Introduction

Two types of cancer arise from the renal parenchyma: renal cell carcinomas and nephroblastomas. Renal cell carcinomas (also known as renal adenocarcinomas and previously as hypernephromas) are confined to adults. Nephroblastomas (Wilms’ tumours) are developmental in origin and present in infancy or early childhood (Ch. 51). Occasional benign renal tumours also occur, e.g. oncocytoma, adenoma and angiomyolipoma (see Box 36.1).

Tumours of the transitional cell epithelium lining the urinary tract (urothelium) are very common. They may arise anywhere in the tract, including the renal pelvicalyceal system, the ureters, the bladder and occasionally the urethra. Pelvicalyceal tumours are uncommon but occur frequently in some parts of the world, e.g. Balkan nephropathy. These urothelial carcinomas, previously known as transitional cell carcinomas, occur exclusively in adults and most commonly in the bladder. Squamous cell carcinomas sometimes occur in the urinary tract and probably arise from metaplastic squamous epithelium, caused by chronic irritation from stones or schistosomiasis. Squamous cell carcinomas also arise occasionally in squamous epithelium at the urethral meatus. Very rarely, an adenocarcinoma develops in the bladder from glandular epithelial remnants of the embryological urachus, or a sarcoma may develop from connective tissue elements.

Pathology of renal cell carcinoma

Renal cell carcinoma accounts for about 3% of adult malignancies and is twice as common in males as females. It rarely develops before puberty but may occur at any age thereafter, with the peak incidence between 50 and 70 years. Renal cell carcinoma mainly occurs sporadically but there are rare familial forms such as von Hippel–Lindau disease. The only proven environmental risk factor is tobacco use.

Renal cell carcinoma originates in renal tubules. Tumour cells are characteristically large and polygonal, with clear cytoplasm representing accumulation of glycogen and lipid. For this reason, these tumours are sometimes known pathologically as clear cell carcinomas. In other variants, the cells are granular and stain more intensely.

Renal cell carcinomas vary in grade of malignancy. Small isolated tumours are often found incidentally at autopsy. Many pathologists regard tumours of less than 2 cm as virtually benign as they rarely display invasion or metastasis. Bilateral tumours are present in about 5%. Large tumours invade surrounding tissues and may metastasise to para-aortic lymph nodes. Advanced renal cell carcinoma characteristically extends into the lumen of the renal vein and into the inferior vena cava (‘tumour thrombus’—see Fig. 36.1). Distant spread is typically to lung, liver and bone. Lung metastases are often typical discrete ‘cannonball secondaries’. Isolated metastases occasionally develop in the brain, bone and elsewhere.

Staging of renal cell carcinoma

Stage I tumours are confined by the renal capsule; stage II tumours have penetrated the renal capsule but remain confined by Gerota’s perinephric fascia; stage III tumours have renal vein involvement or nodal spread; stage IV have distant metastases.

Clinical features of renal cell carcinoma

The classic presentation is with the triad of haematuria, a mass and flank pain; although all three features only occur in about 15% of cases (see Fig 36.2), one is present in 40% of patients. Commonly, diagnosis is made incidentally by discovering a tumour on ultrasonography or CT scanning. Renal cell carcinomas often become large before diagnosis owing to their retroperitoneal position; unfortunately, tumours larger than 8 cm have an 80% chance of having already metastasised. Common and uncommon presenting features of renal cell carcinoma are summarised in Box 36.2.

Approach to investigation of suspected renal cell carcinoma

Ultrasound investigation reliably distinguishes simple benign cysts from solid masses most likely to be tumours, and can demonstrate tumour thrombus in the inferior vena cava. CT scanning is used to stage the disease by assessing invasion of perinephric tissues and by demonstrating regional lymph node or liver metastases (see Fig. 36.3).

Arteriography is still occasionally employed in the case of solitary unilateral or bilateral tumours to assess the prospects for segmental resection. Renal tumours have a characteristic circulatory pattern distinct from normal kidney (see Fig. 36.4a). Arteriography is also employed if therapeutic embolisation is being considered to reduce the vascularity of a tumour before surgery.

A full blood count is performed to look for anaemia or polycythaemia and a chest X-ray taken to look for pulmonary metastases (see Fig. 36.4b, c). No other preoperative investigations are usually required.

Management of renal cell carcinoma

In most patients, the kidney involved by tumour is excised (nephrectomy). Partial nephrectomy has gained popularity in suitable cases in order to preserve as much renal function as possible. Most surgeons prefer an anterior transperitoneal approach which allows clinical staging, permits control of the inferior vena cava and provides access to the renal artery and vein during extensive resections. If the tumour is large, a postero-lateral thoraco-abdominal approach allows early access to the inferior vena cava and renal arteries. In radical nephrectomy, the kidney, perinephric fat and lymph nodes should be taken en bloc wherever possible. There is probably no role for radiotherapy, chemotherapy or hormonal therapy, although immunotherapy with interleukins or interferon may help, despite their toxicity. Tyrosine kinase inhibitors and anti-angiogenic drugs are also gaining popularity. Increasingly, nephrectomies are performed laparoscopically, allowing shortened hospital stay and earlier return to normal activity.

Renal cell carcinoma is unusual in that surgical removal of isolated pulmonary or cerebral metastases occasionally results in cure. These isolated metastases may present years after the primary surgery. For palliation of multiple metastases, chemotherapy or immunotherapy is sometimes used but treatment is generally ineffective.

Epidemiology and aetiology of urothelial carcinoma

Tumours of urothelium are common. Histologically, they are nearly all urothelial carcinomas (UCs); other than rarities, the rest are squamous cell carcinomas (7%) or adenocarcinomas (1%). Most arise primarily in the bladder but they also occur in the pelvicalyceal system and ureters and rarely in the urethra. Urothelial tumours are uncommon below the age of 50 and the incidence increases with age. Men are affected three times more often than women. UC is at least four times more common than renal cell carcinoma.

Cigarette smoking is associated with a four-fold increase in incidence of urothelial tumours; this is probably mediated by urinary excretion of inhaled carcinogens. Urothelial cancers have been strongly associated with exposure to industrial carcinogens, once widely used in the rubber, cable, dye and printing industries. The likely carcinogens, benzidine, nigrosine and beta naphthylamine, are now banned in most countries but tumours can develop as long as 25 years after exposure and so a detailed occupational history should be taken in suspected cases. Prolonged exposure to carcinogens causes a 20–60 times increased risk of developing urothelial cancer. These carcinogens are excreted in the urine and the more prolonged presence of urine in the bladder compared with the rest of the tract probably explains why urothelial tumours most often arise in the bladder.

Pathology of urothelial carcinoma

Well-differentiated UCs histologically resemble normal transitional epithelium. Less well-differentiated tumours become increasingly unlike their tissue of origin so that the most anaplastic tumours can only be classified as urothelial because they are known to have arisen in the urinary tract. The degree of differentiation tends to be reflected in the tumour morphology as visualised at cystoscopy. Well-differentiated tumours form papillary frond-like lesions, whereas more aggressive tumours form plaque-like lesions which invade underlying muscle and surrounding tissues.

Most aetiological factors act on the whole urothelium, predisposing it to malignant transformation. Consequently, urothelial tumours can be multifocal and there may already be multiple tumours at presentation. When the primary tumour is in the pelvicalyceal system or ureter, there is a high risk of tumours developing later in the urothelium distal to the primary. About 50% of patients with upper tract urothelial tumours will ultimately develop bladder urothelial tumours.

A sinister form of urothelial carcinoma is carcinoma-in-situ. This presents with frequency and dysuria, aptly named ‘malignant cystitis’. These symptoms are often misdiagnosed as bacterial prostatitis in men. The lesions desquamate easily and have a high pick-up rate on urine cytology. Untreated, they infiltrate rapidly.

Clinical features of urothelial carcinoma

urothelial carcinoma usually presents with painless haematuria (see Fig. 36.5). Very occasionally, an upper tract lesion may cause ureteric colic (clot colic) and long stringy clots are seen in the urine. If bleeding is gross, clots may cause ureteric obstruction. Rapid bleeding from a bladder tumour may cause clot retention, i.e. acute retention of urine due to clot obstruction. Bladder tumours arising near a ureteric orifice can obstruct one ureter, causing hydronephrosis. Rarely, bilateral obstruction causes uraemia. Bladder tumours also predispose to infection; unexplained recurrent urinary tract infections need investigating to exclude UC as a cause. Tumour invasion near the bladder neck may cause incontinence but this is usually preceded by haematuria or infection.

Investigation of suspected urothelial carcinoma

Confirmed haematuria in the absence of infection must be investigated. Ultrasound examination may reveal hydronephrosis if there is ureteric involvement by UC. Contrast CT scanning will outline the upper tract as well as the renal parenchyma. IVU can also outline the upper tract, but is becoming obsolete (see Fig. 36.6). Imaging is followed by cystoscopy, the only reliable method of examining the lining of the bladder and urethra. If there is an upper tract tumour, cystoscopy may reveal blood emerging from a ureteric orifice.

Staging of urothelial tumours of the bladder

Staging is achieved mainly by cystoscopic examination and palpation under anaesthesia, combined with histological examination of resected specimens. For small and superficial lesions, histology shows the extent of bladder wall invasion, degree of tumour differentiation and whether the tumour has been completely removed. Lesions near a ureteric orifice that appear to be superficial should be treated as having invaded underlying muscle. For larger or deeper lesions, palpation of the bladder under general anaesthesia bimanually between a finger in the rectum and a hand on the anterior abdominal wall should be performed before and after resection of the tumour. This gives an idea of the extent of bladder wall penetration and spread into the pelvis, but can be misleading, especially in the obese. CT scanning is a more reliable indication of spread into the bladder wall or beyond. Note, however, that CT scanning can also be misleading if performed soon after resection of a bladder tumour.

The TNM clinical system widely used in staging bladder tumours is illustrated in Figure 36.7 (the ‘T’ is the clinical stage of the tumour). In addition, some pathologists grade bladder tumours according to P and G pathological criteria. The ‘P’ system (small p for the biopsy specimen and capital P for the whole specimen) classifies the extent of invasion on gross anatomical and histological grounds. The ‘G’ system grades the lesion by degree of histological differentiation (G1 = well differentiated, G2 = moderately differentiated and G3 = poorly differentiated or undifferentiated). Thus, as an example, a pathologist may report a biopsy as pT₂, G3.

Management of urothelial carcinoma