Watchful waiting is an option for non-metastatic T3 disease in an elderly asymptomatic patient who may prefer to avoid side effects of treatment. Palliative treatment of locally advanced disease See also b p. 362. Palliative TURP or medi cal therapy for LUTS or uri- nary retention may be necessary. Incontinence can be a problem due to sphincter involvement, though bladder out \202 ow obstruction and instability shou ld be considered. A urinary convene sheath or catheter may be re- quired. Patients may pres ent in renal failure; percutaneous nephrostomy or ureteric stenting are occasionally necess ary for bypassing ureteric ob- struction. ADT in this setting may relieve this tumor compre ssion of the distal ureters. Very rarely, a colostomy is necessary to bypass a rectal ste- nosis. Palliative EBRT may be useful for treatment of persistent prostatic haematuria or pe rineal pain. 1 Zelefsky MJ et al., (2010) Metastasis after radical prostatectomy or external beam radiot herapy for patients with clinically localized prostate cancer: a comparison of clinical coh orts adjusted for case mix. J Clin Oncol 28: 1508 \200\22313. 2 Bolla M, Gonzalez D, Warde P, et al. (1997) Improved survival in patients with locally ad vanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337:295 \200 \223300. CHAPTER 7 Urological neoplasia 352 Prostate cancer: management of advanced disease \200\224hormone therapy I Metastatic diseas e is the cause of nearly all prostate cancer-related death. Currently incurable, the 5y sur vival is about 35%; 10% survive <6 months, while <10% survive >10y. The gold standard treat ment is hormone thera- py (usually androgen ablation), with cytotoxic chemotherapy for prog res- sion and novel treatments (such as growth factor inhibitors, angiogenesis inhibitors, immunotherapy) in development. The concept of hormone therapy was realized in 1941 when Chi cago physicians, Charles Huggins and Clarence Hodges, reported favorable symptomatic and bi ochemical (acid and alkaline phosphatase) responses in metastatic PC patients when castrate d or given oestrogens.1 Hormone dependence of prostate cancer All prostate epithelial cells, with the exception of rare undifferentiat- ed stem cells, are dependent on androgens and fail to grow or under- g o programmed cell death (apoptosis) in their absence. Similarly, most previously untreated prostate cancer cells are dependent on androgens. In men, 95% of circulating androgen, main ly testosterone, is produced by the testicular Leydig cells under the in \202 uence of lut einising hormone (LH). The anterior pituitary synthesizes LH, stimulated by hypothalamic LH -releasing hormone (LHRH). The remaining 5% of circulating andro- gen (mainly dehydoepiandr osterone) is synthesized by the adrenal cortex from cholesterol, under the in \202 uence o f pituitary ACTH. Testosterone is metabolized to the more 5-fold more potent dihydrotestost erone (DHT), by 5A-reductase (5AR) enzymes types 1 and 2. DHT binds cytoplasmic androgen re ceptor which translocates to the nucleus, there activating transcription of androgen-respon sive genes which drive the cell cycle or inhibit apoptosis. Androgen deprivation results in a reduction in PSA and clinical improve- ments in >70% of p atients. However, most patients with metastatic disease will still die within 5y due to the emergence of castrate-resistant growth. This may be due to selection of androgen-independe nt cell clones or intra- cellular androgen biosynthesis. The mean time to disease progressi on after androgen deprivation is 14 months in men with metastatic disease. Prognostic factors Predictors of poor hormone therapy response include: (cid:116)- 5 metast atic lesions at presentation. - - - - Elevated alkaline phosphatase at presentation. Anemia at presentation. Poor performance sta tus (level of activity) at presentation. Low serum testosterone at presentation. PROSTATE CANCER: HORMONE THERAPY I 353 Failure of bone pain to improve within 3 months of treatment. PSA to normalize (to <4ng/mL) within 6 months of Failure of treatment; (conversely a PSA nadir (= lowest value) of <0.1n g/mL predicts a long-term response). 1 Huggins C, Hodges CV (1941) Studies on prostate cancer: I. The effect of castration, of e strogen and of androgen injection on serum phosphatases in metastatic carcinoma of the pros tate. Cancer Res 1: 293 \200\2237. CHAPTER 7 Urological neoplasia 354 Prostate cancer: management of advanced disease \200\224hormone therapy II Methods of andro gen ablation therapy - - Surgical castration: Medical castration: agonists. \200 \200 antagonists. \200 Maxima l androgen blockade ( antiandrogen. bilateral orchidectomy. LHRH LHRH Oestrogens. MAB): medical or surgical castration plus Both forms of castration have equivalent ef \201 cacy so patients can be given the choice. Oestrogens are no longer used \201 rst-line due to the signi \201 cant cardiovascular m orbidity observed when they were the only alternative to orchidectomy. MAB has a theoretica l advantage over castration in blocking the effects of the adrenal androgens; signi \201 c ant clinical advan- tages (>5% improved 5y survival) have not been demonstrated by trial me ta-analyzes. Bilateral orchidectomy (subcapsular technique) A simple procedure, usually carried out unde r general anesthesia. Through a midline scrotal incision, both testes may be accessed. The tunica albug- inea of each testis is incised and the seminiferous tubules removed, after wh ich the capsule is closed. The epididymes and testicular appendages are preserved. Post-ope rative complications include scrotal haematoma or in- fection (both rare). Serum testostero ne falls within 8h to <50ng/dL. LHRH agonists LHRH agonists (or analogs) were developed in the 1980 \200\231s, giving pa- t ients an alternative to bilateral orchidectomy, with which they are consid- ered clinically equivalent. They are given by subcutaneous or intramuscu- lar injection, as monthly or 3-m onthly depots. Examples include goserelin, triptorelin, and leuprorelin acetates. A 6-month ly triptorelin formulation is recently available. When the anterior pituitary is overstimulated by an agonist of LHRH, it switches off LH syn thesis, although serum testosterone rises in the \201 rst 14 days due to a surge of LH. T his can result in \200\230tumor \202 are \200\231, manifest in a small number of patient s by increased symptoms, including catastrophic spinal cord compression. To prevent this, c over with antiandrogen is rec- ommended for a week before and two weeks after the \201 rs t dose of LHRH agonist. There is awareness that on occasions, the serum testosterone level may not be suppressed to castrate levels by all LHRH agonists. One LHRH antagonist, degarelix, is currently licensed in Europe. Given by monthly subcutane ous injection, it rapidly reduces serum testosterone to castrate, abolishing the issue of t umor \202 are and antiandrogen cover. To date there are no published clinical trials comp aring immediate or long- term outcomes of LHRH agonists and antagonists. PRSOTATE CANCER: HORMONE THERAPY II 355 Side effects of bilateral orchidectomy and LHRH agonists/antagonists - - Loss of sexual interest and Hot \202 ushes and sweats can be frequent and troublesome dur ing work or social activity. Weight gain. Lethargy, fatigue. Gynaecomastia. Anemia. Cogniti ve changes, depression, and memory loss. Osteoporosis and pathological fracture (particular ly of the hip): secondary to osteoporosis may occur in patients on long-term (>5y) treatmen t. A single yearly dose of the bisphosphonate, zoledronic acid, appears to maintain bone mi neral density, though the clinical advantage this may confer remains uncertain. ED. - - - - Antiandrogens These are orally bioavailable blockers of the androgen receptor. Examples inc lude bicalutamide (monotherapy dose is 150mg daily or 50mg daily for \202 are cover or MA B in combination with androgen ablation therapy), \202 utamide, and cyproterone acetate ( CPA). The \201 rst two raise the se- rum testosterone slightly so sexual interest and per formance should be maintained although many such patients have pre-existing ED due to the a dvancing age and disease. Bone demineralization, lethargy, and cognitive changes are not se en with antiandrogens. Antiandrogen monotherapy with bicalutamide 150mg daily is less effective than ADT in treati ng metastatic disease, but equivalent for non-metastatic locally advanced disease. It could be offered to such patients who were unsuitable or refusing radiotherapy. Side effects inc lude frequent gynaeco- mastia, breast tenderness, and occasional liver dysfunction. The tro uble- some breast toxicity may be reduced or prevented by tamoxifen 20mg twice weekly. Flut amide not uncommonly causes diarrhea and is now rarely used. Similarly, CPA is rarely used as monotherapy at its full dose of 100mg tds because it is less effective than androgen abl ation; it can also cause unpleasant, but reversible, dyspnoea. At 50mg bd, CPA may be helpf ul for prevention of castration-induced hot \202 ushes. A new, highly potent antiandrogen, MDV3100, is presently undergoing clinical trials in patients with castration-resistant PC. CHAPTER 7 Urological neoplasia 356 Prostate cancer: management of advanced disease \200\224hormone therapy III Monitoring trea tment during ADT Typically, patients will have baseline PSA, full blood count, renal and li v- er function tests, a renal ultrasound, and a bone scan. The PSA is re- peated after 3 mo nths, 6 months, and 6-monthly thereafter until it rises. Liver function is checked 3-monthl y if antiandrogen monotherapy is used. Physical examination including DRE and serum renal f unction is checked on disease progression; imaging if clinically indicated. While PSA is ve ry useful as a marker for response and progression, 5% of patients show clin- ical progress ion without PSA rise. This may occur in anaplastic tumors that fail to express PSA. Advice on exercise, diet, and treatment of erectile dysfunction is often sought by patients during treatment. Exercise and vitamin D supplements should be encouraged to minimize risk of osteoporotic complications. Patients with bone metastases should be advised to react to symptoms and signs of possible spinal cord compression. If there is a history of bone frac tures or osteoporosis, bisphosphonates should be prescribed and bone mineral densitomtry ca rried out. Specialist nursing and counseling support is much needed by many of these patien ts. Immediate vs delayed hormone therapy Traditionally hormone therapy was reserved for patient s with sympto- matic metastatic disease. Arguments against immediate use of hormone therapy focused on its side effects and cost. However, studies of patients with locally advanced a nd metastatic PC have demonstrated slower di- sease progression and reduced morbidity when treated with androgen ablation early (i.e. before the onset of symptoms). Improved survival has also been reported in patients without bone metastases (but including node-positive di sease) when treated immediately. Subgroups of patients <70y old, those with PSA doubling ti mes <12 months and patients with baseline PSA >50ng/mL appear to bene \201 t most. Trials have demonstrated slower disease progression in patients given bicalutamide 150mg da ily (compared with placebo) for 2y after treatment of high-risk locally advanced prostate c ancer with RP or RT. This bene \201 t is not seen in patients managed by watchful waiting. The survival advantage for high-risk patients undergoing EBRT combined with ADT provides f urther evidence of bene \201 t in immediate hormone therapy. PROSTATE CANCER: HORMONE THERAPY III 357 Intermittent hormone therapy The potential advantages of stopping hormone therapy when the disease has remitted (PSA <4ng/mL), then restarting it when the PSA has risen again (to per haps 10 or 20 ng/mL) are the reduced side effects, improved quality of life during the \200\230off treatment \200\231 periods, and cost. These have been demonstrated in phase II trials. Of several ongoing phase III studies com- paring long-term outcomes of intermittent vs continuous ADT or MAB, only one has so far reported equivalent survival at 5y in men wi th locally advanced or metastatic disease. Recently another randomized trial of sim- ilar d esign conducted on patients with biochemical failure following radio- therapy has shown no differences in overall survival or CSS after a median follow-up of 7y.1 None of the LHRH ag onists/antagonist or antiandrogens are currently licensed for intermittent therapy, though it is already an op- tion for patients enjoying disease remission who are intolerent of sid e effects. 1 Crook JM et al. (2012) Intermittent Androgen Suppression for Rising PSA Level after Radio therapy. N Engl J Med 367: 895 \200\223903. CHAPTER 7 Urological neoplasia 358 Prostate cancer: management of advanced disease \200\224castrate-resistant prostate cancer (CRPC) CRPC is de \201 ned by two consecutive PSA rises from its nadir or symp- tomatic pr ogression despite a favorable biochemical response, following androgen ablation therapy in the presence of a castrate serum testoster- one level (<50ng/dL). Biologically, this state may be due to proliferation of androgen-independent clones, androgen receptor ampli \201 c ation, aberrant stimulation of androgen-dependent transcription pathways, or a block to apo ptosis induced by androgen withdrawal. It is recently recognized that intracellular androge n synthesis occurs in cancer cells, which has provid- ed a new therapeutic target. Clinical ly, CRPC is an incurable, debilitating condition requiring multidisciplinary management, of ten of frail elderly patients. Treatment of CRPC, especially with a rapid (<12 months) PSA dou- bling time, is initially w ith second-line hormone therapy. Up to 25% of patients respond by adding an antiandrogen, e .g. bicalutamide 50mg daily, to establish MAB. If MAB was used from initiation of hormone t herapy, withdrawal of the antiandrogen paradoxically elicits a favorable response in 25% of patients. A further rise in PSA may require third-line hormonal therapy, such as the addition of oest rogens or corticosteroids. For example, diethylstilboe- strol 1mg daily with 75mg aspirin f or thromboembolic prophylaxis elicits a response in up to 60% of these patients. The mean d uration of response is 4 months. The prognostic factors for survival with CRPC are identical to the fac- tors predicting res ponse to hormone therapy (see b p. 352 Hormone therapy I); also time from initiation of hor mone therapy to initiation of chemotherapy and visceral metastasis status. The mean survival at this point ranges from 9 months, in the presence of extensive metastat ic disease, to 27 months in asymptomatic patients without demonstrable metastases. Cytotoxic chemotherapy Systemic chemotherapy is offered to appropriate patients with CRPC b y the medical oncologist. Men with low-volume disease who have failed rad- ical local treat ment and hormone therapy are also candidates for chemo- therapy. Frail and in \201 rm pati ents with renal impairment or hematological abnormalities are unsuitable. Correction of ren al and bone marrow dys- function is necessary prior to treatment. Symptom palliation This is discussed in further detail on b p. 362. Symptomatic improve- me nts may be achieved with cytotoxic chemotherapy. In a randomized trial of mitoxantrone plus prednisolone vs prednisolone alone, 29% in the combination group experienced a reduction i n pain and analgesic use com- pared with 12% in the \200\230prednisolone alone \200\231 gr oup. PSA response did not predict palliative response. In another study, docetaxel plus pre dnisolone PC: MANAGEMENT OF ADVANCED DISEASE \200\224CRPC 359 produced a pain reduction in 35% compared to 22% of patients given mi- toxantrone and predn isolone, resulting in improved quality of life scores. Bisphosphonates (in particular zoled ronic acid) have been shown to reduce skeletal-related events (SRE), such as pathological f ractures, in CRPC. Denosumab, an antiosteolytic fully human monoclonal anti- RANKL antibody , is even more effective at preventing SREs and reducing bone pain. Neither agent is curren tly approved for CRPC by NICE. These agents should be discussed with patients, although sid e effects can include hypocalcaemia and (rarely) osteonecrosis of the jaw. Other palliative treatments may include opiate analgesics, external beam radiotherapy to sy mptomatic primary or metastatic bone lesions, systemic radionuclides (e.g strontium) for wi despread bone pain, surgery or drainage procedures for urinary obstruction, and neurosurger y for spi- nal cord compression (see also b p. 548). Cancer control Most single agent cytot oxic chemotherapy trials de \201 ne response as >50% decrease in PSA. Responses are report ed in 20 \200\22340% of patients, with hematological toxicity (especially neutropenia), usi ng most agents. Better responses (up to 75%) are reported with combination regimes (for ex- ample, estramustine phosphate plus docetaxel), but with greater toxicity. The median survi val following chemotherapy ranges from 24 to 44 weeks. Results of two randomized studies co mparing docetaxel 3-weekly cycles with mitoxantrone plus prednisolone have shown a 2.4 \200 \2233 month median survival advantage in favor of docetaxel. This is now the standard care of established CRPC. Toxicity includes neutopenic sepsis in 75%. While there is interest is evaluating its use in earlier stage disease (for example, in the UK STAMPEDE RCT), docetax el maintenance and salvage regimens using cabazitaxel (confering a 2.5 month survival advan tage compared with mitoxantrone) are already in clinical use. Novel therapies While clinical trials of tyrosine kinase and endothelin-1 receptor antago- nists have so far yielded disappointing results, promising results are re- ported for sever al effective and relatively well tolerated new treatment options for CRPC, including the fo llowing agents: - Abiraterone biosynthesis within cancer cells (Fig. 7.11). Administered orally with predniso lone, it prolongs overall survival in men who have failed docetaxel by 3.6 months compared with prednisolone alone. Mineralocorticoid side effects (hypokalaemia, hypertension, cardia c failure) occur in 8% (3% serious). FDA and European licensing approval is granted; NICE h as approved the use of Abiraterone in 2012 for patients with CRPC who are progressing after docetaxel. Enzalutamide: 5-fold more potent than bicalutamide, which also inhibits the pro cess by which the receptor \200\223hormone complex is transported to the cell nucleus. Tria ls in men with chemorefractory and chemonaive CRPC have shown median times to PSA progressi on of 21 and 41 weeks, respectively. A placebo-controlled RCT has demonstrated a 4.8 month : a CYP450c17 enzyme inhibitor which blocks androgen an orally bioavailable androgen receptor antagonist, CHAPTER 7 Urological neoplasia 360 median overall survival advantage in patients with docetaxel-refractory disease when treate d with oral Enzalutamide.1 Provenge approved CRPC immunotherapy against prostatic acid phos phatase. A 4-month survival advantage has been demonstrated over placebo in trials of men s uffering minimally symptomatic CRPC. Serious infusion- related adverse events occur in 3% o f patients. It is estimated to cost around 60 000 for three doses. Radium-223 (alpharadin ) : reduced bone SREs and prolonged survival by 3 months in a UK placebo-controlled RCT of 922 CRPC patients. (sipuleucel-T) vaccine: this is the \201 rst patient-derived FDA- The future challenge in treating patients with advanced CRPC will be the sequencing and/or combination of agents in order to obtain the best results in terms of survival, quality of life, and cost-effectiveness. Steroid Synthesis: actions of Abiraterone Low-dose steroid replacement minimizes mineralocorticoid-related toxicity Cholesterol Deoxy- corticosterone Corticosterone Pregnenolone Progesterone Aldosterone CYP17 17 -hydroxylase X X 17 -OH- pregnenolone 17 \200\223OH- progesterone Cortisol ACTH 11-Deoxy- cortisol CYP17 C17,20-lyase X X 5 -reductase Androstenedione DHEA DHT Testosterone CYP19: aromatase Estradiol Fig. 7.11 A diagram showing testicular, adrenal, and prostatic metabolism of cholesterol, w ith inhibition of CYP17 17-alpha hydroxylase, C17,20 lyase by abiraterone. 1 Scher HI, et al. (2012) Increased Survival with Enzalutamide in Prostate Cancer after Che motherapy. N Engl J Med DOI: 10.1056/NEJMoa1207506. This page intentionally left blank CHAPTER 7 Urological neoplasia 362 Prostate cancer: management of advanced disease \200\224palliative care Multidisciplinary i nvolvement of the oncologist, urologist, cancer nurse specialist, palliative care, and acut e pain teams is often necessary in the terminal phase of the illness to optimize the patien ts comfort and quality of life. Pain is undoubtedly the most debilitating symptom of advanced pros- tate cancer. The pathog enesis of this pain is poorly understood, but there is known to be increased osteoclastic a nd osteoblastic activity. Table 7.22 categorizes the pain syndromes and their management. A ndrogen ablation therapy is effective in newly presenting disease. In castrate-resistant di s- ease, bisphosphonates (especially zolendronic acid) can reduce bone pain in up to 80% pa tients and the risk of skeletal complications such as patho- logical fracture. Chemotherapy also has a palliative role. Table 7.22 Pain syndromes and their management Pain type Initial management Other options Surgical \201 xation of pathological fracture or extensive lytic metastasis Focal bone pain Medical: simple, NSAIDs, opiates Single-shot radiotherapy, 800cGy (75% respond up to 6 months) Diffuse bone pain Medical: NSAIDs, opiates Steroids; bisphosphonates (eg. zolendronic acid); denosumab; chemotherapy Multi-shot radiotherapy or radiopharmaceutical (e.g. strontium89) b See p. 548 Epidural metastasis and cord compression Plexopathies (rare \200\224caused by direct tumor extension) Medical: NSAIDs, opiates Tricyclics; anticonvulsants Radiotherapy; nerve blocks Other pain syndromes: skull/ cranial nerve, liver, rectum/perineum Radiotherapy Intrathecal chemotherapy for meningeal involvement Medical: NSAIDs, opiates, steroids Spinal cord compression See b p. 548. PC: MANAGEMENT OF ADVANCED DISEASE \200\224PALLIATIVE CARE 363 Lower urinary tract symptoms/urinary retention A TURP may be required for bladder out \202 ow obstruction (BOO) or retention. Instrumentation can be dif \201 cult if there is a bul ky \201 xed pros- tate cancer. The prostate may be friable and bleed spontaneously, caus- ing intractable haematuria; this may temporarily settle following bladder washouts and TUR P, but palliative radiotherapy can be helpful for longer- term control; some advocate the u se of tranexamic acid with appropri- ate thromboprophylaxis. The bladder may be contracted due to disease involvement, causing misery even after relief of BOO. This may perhaps respo nd to anticholinergic therapy or a long-term urethral or suprapubic catheter may be require d for persistent voiding symptoms or recurrent retention. Ureteric obstruction This is a uro-oncological emergency (see b p. 546). Locally advanced P C and bladder cancer may cause bilateral ureteric obstruction. The pa- tient presents eithe r with symptoms and signs of renal failure, anuric with- out a palpable bladder, occasional ly with signs of sepsis. Renal ultrasound will demonstrate bilateral hydronephrosis and an empty bladder. After treating any life-threatening hyperkalaemia, treatment options include bi- lateral percutaneous nephrostomies or ureteric stents. A clotting screen is required p rior to nephrostomy insertion. Antegrade ureteric stenting following placement of nephrosto mies is usually successful. Insertion of retrograde ureteric stents in this scenario is usu ally unsuccessful because tumor affecting the trigone obscures the ureteric ori \201 ces. Hormone therapy should be commenced if not previously used. Unilateral ureteric obstruction is occasionally observed at presenta- tion or on progressio n. Usually asymptomatic, this may be managed con- servatively provided there is a normal co ntralateral kidney. Preservation of renal function becomes important if cytotoxic chemother apy is being considered. Anemia, thrombocytopenia, and coagulopathy Some patients with extensive bone marrow replace ment by tumor rap- idly and regularly become symptomatic with anemia. This tends to be norm ochromic and normocytic, often occurring without other symptoms and with normal renal funct ion. They require regular blood transfusions. Platelet transfusions are rarely required for bleeding/thrombocytopenia. Terminal patients may develop a clinical picture similar to dis seminated intravascular coagulation, also leading to problematic haematuria. CHAPTER 7 Urological neoplasia 364 Urethral cancer Primary urethral cancer is very rare, occurring in elderly patients, four t imes more commonly in women. Risk factors include urethral stricture and sexually transmitted disease are implicated. Di rect spread from tumor in the bladder or prostate is more common. Pathology and staging Seventy- \201 ve percent are squamous cell carcinomas occurring in t he anteri- or urethra, 15% are TCC occurring in the posterior/prostatic urethra, 10% are ad enocarcinomas, and the remainder include sarcoma and melanoma. Urethral cancer metastasises to the pelvic lymph nodes from the poste- rior urethra and to the inguinal nodes from the anterior urethra in 50% of patients. Staging is by the TNM system (Table 7.23). Presentation - - - - - - Often late; many patients have metastatic disease at presentation. Painless haematuria , in itial, terminal or a bloody urethral discharge. Voiding-type Perineal pain Periurethral abs cess or urethrocutaneous \201 stula (rare). Past history of sexually transmitted or stric ture disease. LUTS (less common). (less common). Examination may reveal a hard palpable mass at the female urethral me- atus or along the co urse of the male anterior urethra. Inguinal lymphade- nopathy, chest signs, and hepatomegal y may suggest metastatic disease. The differential diagnosis in men is: Urethral stricture. Perineal abscess. Metastatic dise ase involving the corpora cavernosa. Urethrocutaneous \201 stula. - - The differential diagnosis in women is: - - - - - - Urethral caruncle. Urethral cyst. Urethral diverticulum. Urethral wart ( Urethral prolapse. Periurethral abscess. Condylomata acuminata). Investigations Cystourethroscopy, biopsy, and bimanual examination under anesthesia will ob tain a diagnosis and local clinical staging. Chest radiography and abdominopelvic CT scan w ill enable distant staging. URETHRAL CANCER 365 Treatment For localized anterior urethral cancer, radical surgery or radiotherapy are the o ptions. Results are better with anterior urethral disease. Male pa- tients would require pe rineal urethrostomy. Post-operative incontinence due to disruption of the external sphincte r mechanism is minimal unless the bladder neck is involved, but the patient would need to s it to void. For posterior/prostatic urethral cancer, cystoprostatourethrectomy should be co nsidered for \201 t men while anterior pelvic exenteration (excision of the pelvic lymph nodes, bladder, urethra, uterus, ovaries, and part of the vagi- na) should be considered fo r women. In the absence of distant metastases, inguinal lymphadenectomy is performed if nod es are palpable since 80% contain metastatic tumor. For locally advanced disease, a combination of preoperative radiother- apy and surgery is recommended. For metastatic disease, cytotoxic chemotherapy is the only option. Table 7.23 5y survival Surgery: anterior urethra 50% Surgery: posterior urethra 15% Radiotherapy 34% Radiotherapy and surgery 55% Staging is by the TNM (1997) classi \201 cation following histological con- \201 rmation of the diagnosis (Table 7.24). All rely upon physical examination and imaging, the patholo gical classi \201 cation (pre \201 xed \200\230p \200\231) corresponding to the TNM cate gories. CHAPTER 7 Urological neoplasia 366 Table 7.24 TNM staging of urethral carcinoma Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Urethra (male and female) Ta Non-invasive papillary carcinoma Tis Carcinoma in situ T1 Tumor invades subepithelial connective tissue T2 Tumor invades corpus spongiosum, prostate, or periurethral muscle T3 Tumor invades corpus cavernosum, prostatic capsule, vagina, or bladder neck T4 Tumor invades adjacent organs, including bladder Transitional cell carcinoma of the prostatic urethra Tis Carcinoma in situ, prostatic urethra (pu), or prostatic ducts (pd) T1 Tumor invades subepithelial connective tissue T2 Tumor invades prostatic stroma, corpus spongiosum, or periurethral muscle T3 Tumor invades through prostatic capsule, corpus cavernosum, or bladder neck T4 Tumor invades adjacent organs, including bladder Nx Regional (deep inguinal and pelvic) lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node up to 2cm in greatest dimension N2 Metastasis in a single lymph node >2cm in greatest dimension Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis present This page intentionally left blank CHAPTER 7 Urological neoplasia 368 Penile neoplasia: benign, viral-related, and premalignant lesions Benign cutaneous lesions - Pearly penile papules: around the circumference of the corona of the glans, occur in 15% of post-pubertal males. They may be mistaken for warts, are not infectious, and require no tr eatment. Zoon \200\231s balanitis: inner prepuce. Lichen planus: Lichen sclerosus: this is a common sclerosing condition of glans and prepuce. It occurs at all ages and most commonly presents as non-retractile foreskin (phimosis). The meatus and fossa navicularis may be af fected, causing obstructed and spraying voiding. The histological diagnosis is usually made after circumcision, with epithelial atrophy, loss of rete pegs, and collagenization of the dermis. Non-speci \201 c balanoposthitis: foreskin. Can be caused by bacterial and candid al infections. Psoriasis: de \201 ned edges and often has a scaly surface. multiple, small (about 1 \200\2233mm) papules running bright red shiny, erythematous plaque on glans or \202 at-topped violacious papule. also known as balanitis xerotica obliterans (BXO), in \202 ammatory condition of glans and appears as thickened red papules or plaques with well- Benign subcutaneous lesions - appears in response to microtrauma to small Peyronie \200\231s plaque: blood vessels. There is strong evidence that genetic factors and drug factors also in \202 uence the start of Peyronie \200\231s disease. Retention cysts. Syringomas (sweat gland tumors). Neurilemoma. Angioma, lipoma. Iatrogenic pseudotumour fol lowing injections. Pyogenic granuloma following injections. - - - - Viral-related lesions - Condyloma acuminatum: human papillomavirus (HPV) infection. Soft, usually multiple benign l esions on the glans, prepuce, and shaft; may occur elsewhere on genitalia or perineum. A bi opsy is worthwhile prior to topical treatment with podophyllin; 5% have urethral involvemen t, which may require diathermy. HPV infection (particularly types 16 and 18) is potentially carcinogenic and condylomata have been associated with penile SCC. Bowenoid papulosis: wit h a benign course. Multiple papules appear on the penile skin or a \202 at glanular lesio n. These should be biopsied. HPV is the suspected cause. also known as genital warts, related to a condition resembling carcinoma in situ, but BENIGN, VIRAL-RELATED, AND PREMALIGNANT LESIONS 369 Kaposi \200\231s sarcoma: tumor has become the second commonest malignant penile tumor. It presents as a raised, painful, bleeding violacious papule, or as a bluish ulcer with local oedema. It is slow-growing, solitary, or diffuse. It occurs in immunocompromised men, parti cularly in homosexuals with HIV-AIDS. Urethral obstruction may occur. Treatment is palliati ve; intralesional chemotherapy, laser or cryoablation, or radiotherapy. \201 rst described in 1972, this reticuloendothelial Premalignant lesions Some histologically benign lesions are recognized to have malignant po - tential or occur in close association with squamous cell carcinoma (SCC) of the penis. Th e extent to which SCC is preceded by premalignant le- sions is unknown. - Bowenoid papulosis: with a relatively benign course. Single or multiple papules appear on t he penile skin. These should be biopsied. HPV is the suspected cause. Bowen \200\231s disea se: this is carcinoma in situ of the keratinizing genital or perineal skin. Treatment is wi de local excision, laser, or cryoablation. also known as carcinoma in situ or penile Erythr oplasia of Queyrat: intraepithelial neoplasia of the glans or inner prepuce. A red velvety circumscribed painless lesion though it may ulcerate, resulting in discharge and pain. Trea tment is excision biopsy if possible; radiotherapy, laser ablation, or topical 5- \202 uor ouracil may be required. Buschke \200\223L wenstein tumor: acuminatum, this is an aggressi ve locally invasive tumor of the glans. Metastasis is rare, but wide excision is necessary to distinguish it from SCC. Urethral erosion and \201 stulation may occur. Extramammary P aget \200\231s disease: mainly observed in the elderly. It is an intraepithelial adenocarci noma that involves the area rich in apocrine glands. Verrucous hyperplasia: endophytic lesi on that typically develops at sites of chronic irritation and in \202 ammation. It is a pr emalignant lesion that may transform into a slow-growing verrucous carcinoma or squamous ce ll carcinoma. Cutaneous horn: the base may be malignant; treatment is wide local excision. a condition resembling carcinoma in situ, but also known as giant condyloma is a rare slow-growing condition manifests as a verrucous, exophytic, or rare solid skin overgrowth; extreme hyperkeratosis, A chronic red or pale lesion on the glans or prepuce is always a cause for concern. Note sh ould be made of its color, size, and surface features. Early review following steroid, anti bacterial, or antifungal creams is recom- mended; if persistent, biopsy should be recommend ed. CHAPTER 7 Urological neoplasia 370 Penile cancer: epidemiology, risk factors, and pathology Squamous cell carcinoma (SCC) is t he commonest primary penile can- cer, accounting for 95% of penile malignancies. Others inc lude Kaposi \200\231s sarcoma (3%); rarities include basal cell carcinoma, malignant melano ma, sarcoma, and Paget \200\231s disease. Metastases are very rarely seen from blad- der, p rostate, rectum, and other primary sites. Incidence and etiology of SCC Penile cancer is rare, representing 1% of male cancers. The i ncidence appears to be decreasing, most occurring in elderly men. Approximately 400 new cas es and 100 deaths are reported annually in the UK. Risk factors for SCC - Age: the sixth decade. It is unusual below the age of 40. Premalignant lesions: reported to have had a pre-existing penile lesion. Phimosis: virtually non-existent in Israel. It is t hought that chronic irritation with smegma and in \202 ammation (balanitis) is contributor y. Geography: America, where it accounts for 10 \200\22320% of male cancers. Paraguay has t he highest worldwide incidence. Human papilloma virus ( and 18, appear to be associated wit h 50% of cases. Smoking. Immunocompromised patients. History of priapism. Affected \201 r st-degree relative. penile cancer incidence rises during the \201 fth decade and peaks in around 40% of patients with penile SCC are penile cancer is rare in men circumcised neonatally. It is more common in parts of Asia, Africa, and South HPV) wart infection, especially with types 16 - - Pathology and staging of penile SCC Believed to be preceded by carcinoma in situ, SCC start s as a slow-grow- ing papillary, \202 at, or ulcerative lesion on the glans (48%), prepuc e (21%), glans and prepuce (9%), coronal sulcus (6%), or shaft (2%). The remainder are inde terminate. It grows locally by super \201 cial spread beneath the fore- skin before enteri ng a vertical phase growth pattern, invading the corpo- ra cavernosa, urethra and eventuall y, the perineum, pelvis, and prostate. Metastasis is initially to the super \201 cial, the n deep inguinal lymph nodes and subsequently, to iliac and obturator nodes. Skin necrosis, ulceration, and infection of the inguinal lymph nodes may lead to sepsis or hemorrhage from the femoral vessels. Ten percent metastasize, most commonly to lung(s). Histologically, SCC exhibits keratinization, epithelial pearl formation, and mitoses. There are \200\230classic \200\231, basaloid, verrucous, sarcomatoid, and ade- nosquamous histo logical subtypes. Grading is G1 (20%), G2 (50%), or G3 (30%); grading correlates with progn osis as does the presence of vascular invasion. Staging is by the TNM classi \201 cation ( Table 7.25 and Fig. 7.12). EPIDEMIOLOGY, RISK FACTORS, AND PATHOLOGY 371 Prognostic factors for penile SCC The presence of metastatic node disease is the most impor tant prognostic indicator. Risk groups for N+ disease have been de \201 ned, based on the location, size, histological grade, depth of invasion, presence of corporal invasion, and v ascular or lymphatic invasion. Table 7.25 UICC (2009) TNM clinical and pathological classi \201 cation of penile cancer T \200\223 Primary tumor Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ Ta Non-invasive verrucous carcinoma, not associated with destructive invasion T1 Tumor invades subepithelial connective tissue T1a Tumor invades subepithelial connective tissue without lymphovascular invasion and is not po orly differentiated or undifferentiated (T1G1 \200\2232) T1b Tumor invades subepithelial connective tissue without or with lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3 \200\2234) T2 Tumor invades corpus spongiosum/corpora cavernosa T3 Tumor invades urethra T4 Tumor invades other adjacent structures N \200\223 Regional lymph nodes Nx Regional lymph nodes cannot be assessed N0 No palpable or visibly enlarged inguinal lymph node N1 Palpable mobile unilateral inguinal lymph node N2 Palpable mobile multiple or bilateral inguinal lymph nodes N3 Fixed inguinal nodal mass or extranodal extension of regional lymph node metastasis or unil ateral/bilateral pelvic lymphadenopathy M \200\223 Distant metastases M0 No distant metastasis M1 Distant metastasis CHAPTER 7 Urological neoplasia 372 Carpus cavernosum (a) Urethra T1 Subepithelia tissue invaded T1s or Ta Epithelium only T2 Corpus cavernosum or spongiosum invaded T3 Urethra/prostate invaded T4 Scrotum, perineum bone invaded (b) N1 \200\224 single superficial ingunal node N2 \200\224 multiple or bilateral superficial ingunal nodes N3 \200\224 unilateral or bilateral ingunal or Intra-pelvic nodes M1 \200\224 distant metastasis (e.g. pulmonary) Fig. 7.12 The TNM staging of penile cancer. 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