ cell tumour, previous or contralateral TC (5%), atrophic contralateral testis, 45XO karyotype, and infertility.
  • Human immunodeficiency virus (HIV): patients infected with the HIV virus are developing seminoma more frequently than expected.
  • Genetic factors appear to play a role, given that first-degree relatives are at higher risk, but a defined familial inheritance pattern is not apparent.
  • Maternal oestrogen ingestion during pregnancy increases the risk of cryptorchidism and TC in the male offspring.

Trauma and viral-induced atrophy have not been convincingly implicated as risk factors for TC. Bilateral testicular cancer occurs in 1–2% of cases. P.291
Testicular cancer: clinical presentation Symptoms Most patients present with a scrotal lump, usually painless or slightly aching. Delay in presentation is not uncommon, particularly those with metastatic disease. This may be due to patient factors (fear, self-neglect, ignorance, denial) or earlier misdiagnosis. Occasionally (5%) acute scrotal pain may occur, due to intra-tumoural haemorrhage, causing diagnostic confusion. The lump may have been noted by the patient, sometimes after minor trauma, or by his partner. In 10%, symptoms suggestive of advanced disease include weight loss, lumps in the neck, chest symptoms, and bone pain. Signs Examination of the genitalia should be carried out in a warm room with the patient relaxed. Observation may reveal asymmetry or slight scrotal skin discolouration. Using careful bimanual palpation, the normal side is first examined, followed by the abnormal side. This will reveal a hard, non-tender, irregular, non-transilluminable mass in the testis, or replacing the testis. Care should be taken to assess the epididymis, spermatic cord, and overlying scrotal wall, which may be normal or involved in 10–15% of cases. Rarely, a secondary hydrocoele may be present if the tunica albuginea has been breached. General examination may reveal cachexia, supraclavicular lymphadenopathy, chest signs, hepatomegaly, lower limb oedema, or abdominal mass—all suggestive of metastatic disease. Gynaecomastia is seen in ~5% of patients with TC, due to endocrine manifestations of some tumours. Differential diagnosis Testicular torsion, epididymo-orchitis, hydrocoele, epidiymal cyst, hernia, haematoma, or syphilitic gumma (rare). The majority of scrotal lumps are harmless lesions, but no risks should be taken. Every patient who is concerned should be seen, examined, and if any doubt persists, should be investigated further. Investigations Ultrasound is an extension of the physical examination and will confirm that the palpable lesion is within the testis, distorting its normally regular outline and internal echo pattern. Any hypoechoic area within the tunica albuginea should be regarded with suspicion. It may distinguish a primary from a secondary hydrocoele. Ultrasound may also be used to identify impalpable lesions as small as 1–2mm—an ‘occult’ primary tumour in a patient presenting with systemic symptoms and signs or an incidental finding. Abdominal and chest CT scans are usually obtained for staging purposes if the diagnosis of TC is confirmed or considered likely. Serum tumour markers are measured prior to any treatment of a confirmed testicular mass (p.294). P.293
Treatment Radical orchidectomy The final investigation and the primary treatment for all testicular tumours, unless tissue diagnosis has been made from a metastasis. This involves excision of the testis, epididymis, and cord, with their coverings, through a groin incision. The cord is clamped, transfixed, and divided near the internal inguinal ring before the testis is manipulated into the wound, preventing inadvertent metastasis. A silicone prosthesis may be inserted at the time or at a later date. This treatment is curative in ~80% of patients. Fertility prophylaxis by freezing sperm should be offered to patients without a normal contralateral testis. Contralateral testis biopsy should be considered in patients at high risk for IGCN (see p.290). P.294
Testicular cancer: serum markers Germ cell tumours may express and secrete into the bloodstream relatively specific and readily measurable proteins. These tumour markers (with the exception of PLAP) are useful in diagnosis, staging, prognostication (see p.301), and monitoring of response to treatment (see pp.302–4). Onco-fetal proteins Alpha-fetoprotein (AFP) is expressed by trophoblastic elements within 50–70% of teratomas and yolk sac tumours. With respect to seminoma, the presence of elevated serum AFP strongly suggests a non-seminomatous element. Serum half-life is 3–5 days; normal <10ng/ml. Human chorionic gonadotrophin (hCG) is expressed syncytiotrophoblastic elements of choriocarcinomas (100%), teratomas (40%), and seminomas (10%). Serum half-life is 24–36h. Assays measure the ?-subunit; normal <5mIU/ml. When used together, 90% of patients with advanced disease have elevation of one or both markers; less among patients with low-stage tumours. Cellular enzymes Lactate dehydrogenase (LDH) is a ubiquitous enzyme, elevated in serum for various causes, therefore less specific. It is elevated in 10–20% of seminomas, correlating with tumour burden, and is most useful in monitoring treatment response in advanced seminoma. Placental alkaline phosphatase (PLAP) is a fetal isoenzyme, elevated in up to 40% of patients with advanced germ cell tumours. It is not widely used as it is non-specific. May be elevated in smokers. Clinical use These markers are measured at presentation, 1–2 weeks after radical orchidectomy, and during follow-up to assess response to treatment and residual disease. Normal markers prior to orchidectomy do not exclude metastatic disease; normalization of markers post orchidectomy cannot be equated with absence of disease; and persistent elevations of markers post- orchidectomy may occur with liver dysfunction and hypogonadotrophism, but usually indicate metastatic disease. S Staging

• Sx Markers not available
• S0 Markers normal
• S1 LDH 1–1.5 × normal upper limit; hCG <5000 mIU/ml; and AFP <1000ng/ml
• S2 LDH 1.5–10 × normal; hCG 5000–50,000; and AFP 1000–10,000
• S3 LDH >10 × normal; hCG >50,000; and AFP >10,000

Testicular cancer: pathology and staging 90% of testicular tumours are malignant germ cell tumours (GCT), split into seminomatous and non-seminomatous (NS) GCTs for clinical purposes. Seminoma, the most common germ cell tumour, appears pale and homogeneous. NSGCTs are heterogeneous and sometimes contain bizarre tissues such as cartilage or hair. Metastases to the testis are rare, notably from the prostate (35%), lung (19%), colon (9%), and kidney (7%). Table 7.14 shows the WHO histopathological classification of testicular tumours. The right testis is affected slightly more commonly than the left; synchronous bilateral TC occurs in 2% of cases. TC spreads by local extension into the epididymis, spermatic cord, and, rarely, the scrotal wall. Lymphatic spread occurs via the testicular vessels, initially to the para-aortic nodes. Involvement of the epididymis, spermatic cord, or scrotum may lead to pelvic and inguinal node metastasis. Blood-borne metastasis to the lungs, liver, and bones is more likely once the disease has breached the tunica albuginea. TC is staged using various classifications, most recently the TNM (2002) system (see Fig. 7.9 and Table 7.15). Herein, T stage is pathological, N stage involves imaging, and M stage involves physical examination, imaging, and biochemical investigations. An additional S category is appended for serum tumour markers (see p.294).

Table 7.14 The WHO histopathological classification of testicular tumours
Germ cell tumours (90%)
Seminoma (48%)
• Spermatocytic, classical, and anaplastic subtypes
Non-seminomatous GCT (42%)
• Teratoma:
• Yolk sac tumour
• Choriocarcinoma
• Mixed NSGCT
Mixed GCT (10%)
Other tumours (7%)
• Epidermoid cyst (benign)
• Adenomatoid tumour
• Adenocarcinoma of the rete testis
• Carcinoid
• Lymphoma (5%)
• Metastatic, from another site (1%)
Sex cord stromal tumours (3%) (10% malignant)
• Leydig cell
• Sertoli cell
• Mixed or unclassified
Mixed germ cell/sex cord tumours (rare)
Fig. 7.9 Pathological staging of testicular cancer. (a) Primary tumours T1–T4. If radical orchidectomy has not been used, Tx is used. (b) Node/metastasis: para-aortic lymphadenopathy, measured in long axis on CT scan (upper figures); supraclavicular lymphadenopathy and/or pulmonary metastases—M1a, other distant metastases (e.g. liver, brain)—M1b (lower figure)
Table 7.15 TNM staging of testicular germ cell tumours
Tx The primary tumour has not been assessed (no radical orchidectomy)
T0 No evidence of primary tumour
Tis Intratubular germ cell neoplasia (carcinoma in situ)
T1 Tumour limited to testis and epididymis without vascular invasion; may invade tunica albuginea but not tunica vaginalis
T2 Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour involving tumica vaginalis
T3 Tumour invades spermatic cord with or without vascular invasion
T4 Tumour invades scrotum with or without vascular invasion
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis with a lymph node ≤ 2cm or multiple lymph nodes, none >2cm
N2 Metastasis with a lymph node size 2–5cm or multiple lymph nodes, collected size 2–5cm
N3 Metastasis with a lymph node mass >5cm
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1a Non-regional lymph node or pulmonary metastasis
M1b Distant metastasis other than to non-regional lymph node or lungs

Testicular cancer: prognostic staging system for metastatic germ cell cancer The International Germ Cell Cancer Collaborative Group (IGCCCG) has devised a prognostic factor-based staging system for metastatic germ cell cancer that includes good and intermediate prognosis seminoma and good, intermediate, and poor prognosis non-seminomatous germ cell tumours (NSGCT) (Table 7.16). See p.294 for discussion on testicular tumour markers, including S staging.

Table 7.16 IGCCCG staging system for metastic germ cell cancer
  Seminoma NSGCT
Good 90% of patients 56% of patients
5-year progression-free survival 86% 92%
All factors listed present: Any primary site;no non-pulmonary visceral metastases; normal AFP;any hCG or LDH Testis or retroperitoneal primary site; no non-pulmonary visceral metastases; AFP <1000ng/ml;hCG <5000mIU/l; and LDH <1.5×normal upper limit (S1)
Intermediate 10% of patients 28% of patients
5-year progression-free survival 73% 80%
All factors listed present: Any primary site;non-pulmonaryvisceral metastases present; normal AFP;Any hCG or LDH Testis or retroperitoneal primary site; no non-pulmonary visceral metastases; AFP 1000–9999ng/ml or hCG 5000–49999mIU/l;LDH 1.5–10×normal upper limit (S2)
Poor   16% of patients
5-year progression-free survival No patients classified as poor prognosis 48%
All factors listed present:   Mediastinal primary;non-pulmonary visceral metastases present; AFP >10,000ng/ml or hCG >50,000mIU/l; LDH >10×normal upper limit (S3)

Testicular cancer: management of non-seminomatous germ cell tumours (NSGCT) Following radical orchidectomy and formal staging, the patient is normally managed by the oncologist, though the urologist may be asked to perform retroperitoneal lymph node dissection (RPLND) in selected cases. In the presence of elevated AFP, a seminoma would be managed as for teratoma. Combination chemotherapy, introduced in the 1980s, revolutionized the treatment of metastatic testicular teratoma, which was hitherto virtually untreatable. Treatment and follow-up varies between the UK and USA. In the UK, it depends largely on the IGCCCG prognostic staging (see p.301), as follows: Non-metastatic disease T1–4N0M0S0: surveillance or chemotherapy (bleomycin, low-dose etoposide, cisplatin × 2 cycles) depending on risk factors for relapse (lymphatic or vascular invasion, T2–4); surveillance in presence of risk factors results in 25% relapse rate, most <1 year post orchidectomy. Metastatic disease Good prognosis: chemotherapy (bleomycin, etoposide, cisplatin × 3 cycles); RPLND for residual or recurrent mass; salvage chemotherapy if histology confirms tumour. Intermediate and poor prognosis: chemotherapy (bleomycin, etoposide, cisplatin × 4 cycles); RPLND for residual or recurrent mass; salvage chemotherapy if histology confirms tumour. Surveillance and follow-up after treatment Surveillance requires the following:

  • Year 1: monthly clinic visit with serum markers and chest X-ray, abdominal CT months 3,6,9, and 12 months
  • Year 2: 2-monthly clinic visit with serum markers and chest X-ray, abdominal CT month 24
  • Years 3,4, and 5: 3-monthly clinic visit with serum markers and chest X-ray
  • Annual clinic visit with serum markers and chest X-ray, thereafter to 10 years

Follow-up after treatment is slightly less intensive, also to 10 years. The risk of relapse is highest in the first 2 years. RPLND

  • Retroperitoneal lymphadenopathy is usually the first and only evidence of extra-gonadal metastasis of teratoma.
  • In the UK, RPLND is used only to remove or de-bulk residual mass post chemotherapy.
  • P.303

  • RPLND may remove viable tumour in 10–30% of patients, taking para-aortic nodes up to the origin of the superior mesenteric artery and down to the iliac bifurcation.
  • Complications: 1% mortality and 25% morbidity includes lymphocoele, pancreatitis, ileus and ejaculatory failure.
  • Modified techniques reduce the risk of ejaculatory disturbance, by taking nodes on the unaffected side only down to the inferior mesenteric artery.
  • In the USA, RPLND remains the gold standard staging investigation following radical orchidectomy.

Testicular cancer: management of seminoma, IGCN, and lymphoma Of all seminomas, 75% are confined to the testis at presentation and are cured by radical orchidectomy; 10–15% of patients harbour regional node metastasis; and 5–10% have more advanced disease. Following radical orchidectomy and formal staging, the patient is managed by the oncologist. Treatment and follow-up depends largely on disease stage according to presence of metastases and size of nodal disease, as follows: Non-metastatic disease T1N0M0S0–1: risk of subsequent para-aortic node relapse is 20%. Adjuvant radiotherapy (RT)—20Gy in 10 fractions—reduces risk to 1%. RT includes para-aortic nodes. Early results of a randomized MRC study comparing one cycle of carboplatin with radiotherapy suggest equivalence. Spermatocytic subtype usually warrants surveillance. Metastatic disease T1–3 N1 M0S0–1: RT T1–3 N2 M0 S0–1: RT; chemotherapy if nodes near kidneys. T1–4 N3 M0 S0–1: chemotherapy (either bleomycin, etoposide, and cisplatin or etoposide and cisplatin); if residual node mass >3cm (rare), retroperitoneal lymph node dissection (RPLND) considered; if histology reveals tumour (30%), salvage chemotherapy. T1–4N0–3M1–2S0–3: chemotherapy; if residual node mass (rare), RPLND considered; if histology reveals tumour (30%), salvage chemotherapy. Patients should also be classified into prognostic grouping classification (IGCCCG—see p.301) as this provides an overall prognosis for patients. These patients require careful long-term follow-up, according to national guidance. Management of intratubular germ cell neoplasia

  • Observation or orchidectomy for unilateral disease.
  • Radiotherapy for unilateral disease in the presence of a contralateral tumour.
  • Radiotherapy for bilateral disease, to preserve Sertoli cells.
  • Systemic chemotherapy (e.g. cisplatin) controversial, not currently adopted in UK.
  • Frozen sperm storage must be offered.

Management of testicular lymphoma This may be a primary disease or a manifestation of disseminated nodal lymphoma. The median age of incidence is 60 years, but has been reported in children. 25% of patients present with systemic symptoms; 10% have bilateral testicular tumours. These patients have a poorer prognosis following radical orchidectomy and chemotherapy, while those with localized disease may enjoy long-term survival. P.305
Penile neoplasia: benign, viral-related, and premalignant lesions Benign tumours and lesions Non-cutaneous

  • Congenital and acquired inclusion cysts
  • Retention cysts
  • Syringomas (sweat gland tumours)
  • Neurilemoma
  • Angioma, lipoma
  • Iatrogenic pseudo-tumour following injections
  • Pyogenic granuloma following injections
  • Peyronies plaque (early or atypical)


  • Pearly penile papules (normal in 15% of post-pubertal males)
  • Zoon’s balanitis (shiny, erythematous plaque on glans or prepuce)
  • Lichen planus (flat-topped violacious papule)

Viral-related lesions

  • Condyloma acuminatum: also known as genital warts, related to human papillomavirus (HPV) infection. Soft, usually multiple benign lesions on the glans, prepuce, and shaft; may occur elsewhere on genitalia or perineum. A biopsy is worthwhile prior to topical treatment with podophyllin. 5% have urethral involvement, which may require diathermy. HPV infection (particularly types 16 and 18) is potentially carcinogenic and condylomata have been associated with penile SCC.
  • Bowenoid papulosis: a condition resembling carcinoma in situ, but with a benign course. Multiple papules appear on the penile skin, or flat glanular lesion. These should be biopsied. HPV is the suspected cause.
  • Kaposi’s sarcoma: first described in 1972, this reticulo-endothelial tumour has become the second most common malignant penile tumour. It presents as a raised, painful, bleeding violacious papule, or as a bluish ulcer with local oedema. It is slow-growing, solitary, or diffuse. It occurs in immunocompromised men, particularly in homosexuals with HIV/AIDS. Urethral obstruction may occur. Treatment is palliative; intralesional chemotherapy, laser, cryoablation, or radiotherapy.

Premalignant cutaneous lesions Some histologically benign lesions are recognized to have malignant potential or occur in close association with SCC of the penis.

  • Cutaneous horn: rare, solid skin overgrowth; extreme hyperkeratosis, the base may be malignant; treatment is wide local excision.
  • Pseudoepitheliomatous micaceous and keratotic balanitis: unusual hyperkeratotic growths on the glans; require excision, histological examination, and follow-up, as they may recur.
  • Balanitis xerotica obliterans (BXO): also known as lichen sclerosus et atrophicus, this is a common sclerosing condition of glans and P.307
    prepuce. It occurs at all ages and most commonly presents as non-retractile foreskin (phimosis). The meatus and fossa navicularis may be affected, causing obstructed and spraying voiding. The histological diagnosis is usually made after circumcision, with epithelial atrophy, loss of rete pegs, and collagenization of the dermis. BXO occurs in association with penile SCC, but most pathologists would regard the lesion as benign unless epithelial dysplasia was present.
  • Leukoplakia: solitary or multiple whiteish glanular plaques that usually involve the meatus. Treatment is excision and histology. Leukoplakia is associated with in situ SCC; follow-up is required.
  • Erythroplasia of Queyrat: also known as carcinoma in situ of the glans, prepuce, or penile shaft. A red, velvety, circumscribed painless lesion, though it may ulcerate resulting in discharge and pain. Treatment is excision biopsy if possible; radiotherapy, laser ablation, or topical 5-fluorouracil may be required. Histology reveals hyperplastic mucosal cells with malignant features.
  • Bowen’s disease: this is carcinoma in situ of the remainder of the keratinizing genital or perineal skin. Treatment is wide local excision, laser, or cryoablation.
  • Buschke–Löwenstein tumour: also known as verrucous carcinoma or giant condyloma acuminatum, this is an aggressive locally invasive tumour of the glans. Metastasis is rare, but wide excision is necessary to distinguish it from SCC. Urethral erosion and fistulation may occur.

A chronic red or pale lesion on the glans or prepuce is a cause for concern. Note should be made of its colour, size, and surface features. Early review following steroid, antibacterial, or antifungal creams is recommended; if persistent, biopsy is advised. P.308
Penile cancer: epidemiology, risk factors, and pathology Squamous cell carcinoma (SCC) is the most common penile cancer, accounting for 95% of penile malignancies. Others include Kaposi’s sarcoma (see p.306) and, rarely, basal cell carcinoma, melanoma, sarcoma, Paget’s disease. Metastases are occasionally seen from bladder, prostate, rectum, and other primary sites. Incidence and aetiology of SCC Penile cancer is rare, representing 1% of male cancers. The incidence appears to be decreasing, most occurring in elderly men. ~400 new cases and 100 deaths are reported annually in the UK. Risk factors for SCC

  • Age: penile cancer incidence rises during the 6th decade and peaks in the 8th decade. It is unusual <40 years, but has been reported in children.
  • Premalignant lesions: 42% of patients with penile SCC are reported to have had a pre-existing penile lesion (see pp.306–7).
  • A prepuce (foreskin): penile cancer is rare in men circumcised at a young age. It is virtually non-existent in Israel. It is thought that chronic irritation with smegma and inflammation (balanitis) is contributory.
  • Highest incidence worldwide is in Brazil.
  • Human papilloma virus (HPV) wart infection, especially with types 16, 18, and 21.
  • Smoking and tobacco products.

Pathology and staging of penile SCC Believed to be preceded by carcinoma in situ, SCC starts as a slow-growing papillary, flat or ulcerative lesion on the glans (48%), prepuce (21%), glans and prepuce (9%), coronal sulcus (6%), or shaft (2%). The remainder are indeterminate. It grows locally beneath the foreskin before invading the corpora cavernosa, urethra, and, eventually, the perineum, pelvis, and prostate. Metastasis is initially to the superficial then deep inguinal and, subsequently, iliac and obturator lymph nodes. Skin necrosis, ulceration, and infection of the inguinal lymph nodes may lead to sepsis or haemorrhage from the femoral vessels. Blood-borne metastasis to lungs and liver is rare (1–10% of cases). Histologically, SCC exhibits keratinization, epithelial pearl formation, and mitoses. Grading is low (75%), intermediate (15%), or high (10%); grading correlates with prognosis, as does the presence of vascular invasion. Staging is by the TNM system (see Fig. 7.10 and Table 7.17).

Fig. 7.10 Pathological staging of penile cancer. (a) Primary tumour; (b) N and M stages
Table 7.17 TNM staging of penile carcinoma
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
Ta Non-invasive verrucous carcinoma
T1 Tumour invades sub-epithelial connective tissue
T2 Tumour invades corpus cavernosum or spongiosum
T3 Tumour invades urethra or prostate
T4 Tumour invades other structures
Nx Regional nodes cannot be assessed
N0 No regional lymph node metastases
N1 Single superficial inguinal lymph node metastasis
N2 Multiple or bilateral superficial inguinal lymph node metastases
N3 Metastases in deep inguinal or pelvic lymph nodes, unilateral or bilateral
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

Squamous cell carcinoma of the penis: clinical management Presentation A hard, painless lump on the glans penis is the most common presentation. 15–50% of patients delay presentation for >1 year due to embarrassment, personal neglect, fear, or ignorance. A bloody discharge may be confused with haematuria. Rarely, a groin mass or urinary retention are presenting symptoms. Examination reveals a solid non-tender mass or ulcer beneath or involving the foreskin. There is usually evidence of local infection. In more advanced disease, prepuce, glans, shaft, scrotum, and even perineum are replaced by tumour. The inguinal lymph nodes are examined. They may be enlarged, fixed, or even ulcerate overlying skin. Investigations A biopsy is indicated. Chest radiology, pelvic CT scan, serum calcium and liver function tests are usually obtained. Treatment The management of penile cancer should take place in regional or supra-regional centres that can provide multidisciplinary surgical and oncological expertise. The primary tumour

  • The first-line treatment of penile cancer, regardless of the inguinal node status, is surgery.
  • Circumcision is appropriate for preputial lesions, but local recurrence observed in 22–50%.
  • Penis-preserving wide excision of glanular lesions with skin graft glanular reconstruction may be suitable for smaller G1–2 Ta–1 tumours, giving good cosmetic and functional results.
  • Alternatives to surgery include laser or cryoablation, radiotherapy or brachytherapy, photodynamic therapy, or topical 5-fluorouracil.
  • For G3T1 and more advanced tumours, partial or total penile amputation is required, depending on the extent of the tumour. Partial amputation is preferable, provided a 2cm margin of palpably normal shaft can be obtained. The patient must be prepared for poor cosmetic and functional results: inability to have sexual intercourse and need to sit to void urine. Local recurrence occurs in 10%, if the excision margin is positive. Total amputation involves excision of the scrotum and its contents, with formation of a perineal urethrostomy. The most common complication is urethral meatal stenosis. Radiotherapy remains an alternative, but disadvantages include radio-resistance, leading to reported recurrence rates of 30–60%; tissue necrosis and damage leading to urethral stricture, fistula, and pain. Patients with M1 disease are offered palliative surgery.

Lymphadenopathy Six weeks of broad-spectrum antimicrobials (e.g. Augmentin) are given after the primary tumour has been removed. Nodes become clinically insignificant in 50% of patients, who may then be followed-up. For those with persistent inguinal lymphadenopathy, in the absence of demonstrable pelvic or metastatic disease, bilateral inguinal lymphadenectomy should be considered, since 5-year survival is 80%. Even if lymphadenopathy is unilateral, >50% will have contralateral metastases. However, this is major surgery with a high morbidity including lymphoedema, thromboembolism, and wound breakdown, so it is not suitable for elderly or unfit men. Fine needle aspiration cytology is not recommended since a negative result will not alter treatment. Radiotherapy and chemotherapy are alternative or adjuvant treatments for metastatic nodal disease in unfit, elderly, or inoperable patients; 5-year survival 25%. Rarely, lymphadenopathy ulcerates the skin, may encase the femoral vessels, and invade the deeper musculature. In these circumstances, collaboration with plastics and vascular surgeons is necessary if surgery is considered appropriate. Prophylactic lymphadenectomy is currently practised in the USA for tumours exhibiting vascular invasion, high grade, or stages T2–4, without randomized evidence of benefit. It is argued that the risk of metastatic disease with palpably normal groins is greater than 20% and delayed lymphadenectomy could reduce the chance of cure. 20–30% of patients with inguinal metastases will also have pelvic node involvement. Distant metastatic disease is treated using single-agent systemic chemotherapy: cisplatin, bleomycin, or methotrexate. Responses are partial and short-lived in 20–60% of patients. Experience with combination chemotherapy is increasing. 5-year survival

• Node-negative SCC, after surgery 65–90%
• Inguinal node metastases 30%
Metastatic SCC <10%

Carcinoma of the scrotum Originally described in Victorian chimney sweeps, by Percival Pott, it was the first cancer to be associated with an occupation. A rare disease <50 years of age, chronic exposure of the scrotal skin to soot, tar, or oil is the cause. A squamous cell carcinoma, it presents as a painless lump or ulcer, often purulent, on the anterior or posterior (therefore not obvious if the patient is lying or sitting) scrotal wall. Inguinal lymphadenopathy may suggest metastasis or reaction to infection.

  • Treatment of a mass or ulcer on the scrotum is wide local excision.
  • Antimicrobials are administered for six weeks if there is lymphadenopathy, then the groins are re-evaluated.
  • Inguinal lymphadenectomy, with adjuvant chemotherapy, is considered if lymphadenopathy persists.

Supraclavicular lymphadenopathy, haematogenous visceral, and bony metastasis are rare and carry a poor prognosis. P.315
Tumours of the testicular adnexa Epithelial tumours arising from the epididymis and paratesticular tissues are rare; they are mostly of mesenchymal origin. Adenomatoid tumours small solid tumours arising in the epididymis or on the surface of the tunica albuginea; usually present without change for several years; benign vacuolated epithelial and stromal cells; origin unknown; treatment is local excision. Cystadenoma of the epididymis benign epithelial hyperplasia; young adults; often asymptomatic; one third bilateral and associated with VHL syndrome. Mesothelioma presents as a firm, painless, scrotal mass associated with hydrocoele which gradually enlarges; any age group; 15% metastatic to inguinal nodes; treated with orchidectomy and follow-up. Paratesticular tumours Rhabdomyosarcoma: scrotal mass in 1st/2nd decade; in spermatic cord, compresses testis and epididymis; lymphatic spread to para-aortic nodes; treatment is multimodal radical orchidectomy with radiotherapy and chemotherapy; 5-year survival 75%. Leiomyoma/sarcoma: scrotal mass, age 40–70 years; in spermatic cord; 30% malignant, 70% benign; haematogenous distant spread; treatment is wide excision or radical orchidectomy. Liposarcoma: spermatic cord tumour; 70% malignant. P.316
Urethral cancer Primary urethral cancer is rare, occurring in elderly patients; 4 times more common in women. Risk factors urethral stricture and sexually transmitted disease implicated. Direct spread from tumour in the bladder or prostate is more common. Pathology and staging 75% are SCC, occurring in the anterior urethra; 15% are TCC, occurring in the posterior/prostatic urethra; 8% are adenocarcinoma; the remainder include sarcoma and melanoma. Urethral cancer metastasises to the pelvic lymph nodes from the posterior urethra and to the inguinal nodes from the anterior urethra in 50% of patients. Staging is by the TNM system (see Table 7.18) following histological confirmation of the diagnosis. Presentation

  • Often late; many patients have metastatic disease at presentation
  • Painless haematuria; initial, terminal, or a bloody urethral discharge
  • Voiding-type LUTS (less common)
  • Perineal pain (less common)
  • Periurethral abscess or urethro-cutaneous fistula (rare)
  • Past history of sexually transmitted or stricture disease

Examination may reveal a hard palpable mass at the female urethral meatus or along the course of the male anterior urethra. Inguinal lymphadenopathy, chest signs, and hepatomegaly may suggest metastatic disease. Differential diagnosis In men

  • Urethral stricture
  • Perineal abscess
  • Metastatic disease involving the corpora cavernosa
  • Urethro-cutaneous fistula (secondary to benign stricture disease)

In women

  • Urethral caruncle
  • Urethral cyst
  • Urethral diverticulum
  • Urethral wart (condylomata acuminata)
  • Urethral prolapse
  • Periurethral abscess

Investigations Cysto-urethroscopy, biopsy, and bimanual examination under anaesthesia will obtain a diagnosis and local clinical staging. Chest radiography and abdomino-pelvic CT scan will enable distant staging.

Table 7.18 TNM staging of urethral carcinoma
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Urethra (male and female)
Ta Non-invasive papillary carcinoma
Tis Carcinoma in situ
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades corpus spongiosum, prostate, or periurethral muscle
T3 Tumour invades corpus cavernosum, prostatic capsule, vagina, or bladder neck
T4 Tumour invades adjacent organs including bladder
Transitional cell carcinoma of the prostatic urethra
Tis Carcinoma in situ, prostatic urethra (pu) or prostatic ducts (pd)
T1 Tumour invades subepithelial connective tissue
T2 Tumour invades prostatic stroma, corpus spongiosum, or periurethral muscle
T3 Tumour invades through prostatic capsule, corpus cavernosum, or bladder neck
T4 Tumour invades adjacent organs including bladder
Nx Regional (deep inguinal and pelvic) lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single lymph node <2cm in greatest dimension
N2 Metastasis in a single lymph node >2cm in greatest dimension
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis present

Treatment For localized anterior urethral cancer, radical surgery or radiotherapy are the options. Results are better with anterior urethral disease. Male patients would require perineal urethrostomy. Post-operative incontinence due to disruption of the external sphincter mechanism is minimal unless the bladder neck is involved, but the patient would need to sit to void. For posterior/prostatic urethral cancer, cystoprostatourethrectomy should be considered for fit men, while anterior pelvic exenteration (excision of the pelvic lymph nodes, bladder, urethra, uterus, ovaries, and part of the vagina) should be considered for women. In the absence of distant metastases, inguinal lymphadenectomy is performed if nodes are palpable, since 80% contain metastatic tumour. For locally advanced disease, a combination of preoperative radiotherapy and surgery is recommended. For metastatic disease, chemotherapy is the only option. 5-year survival

• Surgery: anterior urethra 50%
• Surgery: posterior urethra 15%
• Radiotherapy 34%
• Radiotherapy and surgery 55%

Staging is by the TNM (1997) classification following histological confirmation of the diagnosis (see Table 7.18). All rely upon physical examination and imaging, the pathological classification (prefixed ‘p’) corresponding to the TNM categories. P.319
Retroperitoneal fibrosis Retroperitoneal fibrosis (RPF) was first clearly described by the French urologist, Albarran, at the beginning of the 20th century. Benign causes

  • Idiopathic RPF comprises two thirds of benign cases. A fibrous plaque extends laterally and downwards from the renal arteries encasing the aorta, inferior vena cava, and ureters, but rarely extends into the pelvis. The central portion of the plaque consists of woody scar tissue, while the growing margins have the histological appearance of chronic inflammation. It may be associated with mediastinal, mesenteric, or bile-duct fibrosis.
  • Drugs including methysergide, betablockers, haloperidol, amphetamines, and LSD.
  • Chronic urinary infections including TB and syphilis.
  • Inflammatory conditions such as Crohn’s disease or sarcoidosis.
  • Abdominal aortic aneurysm (AAA), intra-arterial stents, and angioplasty may induce idiopathic fibrosis due to peri-aortitis, haemorrhage, or an immune response to insoluble lipoprotein.

Malignant causes

  • Lymphoma is the most common cause; also sarcoma.
  • Metastatic or locally infiltratative carcinoma of the breast, stomach, pancreas, colon, bladder, prostate and carcinoid tumours.
  • Radiotherapy may cause RPF, although rare today with precise field localization.
  • Chemotherapy, especially following treatment of metastatic testicular tumours, may leave fibrous masses encasing the ureters. These may or may not contain residual tumour.


  • Idiopathic RPF classically occurs in the 5th or 6th decade of life.
  • Men are affected twice as commonly as women.
  • In the early stage, symptoms are relatively non-specific, including loss of appetite and weight, low-grade fever, sweating, and malaise. Lower limb swelling may develop. Dull, non-colicky abdominal or back pain is described in up to 90% of patients.
  • Later, the major complication of the disease develops: bilateral ureteric obstruction causing anuria and renal failure.
  • Examination may reveal hypertension in up to 60% of patients and an underlying cause such as an AAA.


  • Inflammatory serum markers are elevated in idiopathic RPF (60–90% elevated ESR).
  • Pyuria or bacteriuria are common.
  • Ultrasound will demonstrate uni- or bilateral hydronephrosis.
  • CT, IVU, or ureterography reveal tapering medial displacement of the ureters with proximal dilatation and will exclude calculus disease. P.321
    Up to one third of patients will have a non-functioning kidney at the time of presentation due to longstanding obstruction.
  • CT-guided fine needle or laparoscopic biopsy of the mass may confirm the presence of malignant disease, but a negative result does not exclude malignancy.


  • Emergency management of a patient presenting with established renal failure requires relief of the obstruction by percutaneous nephrostomy or ureteric stenting.
  • Replacement of fluid and electrolyte losses following relief of bilateral ureteric obstruction is vital due to the frequent post-obstructive diuresis.
  • Assess with daily weighing and measurement of blood pressure lying and standing.
  • Steroids may decrease the oedema often associated with RPF and in this way help reduce the obstruction. If used, they are usually discontinued when inflammatory markers return to normal. The anti-oestrogen tamoxifen and cyclophosphamide have been used successfully in some patients.
  • Surgical ureterolysis with omental wrap is often necessary to free and insulate the ureters from the encasing fibrous tissue.
  • Biopsies are taken to exclude malignancy.
  • Monitor for recurrent disease with serum creatinine and ultrasound 3–6 monthly for 5 years.

Wilms’ tumour and neuroblastoma Wilms’ tumour This is a rare childhood tumour, affecting 1 in 10,000 children. It represents 80% of all genitourinary tumours affecting children under 15 years. Males and females are equally affected. 20% are familial and 5% are bilateral. 75% present under the age of 5 years. Pathology and staging Wilms’ tumour is a soft pale grey tumour (it looks like brain). It contains blastema, epithelial and connective tissue components. Mutation or deletion of both copies (alleles) of the chromosome 11p WT-1 tumour suppressor gene results in tumourigenesis. The familial disease exhibits autosomal dominant inheritance, but is recessive at the cellular level. Affected family members harbour a germ-line WT-1 mutation, conferring susceptibility. One further ‘hit’ is required, while two ‘hits’ are required to cause the sporadic disease. This explains why hereditary Wilms’ tumours tend to develop multifocally and at a slightly younger age than sporadic counterparts. Tumour staging relates to the relationship of the tumour to the renal capsule, excision margins, and local lymph nodes at nephrectomy, as well as the presence of soft tissue (typically lung) or bone metastases. Presentation 90% have a mass; 33% complain of abdominal or loin pain; 30–50% develop haematuria; 50% are hypertensive; and 15% exhibit other anomalies such as hemihypertrophy, aniridia, and cryptorchidism. Investigations The first-line investigation for a child with an abdominal mass or haematuria is ultrasound, which will reveal a renal tumour. Further diagnostic imaging and staging is obtained by CT, including the chest. Treatment and prognosis Children with renal tumours should be managed by a specialist paediatric oncology centre. Staging nephrectomy, with or without pre-operative or post-operative chemotherapy, remains the mainstay of treatment. The chemotherapy most frequently used is actinomycin D, vincristine and doxorubicin. Survival is generally good, at 92% overall, ranging from 55% to 97% according to stage and histology. Neuroblastoma The most common extracranial solid tumour of childhood. 80% are diagnosed <4 years old. The tumour is of neural crest origin; 50% occur in the adrenal gland and most of the remainder arise along the sympathetic trunks. Presentation Systemic symptoms and signs are common: fever, abdominal pain/distension, mass, weight loss, anaemia, and bone pain. Retro-orbital metastases may cause proptosis. P.323
Imaging and staging Ultrasound initially; CT of chest and abdomen. Calcification in tumour helps distinguish neuroblastoma from Wilms’ tumour. MIBG scans are very sensitive for detection of neuroblastomas.

• Stage 1 Tumour confined to organ of origin and grossly complete excision
• Stage 2 Unilateral tumour with residual disease post resection or lymphadenopathy
• Stage 3 Tumour crossing midline or contralateral nodes
• Stage 4 Metastatic disease beyond regional nodes; survival 6%
• Stage 4S Unilateral tumour with metastasis limited to liver, skin, or bone marrow; survival 77%

Treatment and prognosis Surgical excision; radiotherapy; combination chemotherapy, possibly with autologous bone marrow transplantation. Stage 4S tumours may resolve with little or no treatment. Prognosis is poor except for Stages 1 and 4S disease. References 1 Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JL (2001) Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millenium. Urology 58(6):843. 2 Albertsen PC, Hanley JA, Gleason DF, et al. (1998) Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically-localized prostate cancer. JAMA 280:975–80 3 Holmberg L, Bill-Axelson A, Helgesen F, et al. (2002) A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. NEJM 347:781–89. An update has recently been published: Bill-Axelson A, Holmberg L, Ruutu M, et al. (2005) Radical prostatectomy versus watchful waiting in early prostate cancer. NEJM 352:1977–84. 4 Pound CR, Partin AW, Eisenberger MA, et al. (1999) Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591–97. 5 Swanson GP, Riggs MW, Earle JD (2002) Long-term follow-up of radical retropubic prostatectomy for prostate cancer. Eur Urol 42:212–16. 6 Brewster SF (1999) Pre-operative p53, bcl-2, CD44 and E-cadherin immunohistochemistry as predictors of biochemical relapse after radical prostatectomy. J Urol 161:1238–43. 7 D’Amico AV, Manola J, Loffredo M, et al. (2004) 6-month androgen suppression plus radiation therapy vs radiation therapy alone for localized prostate cancer, a randomized controlled trial. JAMA 292:821–27. 8 Ragde H, Korb LJ, Elgamal AA, et al. (2000) Modern prostate brachytherapy. Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up. Cancer 89:135–41. 9 Bolla M, Collette L, Blank L, et al. (1997) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. NEJM 337:295–300. 10 Tannock IF, de Wit R, Berry WR, et al. (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. NEJM 351:1502–12. 11 Thompson IM, Goodman PJ, Tangen CM, et al. (2003) The influence of finasteride on the development of prostate cancer. NEJM 349:215–24. 12 Brewster S, Cranston D, Noble J, Reynard J (2001) Urology: A Handbook for Medical Students. BIOS Scientific Publishers, p. 97. 13 Studer UE, Danuser H, Hochreiter W, et al. (1996) Summary of 10 years’ experience with an ileal low-pressure substitute combined with an afferent tubular isoperistaltic segment. World J Urol 14:29–39.

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