Anatomy

The kidneys lie retroperitoneally on the posterior abdominal wall. They are approximately 11   cm long and 6   cm wide in adults. The left kidney is 1   cm higher than the right. The right kidney is related in front to the liver, the second part of the duodenum and the ascending colon. In front of the left kidney are the stomach, the pancreas, descending colon and the spleen. On the top of each kidney lies an adrenal gland. Behind the kidneys lie the diaphragm and the 12th rib. On the medial side of the kidney there is an opening, the hilum, through which pass the renal artery and vein, and the ureter. The renal vein drains into the inferior vena cava. The lymphatic drainage is to the para-aortic nodes. The anatomical relationships are shown in Figure 28.1.

Figure 28.1 Anatomical relationships of the kidney with lymphatic drainage pathways and typical treatment volume when irradiating the renal bed.

(Reproduced with permission from Souhami & Tobias, Cancer and its Management, Blackwells, 1986)

Pathology

The three principal malignant tumours of the kidney are Wilms’ tumour (nephroblastoma) in children (described in Chapter 33), renal cell adenocarcinoma (also called clear cell carcinoma, hypernephroma and Grawitz’s tumour) and transitional cell carcinoma of the renal pelvis. Adenocarcinoma arising from the renal tubules accounts for 80% of tumours. Macroscopically, the tumour appears as a yellowish vascular mass. Microscopically, the tumour cells are large with a foamy or clear appearance to the cytoplasm. The nucleus is small, central and densely staining.

Renal cancer is uncommon, accounting for 3% of all cancers and 1.5% of cancer deaths. Over the last 10 years, the incidence has risen by 23% in men and 29% in women within the UK, a pattern reflected throughout the world. Overall there is a 2:1 male to female ratio in incidence and the disease occurs mainly in the 5th–7th decades of life. The aetiology of renal cell carcinoma is unknown, though smoking and obesity are risk factors. Thirty percent of patients present with metastatic disease.

Clinical features

Presentation is usually with local symptoms. Painless hematuria is the commonest or colicky pain secondary to clots of blood. Other symptoms are aching or a mass in the loin which may be noticed by the patient. A coincidental finding following radiological imaging of the abdomen is an increasingly common presentation. Distant metastasis may be the first presentation, such as pathological bone fracture, haemoptysis from pulmonary metastases or symptoms of raised intracranial pressure from cerebral deposits. Systemic features such as anaemia, loss of weight and unexplained fever may occur. The kidney may be palpably enlarged.

Investigation and staging

The urine may contain frank or microscopic evidence of blood. Urine cytology may show malignant cells. The most important investigation is an intravenous urogram (IVU), which may show distortion of the calyces (the channels that drain urine to the renal pelvis and are outlined by the contrast medium) by the tumour. Calcification within the tumour may be visible on plain radiographs. Ultrasound and computed tomography (CT) scanning (Figure 28.2) are helpful in distinguishing between solid and cystic renal masses. Ultrasound may show extension of tumour into the renal vein or inferior vena cava. CT scanning of the chest, abdomen and pelvis may show direct tumour spread, venous and lymph node involvement and soft tissue metastases in liver and lung. Angiography is an invasive procedure and its use is diminishing. It still has a role in demonstrating the renal artery and new vessel formation when the kidney is to be embolized (i.e. material introduced into the renal arterial to cut off its blood supply and cause death of part or the whole of the kidney). Bone metastases are typically osteolytic (Figure 28.3).

Figure 28.2 CT scan showing a typical renal cell carcinoma in the right kidney.

Figure 28.3 Radiograph showing osteolytic metastasis of the vertebral body from renal cell carcinoma.

No staging system for renal cell cancer has universal acceptance. The UICC 1997 TNM classification is shown in Table 28.1.

Table 28.1 TNM staging of primary renal tumours

Treatment

Surgery is the main treatment for localized renal cell cancer. Radiotherapy and embolization have more limited roles. Chemotherapy is of unproven value. Immunotherapy has been superseded by oral tyrosine kinase inhibitors (TKIs) as first-line therapy for metastatic disease.

Results of treatment

The outlook depends on the stage at diagnosis. For tumours confined to the kidney, 5-year survival varies from 50 to 80%. Extrarenal or renal vein invasion, lymph node and blood-borne metastases all confer a poor prognosis. Patients with metastatic disease at presentation have a median survival of only 12 months, with 20% remaining alive 2 years from diagnosis.

Anatomy

The bladder is related anteriorly to the pubic symphysis, superiorly to the small intestine and sigmoid colon, laterally to the levator ani muscle, inferiorly to the prostate gland and posteriorly to the rectum, vas deferens and seminal vesicles (see Figure 28.7) in the male and to the vagina and cervix in the female. At cystoscopy, the bladder mucosa and ureteric orifices can be inspected. Lymphatic drainage is to the iliac and para-aortic nodes.

Figure 28.7 Prostate, seminal vesicles and vas deferens in a posterior view of the bladder.

(Redrawn from Ellis, Clinical Anatomy, 5th edn, Blackwells, 1975)

Pathology

The bladder, ureters and renal pelvis are lined by transitional cell epithelium (urothelium). The same type of tumours may arise anywhere along the urinary tract but cancers in the renal pelvis and ureter are rare compared with those in the bladder. Prostatic adenocarcinoma and other pelvic tumours also sometimes secondarily involve the bladder.

Aetiology

In the majority of cases of bladder cancer, the aetiology is unknown. However, as discussed in Chapter 14, occupational exposure to certain carcinogens has accounted for some cases. The production of aniline dyes and processing of rubber are associated with 2-naphthylamine, now recognized as a procarcinogen. Workers in these industries are now offered regular cytological examination of urine to detect abnormalities or tumours at an early stage.

Smoking is perhaps the commonest factor that predisposes to bladder cancer. Bladder cancer is up to six times commoner in smokers than non-smokers and increases in frequency with the number of cigarettes smoked. Phenacetin, formerly used as an analgesic drug, and the cytotoxic alkylating agent cyclophosphamide may give rise to urothelial tumours. Squamous carcinoma tends to complicate chronic irritation of the bladder including a parasitic disease, schistosomiasis (formerly known as bilharziasis), which is common in Egypt and Central Africa. Adenocarcinoma occurs on the dome of the bladder in relation to embryological remnants of the urachus, and also from the trigone at the bladder base.

Genetic alterations in bladder cancer are common. Deletion of markers on chromosome 9 is an early event. Subsequent mutation in p53 allows cells with DNA damage to proceed through the cell cycle, replicating genetic errors. Loss of the pRb (retinoblastoma) gene product disrupts cell cycling and increases the mitotic index. Patients with both mutations have higher-grade more advanced disease and a poor response to treatment.

Epidemiology

Bladder cancer is common and accounts for 4.4% of all cancers and 3.4% of cancer deaths. The male to female ratio is 3.8:1 and it has a peak incidence at the age of 65. The impact of smoking in women has seen a greater rise in incidence in this group over the last 10 years compared to men. It is twice as common in Caucasians as in Blacks. Over 90% are transitional cell carcinomas.

Macroscopic appearance

The chief types on inspection of the bladder are (1) papillary and (2) solid. Multiple growths are common.

Papillary carcinoma has a base with surface fronds. The tumours tend to be multiple and to appear in crops. Confined at first to the mucosa and submucosa, they eventually invade the submucosa, muscle coat and then outside the bladder.

Solid carcinoma is nodular, often ulcerated, grows more rapidly and infiltrates early.

From the point of prognosis, a division can be made between superficial (papillary) and invasive (solid) bladder cancer. Superficial bladder tumours are the commonest (80%) and become invasive in 10–20% of cases. By contrast, invasive cancer, untreated, carries a very poor prognosis. The degree of invasion correlates with the risk of metastatic disease. Invasion of the lamina propria (the layer of tissue between the epithelium and the muscle layer of the bladder), superficial and deep muscle is associated with 20%, 30% and 60% incidence of lymphatic invasion.

Clinical features

The presenting symptom is usually painless frank hematuria. Occasionally, clots of blood are passed and are even more suggestive of the diagnosis. Papillomatous types grow slowly and may cause no other symptoms for a long time. When aggressive carcinomas invade muscle, there may be urinary frequency, dysuria and pain, especially when there is extravesical (i.e. outside the bladder) spread into the pelvic soft tissues. Bacterial cystitis may be associated with the tumour and may aggravate symptoms.

Obstruction of one or both ureters can occur at any time, with no symptoms at first. Later, there may be upper urinary tract infection, pain in the flank(s) and eventual renal failure from backpressure. In localized bladder disease, clinical examination is usually unremarkable.

Investigation and staging

Cystourethroscopy

This is the most important investigation of all. Under general anesthesia, the urethra and the whole of the bladder are inspected. The number, site, size and character of the tumours are noted and a biopsy taken. While the patient is relaxed under the anesthetic, a bimanual examination of the pelvis is made, with a finger in the rectum and the other hand on the lower abdomen. In this way, the tumour may be palpated and any extravesical spread assessed.

Clinical staging of bladder cancer is according to the TNM classification (Figure 28.4 and Table 28.2).

Figure 28.4 T staging of bladder cancer – UICC classification.

(Reproduced with permission from Hermanek P, Hutter R V P and Sobin L H (eds) 1997 International Union Against Cancer TNM Atlas. Illustrated guide to the TNM classification of malignant tumours, 4th edn, Springer-Verlag)

Table 28.2 TNM staging of bladder cancer

Stage	Clinical findings
Tumour
Tis	Carcinoma in situ
Ta	Papillary non-invasive carcinoma
T1	Invasion into submucosa but not beyond the lamina propria
T2a	Invasion into superficial detrusor muscle
T2b	Invasion into deep detrusor muscle
T3a	Invasion into perivesicular tissues microscopically
T3b	Invasion into perivesicular tissues macroscopically
T4a	Invasion of prostate or vagina
T4b	Invasion of pelvic side-wall or abdominal wall
Nodes
N0	No evidence of nodal involvement
N1	Single node <2   cm diameter
N2	Single nodal metastasis 2–5   cm diameter or multiple nodes none exceeding 5   cm
N3	Node >5   cm
Metastases
M0	No metastases
M1	Distant metastases

Treatment

Treatment will depend on the stage, histology, size and multiplicity of tumours and the age and general medical condition of the patient.

Radical radiotherapy

The following are criteria for accepting patients for radical radiotherapy:

• age <80 years (unless particularly fit)

• adequate general medical condition

• no inflammatory bowel disease or symptomatic adhesions

• good bladder function

• minimal or no CIS

• transitional cell carcinoma

• single tumour <7   cm maximum diameter

• recurrent T1G3, T2–T4a

• no metastases.

Target volume

The treatment volume is 1–2   cm around the tumour, judged by bimanual examination and CT scanning. The bladder is emptied before CT planning and before each treatment.

Radiation planning technique

The tumour is localized by a CT planning scan and has replaced using a cystogram (Figure 28.5).

Figure 28.5 Simulator radiograph showing anterior treatment volume for radical radiotherapy of a transitional cell carcinoma of the bladder.

CT planning allows greater definition of the planning target volume (PTV). The patient is planned in the same position on the CT scanner as on the simulator and treatment couches (supine with feet in foot stocks and hands by the side). On the planning computer, the width of the target volume to encompass the tumour with a 1–2   cm margin is chosen. The superior and inferior target volume being 1   cm above and below the upper and lower limits of the bladder. It is common practice to cover the prostatic urethra in the PTV in view of the risk of local recurrence. The position of the rectum and femoral heads are marked on the computer and translated to the treatment plan. An open anterior and two lateral wedged or posterior oblique wedged fields are used, treating isocentrically (Figure 28.6). A direct lateral field is preferred at our institution to reduce rectal doses in view of the sharp fall-off of the field. With high-energy photon beams such as 15   MV, femoral-head doses are kept below 50% of the tumour dose. The use of conformal therapy techniques is routine and improves treatment-related morbidity in addition to possible dose escalation in the future. IMRT is increasingly being used to treat patients at risk of pelvic lymph-node involvement in addition; whether this improves survival however is unproven.

Figure 28.6 Isodose distribution for radical radiotherapy of the bladder using anterior and two lateral fields.

Dose and energy

55   Gy in 20 daily fractions over 4 weeks (9–16   MV photons)

or

64   Gy in 32 daily fractions over 6.5 weeks (9–16   MV photons).

Concurrent chemotherapy and radiotherapy (chemo-rt) should be considered for all patients fit enough to receive it and can be given safely after neoadjuvant chemotherapy or on its own… BC2001 reported improved local control at 2 years to 71% after concurrent chemo-rt with 5FU and mitomycin C over RT alone. Similarly, in an attempt to overcome tumour hypoxia in the bladder, nicotinamide and carbogen in combination with radiotherapy within the BCON study has improved local control and survival in comparison to RT alone.

Radiation reaction

Before radiation begins, attention is paid to the patient’s general condition and nutrition. The patient’s hemoglobin level should be maintained over 12   g/dL, by blood transfusion if necessary, since anaemia will reduce the amount of oxygen available to the tumour. It is known that reduced oxygenation in parts of the tumour contributes to resistance to radiation. Urinary infection should be treated with antibiotics. The urine should be made sterile if possible before radiation begins, since inflammation has adverse effects on radiation response. However, with an ulcerated mass this may not be possible until the tumour has shrunk in response to radiation.

Acute reactions

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