Urinary and male genital tracts

Incidence

Renal cell carcinoma arises from epithelial cells in the kidney. About 9000 new cases a year are diagnosed in the UK, 3% of all cancers, with around 4000 deaths a year. The incidence in the UK is gradually increasing but this may be due to higher detection rates on imaging. There is a male : female ratio of 3 : 2. Renal cell carcinoma is rare before the age of 40 years and the peak incidence occurs between the ages of 65 and 80 years.

Predisposing factors

Tobacco smoking, obesity, radiation and acquired renal cystic disease are the main environmental risks for renal cell carcinoma. On average, current smokers have a 50% increased risk and about 25% of all renal cell carcinoma cases can be attributed to smoking. Renal cell cancer risk increases by 7% for each unit increase in body mass index, and overall the obesity risk accounts for about 25% of cases. The radiation risk is usually acquired through treatment of other cancers such as cervical and testicular cancer. Acquired cystic kidney disease, commonly seen in patients with renal failure on dialysis, results in a three-fold to four-fold increased risk of renal cell cancer.

Most cases of renal cell cancer are sporadic but there are some rare inherited disorders that predispose to development of this tumour. The most illustrative is von Hippel–Lindau (VHL) disease where there are germline mutations in the VHL gene, which normally produces a protein responsible for degrading proteins of the hypoxia-inducible factor (HIF) family. Mutation leads to loss of functions and accumulation of HIF proteins. This results in increased transcription of hypoxia-associated genes which promote cell growth, survival and angiogenesis. In VHL disease, the risk of developing renal cell cancer is 70% by the age of 60 years with multiple and bilateral tumours. These patients are also at risk of epididymal, cerebral and other tumours ( Ch. 26 ). The largest subgroup of sporadic renal cell carcinomas (clear cell carcinoma) also shows VHL gene mutations acquired during carcinogenesis rather than inherited as a germline mutation.

Presentation

Some 50% of renal cell cancers present with haematuria as the tumour invades and bleeds into the renal collecting system. Tumours detected on imaging are frequently small tumours more amenable to curative treatment, often conserving the remainder of the kidney. Other presentations may be due to distant effects of the tumour — polycythaemia due to tumour production of erythropoietin, or hypercalcaemia due to lytic bone metastases.

Appearances

Macroscopically, the kidney is distorted by a tumour ( Fig. 20.2 ), which is yellowish-grey with areas of haemorrhage and necrosis. The margins of the tumour are usually well demarcated, but some breach the renal capsule and invade the perinephric fat. Vascular invasion is characteristic, starting in segmental veins in the renal sinus. Extension into the renal vein is sometimes seen grossly; occasionally, a solid mass of tumour extends as an insidious ‘tongue’ into the inferior vena cava and rarely, even into the right atrium.

Microscopically, there are very distinctive different tumour morphologies which have very different cytogenetic abnormalities (and, by inference, differing pathogenesis). Clear cell (conventional) renal cell carcinoma has VHL gene abnormalities and is the largest group and shows abnormalities of the long arm of chromosome 3 (the location of the VHL gene). Next is papillary renal cell carcinoma which has trisomies of chromosomes 7 and 17 and is characterised by papillary structures (but is entirely separate from papillary urothelial carcinoma). The third largest group is chromophobe renal cell carcinoma, which has large eosinophilic cells often similar to renal oncocytoma, a benign tumour. Rarely these tumours are associated with germline mutations of the folliculin gene in Birt-Hogg-Dubé syndrome. There are numerous other types, some associated with rare germline genetic mutations, some of which are Kreb's cycle enzymes.

Prognosis and treatment

Current overall 5-year survival rates in the UK are 50%. Prognosis worsens with increased stage (5-year survival rate of 10% for those with metastatic disease at presentation, but of 90% for early-stage disease) and increased age at presentation. Treatment is primarily by surgical excision, which is usually a complete nephrectomy. However, partial nephrectomy or local ablation by cryosurgery or other means is often done and conserves renal capacity. If the disease is metastatic, there may still be some benefit in removing the primary tumour for control of local symptoms such as loin pain and haematuria. Renal cell carcinoma is not sensitive to conventional chemotherapy but there may be some response with interferon. Currently treatment for metastatic disease centres on the tyrosine kinase inhibitors such as sunitinib. These deliberately target the downstream drivers of renal cell carcinoma growth secondary to VHL mutation and HIF accumulation, and have lengthened survival in late stage disease considerably.

Incidence

Urothelial cell carcinoma accounts for 90% of bladder cancer in North America and Europe. In the UK about 10, 300 new cases are diagnosed each year, 3% of all cancers, with around 5000 deaths a year. The incidence in the UK is gradually decreasing from a peak in the early 1990s. There is a male : female ratio of 5 : 2. Urothelial cell bladder cancer is rare before the age of 50 years and the peak incidence occurs between the ages of 70 and 80 years.

Predisposing factors

Tobacco smoking and occupational exposures are the main environmental risks for urothelial cell bladder cancer. On average, current smokers have a 300% increased risk and about 50% of all urothelial cell bladder cancers can be attributed to smoking. This risk is due to the absorption of aromatic amines from cigarette smoke and their excretion in the urine. Aromatic amines have historically been present in industrial processes used to produce dyes, drugs and rubber, and a significant amount of bladder cancer could be attributed to industrial exposure to these chemicals. Most of these compounds were withdrawn from these processes in the 1950s, but there was a lag phase of new cancers developing from this exposure. Exposure to polycyclic aromatic hydrocarbons is a risk factor and these by-products of combustion are present in many industrial processes. It is estimated that 4% of European bladder cancer cases are due to this exposure, and this effect might be higher in countries with less-regulated industries.

Genetic risk factors fall into two groups: genetic deficiencies of enzymes that would otherwise metabolise chemicals that are risk factors for bladder cancer (e.g. N -acetyl transferase), and genetic alterations in the tumours themselves. Although an oversimplification, there are two distinct genetic patterns in urothelial carcinoma. Papillary superficial tumours have relatively few mutations. In contrast, solid invasive tumours have greater genetic heterogeneity and tend to accumulate multiple abnormalities as they progress. However, molecular or genetic testing is not yet sufficient for diagnosis or follow-up.

Presentation

Some 80% of urothelial cell bladder cancers present with painless haematuria. Other presenting symptoms may include urinary frequency and pain on micturition.

Appearances

At presentation, most bladder tumours are papillary, with fronds lined by a slightly thickened urothelium showing little cytological abnormality ( Fig. 20.4 ). Usually there is no invasion of the lamina propria. Papillary tumours are frequently multiple, consistent with a widespread field change throughout the urothelium including the upper tract, even though it is histologically normal. These tumours may not invade the lamina propria; however, the vast majority are termed carcinomas by convention, and are divided into ‘high-grade’ and ‘low-grade’ urothelial carcinomas with differing progression and recurrence rates. Papillary neoplasms with an even lower risk of recurrence are called ‘papillary neoplasms of low malignant potential’. Papillomas are rarely diagnosed as nearly all these tumours have a risk of recurrence. Some centres also still grade urothelial carcinomas by an older system, from grades 1 to 3.

Carcinoma in situ of the bladder has a higher risk of invasion than most papillary neoplasms and appears to be a second pathogenetic route for urothelial neoplasms. It is composed of flat nonpapillary highly atypical urothelium and may appear as a red patch in the bladder wall.

About 20% of urothelial carcinomas are solid and invasive at presentation, extending into the detrusor muscle, and, if beyond, they render the tumour fixed clinically. These tumours are high grade with marked cytological abnormalities. Aberrant squamous or adenocarcinoma differentiation may be seen, as well as other histological variants. The background urothelium often shows carcinoma in situ.

Prognosis and treatment

Prognosis is closely related to the stage and grade of the tumour. Low-grade superficial tumours (without muscle invasion) can be removed by transurethral resection and have an excellent prognosis. These patients are likely to have a field change and so require regular follow-up cystoscopy, as about 70% of patients will develop further tumours. Progression to more invasive tumours occurs in around 20% of patients. Intravesical treatment with Bacillus Calmette–Guérain or chemotherapy can be used for multiple superficial tumours or carcinoma in situ. Tumours which have invaded muscle require more intensive therapy. A radical cystectomy will remove the tumour and all the dysplastic bladder epithelium but it is a large operation which results in the patient having an ileal bladder, either isotopic or with a stoma. Radiotherapy or adjuvant chemotherapy are also used in invasive neoplasms.

Category I: acute bacterial prostatitis

Patients will be febrile, and have difficulty with voiding, dysuria, frequency and urgency. The usual cause is Escherichia coli , and infection may follow instrumentation. The prostate is firm and tender, and shows neutrophil infiltration, which may progress to an abscess.

Category II: chronic bacterial prostatitis

This may follow acute prostatitis; the symptoms are similar, though the patients are not so ill. The causative organism can be cultured from appropriate specimens.

Category III: chronic pelvic pain syndrome

The presence or absence of neutrophils in specimens distinguishes two subtypes (A and B, respectively). Symptoms may relate to urination or there may be pain on ejaculation. No organisms can be cultured by usual methods, so the causes are uncertain. However, bacterial DNA has been detected in patients, so infection by novel pathogens is a plausible cause.

Category IV: asymptomatic inflammatory prostatitis

Although patients have no symptoms, leucocytes or bacteria are identified from investigations. About 70% of biopsies taken for the investigation of possible cancer show an inflammatory cell infiltrate at least focally.

Granulomatous prostatitis

Granulomatous prostatitis is a heterogeneous group of lesions, all of which may cause enlargement of the gland and urethral obstruction. The inflammatory component and associated fibrosis produce a firm, indurated gland on rectal examination which may mimic a neoplasm clinically.

Idiopathic granulomatous prostatitis may result from leakage of material from distended ducts in a gland enlarged by nodular hyperplasia. There is a periductal inflammatory infiltrate which includes macrophages, multinucleated giant cells, lymphocytes and plasma cells, with associated fibrosis.

Tuberculosis is usually secondary to tuberculous cystitis or epididymitis, the infection spreading along the prostatic ducts or vas deferens. The histological features are of caseating granulomas.

Transurethral resection for benign nodular hyperplasia or carcinoma can cause necrosis and foreign body giant cells.

Aetiology

The glands and stroma of the transition zone proliferate, sometimes substantially. The driver is dihydrotestosterone, which is derived from testosterone by the action of 5-alpha reductase, acting via testosterone receptors; after binding, the complex relocates to the nucleus to bind to DNA where it acts as a gene transcription regulator to promote growth, cell survival and other functions. The underlying cause is not known, but there is some evidence to suggest that persistent inflammation results in the secretion of growth-promoting cytokines. As well as the increased bulk of the prostate gland around the urethra, the smooth muscle tone, mediated via alpha-adrenergic receptors, may make a significant contribution to the symptoms. Although benign prostatic hyperplasia is not premalignant, there are some epigenetic abnormalities, particularly gene methylation, and the gene expression profile is different from normal.

Morphology

The hyperplastic process usually involves the transitional and central zones. In addition, there may be a localised hyperplasia of periurethral glands posterior to the urethra and projecting into the bladder adjacent to the internal urethral meatus ( Fig. 20.6 ), giving a ‘median’ lobe.

The enlarged prostate shows multiple circumscribed solid nodules and cysts ( Fig. 20.7 ). Histological examination reveals two components: hyperplasia both of glands and of stroma including smooth muscle and fibrous tissue. Some of the nodules are solid, being composed predominantly of stroma, and others also contain hyperplastic acini. Oedema and periductal inflammation are common and may contribute to the urinary obstruction.

Clinical features

There are four main factors in the development of obstructive symptoms:

• the hyperplastic nodules compress and elongate the prostatic urethra, distorting its course

• involvement of the periurethral zone at the internal urethral meatus interferes with the sphincter mechanism

• contraction of hyperplastic smooth muscle in the stroma

• inflammatory cell infiltration.

The resulting obstruction to the bladder outflow produces various lower urinary tract symptoms (LUTS), which can be grouped as bladder sensation symptoms, storage symptoms and voiding symptoms. Bladder sensation may be normal, increased or decreased. Storage symptoms include daytime frequency, nocturia, urgency and incontinence. Voiding symptoms include hesitancy, poor or intermittent stream, straining and dribbling.

Digital examination of the gland per rectum reveals prostatic enlargement, often asymmetrical. The gland has a firm, rubbery consistency, and the median groove is still palpable.

Acute urinary retention may develop in a man with previous LUTS; the bladder is palpably enlarged and tender, requiring catheterisation. This condition may be precipitated by voluntarily withholding micturition for some time, by recent infarction causing sudden enlargement of a hyperplastic nodule, or by exacerbation of local inflammation.

Chronic retention of urine is relatively painless. There may be increasing frequency and overflow incontinence, usually at night. The bladder is distended, often palpable up to the umbilicus, but is not tender since the distension is more gradual.

Complications

Continued obstruction of the bladder outflow results in gradual hypertrophy of the bladder musculature. Trabeculation of the bladder wall develops due to prominent bands of thickened smooth muscle between which diverticula may protrude. This compensatory mechanism eventually fails, with resulting dilatation of the bladder. The ureters gradually dilate ( hydroureter ), allowing reflux of urine; if untreated, bilateral hydronephrosis may develop, with dilatation of renal pelvis and calyces ( Fig. 20.8 ).

As the bladder fails to empty completely after micturition, a small volume of urine remains in the bladder. This residual urine is liable to infection , usually by coliform organisms. The resulting cystitis is characterised by painful micturition with increased frequency and haematuria. An ascending infection in the presence of an obstructed urinary tract may result in pyelonephritis and impaired renal function . Repeated infections predispose to the development of calculi , often containing phosphates, within the bladder. Septicaemia may complicate pyelonephritis.

Clinical diagnosis and management

A careful history of LUTS is the usual basis for a diagnosis of benign prostatic hyperplasia.

Further investigation may include:

• microbiological examination of the urine to detect any infection requiring treatment

• blood urea, electrolytes and creatinine to assess renal function

• urinary tract ultrasonography to provide an assessment of the upper urinary tract, indicating the severity of obstruction; it may demonstrate an enlarged prostate as a filling defect in the bladder, and also provides an assessment of the quantity of residual urine after micturition

• cystoscopy to reveal median lobe enlargement not palpable on rectal examination

• histological examination of resected prostatic tissue removed either for diagnosis or to restore flow.

Serum PSA may be elevated in benign prostatic hyperplasia, but this is not usually used in the diagnosis or assessment of it, but rather as an explanation of elevated PSA after prostate cancer has been excluded.

Many patients will not be sufficiently troubled by their symptoms to request treatment. For those who are, pharmacological interventions are the usual initial treatment, using alpha-adrenergic blockers (to reduce smooth muscle tone) or 5-alpha reductase inhibitors (to reduce dihydrotestosterone drive). Antiinflammatory drugs and antibiotics may also be appropriate.

Some patients will require surgical intervention, typically transurethral resection of the hyperplastic prostate tissue. Multiple other methods of selective tissue destruction are possible including heat (using microwaves or other media), lasers, electromagnetic radiation and ultrasound.

Aetiology

The aetiology of prostatic carcinoma is unknown, although it is highly androgen dependent.

Unlike hyperplasia, most tumours arise in the peripheral zone. A family history of the disease is important: there is a two-fold to three-fold risk of the tumour developing in men with a first-degree relative in whom prostatic carcinoma was diagnosed at under 50 years of age. There is a three-fold risk for men of African heritage compared with Caucasians. The risk in China and Japan is substantially lower. Some dietary studies have shown possible associations, but these do not fully explain the marked ethnic differences. The molecular basis of prostate cancer is complex, and so far lacks clinical application. TMPRSS2 (androgen-regulated trans-membrane protease, serine 2) is a serine protease that is secreted by prostate epithelial cells in response to androgen exposure. ERG is one of a family of oncogenes. About half of prostate cancers show an abnormal fusion genes, most commonly TMPRSS-ERG which is very specific for prostate cancer. The phosphatase and tensin homolog ( PTEN ) gene is also commonly deleted.

Benign prostatic hyperplasia is not considered a preneoplastic lesion although it is often found coincidentally in the same gland as a carcinoma, as both lesions are common. Operations for hyperplasia do not remove the peripheral zone, so carcinoma can arise after such a transurethral resection ( Fig. 20.9 ).

Pathology

There may be very little to see on macroscopic examination, particularly for organ-confined disease, though sometimes the tumour is slightly yellow. Locally advanced disease may be more obvious, with invasion of the seminal vesicles or bladder, or fixation to the pelvic wall.

The great majority of tumours are adenocarcinoma , often described as microacinar, though much variety of histological pattern is recognised, and the tumours often show more than one pattern. Rare subtypes include an aggressive small cell carcinoma, which is similar to small cell lung cancer ( Ch. 14 ), and a ductal carcinoma, which arises centrally from the large ducts; these are not discussed further.

Before metastasis the most important prognostic factor determining treatment in prostate cancer is tumour grade. The Gleason grading system initially ran from 1 to 5. Tumours were scored by adding the two most common grades seen to form a score from 2 to 10. The grading system was to note the dominant (primary) pattern and add the next most frequent (secondary) pattern to give a combined score. Where only one pattern was seen, the number was doubled. It has since become apparent that grades 1 and 2 are essentially not malignant. Therefore the lowest score of tumour is a Gleason score 3+3=6 . Gleason pattern 3 comprises separated gland profiles while Gleason pattern 4 has fused glands or cribriform structures ( Fig. 20.10 ). In Gleason pattern 5, acinar differentiation is no longer apparent in strands of tumour cells, or there may be necrosis. Recently an alternative of ‘grade groups’ has been advocated, so that the grading runs from a more simplified grade group 1 to 5 for both patients and clinicians. Also Gleason 3+4=7 tumours behave significantly differently from Gleason score 4+3=7. Grade groups are compared with Gleason grading in Table 20.2 .