Organ
No. of cases in 2012 (in 1,000s)
Percent of all cancers
Prostate
1,112
7.9
Testis
55
0.4
Kidney
338
2.4
Bladder
430
3.1
Incidence rates of prostate cancer in 2008 were highest in Australia/New Zealand, Western and Northern Europe and North America and lowest in Asia [2]. In both sexes bladder cancer is one of the major GU cancers. The details of epidemiology and aetiology have been discussed in respective chapters. This chapter will focus on clinical aspects of genitourinary tumours.
Symptoms Associated with Genito-urinary Cancers
Presenting symptoms of genito-urinary cancers fall into three categories:
Lower urinary tract symptoms related prostate and bladder
Abdominal masses/swellings of testes and
Haematuria. This will be discussed below along with other symptoms, which are less common presentations.
Haematuria
It is one of the commonest symptoms investigated in its various forms in the urology department. It can manifest in renal, bladder and prostate cancers. Diagnosis and management of haematuria will be discussed later in this chapter.
Loin/Back Pain
It usually manifests in an obstructed or a stretched kidney. Patients with upper tract urothelial tumour and renal cancer may present with loin pain and visible haematuria. The classical ‘triad’ of flank pain, haematuria and abdominal mass with renal carcinoma is a rare presentation now because of early detection of renal tumours by imaging. Loin pain is not that commonly seen in transitional cell carcinoma of the ureter in spite of obstruction probably because of gradual ureteric obstruction. Differential diagnosis includes pelvi-ureteric junction obstruction, stone disease, sloughed renal papilla. Prostate cancer patients with metastasis in the spine may also present with back pain.
Suprapubic/Vesical Pain
This is usually manifested in acute urinary retention or in bladder carcinoma in situ. Occasionally suprapubic pain is associated with urethral pain particularly in bladder neck or prostatic lesions.
Lower Urinary Tract Symptoms (LUTS)
Urinary frequency, hesitancy, urgency, sensation of incomplete voiding indicate bladder outlet obstruction, which may be due to benign enlargement of prostate or prostate cancer. Irritative bladder symptoms including urgency and frequency may indicate carcinoma in situ of the bladder. Similarly urethral pain in absence of infection may be an indication of a sinister pathology. Urinary incontinence in prostate cancer may signify tumour infiltration of external sphincter.
Testicular Symptoms
Testicular cancer can present with testicular pain particularly if there is haemorrhage or a rapidly expanding tumour. The most common presenting symptom is painless swelling or nodule of one testis. Patients with cancer in atrophic testes might present with progressive testicular enlargement. Dull ache or heavy sensation in the lower abdomen could be presenting symptom. Progressive enlargement of testis following trauma should be evaluated to rule out testicular cancer.
Penile Symptoms
The presentation of penile cancer is highly variable. The lesion may present anything between a small popular lesion to a large fungating ulcer. The commonest site is glans and prepuce. The first presentation could be phimosis or balanitis like symptoms with or without purulent discharge.
Haematospermia
Presence of blood in the semen is distressing for the patients and generally does not have a sinister cause. This is again discussed in detail later in this chapter.
Urethral Symptoms
Diminished stream, straining to void and other obstructive voiding symptoms may be the presenting symptoms of urethral carcinoma. Frequency, nocturia, and other irritative voiding symptoms are reported in association with bladder carcinoma in situ. Severe urgency might progress to urge incontinence and distortion of the urethral anatomy in females might lead to stress urinary incontinence. Urethral discharge, purulent or otherwise could be the sign of urethral or penile malignancy.
Urinary retention from progressive malignant urethral stricture disease may occur. There might be hard nodular mass may be palpable along the urethra. Hematuria, urethral or vaginal spotting may be seen in late disease. Purulent, foul-smelling/watery discharge, hematospermia, perineal/suprapubic/urethral pain, dyspareunia, priapism also may be presenting symptoms of urethral cancer. Patients with penile cancer may present with phimosis or painless ulcer.
Bone and Neurological Symptoms
Prostate cancer spreads to axial skeleton and first presentation of metastasis could be back pain. Characteristically the pain may get worse even after resting. Nerve root compression pain usually radiates along the course of the nerve. Bone metastasis itself is not threatening but its morbidity stems from the various complications that arise as a result of bony metastases. Skeletal-related events (sres) include debilitating bone pain in up to 80 % of patients with bone metastases, impaired mobility in 65–75 %, vertebral collapse or deformity in 18 %, hypercalcemia in 10–15 %, spinal cord compression in 12 % of prostate cancer patients, and pathologic fracture in 9 % [3–6]. These complications may cause deformity, postural problems, and loss of motor and sensory function (neurologic impairment), leading to decreased overall quality of life (qol) [7].
Paraneoplastic syndromes (PNS) are sometimes seen in prostate and renal cancers. PNS are much less common than direct, metastatic, and treatment related complications of cancer. Paraneoplastic syndromes are a group of rare disorders that are triggered by an abnormal response of the immune system to a cancer [8]. Essentially PNS are nonmetastatic manifestations of a cancerous growth. The presenting symptoms may be endocrine, neuromuscular or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature [9]. Unexplained fever in renal cancer is an example of PNS. Various cytokines normally produced by the kidney (i.e. prostaglandins, renin, and erythropoietin) may be produced in excess quantities, and other substances that the kidney does not usually secrete (i.e. parathyroid hormone-like chemicals, glucagon, and insulin) may be produced. Intrinsic production of such substances leads to manifestation of paraneoplastic syndromes.
The presentation of paraneoplastic syndrome in renal cancer includes anaemia, polycythemia, hypertension, hypoglycemia, Cushing’s syndrome, hypercalcemia, erythrocytosis, and nonmetastatic hepatic dysfunction (i.e. Stauffer’s syndrome). In a study of 1,046 renal cancer patients in the UCLA, Kim et al. observed that hypoalbuminemia, weight loss, anorexia and malaise were the predictors of poor survival that were independent of stage, grade and performance status [10].
Uraemic symptoms can occur from ureteral obstruction caused by local prostate growth, infiltrating bladder cancer or retroperitoneal lymph nodal metastasis. In fact in some unfortunate patients with advanced disease, uremia could be the first manifestation of advanced urological malignancy. The term uremia refers to a syndrome characterized by fluid, electrolytes and metabolic abnormalities including acidosis and accumulation of nitrogenous products. Bilateral ureteric involvement in bladder and prostatic malignancies may be associated with anuria.
Miscellaneous metastatic symptoms due to metastases include cachexia, fever, and night sweats. Metastasis from renal cell carcinoma occurs to lung, soft tissues, bone, liver, cutaneous sites, and central nervous system. Similarly in prostate cancer bony metastasis, anemia and weight loss indicate advanced disease.
Other relevant history: Functional status and co-morbidity are two important aspects that have to be assessed in cancer patients. The Karnofsky Performance Status Scale (KPS) and more recently WHO performance status have been used to quantify the functional status of cancer patients. However, limited data exist documenting its reliability and validity [11]. Similarly medical conditions such as diabetes, stroke, cardiovascular are also important in determining the course of the disease and consideration of various modalities of treatment. History of previous abdominal surgery, peritonitis and difficult anaesthesia is important in patients undergoing major renal or bladder surgery.
Physical Examination
Examination of the patient with suspected urological cancer starts with a cursory look regarding their height, build, obesity, breathing and nourishment. Gynaecomastia may be seen in patients with testicular cancer. Anaemia, weight loss may be seen in renal and prostate cancer. A detailed abdominal examination including genitalia is necessary. Rectal examination in men is important in suspected bladder and prostate cancers. In women vaginal examination may be necessary to carry out bimanual assessment. Attention should be given to the consistency of prostate gland, along with the seminal vesicles and adjacent organs. Hard nodule or surface on rectal examination in men indicates prostatic malignancy. Obliteration of the lateral sulcus or seminal vesicular involvement and restricted mobility of the prostate indicates locally advanced disease. Rectal wall mobility and fixation to the anterior structures is also noted. Normal physical examination does not exclude urological cancer.
Examination of the testes usually starts with the assessment of normal testis first and later the affected testis is looked for abnormal areas and involvement of the spermatic cord. In all suspected testicular tumour patients, testis should be palpated carefully and at no stage the testis is squeezed.
Neurological examination, including determination of external anal sphincter tone, should be done to help detect possible spinal cord involvement/pathological fracture of vertebra.
Haematuria
Haematuria is defined as the presence of blood in the urine on visual inspection (visible haematuria) or quantified on urine analysis (invisible haematuria). Presence of blood in the urine is significant if there are greater than three red blood cells (RBCs) per high power microscopic field on urine sediment examination from two of three properly collected urinalysis specimens [12]. Haematuria of any degree should not be ignored regardless of the quantity of blood. It is considered to be of malignant origin until proven otherwise. In the vast majority of patients microscopic haematuria is detected by dipstick testing (see later). Different dipstick kits vary in their sensitivity to detect blood, but most dipsticks will detect 8 RBCs/HPF. Dipstick haematuria of ‘3+’ equates to approximately 500 RBCs/ml. As dipstick testing is less sensitive compared to urine microscopy, a positive test should be confirmed with a second test and followed by urine microscopy.
Gross (or frank or visible) haematuria is blood in the urine in sufficient quantity to be visible to the naked eye. In fact, visible blood in the urine is thought to be the first presentation in 85 and 40 % of patients with bladder and renal cancers, respectively [13]. It indicates the risk of significant sinister underlying disease i.e. urothelial cancer.
Other Forms of Haematuria
Exercise Haematuria
Microscopic or gross haematuria may occur immediately following non-contact strenuous exercise such as running, cycling or swimming. Although the exact cause is not known this may be due to microcontusions resulting from trauma of the posterior bladder wall against the trigone of the partially filled urinary bladder. It usually resolves with rest in 48–72 h.
Pseudohaematuria
It occurs following ingestion of certain foods (carrots, beetroots, blackberries, riboflavin, vitamin A), drugs (chloroquine, phenacetin, sulfonamides, phenazopyridine, sulfasalazine, rifampin, laxatives containing phenolphthalein).
Factitious Haematuria
It is an extremely rare condition where patients have pathological desire to feign ill health and undergo investigations (Munchausens syndrome). Patients show haematuria by contaminating urine samples with venous blood. It is usually seen in analgesics abusers especially people addicted to opiate drugs.
Postcoital (Post-ejaculatory) Haematuria
It is a rare condition where painless haematuria occurs in men immediately after sexual intercourse. A urethral vascular lesion is usually associated, especially haemangioma. Haematuria may be associated with haematospermia in such a setting.
Causes of Haematuria
Systemic causes: Systemic disorders include Systemic lupus erythematosus (SLE), Henoch- Schönlein purpura (HSP), malaria, sickle cell disease, coagulopathies, endometriosis and alcohol abuse (papillary necrosis).
Drugs
Interstitial nephritis can be caused by penicillin, nonsteroidal antiinflammatory drugs (NSAIDs), cephalosporins, and frusemide. Nephrotoxic drugs include aminoglycosides and cyclosporine. Drug-induced hemorrhagic cystitis can be caused by cyclophosphamide and methicillin. Ketamine, a hallucinogenic drug and short acting anaesthetic causes severe voiding dysfunctional symptoms including haematuria. There is no evidence at present that this drug carcinogenic [14].
Anticoagulation
Anticoagulation should not be discounted as the source of bleeding, as significant urinary tract disease may be present in up to 30 % of patients [15]. The majority of patients have no diagnosis found after thorough evaluation. Table 8.2 lists the urological causes of haematuria.
Table 8.2
Urological causes of Haematuria
Renal | Congenital: PUJ obstruction, arteriovenous (AV) malformations, cystic renal disease (adult polycystic kidney disease, APKD), medullary sponge kidney, renal cysts |
Genetic: renal tubular acidosis type I, cystinuria, von Hippel–Lindau disease, Alport disease, thin basement membrane disease | |
Trauma: iatrogenic (nephrostomy) Neoplastic: Renal cell carcinoma, transitional cell carcinoma, angiomyolipoma Metabolic: calculi Infection: pyelonephritis, genitourinary tuberculosis Inflammatory diseases: interstitial nephritis, poststreptococcal glomerulonephritis, IgA | |
Nephropathy, Goodpasture’s syndrome Radiation: nephritis Vascular: renovascular arterial disease, renal vein thrombosis, left renal vein hypertension due to nutcracker syndrome renal infarction: compression of left renal vein between superior mesenteric artery and aorta, hemangiomas, renal papillary necrosis Foreign bodies: stent, nephrostomy | |
Ureteral | Ureteral Calculi, neoplastic (transitional cell carcinoma, TCC), trauma (including iatrogenic), foreign bodies (stent) |
Urinary bladder | Bladder Neoplastic (TCC, squamous cell, adenocarcinoma, neuroendocrine tumors); anatomic (diverticulae, vesicoureteric reflux); infection (hemorrhagic cystitis, schistosomiasis); metabolic (calculi), post– acute urinary retention (decompression bleeding), trauma |
Prostate | Prostate Benign prostatic hyperplasia, carcinoma, infection (prostatitis), metabolic (calculi) Urethra Hemangioma, tumor, stone, stricture, trauma, foreign bodies (catheter, stents, inserted bodies), iatrogenic (instrumentation) |
Clinical Evaluation
Patients, who are 40 years of age or older, have a higher risk of urological malignancy. The incidence of significant pathology is lower in women. It is important to differentiate rectal and vaginal bleeding from hematuria. Gross hematuria with clots demonstrates significant bleeding and increases the likelihood of malignancy.
The timing of hematuria can give a clue to the anatomical site of bleeding: hematuria at the start of micturition (initial) indicates urethral bleeding; hematuria occurring throughout micturition (total) comes from the bladder or upper tracts; and hematuria at the end of micturition (terminal) indicates that the bleeding is in the prostatic urethra or bladder neck.
Hematuria associated with colicky abdominal flank pain and passage of stringy clots is indicative of upper tract bleeding. Constant severe lower abdominal pain may be due to clot retention. Prostatic bleeding due to benign prostatic hypertrophy (BPH) or urethral stricture is usually associated with lower urinary tract symptoms (LUTS). Dysuria, urgency, and incontinence may be due to prostatitis or urinary tract infection.
Systemic Symptoms
Loss of appetite, weight loss, and night sweats could be due to underlying carcinoma. Recent history of an upper respiratory tract infection is associated with nephrological causes of hematuria such as poststreptococcal glomerulonephritis. A viral illness with hemoptysis and abnormal renal function is typical of Goodpasture’s syndrome. Timing of the menstrual period must be noted along with any history of endometriosis. Unprotected sexual intercourse increases the likelihood of acquiring sexually transmitted infections.
A history of previous instrumentation may lead to a history of urethral stricture. Pelvic radiotherapy could cause radiation cystitis. Chronic atrial fibrillation or recent myocardial infarct may result in renal emboli and hematuria. In endemic regions a history of tuberculosis may indicate genitourinary tuberculosis. Urological cancer may be prevalent in first-degree relatives (prostate, renal cancer-von Hippel-Lindau disease). A family history of urolithiasis may point toward calculi as the cause of hematuria.
Clinical assessment of hemodynamic status is essential against a background of significant gross hematuria. Other features such as fever, sepsis, lymphadenopathy, hypertension (due to glomerulonephritis, renal parenchymal disease, renal failure, renal cystic disease, or vascular disease) and pulse rhythm (atrial fibrillation) will give clues to the diagnosis. Generalized edema may be due to glomerular disease.
Abdominal examination is done to rule out renal and bladder masses. Rectal examination helps in assessing the size, consistency, nodules, and tenderness of the prostate gland and finding rectal bleeding. The genitalia should be examined for signs of infection, bleeding, or discharge. In men, the penis is examined for growths, meatal stenosis, and phimosis.
Laboratory Investigations
Mid-stream Urine (MSU)
For optimal analysis, a clean catch mid-stream urine specimen non-contaminated from external genitalia should be obtained and examined within 1 h or refrigerated at 4 °C. False negative results arise when urine is stored at room temperature for longer than an hour due to changes in pH and disintegration of white or red cells.
Dipstix (Dipstick) Testing
The dipstick test is based upon the liberation of oxygen from peroxide in the reagent strip because of the peroxidase like activity of heme from erythrocytes, free haemoglobin and myoglobin. The reaction causes the reagent strip to change colour and turn green. The degree of colour change is related to the amount of heme, haemoglobin and myoglobin in the urine. Intact red cells cause a punctate colour change on the strip whereas free haemoglobin leads to uniform staining. When >250 RBCs/ml is present in the urine, the number of punctate dots increases to become uniform.
The overall sensitivity for the dispstick compared to phase contrast microscopy is over 90 % with specificity ranging from 65 to 90 % [16]. False negative results occur in the presence of acidic urine (pH <5), high levels of ascorbic acid or certain drugs (captopril, rifampicin, phenolphthalein).
Free myoglobin, haemoglobin, povidone and microbial peroxidase from bacterial infection can lead to false positive readings. False positive readings are much less common than false-negative results, and up to 40 % of patients with dipstick haematuria may not have haematuria confirmed on bright-field urine microscopy [16]. A positive dipstick result in the presence of a negative urine microscopy or repeated dipstick test should not be discounted. The ideal standard for urine microscopy is phase-contrast microscopy, which is often not the standard investigation in most centres. One positive dipstick result, even if intermittent, should be considered worthy of full investigation, especially if risk factors for malignancy are present. The combination of proteinuria indicates a likely glomerular origin for the haematuria.
Microscopy
The two main methods of microscopic examination of urine are bright field microscopy and phase contrast microscopy.
Red Blood Cells (RBCs)
Bright-field microscopy: This is the direct examination of centrifuged urinary sediment under a cover slip (sediment count), which is reported as the number of RBCs per high power field (HPF). The upper limit of normal of RBC excretion in the urine is approximately equal to 2 RBCs/HPF.
The speed of centrifugation, its timing the volume in which sediment is re-suspended, and the power of the HPF vary from laboratory to laboratory. Another method of analyzing RBCs in the urine is by using counting chambers in the microscope, which determine the number of RBCs per milliliter of urine. The chamber count has greater sensitivity and precision than the sediment count but the sediment count is easier to perform, less time consuming and more cost effective.
Phase-contrast microscopy: This is regarded as the gold standard microscopic examination. It is able to show components in a cell or bacteria that would be difficult to see in an ordinary light microscope. Not only are RBCs detected better, their morphology can be better determined with the phase contrast microscopy.
Circular isomorphic erythrocytes are characteristic of nonglomerular bleeding, whilst glomerular bleeding results in dysmorphic erythrocytes associated with proteinuria and RBC casts.
White Blood Cells (WBCs)
Presence of greater than 10 WBCs/HPF is seen in significant inflammation. Persistent pyuria with a negative culture may be indicative of urolithiasis, tuberculosis or tumour.
Casts
A cast is a protein coagulum that is formed in the renal tubule and traps any tubular luminal contents within the matrix. Haematuria of glomerular origin is associated with casts. RBC casts are diagnostic of glomerular bleeding. WBC casts may also be found in acute glomerluonephritis, pyelonephritis and tubulointerstitial nephritis.
Crystals
Crystals of urate, calcium oxalate or triple phosphate may be seen in those with urinary tract stones.
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