Risk factors

The risk factors for urothelial cell cancers are well established (Table 21.18.1) and include male sex, increasing age, and smoking. Occupational exposure to aromatic amines, dyes, and anilines in the dye, rubber, textile and chemical industries increases the risk. The metabolism of aromatic amines involves acetylation through a polymorphic enzyme (N-acetyltransferase 2), with slow acetylator status appearing to be a risk factor. Chronic inflammation associated with schistosomiasis infection predisposes to squamous cell carcinoma and treatment with cyclophosphamide (through its metabolite acrolein) predisposes to bladder cancer. Radiotherapy to the pelvis for the treatment of gynaecological malignancy increases the risk of distal ureteric transitional cell carcinoma fourfold.

The vast majority of bladder cancer is sporadic and related to cigarette smoking, but one rare genetic syndrome (Lynch’s syndrome—hereditary nonpolyposis colon cancer, OMIM 120435) caused by mutations in DNA mismatch repair genes increases the risk of right-sided colon cancer and transitional cell carcinoma of the upper urinary tract.

Some Chinese medicines containing aristocholic acid are a cause of Chinese herb nephropathy, and this agent is likely to be the cause of Balkan nephropathy, both of which are strongly associated with upper urinary tract urothelial cell carcinoma (see Chapter 21.9.2).

Genetic changes

Oncogenes and tumour suppressor genes are involved in the pathogenesis of bladder cancer, and there are mutually exclusive genetic alterations that lead to the development of either papillary noninvasive transitional cell carcinoma (stage pTa) or high-grade invasive carcinomas. The most common sporadic genetic mutations in low-grade transitional cell carcinoma are loss of heterozygosity of chromosome 9 and alterations in fibroblast growth factor (FGF) 3. By contrast, high-grade invasive cancers most frequently show loss of tumour suppressor genes which affect the cell cycle such as TP53, RB, and E2F3. Loss of chromosome 8p and alterations in methylation of cytosine residues of particular genes in DNA are also associated with tumour progression in this high-grade invasive group. In the future such alterations may lead to new biomarkers of bladder cancer.

Staging and grading

Histological grade is usually ascribed as grade (G) 1, 2 or 3, with grade 1 tumours being at low risk of future progression and—regardless of tumour stage—grade 3 disease being at high risk for progression and development of metastatic disease.

Clinical bladder cancer staging follows the TNM classification (Table 21.18.2; Fig. 21.18.1). The most important issues are whether the local tumour is muscle invasive (T2 or above) or localized to the urothelium only (Ta), or invading lamina propria (pT1)and whether there is any evidence of metastatic disease to pelvic lymph nodes, bone or lung. Traditionally, bladder cancers were described as either superficial (located in the urothelium or lamina propria—pTa or pT1) or muscle invasive. This division arose on the basis that superficial disease may be resected completely endoscopically via the urethra using electrocautery, but unfortunately this distinction does not truly reflect the risk to patients from a T1G3 bladder cancer or carcinoma in situ, up to one-third of whom will die of bladder cancer.

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Fig. 21.18.1

Staging of bladder cancer.

Low-risk noninvasive bladder cancer—TaG1, TaG2

These tumours comprise most of all new bladder cancers (60%), usually present with painless macroscopic haematuria, and are easily diagnosed using flexible cystoscopy under local anaesthetic. Treatment is by endoscopic resection under either spinal or general anaesthesia: a cystoscope is inserted into the bladder through the urethra and electrocautery is used to remove the lesion.

The tumours are usually papillary and are often found on a stalk and fronded, but may be multifocal and will recur locally in the bladder in about 75% of patients in the long term. The risk of progression to muscle-invasive disease with TaG1 disease is extremely low. The risk of recurrent superficial disease can be reduced by the instillation of chemotherapeutic agents (mitomycin C) into the bladder immediately following endoscopic resection. These chemotherapeutic drugs have a high molecular weight, which means that they are usually not absorbed through the bladder mucosa or associated with neutropenia or other systemic side effects.

Patients with noninvasive bladder cancer require long-term endoscopic surveillance of the bladder until they have been free of recurrence disease for 5 years.

High-risk superficial bladder cancer—TaG3, T1G3, carcinoma in situ

Poorly differentiated high-grade bladder tumours have a different genetic profile from low-risk tumours, more akin to muscle-invasive tumours. It is uncommon for a low-risk cancer (pTa, G1, or G2) to progress to a high-risk one, but progression of pT1 or pTa G3 disease to muscle invasion occurs commonly. Isolated TaG3 disease progresses to muscle-invasive disease in up to 40% of patients after 5 years in the absence of aggressive local therapy following endoscopic resection. Adjuvant treatment in the form of intravesical immunotherapy with BCG (bacille Calmette–Guérin) is offered to such patients. This is instilled in to the bladder once per week for 6 weeks, its mechanism of action being via stimulation of T cells that coordinate an immune response to destroy residual disease and reduce the risk of future recurrence. A diagnosis of TaG3 or T1G3 disease should prompt an early second endoscopic resection as the risk of understaging of the first resection is around 20% and some patients will have muscle-invasive disease. If no evidence of muscle invasion is found on repeat resection, a 6-week course of BCG with maintenance dosing every 3 months is advised, or cystectomy can be offered.

Carcinoma in situ is an aggressive intraepithelial neoplasia with a high risk of progression to solid muscle-invasive tumours. It is also treated with intravesical BCG, to which up to 65% of people will respond. Recurrent disease should be treated by cystectomy, if the patient is fit.

Muscle invasive bladder cancer

One in four new bladder tumours are found to be muscle invasive on resection, and up to 50% of these have overt or covert metastases at presentation. Patients with muscle-invasive bladder tumour require staging with a bimanual rectal or vaginal examination at the time of resection to designate a clinical T stage. Staging is completed with a CT scan of the abdomen, pelvis, and chest (Fig. 21.18.2). Routine biochemistry should be checked and if the alkaline phosphatase is elevated a bone scan should be performed.

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Fig. 21.18.2

CT scan of the pelvis showing a transitional cell carcinoma of the bladder (arrowhead) demonstrating muscle invasion (arrows).

A patient with muscle-invasive bladder cancer and no evidence of metastatic disease requires aggressive local treatment. Treatment options for the local tumour include either surgery or radiotherapy. Based on a recent Cochrane analysis, radical cystectomy has an overall survival benefit compared to radiotherapy. It is also generally accepted that surgery provides better local control at the expense of higher risk. Some patients (e.g. those with small pT2 lesions away from the trigone of the bladder) will respond well to resection and radiation, or chemoradiation. Radical surgery involves cystoprostatectomy in men and cystectomy, hysterectomy, and oophorectomy in women (anterior exenteration). An extended pelvic lymph node dissection is also performed: this provides prognostic information and is therapeutic for patients with low-volume micrometastatic disease. Urinary diversion is then established by means of an ileal conduit (incontinent cutaneous diversion), or bladder substitution (folding 55 cm of small bowel into a sphere and anastomosing it to the urethra—continent urethral diversion), or a continent cutaneous reservoir (less common, as it frequently requires reoperation).

Alternative local therapy can be provided by means of radiotherapy to the bladder. The major benefit of this approach is that it allows bladder preservation, thereby avoiding the many long-term side effects of urinary diversion. However, it does place the patient at risk of developing a second muscle-invasive bladder cancer. Overall up to 50% of patients have persistent or subsequent recurrent disease in the bladder, and up to 30% will require a subsequent cystectomy.

Bladder cancer is moderately chemosensitive, hence systemic chemotherapy is an option as either neo-adjuvant or adjuvant treatment for patients with muscle-invasive bladder cancer. Neo-adjuvant treatment in the form of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) provides a 5 to 7.5% overall survival benefit for patients who subsequently undergo radical cystectomy or radiation treatment. Chemotherapy is also used in patients with node-positive disease or lymphovascular space invasion at the time of cystectomy, although many are too debilitated following surgery to receive chemotherapy.

Metastatic transitional cell carcinoma

Patients with regional metastatic disease to lymph nodes in the pelvis can be given chemotherapy if they are fit enough. This may result in complete radiological resolution, after which cystectomy can be performed. If residual active cancer is identified in the pelvic lymph nodes or there is invasion of the lymphovascular space, then the patient has a very poor prognosis.

Patients with nonregional metastatic disease to bones, liver, lungs, or abdominal lymph nodes have a very low 5-year survival. Chemotherapy can be offered if the patient has good performance status. Palliative radiotherapy to the bladder helps in local control and reduces haematuria, or ureteric obstruction which can lead to renal failure.

Transitional cell carcinoma of the kidney or ureter

Patients with high-grade bladder cancer are at risk of developing upper-tract transitional cell carcinoma (c.5%). Other specific risk factors for its development are listed in Table 21.18.1. Presentations can include haematuria, loin pain or loin mass. Investigations for assessment of upper tract tumours include intravenous urograms and CT urograms to assess for filling defects in the collecting system. Ureteropyeloscopy with washings and biopsy are used to visualize the tumour and obtain a cytological and histological diagnosis. Accurate staging, grading, and surveillance of the upper tracts is difficult and recurrence rates are high, hence these patients are generally best treated with nephroureterectomy if the contralateral kidney is normal. Ureteropyeloscopy and laser can be used for treatment of small, low grade tumours. Annual cystoscopy is recommended thereafter because over 50% of patients with new upper-tract transitional cell carcinoma will go on to develop transitional cell carcinoma of the bladder.

Risk factors

The risk factors for sporadic renal cell carcinoma include increasing age, male sex, and cigarette smoking, obesity and hypertension. Smoking conveys a relative risk of twofold for developing conventional renal cell carcinoma and is the most consistent of studied risk factors. Patients on dialysis may develop acquired cystic disease of the kidneys, which increases the risk of renal cell carcinoma between 5 and 30 times. Patients with a previous history of sporadic renal cell carcinoma treated with radical nephrectomy have a 1% risk per decade of developing a metachronous tumour.

Patients with inherited cancer syndromes associated with renal cell carcinoma develop multifocal tumours at a younger age than those with sporadic renal cell carcinoma. Von Hippel–Lindau syndrome (OMIM 193300) has several different subtypes, with differing likelihood of developing renal cell carcinoma. Family members tend to develop renal tumours at the same age as the index case, hence screening is performed at the appropriate ages in younger probands. Cumulative exposure to radiation is an important consideration in the long-term follow-up of such patients: wherever possible MRI and ultrasonography are used for screening.

Genetic changes

There are both sporadic and genetic (familial) forms of renal cell carcinoma. Genetic renal cell carcinoma is associated with Von Hippel–Lindau syndrome. Hereditary papillary renal cell carcinoma comes in two forms: type I associated with mutations in the receptor for hepatocyte growth factor, c-MET; and type II associated with mutations in the fumarate hydratase gene. Birtt–Hogge–Dube syndrome (OMIM 135150) is associated with chromophobe carcinoma, and there are other rare inherited syndromes. Knowledge of kidney cancer genetics has been derived mainly from studying these several rare inherited syndromes.

The genetic alterations in von Hippel–Lindau syndrome are found in a tumour suppressor gene located on chromosome 3 at locus 3p25–26. Individuals with von Hippel–Lindau syndrome inherit the abnormality of this tumour suppressor gene as a germ-line mutation, with tumours developing in an individual with subsequent knock-out of the single normal gene either by mutation, deletion, or methylation, hence this tumour follows Knudson’s two-hit hypothesis (see Chapter 6.2). In sporadic renal cell carcinoma nearly 100% of tumours also show loss of 3p 25–26, with the mutations in chromosome 3 in sporadic RCC forming a wider spectrum than those seen in von Hippel–Lindau syndrome. A protein known as hypoxia inducible factor 1 α (HIF-1α) is part of the normal cellular mechanism for adaptation to hypoxia, allowing cells to grow and survive under hypoxic conditions (such as those seen with rapid growth of solid tumours) by inducing the expression of angiogenic growth factors such as VEGF. The von Hippel–Lindau tumour suppressor gene product normally targets HIF1-α for destruction in the proteosome by means of ubiquitinylation. In its absence the end result is that high levels of VEGF drive tumorigenesis, and drive the marked angiogenesis that is such a feature of renal cell carcinoma (Fig. 21.18.3).Small-molecule inhibitors of VEGF have now been developed for clinical use.

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Figure 21.18.3

VHL gene mutation leading to decreased degradation of HIF and accumulation of cytokines that drive tumour genesis. From Linehan WM, Walther MM, Zbar B (2003). The genetic basis of cancer of the kidney. J Urol, 170, 2163–72. Copyright Elsevier.

There are also well-established genetic abnormalities for papillary renal cell carcinoma, including mutation in the c-met oncogene, gains in chromosomes 7 and 17, loss of chromosome Y, and mutations in fumarate hydratase. The genetic locus involved in the hereditary form of chromophobe renal cell carcinoma has recently been identified, which should allow further research in to the abnormalities found in sporadic chromophobe renal cell carcinoma.

Diagnosis, staging, and grading

Renal cell carcinoma is staged by the TNM classification (Table 21.18.3). If a solid mass is detected in the kidney on ultrasonography, a contrast-enhanced CT scan of the abdomen and chest is performed to evaluate the mass, and to assess for metastatic disease. Solid masses in the parenchyma typically enhance with intravenous contrast, and more than 90% of such masses are malignant. Percutaneous core biopsy has a 10 to 20% nonconclusive rate and is not routinely done for large masses as the positive predictive value for imaging is high. It is useful if there is a strong suspicion that lymphoma may be responsible, or there is a suspicion that the renal lesion is metastatic, or where surgery may lead to renal failure because there is significant renal impairment.

Simple cystic masses with no internal echoes or septation occur in the renal parenchyma of 50% of 50-year-olds and are benign. Complex cysts (meaning those with septation, calcification, or solid elements) on ultrasonography require CT scanning to detect enhancing elements and are likely to be well-differentiated cystic renal cell carcinomas.

Clinical staging with CT allows identification of metastatic disease to lymph nodes, adrenal glands, liver, and chest. Renal cell carcinoma also frequently metastasizes to bone, where lytic lesions are typically found. A bone scan is performed if the patient has bone pain or an elevated alkaline phosphatase. Another important feature of renal cell carcinoma is the propensity for the tumour to invade the renal vein and subsequently the inferior vena cava (Fig. 21.18.4), even extending as far as the right atrium. Staging with multislice CT or MRI or Doppler ultrasound is important to determine the distal extent of the tumour thrombus as this affects the surgical approach required.

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Fig. 21.18.4

Left renal cell cancer (RCC) spreading through the renal vein (arrows) into the inferior vena cava (arrowhead).

The Fuhrman grading system for renal cell cancer is a histological grading system based on the architecture and size of the nucleus assessed at low power. This is graded 1–4, with 4 designating a worse prognosis, and carries independent prognostic information.

Paraneoplastic phenomena

Paraneoplastic syndromes are common in renal cell carcinoma and include hypercalcaemia, polycythaemia from erythropoietin production, anaemia, weight loss, leucocytosis, hypertension and elevated ESR. Stauffer’s syndrome comprises abnormal liver function tests and coagulation defects that normalize after nephrectomy. If suspected paraneoplastic syndromes do not disappear following nephrectomy, then it is likely that there is undiagnosed metastatic disease.

Treatment

Renal cell cancer is not responsive to conventional chemotherapy and is not radiosensitive. Surgery is therefore the primary treatment for localized renal cell carcinoma. Radical nephrectomy involves removal of the kidney within Gerota’s fascia (renal fascia), with en bloc removal of the ipsilateral adrenal gland and hilar lymph nodes. Partial nephrectomy is increasingly used to excise small solid masses in patients with a solitary kidney, impaired renal function, or bilateral tumours, and also as primary treatment in people with normal renal function. In patients with limited long-term survival, small renal tumours are being increasingly managed with surveillance regimens and also minimally-invasive techniques such as cryoablation and radiofrequency ablation. The surgical approach to the kidney may be with open or laparoscopic surgery.

Prognosis

As for many malignancies, long-term prognosis in renal cell carcinoma is strongly dependent on the initial clinical stage. Table 21.18.4 shows 5-year survival according to the original Robson classification. The presence of metastatic disease portends a very poor prognosis, with a median survival of only 8 months. The AJCC 1997 classification of primary renal tumour size designated a cut-off point of 7 cm to differentiate between T1 and T2 tumours: T1 tumours have now been separated into T1a (<4 cm) and T1b (4–7 cm), reflecting the excellent prognosis of small renal masses that are detected incidentally.

The outcome of small asymptomatic renal masses that are detected incidentally (‘incidentalomas’) is not yet clear, but it appears that in many cases they grow very slowly and may not threaten an individual’s life expectancy. Historically renal masses less than 3 cm in size were classified as renal adenomas, although histologically some of these were likely to have been papillary tumours. Elderly patients or others who would be high risk for surgery can be offered monitoring with 3-monthly ultrasonography when a small (<4 cm) mass is diagnosed: if the size (volume) of the tumour is unchanged over 12 months, then most such lesions appear to remain stable over time. However, this approach is not yet validated and should not be recommended for young patients with small solid renal masses, because once renal cell cancer has metastasized there is little chance of cure.

Risk factors

Increasing age is a strong risk factor, but genetic risk factors are also important. Some men with first degree relatives affected by prostate cancer have a two- to threefold higher risk, the risk being higher if the first-degree relative is a brother as opposed to a father. Ethnicity also influences the risk of prostate cancer, with African-Americans having the highest risk and Asian men the lowest risk. Dietary factors may play a role: lycopene (found in tomatoes), selenium, and vitamin E are potentially protective; a Western-style high-fat diet is associated with a high risk for prostate cancer in the developed world, and probably plays a role in the increasing risk of such cancer in Japanese men who migrate to the United States of America. As for many cancers, it is likely that there is an interaction between environmental factors and an inherited genetic predisposition leading to prostate cancer.

Genetic changes

Around 5 to 10% of all prostate cancer is thought to be related to a highly penetrant genetic predisposition, and genetic factors may be responsible for as many as 40% of those prostate cancers appearing at an early age (diagnosed prior to age 50 years). Several different putative prostate cancer genes are under evaluation, including HPC1 (chromosome 1), HPC2 (chromosome 17), MSR1 (macrophage scavenging receptor 1—chromosome 8), and RNASEl. Men from families harbouring a BRAC2 mutation have a fivefold increase in risk of prostate cancer. Recent genome wide scans have found more than 30 predisposition alleles known as single nucleotide polymorphisms [SNPs]. Many prostate cancers demonstrate a translocation between the androgen-regulated TMPRS2 gene and the ETS transcription factor, putting the latter under the control of an androgen-regulated promoter.

The androgen receptor plays an important role in cell signalling, progression, and metastases in prostate cancer, and androgen blockade (antitestosterone agents) can produce clinical regression of local and metastatic disease. Mutations in the androgen receptor leading to overexpression or altered ligand binding are associated with the development of later hormone independence.

Diagnosis, staging, and grading

The prostate is divided into different zones (peripheral, central, transitional, periurethral, and fibromuscular) based on different embryological origins, with most prostate cancers (75%) arising in the peripheral zone. Early prostate cancer does not give rise to any symptoms, whereas locally advanced disease may cause lower urinary tract symptoms or haematuria, and metastatic disease may present with bone pain from sclerotic metastases. As early prostate cancer is asymptomatic, diagnosis is currently achieved by combining a digital rectal examination (DRE) with a PSA measurement linked to transrectal ultrasound scanning and biopsy of the prostate (TRUSP).

PSA is a serum protease that is secreted by prostatic epithelium. It is not a specific marker for cancer as there are many nonmalignant processes that also elevate PSA, such as benign prostatic hyperplasia (BPH), urinary tract infection, urinary tract instrumentation, ejaculation, and traumatic catheterization. Age-adjusted norms for PSA are available to improve the sensitivity and specificity of the measurement in clinical practice, an alternative approach being to set a predetermined cut-off above which further evaluation is recommended. PSA kinetics may be more valuable in making treatment decisions than a single value: a rapidly rising PSA with a short doubling time (even if starting at a very low number) indicates that a man is likely to have high-risk prostate cancer.

If a man has an elevated PSA or an abnormal DRE and there is no evidence of urinary or prostatic infection which might explain the elevation, then it is recommended that the patient undergoes a transrectal ultrasound-guided needle biopsy of the prostate under local anaesthesia, taking about 10 separate biopsies which will detect 80 to 85% of clinically significant prostate cancers.

Histological analysis is carried out by Gleason grading. The architecture is graded into five categories (1–5) for the most prominent pattern, the second most prominent pattern is assigned a secondary Gleason score, and the two scores are added together to give a Gleason sum (e.g. 3 + 4 = 7). Well-differentiated disease has a Gleason sum of 6 or less, moderately differentiated disease is 7, and poorly differentiated disease 8 to 10. It is unusual to diagnose a Gleason sum of less than 6 on needle biopsy; very well differentiated prostate cancers (Gleason <5) may be diagnosed following a transurethral resection of prostate and are usually indolent. The Gleason score is predictive of outcome: large observational studies show that men with poorly differentiated disease have a 60 to 80% chance of dying from prostate cancer within 15 years of diagnosis. The biggest problem is predicting outcome in the individual with Gleason 6 or 7 disease.

Prostate cancer is staged using the AJCC system (Table 21.18.5). When prostate cancer metastasizes it frequently goes to the pelvis, to non-regional lymph nodes, other bones (sclerotic metastases), and also local pelvic structures. It rarely invades the rectum, with Denonvillier’s fascia providing a natural barrier. Digital rectal examination provides clinical T stage. Endorectal MRI may allow for improved pre-operative staging when interpreted by experienced radiologists. A bone scan is performed to evaluate for metastatic disease.

Screening

Screening for prostate cancer is a controversial issue. There are several large trials currently evaluating whether prostate cancer screening should be recommended. In the United Kingdom screening is not recommended as it does not fulfil World Health Organization or United Kingdom national screening guidelines. There is no doubt that prostate cancer is an important health problem, but with PSA screening most cancers currently detected are low volume, well differentiated, often indolent, and do not threaten an individual’s life expectancy.

Several large observational studies have aided our understanding of the risk of prostate cancer death following diagnosis. Screening with a PSA and DRE is imperfect as there are many nonmalignant reasons for PSA elevation, thus subjecting many men to a potentially morbid prostate biopsy (with complications including sepsis, haemorrhage, pain, and urinary symptoms). Assigning age-derived normal PSA values with a cut-off point does not detect all clinically relevant prostate cancer, as shown in the prostate cancer prevention trial where a significant number of Gleason 3 + 4 cancers were found with a PSA between 0 and 2.5 ng/ml (normal).

Although there are well-established treatment options for screen-detected prostate cancer, there are no robust randomized trials demonstrating efficacy of treatment or revealing which option provides the best outcome. One important clinical trial randomized patients in a pre-PSA era to watchful waiting or radical prostatectomy, showing an improvement in overall and prostate cancer specific survival for patients treated with radical prostatectomy. The ProtecT (United Kingdom) and PIVOT (United States of America) trials should provide useful further information, but it must be remembered that treatments for prostate cancer are not without significant morbidity, including impotence and incontinence (discussed below). One recent large randomized trial of screening, the European Randomized Study of Screening for prostate cancer (ERSPC), has shown a 20% reduction in prostate cancer deaths. However, this was at the price of considerable overdiagnosis and over treatment, with 1400 men needed to be screened and 50 men required to be treated to save one life. A recent meta-analysis of randomized controlled trials concluded that screening for prostate cancer does not have a significant impact on overall mortality or mortality specific to prostate cancer, but this will not be the last word on the issue.

Treatment

Treatment options for prostate cancer are dependent on many factors, including patient age, life expectancy, stage, Gleason grade, PSA kinetics, and tumour volume. For practical purposes patients are classified into having localized disease, locally advanced disease, or metastatic disease. One very important factor in the choice of treatment for a man with low- or intermediate-risk localized prostate cancer is the patient’s view of the risks and benefits of treatment.

Localized disease

Disease localized to the prostate may be treated with curative intent, with either surgery or radiotherapy. Patients are eligible for radical treatment if they have a life expectancy greater than 10 years, reflecting the fact that because prostate cancer is generally slow growing, the benefit from treatment of early-stage prostate cancer is not gained unless the patient lives at least another decade. More conservative approaches such as ‘active monitoring’ are very reasonable options for patients with low volume localized disease and favourable Gleason grade. This form of management involves regular PSA testing and rectal examination and aims to treat prostate cancer once there is evidence of progression (increasing PSA or increases in local stage on rectal examination), but before there is metastatic disease.

Radical surgery

Radical prostatectomy involves removal of the prostate gland and seminal vesicles, plus or minus a pelvic lymph node dissection, followed by anastomosis of the bladder to the urethra. This can be performed by open or laparoscopic surgery, and the latter can be performed using a robotic three-dimensional system with superior instruments and vision over standard laparoscopy (Figs. 21.18.5 and 21.18.6).

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Fig. 21.18.5

Patient in theatre undergoing robotic prostatectomy.

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Fig. 21.18.6

One of the authors sitting at robotic console during radical prostatectomy.

After surgery there should be no detectable PSA in the serum, with PSA recurrence (rising PSA after surgery) indicating either local recurrence or metastatic disease. The long-term outcomes for screen-detected prostate cancer are good, with 80 to 90% 5-year biochemical-free survival (undetectable PSA). Local recurrent disease may follow where there are positive margins on the radical prostatectomy specimens, the chances of which can be reduced by low-dose radiotherapy in men at high risk of this complication.

The neurovascular bundles which produce penile erection and a sense of orgasm run very close to the prostate and are at risk during the operation (Fig 21.18.7 and Fig 21.18.8).Their preservation depends on the skill of the surgeon, and whether the stage and grade of the tumour argue for a more radical excision of periprostatic tissue. The seminal vesicles are removed with the prostate, hence ejaculation is invariably absent. The risk of urinary incontinence is related to the potential for injury to the external urinary sphincter, just distal to the prostate, and is also dependent on the skill of the surgeon. The best outcomes from surgery are achieved in centres where surgeons perform a large number of operations.

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Fig. 21.18.7

A. Cross-section through the apex of the prostate demonstrating the relationship between fascia surrounding the striated sphincter, neurovascular bundles, the striated sphincter, and the smooth muscle on the urethra. B. Cross-section through mid portion of prostate demonstrating relationship between the neurovascular bundles between levator fascia and prostatic fascia, anterior to Denonvillier’s fascia. When doing radical prostatectomy it is important that the prostatic fascia remain intact. From Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (eds) (2007). Campbell-Walsh Urology, 9th edition. Volume 3, figure 97-4, p. 2958. Copyright Elsevier.

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Figure 21.18.8

Retrograde dissection of the prostate (open technique) with progressive branches of the neurovascular bundles being clipped. From Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (eds) (2007). Campbell-Walsh Urology, Volume 3, figure 97-8, p. 2969. Copyright Elsevier.

Radical radiotherapy

Radical radiotherapy may be delivered using either external beam treatment or internally via brachytherapy (radioactive seeds implanted into the prostate). The cancer cure rates for surgery and radiotherapy are similar, with patient choice being the most important factor in deciding which treatment option is preferred. Overall there is slightly less urinary morbidity from radiotherapy. However, the risks of radiotherapy include rectal bleeding, diarrhoea, urinary frequency and urgency, haematuria and erectile dysfunction. There also appears to be an increase in the risk of secondary cancers following pelvic radiotherapy, including rectal carcinoma.

Risk factors

Cryptorchidism (undescended testis) is a risk factor for the development of testicular cancer, with the risk in the undescended gonad increasing with the severity of maldescent. The risk is at least 10-fold increased for a testis descended to or below the inguinal canal, and even greater for testes with arrested descent in the abdomen. Such patients also have an increased risk (c.5%) of developing a tumour in the normally descended contralateral gonad, particularly if the testis is small and atrophic. Patients with inherited syndromes, including Kleinfelter’s and Down’s syndrome, are also at increased risk of testicular cancer. Between 1 and 3% of patients report a positive family history of testicular cancer.

The pathogenesis of testicular cancer is thought to involve a noninvasive precursor stage, termed intratubular germ cell neoplasia (IGCN) or carcinoma in situ. Although the natural history of this condition is not completely defined, it would appear that most men with it eventually progress to invasive testicular cancer.

Presentation and diagnosis

Patients present with a testicular swelling that is usually painless and may grow rapidly. Symptoms and signs including back pain, weight loss, lymphadenopathy, headache, shortness of breath, and haemoptysis all suggest metastatic disease. Clinical examination of scrotal swellings is crucial, with key questions being: (1) is it arising in the scrotum? (a hernia comes down from above); (2) is it confined to the body of the testis (a testis cancer is within the testis); and (3) does it transilluminate (i.e. is it cystic or solid). A solid swelling in the body of the testis is a testicular tumour until proved otherwise.

When a testicular mass is detected on clinical examination, a scrotal ultrasound examination (Fig 21.18.9)is performed to determine if the mass is solid or cystic—cystic scrotal masses are benign and include epididymal cysts and hydroceles. Solid testicular masses are usually malignant, but may be difficult to differentiate from focal infection, infarction, and epidermoid tumours. Preoperative blood is taken for serum tumour markers—α-fetoprotein, β-hCG, and LDH.

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Figure 21.18.9

Ultrasound scan of testis showing lesion of heterogenous echogenicity replacing most of testis. (Courtesy of Addenbrooke’s Hospital, Urology and Radiology departments.)

About 5% of germ-cell tumours present at an extragonadal site, usually in either the retroperitoneum or mediastinum. Some such patients will have carcinoma in situ of the testis, or a burnt-out primary testicular tumour manifested as a focal testicular scar on ultrasonography.

Histological subtypes of testicular cancer

Over 90% of testicular cancer is of germ-cell origin: a few tumours are derived from stromal and supporting cells, either Leidig or Sertoli cell tumours. Testicular tumours in men over the age of 50 are commonly either lymphoma or metastatic, although a subtype of germ-cell cancers known as spermatocytic seminoma occur in older men. Germ-cell tumours are classified as shown in Table 21.18.6. For clinical purposes testicular cancer is divided into seminomatous or nonseminomatous germ cell tumours (NSGCT), the treatment of these two categories being different. Mixed tumours are classified as nonseminomatous tumours. Serum tumour markers for testicular cancer are very useful in diagnosis and in follow-up after orchidectomy.

Staging

Testicular cancer is initially staged with a CT scan of the abdomen, pelvis, and chest. Clinical stage is determined using the TNM classification. The degree of tumour marker elevation carries independent prognostic information and is incorporated into the TNM classification—‘TNMs’, where ‘s’ designates the serum tumour marker level.

Testicular lymphatic drainage is based on the embryological origin of the testis from the mesonephric ridge in the retroperitoneum, hence the most common sites for metastatic disease are the retroperitoneal para-aortic lymph nodes and the chest (Fig. 21.18.10).

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Fig. 21.18.10

CT scan showing a very large metastatic para-aortic lymph node mass (arrows) from a testicular seminoma.

Treatment

A solid testicular mass is usually treated with radical inguinal orchidectomy through an inguinal incision, with excision of the testis, cord and all of their coverings (spermatic fascia). Testicular cancer is the model par excellence of a curable solid malignancy. Treatment strategies are tailored to the clinical stage and involve combinations of surgery, chemotherapy, and radiotherapy. The excellent overall cancer cure rates for the young men presenting with this disease mean that the long-term effects of chemotherapy and radiotherapy are potential significant issues (such as the development of secondary malignancy). Much effort is therefore placed on minimizing side effects of treatment while maintaining excellent cure rates.

Diagnosis and staging

Penile cancer presents either as in situ carcinoma or as invasive malignancy. The former presents as a red velvety lesion and the latter as a firm mass or as ulceration. Penile squamous-cell cancer most commonly arises from the glans penis or prepuce, but may also originate on the penile shaft. Delayed presentation is common because of embarrassment or neglect.

Histological diagnosis is achieved by way of a penile incision biopsy that also provides a T stage and grade.(Fig 21.18.11)Squamous-cell cancer of the penis metastasizes in orderly fashion, without skip lesions, first to the superficial and then to the deep inguinal lymph nodes. The lymphatic drainage of the penis is bilateral and therefore laterality of the primary lesion is not relevant to the likely site of lymph node metastasis. Metastases also occur to bone and lungs.

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Figure 21.18.11

T-staging of penile cancer. T, carcinoma in situ; Ta, noninvasive verrucous carcinoma; T1, tumour invades subepithelial connective tissue; T2, tumour invades corpus spongiosum or cavernosum;* T3, tumour invades urethra or prostate; T4, tumour invades other adjacent structures.

* It has been proposed that invasion into corpus cavernosum be upgraded to T3, with urethra/prostate and adjacent structures T4, as there is a difference in prognosis between corpus spongiosum and cavernosum involvement (European Society of Urology guidelines on penile cancer, 2008). From Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (eds). (2007). Campbell-Walsh Urology, 9th edition, Volume 1, fig 31-1, p. 972. Copyright Elsevier.

Staging of penile cancer follows a TNM classification. A histological grade is also assigned. The combination of stage and grade helps to predict the risk of occult groin node metastases.

Treatment

This depends on the site, the clinical stage, and the grade of the lesion. In general the primary lesion should be treated by an adequate but relatively conservative approach, whereas the lymph nodes may require aggressive treatment if the cancer is high risk. Squamous-cell cancer in situ or superficial well-differentiated disease may be treated by penile-preserving therapies such as topical 5 fluorouracil, local excision or laser therapy. Lesions exclusively located on the prepuce may be treated with a circumcision. Larger lesions are best treated with partial penectomy (T2) or total penectomy (T3), which involves a perineal urethrostomy.

Patients refusing surgical management of the primary lesion may be treated with radiotherapy with local control rates of 60% at 5 years.