Sign or symptom	Pathological basis
Abnormal micturition
• Dysuria (pain)	Inflammation of the urethra, often accompanying a urinary tract infection
• Hesitation, poor stream and dribbling	Obstructed urinary outflow, usually due to prostate gland enlargement
• Frequency	Incomplete bladder emptying due to obstructed urinary outflow
• Urinary retention	Severe obstruction to bladder outflow, usually due to prostate gland enlargement
Urethral discharge	Urethritis, possibly due to sexually transmitted infections (e.g. gonorrhoea)
Scrotal swelling
• Painful	Inflammation or ischaemia of the testis
• Painless	Enlargement of scrotal contents due to hernia, fluid (e.g. hydrocele), varicocele or tumour
Genital ulceration	Often sexually transmitted infection (e.g. syphilis)
Bone pain	If associated with male genital tract disease, possibly due to metastases from prostatic adenocarcinoma
Raised serum prostate specific antigen	Secreted by prostatic carcinoma
Raised serum alpha-fetoprotein and/or human chorionic gonadotrophin	Testicular germ cell neoplasia, particularly teratoma/non-seminomatous germ cell tumour
Gynaecomastia	Possible manifestation of Leydig cell or germ cell tumour of testis
Infertility	Impaired spermatogenesis due to endocrine disorders or to testicular lesions, or impaired ejaculation due to obstruction or to neurological disorders

URINARY CALCULI

Urinary calculi (stones) occur in 1–5% of the population in the UK, mainly those aged over 30 years, and with a male preponderance. They may form anywhere in the urinary tract, but the commonest site is within the renal pelvis. They present as:

• renal colic, an exquisitely painful symptom due to the passage of a small stone along the ureter

• a dull ache in the loins

• recurrent and intractable urinary tract infection.

Calculi form in the urine either because substances are in such an excess that they precipitate, or because other factors affecting solubility are upset. Factors influencing stone formation include the pH of the urine, which can be influenced by both bacterial activity and metabolic factors. Substances in the urine normally inhibit precipitation of crystals, notably pyrophosphates and citrates. The mucoproteins in the urine are thought to provide the organic nidus on which the crystals focus.

Calculi are classified according to their composition. The categories are:

• calcium oxalate, often mixed with calcium phosphate and uric acid (75–80% of all calculi)

• triple (struvite) stones composed of magnesium ammonium phosphate (15%); these form the large ‘staghorn’ calculi (Fig. 20.1)

• uric acid stones (6%)

• calculi in cystinuria and oxalosis (1%).

Fig. 20.1 ‘Staghorn’ calculus. The shape of the stone is moulded to that of the pelvis and calyceal system in which it has formed.

Only 10% of patients with calcium-containing stones have hyperparathyroidism or some other cause of hypercalcaemia. However, most have increased levels of calcium in the urine, attributable to a defect in the tubular reabsorption. In the remaining patients, with idiopathic hypercalciuria, no known cause has been identified. The association of uric acid with calcium stones is probably because urates can initiate precipitation of oxalate from solution.

Magnesium ammonium phosphate stones are particularly associated with urinary tract infections with bacteria, such as Proteus, that are able to break down urea to form ammonia. The alkaline conditions thus produced, together with sluggish flow, cause precipitation of these salts, and large staghorn calculi form a cast of the pelvicalyceal system. Staghorn calculi remain in the pelvis for many years and may cause irritation, with subsequent squamous metaplasia or, in some cases, squamous carcinoma.

Uric acid stones occur in patients with gout (Ch. 7). Uric acid precipitates in acid urine. The stones are radiolucent.

RENAL CELL CARCINOMA

Incidence

Renal cell carcinoma arises from epithelial cells in the kidney. About 7400 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 by improved imaging techniques. 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- 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 mutations in the VHL gene, which normally produces a protein responsible for degrading proteins of the hypoxia-inducible factor (HIF) family. In the absence of this functioning protein there is accumulation of the HIF family of proteins, which in turn 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 carcinoma (clear cell carcinoma) has loss of expression of the VHL gene.

Presentation

Some 50% of renal cell cancers present with haematuria as the tumour invades and bleeds into the renal collecting system. 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. A substantial proportion of cases are identified almost incidentally by ultrasonography or computed tomography while investigating a wide range of non-specific symptoms. This results in the diagnosis of many small tumours amenable to curative treatment, often conserving the rest of the kidney.

Macroscopically, the kidney is distorted by a large tumour, found most often at the upper pole (Fig. 20.2). The cut surface reveals a solid yellowish-grey tumour 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. Extension into the renal vein is sometimes seen grossly; occasionally, a solid mass of tumour extends into the inferior vena cava and, rarely, into the right atrium.

Fig. 20.2 Renal cell carcinoma (hypernephroma). Renal cell carcinoma (hypernephroma).

Microscopically there are distinctive different tumours with very different cytogenetic abnormalities (and by inference differing pathogenesis). Clear cell (conventional) renal cell carcinoma has VHL gene abnormalities and is the largest group. Next is papillary renal cell carcinoma which has trisomies of chromosomes 7 and 17; this has papillary structures lined by cuboidal cells and is the variant associated with acquired cystic disease in renal failure. The third largest group is chromophobe renal cell carcinoma, which has large eosinophilic cells often similar to renal oncocytoma, a benign tumour.

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 oblation 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 or newer oral tyrosine kinase inhibitors such as sunitinib.

NEPHROBLASTOMA

Nephroblastoma (Wilms’ tumour) is a kidney tumour derived from embryonal tissue. It is rare, with 45 cases per year in the UK, and has a peak incidence between the ages of 1 and 4 years. Although it is usually biologically aggressive, often with lung metastases at presentation, combined chemoradiotherapy and surgery has improved the 5-year survival rate from 35% in the 1970s to over 80% at present. The Wilms’ tumour gene (WT1) has long been known to be abnormal in nephroblastoma, but the molecular mechanisms of this have still not been coherently elucidated.

CARCINOMA OF THE RENAL PELVIS

The renal pelvis is lined by transitional cell epithelium and so transitional cell carcinomas can arise at this site, accounting for 5–10% of all renal tumours. As they project into the pelvicalyceal cavity, they present early with haematuria or obstruction (Fig. 20.3). Their risk factors, histology and treatment are similar to those for transitional cell carcinomas of the ureters and bladder described below.

Fig. 20.3 Carcinoma of the renal pelvis. These malignant tumours arise from the transitional cell epithelium (urothelium) lining the renal pelvis. These patients commonly develop synchronous or metachronous urothelial tumours elsewhere in the ureters or bladder.

BENIGN RENAL TUMOURS

Renal oncoctyoma is composed of large eosinophilic cells, sometimes difficult to distinguish from renal cell carcinoma. Its imaging features also overlap with those of renal cell carcinoma, so, even though benign, is it usually diagnosed after surgical removal.

Angiomyolipoma typically has a combination of abnormal blood vessels, smooth muscle and adipose tissue. This gives it a characteristic radiological appearance, so small masses need not be resected; however, large masses have a risk of spontaneous haemorrhage. Some 20% of cases arise in patients with tuberous sclerosis complex, an inherited disorder involving the central nervous system, skin and other viscera.

URETERS

NORMAL STRUCTURE AND FUNCTION

The ureters form in continuity with the calyceal system and collecting ducts from an outgrowth of the Wolffian duct. Urine is conveyed to the bladder by peristaltic activity; this activity is reduced in pregnancy, predisposing to stasis and infection.

The lumen is lined by urothelium; the muscle layer is predominantly circular with a thin, inner longitudinal layer, and is invested in a fibrous adventitia. The ureteric orifice is slit-like, and the course of the terminal part of the ureter through the bladder wall is oblique to form a valve (see Fig. 21.14B, p. 591).

CONGENITAL LESIONS

A congenitally short terminal segment of the ureter, which is not oblique, results in vesico-ureteric reflux, an important cause of renal infection and scarring. Hydroureter is dilatation and often tortuosity of the ureter; this condition may occur as a congenital lesion, when it is thought to reflect a neuromuscular defect. The most frequent causes of hydroureter in the adult are low urinary obstruction and pregnancy.

OBSTRUCTION

Obstruction of the ureter is the most frequent problem requiring clinical attention. Acute ureteric obstruction causes intense pain known as renal colic. The consequences of chronic ureteric obstruction are hydroureter and hydronephrosis. In both acute and chronic ureteric obstruction there is an increased risk of ascending infection, causing pyelonephritis. Ureteric obstruction may be either intrinsic or extrinsic.

Intrinsic lesions are within the ureteric wall or lumen; the most common is a urinary calculus. Calculi become impacted where the ureter is normally narrowed, that is at the pelvi-ureteric junction, where it crosses the iliac artery, and where it enters the bladder. Strictures may be congenital, when they occur at the pelvi-ureteric junction or in the transmural terminal segment of the ureter. Acquired strictures occur as a result of trauma and involvement by adjacent inflammatory conditions such as diverticulitis and salpingitis. Severe haematuria may cause obstruction due to blood clot.

Extrinsic factors cause pressure from without, and include primary tumours of the bladder and rectum, metastatic carcinoma in pelvic lymph nodes and benign hyperplasia of the prostate. Aberrant renal arteries may compress the ureter. Retroperitoneal fibrosis causes narrowing and medial deviation of the ureters and may either be due to drugs, such as methysergide, or be idiopathic.

Primary tumours of the ureter are transitional cell carcinomas. They may be multiple and are associated with urothelial tumours in the renal pelvis and bladder.

BLADDER

NORMAL STRUCTURE AND FUNCTION

The urinary bladder is a cavity lined by transitional cell epithelium—the urothelium, surrounded by connective tissue—the lamina propria, and smooth muscle. Histologically, the normal bladder urothelium is seven to eight cells thick and has three zones: basal, intermediate and a surface layer of umbrella cells. The smooth muscle is arranged in bundles that interlace rather than form defined layers. Urine drains into the bladder from the kidneys, via the ureters, for storage until a convenient time and place is found for its discharge through the urethra. The bladder responds to obstruction to the outflow by undergoing muscular hypertrophy. The proximity of the bladder to the genital tract in females, to the prostate in males, and to the bowel in both sexes, means that it is often invaded by tumours arising in, or affected by other changes in, these nearby organs.

DIVERTICULA

Diverticula are outpouchings of the bladder mucosa. Bladder diverticula are either congenital or acquired. They are clinically important because urinary stasis within them predisposes to calculus formation and infection.

Congenital diverticula are usually solitary. They arise from either a localised developmental defect in the muscle or urinary obstruction during fetal life.

Acquired diverticula are small and multiple. They are most often associated with outflow obstruction, and the high incidence in elderly males correlates with prostatic enlargement. They occur between the bands of hypertrophic muscle, known as trabeculae, which form in response to obstruction.

CONGENITAL LESIONS

Exstrophy of the bladder is a serious developmental defect affecting the anterior abdominal wall, bladder and, in some cases, the symphysis pubis. The bladder opens directly on to the external surface of the lower abdomen. Infection and pyelonephritis, together with a predisposition to adenocarcinoma, are important sequelae.

Vesico-ureteric reflux (VUR) is an important consequence of a developmental abnormality of the terminal part of the ureter that appears to correct itself as the patient matures. However, during early childhood reflux occurs, which results in substantial scarring of the renal parenchyma. This condition is an important cause of renal impairment and infection in adult life.

Persistence of the urachus may be partial or complete. Retention of the entire structure results in a fistula connecting the bladder with the skin at the umbilicus. Partial retention results in a diverticulum arising from the dome of the bladder. Alternatively the central area may persist and present as a cyst. Adenocarcinomas may develop in these urachal remnants.

CYSTITIS

Inflammation of the bladder (cystitis) is a common occurrence as part of a urinary tract infection. The causative organism is usually derived from the patient’s faecal flora. Unusual organisms do occur; for example, Candida is seen in patients on prolonged antibiotic therapy, and tuberculous cystitis almost always reflects tuberculosis elsewhere in the urinary tract. Radiation and trauma due to instrumentation cause cystitis, which is often sterile.

Cystitis presents with frequency, lower abdominal pain and dysuria (scalding or burning pain on micturition), and occasionally haematuria. In some patients there is general malaise and pyrexia. Cystitis usually responds readily to treatment. However, its clinical importance lies in the predisposition to pyelonephritis, a serious complication.

Schistosomiasis causes a granulomatous cystitis, in which the parasite ova are demonstrable; it is notable for the increased risk of squamous cell carcinoma.

BLADDER CALCULI

Diverticula, obstruction and inflammation are all important in the development of stones within the bladder. Alternatively, calculi may be passed down the ureter from the kidney. Bladder stones may be asymptomatic, but eventual chronic irritation and infection lead to frequency, urgency, dysuria and sometimes haematuria. There is an increased risk of bladder carcinoma; this is often of squamous type, arising from metaplastic squamous epithelium.

TRANSITIONAL (UROTHELIAL) CELL CARCINOMA OF THE BLADDER

Incidence

Transitional cell carcinoma accounts for 90% of bladder cancer in North America and Europe. In the UK about 10 500 new cases are diagnosed each year, 4% 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. Transitional 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 transitional cell bladder cancer. On average, current smokers have a 300% increased risk and about 50% of all transitional 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 and stable abnormalities. In contrast, solid invasive tumours have different alterations 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 transitional 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 low-grade and 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.

Fig. 20.4 Transitional cell carcinoma of the bladder. These common tumours usually project into the bladder lumen before invading the underlying bladder wall.

In contrast, about 20% of tumours 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, and there are other histological variants too. The background urothelium often shows carcinoma in situ, which is considered to be the precursor lesion, and may give rise to further high-grade invasive tumours.

Between these two extremes of tumour type there are some high-grade papillary tumours; these may have background carcinoma in situ, and are more likely to progress to invasive carcinoma.

Prognosis and treatment

Prognosis is closely related to the stage of the tumour. 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. Intra-vesical treatment with BCG 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 is another possible treatment modality.

SQUAMOUS CELL CARCINOMA OF THE BLADDER

As the bladder is normally lined by transitional epithelium, squamous cell carcinoma can arise only from metaplastic squamous epithelium in the bladder. This metaplasia commonly occurs with chronic infection with schistosome parasites. In countries where schistosomiasis is endemic, such as Egypt, squamous cell bladder cancer is the most common tumour in men, presenting in the fifth decade, usually at a more advanced tumour stage with corresponding worse prognosis. Long-term catheterisation following paraplegia carries similar risks.

PROSTATE GLAND

NORMAL STRUCTURE AND FUNCTION

The prostate gland surrounds the bladder neck and proximal urethra (Fig. 20.5). It consists of five lobes, separated by the urethra and ejaculatory ducts. Two lateral lobes and an anterior lobe enclose the urethra. The two lateral lobes are marked by a posterior midline groove, palpable on rectal examination. The middle lobe lies between the urethra and ejaculatory ducts and the posterior lobe lies behind the ejaculatory ducts. The normal gland weighs about 20g and is enclosed in a fibrous capsule.

Fig. 20.5 Male pelvic organs. Sagittal section showing that the prostate can be palpated easily by inserting a finger into the rectum.

From a pathology perspective, it is more useful to divide the prostate into zones. In early adult life the peripheral zone accounts for 70% of the organ, the transition zone (both sides of the proximal urethra) 5% and the central zone 20%. Prostate cancers arise almost exclusively from the peripheral zone. The transition zone gradually enlarges with age, and is the site of considerable enlargement in benign prostatic hyperplasia. Concentric groups of glands in all zones converge on ducts and open in the urethra.

Individual glandular acini have a convoluted outline, the epithelium varying from cuboidal to a pseudostratified columnar cell type depending upon the degree of activity of the prostate and androgenic stimulation. The epithelial cells produce prostate-specific antigen (PSA), acid phosphatase and the prostatic secretion that forms a large proportion of the seminal fluid for the transport of sperm. The normal gland acini often contain rounded concretions of inspissated secretions (corpora amylacea). The acini are surrounded by a stroma of fibrous tissue and smooth muscle.

The blood supply to the prostate gland is from the internal iliac artery by the inferior vesical and middle rectal branches. The prostatic veins drain to the prostatic plexus around the gland and then to the internal iliac veins. The nerves are from the pelvic plexus.

INCIDENCE OF PROSTATIC DISEASE

Diseases of the prostate are common causes of urinary problems in men, the incidence of which increases with age, particularly beyond 60 years. Most prostatic diseases cause enlargement of the organ resulting in compression of the intraprostatic portion of the urethra; this leads to impaired urine flow, an increased risk of urinary infections, and, in some cases, acute retention of urine requiring urgent relief by catheterisation. The most important and common causes of these signs and symptoms are prostatic hyperplasia and prostatic carcinoma. Inflammation of the prostate gland—prostatitis—is also common, but it less often gives rise to serious clinical problems; indeed, small foci of prostatic inflammation are not uncommon coincidental findings in prostatic tissue removed because of hyperplasia or carcinoma.

The principal clinicopathological features of the common types of prostatic pathology are compared in Table 20.1.

Table 20.1 Differences between the three most common types of prostate pathology

PROSTATITIS

Prostatitis means inflammation of the prostate; however, it is a confusing subject because of the substantial lack of correlation between the clinical symptoms, detection of neutrophils in prostatic secretions and an inflammatory infiltrate in histological samples. A causative organism is found in only 5–10% of cases; symptoms overlap with those of benign prostatic hyperplasia. The US National Institutes of Health (NIH) has published a consensus categorisation of prostatitis, and also a chronic prostatitis symptom index to tighten up clinical diagnosis:

• Category I: Acute bacterial prostatitis

• Category II: Chronic bacterial prostatitis

• Category III: Chronic pelvic pain syndrome

— A Inflammatory

— B Non-inflammatory

• Category IV: Asymptomatic inflammatory prostatitis.

In addition, there are patients with granulomatous inflammation of the prostate.

BENIGN PROSTATIC HYPERPLASIA

A common non-neoplastic lesion

Involves peri-urethral transition zone

Nodular hyperplasia of glands and stroma

Not premalignant

Benign prostatic hyperplasia (BPH) is the histological basis of a non-neoplastic enlargement of the prostate gland, benign prostatic enlargement (BPE), which occurs commonly and progressively after the age of 50 years. About 75% of men aged 70–80 years are affected and develop variable symptoms of urinary tract obstruction, benign prostatic obstruction (BPO). If severe and untreated, the hyperplasia may lead to recurrent urinary infections and, ultimately, impaired renal function.

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 both lateral lobes of the gland. In addition, there may be a localised hyperplasia of peri-urethral glands posterior to the urethra and projectinginto the bladder adjacent to the internal urethral meatus (Fig. 20.6). This hyperplasia is described as ‘median’ lobe enlargement but does not correspond to the anatomical middle lobe.

Fig. 20.6 Prostatic hyperplasia. Sagittal section showing the hyperplastic median lobe protruding into the bladder.

The cut surface of 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. The acini are larger than normal (some may be cystic) and are lined by columnar epithelium covering papillary infoldings (Fig. 20.8). The acini may contain numerous corpora amylacea. Phosphates and oxalates may be deposited around these to form prostatic calculi.