HIV in urological surgery Human immunode \201 ciency virus (HIV) Causes a spectrum of illn ess related to immune system de \201 ciency. HIV-1 is pandemic and accounts for signi \201 cant mortality in developing coun- tries. HIV-2 has less pathogenicity and is predomin ant in West Africa. Transmission is via unprotected sexual intercourse, contaminated needle s, mother-to-fetus transmission, infected blood, and blood products (blood transfusion risk s are now minimal). Pathogenesis HIV is a retrovirus. It possesses the enzyme, reverse transcriptase, that enab les viral RNA to be transcribed into DNA, which is then incorpo- rated into the host cell g enome. HIV binds to CD4 receptors on helper T-lymphocytes (CD4 cells), monocytes, and neura l cells. After an extended latent period (8 \200\22310y), CD4 counts decline. Acquired immu node \201 ciency syndrome (AIDS) is de \201 ned as HIV positivity and CD4 lymphocyte coun ts <200 x 106/L. The associated immunosuppression increases the risk of opportunistic infec tions and tumors. Diagnosis ELISA testing of serum detects antibodies against HIV antigens. The sec- ond con \201 rmatory test is Western blot. Informed consent is required for the test. Urological sequelae of HIV infection Renal - Opportunistic infections aspergillosis, mycobacteria, and cryptococcus infections. Can lead to pyelonephritis, acute tubular necrosis, and abscess formation. Renal impairment and fai lure Renal stones Tumors : including cytomegalovirus (CMV), - : HIV and AIDS-associated nephropathy. : secondary to indinavir (antiretroviral treatment). : Kaposi \200\231s sarcoma, lymphoma. Bladder - Voiding dysfunction toxoplasmosis), bladder overactivity or underactivity. Opportunistic in fections Tumors : urinary retention (associated with causing UTI. : squamous cell carcinoma, Kaposi \200\231s sarcoma, lymphoma. Urethra - Reiter \200\231s syndrome (urethritis, conjunctivitis, arthritis) is associated with AIDS. Bacterial urethritis. Prostate - - Bacterial prostatitis and abscesses (including opportunistic organisms). Reported increased progression rate for prostatic carcinoma. HIV IN UROLOGICAL SURGERY 227 External genitalia - - - - Chronic or recurrent genital herpes. Atypical syphilis. Opportunistic infections of testicl e and epididymis. Testicular cancers (increased risk of germ cell and non-germ cell tumors, lymphoma). Testicular atrophy Scrotal and penile Kaposi \200\231s sarcoma (seen as purple/ red lesions). Fournier \200\231s gangrene. Sexual dysfunction: due to the underlying neurop athy, encephalopathy, or lipodystrophy) and/or due to HIV drug therapies (antiretroviral th erapy). - - 9 hypogonadism. HIV pathology (HIV Of note, circumcision has been shown to reduce the risk of acquiring HIV infection in heter osexual men. Occupational needle stick injury The risk of HIV transmission after percutaneous exposure t o HIV-infected blood is 3 per 1000 injuries.1 Risks are increased if the patient has termin al HIV-related illness, a deep injury, visible blood on the device causing the injury, and injury with a needle previously placed in the source patient \200\231s vein or artery.1 Aft er mucocutaneous exposure, the risk is <1 in 1000.1 Management Immediately wash the area well and encourage free bleeding of puncture wounds. I rrigate exposed mucous membranes with water. Report to occu- pational health (A & E or equi valent out-of-hours service) for a risk assess- ment and baseline blood sample for storage. The source patient will be approached and counseled on undergoing HIV testing. Health care worker follow-up testing is recommended at 12 and 24 weeks post-exposure (or 24 weeks afte r antiretroviral prophylaxis if prescribed). Occupational HIV exposure is reported to the H PA Center for Infections. Post-exposure prophylaxis (PEP) is recommended if there has been sig- ni \201 cant occupat ional exposure to blood or another high-risk body \202 uid from a patient or other source , either known to be HIV-infected or con- sidered high risk of HIV infection (but where the result of a HIV test has not or cannot be obtained). PEP should be initiated ideally withi n 1h and continued for at least 28 days. The PEP starter pack contains one Truvada tablet ( tenofovir and emtricitabine) taken once a day plus two Kaletra tablets (lopinavir and riton avir) taken twice a day.1 1 Department of Health (2008) HIV post exposure prophylaxis: Guidance from the UK Chief Med ical Of \201 cers \200\231 Expert Advisory Group on AIDS [online]. Available from: M http: //www.dh.gov. uk/publications. CHAPTER 6 Infections and in \202 ammatory conditions 228 Phimosis A condition where the contracted foreskin (prepuce) has a tight, nar- rowed ori \201 ce and cannot be retracted back over glans of the penis. A physiological phimosis is p resent at birth due to adhesions between the epithelium of inner foreskin and glans. Penile growth, erections, and accu- mulation of epithelial debris (smegma) under the foreskin cau ses gradual separation. Ninety percent of foreskins are retractile at age 3.1 Few persist i nto adulthood (<1% phimosis at age 17).2 Recurrent balanitis and in \202 am- matory condit ions such as BXO in uncircumcised males can cause new pathological phimosis (see b p. 230). Presentation Physiological phimosis is usually asymptomatic. Patients may describe bal- loo ning of the foreskin on voiding and an inability to fully retract the fore- skin which, in sexually active men, may also cause skin trauma during sexual intercourse. In \202 ammatio n or infection (balanitis and balanoposthisis) may cause bleeding, pain, discharge, or dysu ria (see b p. 230). Phimosis associ- ated with BXO presents with white, itching plaques aff ecting the foreskin and glans and may have associated voiding problems. Treatment Adults: treat any associated infection. If symptomatic or a pathological phi- mos is, surgical treatment is circumcision (see b p. 750). Preputioplasty (longitudinal incisio n on foreskin which is closed transversely) is an alter- native for milder cases. It is eff ective in around 50%; a circumcision is then required for those who do not respond. It is n ot suitable for BXO. Children: older children with phimosis suffering infection (balanitis) can be treated with antibiotics and a course of topical 0.1% betamethasone (bet- novate) cream which acts to so ften the phimosis and allow foreskin retrac- tion. The recommendations are to avoid circumc ision where possible.1 Indications for circumcision in children include phimosis associated with recurrent balanit is, BXO, (recurrent) UTI associated with an underlying abnormality (i.e. VUR,3 posterior ur ethral valves, neuropathic bladder dys- function), recurrent UTI,3 failed medical therapy f or UTI, stone disease, and for religious reasons. Contraindications to (neonatal) circumcision include the presence of hypospadias (9 chordee or hooded foreskin), small penis, or large hernia or hydrocele (where repair after circumc ision may cause a buried penis or secondary phimosis). Complications of phimosis - Paraphimosis : the foreskin is retracted behind the glans, but cannot be replaced again. An existing degree of phimosis and/or prolonged retraction produces a tight ring of tissue at the corona, leading to venous congestion, oedema, and swelling of the glans, which can pro gress to arterial occlusion and necrosis (see b p. 533) Recurrent balanitis PHIMOSIS 229 Balanoposthitis in \202 ammatory secretions and pus are trapped in the foreskin by the phi motic band. Chronic in \202 ammation . Penile cancer (squamous cell carcinoma) uncircumcis ed males. Sexually transmitted infection transmission) in uncircumcised males (see b p. 227 ). : severe balanitis and infection of the foreskin, where : increased risk in : increased risk (including HIV 1 Gairdner D (1949) The fate of the foreskin. A study in circumcision. BMJ 2:1433 \200\2237 . 2 Oster J (1968) Further fate of the foreskin. Incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys. Arch Dis Child 43:200 \200\2233. 3 Singh-Grewal D, Macdessi J, Craig J (2005) Circumcision for the prevention of urinary tra ct infection in boys: a systematic review of randomized trials and observational studies. A rch Dis Child 90:853 \200\2238. CHAPTER 6 Infections and in \202 ammatory conditions 230 In \202 ammatory disorders of the penis Balanitis and balanoposthitis Balanitis is in \202 ammation of the glans penis. Balanoposthitis is in \202 ammation of the prepuce (fore skin) and glans. Increased risk with phimosis and uncir- cumcised males. Causes are shown i n Table 6.6. Clinical features include pain, erythema, discharge, dif \201 culty retractin g the prepuce, and voiding dysfunction. Treat any proven infection, instruct on good hygien e, and avoid irritants. A short course of topical steroid cream (i.e. 0.1% betham- ethasone ) can be applied to improve retractability of the prepuce. Surgical options for recurrent i nfections include circumcision. Table 6.6 Causes of balanitis Lifestyle-related Poor hygiene, local irritants (soaps, spermicides) Fungal infection Candida Bacterial infection Non-sexually transmitted: coliforms, group B streptococci Sexually transmitted: N. gonorrhoeae, C. trachomatis, syphilis, Herpes simplex In \202 ammatory dermatoses Lichen sclerosis, Lichen planus, Zoon \200\231s balanitis, Reiter \200\231s syn-drome, psor iasis, eczema, irritant contact dermatitis Drugs Examples: amoxicillin, paracetamol, salicylates, tetracyclines, propranolol, quinine, chlor diazepoxide Lichen sclerosis - A chronic in \202 ammatory skin condition of unknown etiology. On the penis, it is called balanitis xerotica obliterans (BXO). Presentation: phimosis, itching, and discomfort with i tchy, \202 at-topped white papules that coalesce to form white patches on the glans penis and prepuce. May be associated with voiding dysfunction. Complications include meatal sten osis, urethral strictures, and dense adhesions, causing fusion between the prepuce and glan s. Pathological features are thinning and hyperkeratosis of the epithelium, hyalinization o f keratin in the upper dermis, in \201 ltration of lymphocytes and plasma cells in the der mis, and degeneration of the basal cell layer. BXO is thought to be a premalignant conditio n in adults, although progression to SCC is rare. BXO is an associated \201 nding in arou nd 28% of patients presenting with penile carcinoma in contemporary series,1 although large r series report lower rates (2%).2 Treatment: a trial of topical corticosteroids may be tri ed for mild conditions, but generally, men require circumcision (9 meatal dilatation). The prepuce should be sent for histological analysis. Surgery is usually curative, but any resi dual BXO after circumcision should be followed INFLAMMATORY DISORDERS OF THE PENIS 231 up, with further topical therapy (steroid, antibiotic, or antifungal) as indicated. Biopsy may be needed if the lesion persists, progresses, or changes (despite appropriate treatment ). Zoon \200\231s balanitis Also referred to as \200\230plasma cell balanitis \200\231. It te nds to occur in older, uncir- cumcised men. Patients present with well-circumscribed, shiny , moist, erythematous plaque on the glans (sometimes described as having a \200\230cay- en ne pepper \200\231 appearance), with a corresponding lesion on the prepuce. Pathological fe atures are chronic in \202 ammatory cell (plasma cell) in \201 ltrate in the dermis. It i s usually asymptomatic, but may present with irritation, pain, or discharge. Differential d iagnosis is erythroplasia of Queyrat, lichen planus, \201 xed drug eruption, or psoriasis and a skin biopsy is often indicated to con \201 rm the diagnosis. A swab should be taken for microbiological anal- ysis as secondary infection is common and requires antibiotic tr eatment. Conservative therapies include advice on hygiene, topical corticosteroids (9 antib iotics or antifungals as clinically indicated), but the disorder tends to persist or recur. De \201 nitive treatment is with circumcision. Carbon dioxide laser therapy also has repo rted success. Lichen planus It affects all age groups and can occur in isolation on the penis or as part of a generalized eruption. It presents as an itchy, papular rash. It consists of mauve papu les which have a \202 at top covered in white streaks (Wickham \200\231s striae). It affe cts \202 exor surfaces (wrists, elbows), genitalia (appearing as a white annular lesion o r erythematous plaques on the glans penis), buccal mucosa, lumbar region, and ankles. The d iagnosis is made clinically; biopsy can be used if the diagnosis is unclear or the lesions fail to respond to appropriate treatment. It is often self-limiting, but topical steroids c an be prescribed for symptomatic lesions. Psoriasis Chronic papulosquamous in \202 ammatory skin disease, presenting with itchy pink plaques covered in silver white scales on hair-bearing areas and extensor surfaces (knees and elbows). It also causes pitting of the nails. Lesions may be guttate (raindrop-shaped), circinate (rings), or geographic. Genital psoriasis may present as itching and soreness of the groins and glans and a red penile rash. It may also involve the prepuce. It is treated with topical emollients, soap substitutes, and short courses of topical low- dose steroid creams. Reiter \200\231s syndrome The typical triad of symptoms is urethritis, conjunctivitis, and seronega- tive arthritis. It tends to present in younger men. It can be caused by STI (Chla mydia trachomatis) and there is an association with HIV. Penile, oral, and skin lesions may occur, which can be confused for psoriasis. Genital manifestations include circinate balan itis (ring-shaped eroded lesions on the glans penis) in uncircumcised men, which can appear as a crust lesion in circumcised patients. Patients should be under STI screening. The con di- tion is self-limiting and usually resolves spontaneously. CHAPTER 6 Infections and in \202 ammatory conditions 232 Beh et \200\231s syndrome An uncommon disorder of unknown cause characterized by painful g eni- tal (scrotum, prepuce, glans) and oral (aphthous) ulceration, polyarthritis, uveitis, and neurological syndromes. Treatment of genital lesions is with topical steroids (corticos teroids). 1 Pietrzak P, Hadway P, Corbishley CM, et al. (2006) Is the association between balanitis x erotica obliterans and penile carcinoma underestimated? BJU Int 98:74 \200\2236. 2 Depasquale I, Park AJ, Bracka A (2000) The treatment of balanitis xerotica obliterans. BJ U Int 86:459 \200\22365. This page intentionally left blank Basic pathology and molecular biology 236 Wilms \200\231 tumor and neuroblastoma 238 Radiol ogical assessment of renal masses 242 Benign renal masses 244 Renal cell carcinoma: patholo gy, staging, and prognosis 246 Renal cell carcinoma: epidemiology and etiology 250 Renal ce ll carcinoma: presentation and investigation 252 Renal cell carcinoma (localized): surgical treatment I 254 Renal cell carcinoma: surgical treatment II and non-surgical alternatives for localized disease 256 Renal cell carcinoma: management of metastatic disease 258 Upper urinary tract transitional cell carcinoma (UUT-TCC) 260 Bladder cancer: epidemiology and etiology 264 Bladder cancer: pathology, grading, and staging 266 Bladder cancer: clinical presentation 270 Bladder canc er: haematuria, diagnosis, and transurethral resection of bladder tumor (TURBT) 272 Bladder cancer (non-muscle invasive TCC): surgery and recurrence 276 Bladder cancer (non-muscle invasive TCC): adjuvant treatment 280 Bladder cancer (muscle-invasive): staging and surgical management of localized (pT2/3a) dis ease 282 Bladder cancer (muscle-invasive): radical radiotherapy and palliative treatment 286 Bladder cancer: management of locally advanced and metastatic disease 288 Bladder cancer: urinary diversion after cystectomy 290 Prostate cancer: epidemiology and et iology 294 Prostate cancer: incidence, prevalence, mortality, and survival 296 Prostate cancer: prevention 298 Prostate cancer: pathology of adenocarcinoma 302 Prostate c ancer: grading 304 Prostate cancer: staging and imaging 306 Prostate cancer: clinical prese ntation 315 Prostate cancer: screening 316 Prostate cancer: prostate-speci \201 c antigen (PSA) 318 Prostate cancer \200\224PSA derivatives and kinetics: free-to-total, density, velocity, and doubling time 320 Prostate cancer: counseling before PSA testing 322 Prostate cancer: other diagnostic marker s 324 Prostate cancer: transrectal ultrasonography and biopsy 326 Prostate cancer: suspicio us lesions 330 Prostate cancer: general considerations before treatment (modi \201 ed from the 2008 UK NICE Guidance) 331 235 Chapter 7 Urological neoplasia Prostate cancer: watchful waiting and active surveillance 332 Prostate cancer: radical pros tatectomy and pelvic lymphadenectomy 334 Prostate cancer \200\224radical prostatectomy: post-operative care and complications 338 Prostate cancer: oncological outcomes of radical prostatectomy 340 Prostate cancer: radical external beam radiotherapy (EBRT) 344 Prostate cancer: brachytherapy (BT) 346 Prostate cancer (minimally invasive management of l ocalized and radio-recurrent prostate cancer): cryotherapy, high-intensity focused ultrasound, and p hotodynamic therapy 348 Prostate cancer: management of locally advanced non- metastatic disease (T3 \200\2234 N0M0) 350 Prostate cancer: management of advanced disease \200\224hormone therapy I 352 Prostate cancer: management of advanced disease \200\224hormone therapy II 354 Prostate cancer: management of advanced disease \200\224hormone therapy III 356 Prostate cancer: management of advanced disease \200\224 castrate-resistant prostate cancer (CRPC) 358 Prostate cancer: management of advanced disease \200\224palliative care 362 Urethral cancer 364 Penile neoplasia: benign, viral-related, and premalignant lesions 368 Penile cancer: epidemiology, risk factors, and pathology 370 Penile cancer: clinical manage ment 374 Scrotal and paratesticular tumors 377 Testicular cancer: incidence, mortality, epi demiology, and etiology 378 Testicular cancer: pathology and staging 380 Testicular cancer: clinical presentation, inve stigation, and primary treatment 384 Testicular cancer: serum markers 386 Testicular cancer: prognostic staging system for metas tatic germ cell tumors (GCT) 388 Testicular cancer: management of non-seminomatous germ cell tumors (NSGCT) 390 Testicular cancer: management of seminoma, IGCN, and lymphoma 392 CHAPTER 7 Urological neoplasia 236 Basic pathology and molecular biology Neoplasia (the formation and growth of a tumor) may b e a benign or malignant process. Malignant neoplasms, characterized by local invasion of no rmal tissue or distant spread (metastasis) via lymphatic or vascular channels, may be prima ry or secondary. Neoplasms are considered to arise by clonal expansion of a single abnormal cell through uncontrolled aberrant divisions. This cell may be a stem cell rather than a t erminally differentiated cell. Tumor formation results from the loss of balance be- tween c ell division and withdrawal from the cell cycle by differentiation or programmed cell death (apoptosis). Signals regulating cell proliferation and interactions come from proteins enc oded by messenger RNA that is in turn transcribed from genomic DNA. An identi \201 able pr ecursor lesion may exist. Urological neoplasms most commonly arise from the lining epithelium of the genitourinary tr act. Benign epithelial neoplasms from glandular or transitional epithelium are, respectivel y, termed adenoma or transitional cell papilloma. Malignant epithelial neoplasms are carcin omas; they may be further characterized histologically by pre \201 xing either adeno if th e neoplasm is glandular or squamous cell or transitional cell, according to the epithelium from which it has arisen. Carcinomas arise from non- invasive epithelial lesions, some of w hich are identi \201 able histologically: in the bladder, it is \202 at carcinoma in sit u (CIS) while in the prostate, it is prostatic intraepithelial neoplasia (PIN). Connective tissue neoplasms are described according to their components, adding benign (-oma) or malig nant (-sarcoma) suf \201 xes. For example, a benign neoplasm com- posed of blood vessels, fat, and smooth muscle is an angiomyolipoma; a malignant neoplasm composed of smooth muscle is a leiomyosarcoma. Genitourinary sarcomas are rare, constituting 1% of all neoplasms. There are exceptions. In the testis, the most common primary neo- plasms arise from seminif erous tubules and are termed germ cell tumors. Rarely, primary malignant lymphoma can arise in the testis. In the kidney, the childhood Wilms \200\231 tumor arises from the embryonic mesenchyme of the metanephric blastema while the benign oncocytoma is thought to arise fro m cells of the collecting ducts. Secondary malignant neoplasms within urological tissues are uncom- mon; they may arise by d irect invasion from adjacent tissues (for example, adenocarcinoma of the sigmoid colon may invade the bladder) or hae- matogenous metastasis from a distant site such as the lung. Neoplasia is a genetic disease: it may be hereditary or sporadic, depend- ing on whether th e genetic abnormalities are constitutional (germ-line) or somatic (acquired). Hereditary tu mors tend to appear at a younger age than their sporadic counterparts and are often multifo cal due to an under- lying constitutional genetic abnormality. Genetic and epigenetic abnormalities may promote tumor develop- ment or growth in a number of ways. - Activation (overexpression) of factors, e.g. c-myc. I nactivation (reduced expression) of diverse protein products stabilize the cell, ensuring d ifferentiation oncogenes encoding transcription tumor suppressor genes; their BASIC PATHOLOGY AND MOLECULAR BIOLOGY 237 and a \201 nite lifespan in which it performs its function. Inactivation of such genes by deletion or mutation may result in loss of this negative growth control. For example, PTEN (chromosome 10q) is a prostate tumor suppressor gene, encoding a phosphatase that is activ e against protein and lipid substrates. It is present in normal epithelium, but is commonly reduced in prostate cancer due to allele loss of chromosome 10q. It inhibits one of the in tracellular signaling pathways, PI3 kinase-Akt, that is essential for cell cycle progressio n and cell survival. Inactivation of PTEN, therefore, promotes cell immortalization and pro liferation. Overexpression of factor type 1 in prostate cancer or the highly angiogenic vas cular endothelial growth factor in renal cancer. Promoter methylation or acetylation detoxi \201 cation enzymes, e.g GSTP1. Gene fusions promoter gene adjacent to a transcription fa ctor gene on a particular chromosome, resulting in overexpression of this factor and abnorm al positive growth control, e.g. TMPRSS2-ERG fusions are found in 50% of prostate cancers. Micro RNA: tissue-speci \201 c, non-coding, short ssRNA; regulate gene expression by inter acting with mRNA; multifunctional, measurable, and potentially reversible; postulated to be the key to individualized cancer treatment. peptide growth factors, e.g. insulin-like growth inactivating genes encoding : a translocation occurs during mitosis to bring a Interest in the molecular pathology of urological neoplasia has begun to result in the deve lopment of screening tests for hereditary diseases, di- agnostic or prognostic gene pro \201 ling, and new strategies for treatment. Examples include the PCA3 test for prostate ca ncer and the development of targeted therapies for advanced renal cancer. CHAPTER 7 Urological neoplasia 238 Wilms \200\231 tumor and neuroblastoma Wilms \200\231 tumor (nephroblastoma) First describe d by the German surgeon, Max Wilms (1867 \200\2231918), this is a rare childhood tumor, aff ecting 1 in 10 000 children. It is, however, the commonest intra-abdominal tumor of childho od (20% of all childhood malignancies) and it represents 80% of all genitourinary tumors af fecting children under 15y. Male and female are equally affected, 20% are familial, and 5% are bilateral. Seventy- \201 ve percent present under the age of 5y. Children of African d escent are at greatest risk. Pathology and staging Wilms \200\231 tumor is a soft pale gray tumor (it looks like brain). It contains metanephric blastema, primitive renal tubular epithelium, and connective tissu e components. Two distinct histological subtypes are described: fa- vourable (well differen tiated) and anaplastic (poorly differentiated). In at least 20% of cases, mutation or deletion of both copies (alleles) of the chromosome 1 1p13 WT1 tumor suppressor gene results in tumouri- genesis. The familial disease exhibits a utosomal dominant inheritance, but is recessive at the cellular level. Affected family memb ers harbor a germ-line WT1 mutation, conferring susceptibility. One further \200\230hit \200\231 is required while two \200\230hits \200\231 are required to cause the sporadic di sease. This explains why hereditary Wilm \200\231s tumors tend to develop multifocally and at a slightly younger age than its sporadic counterpart. Mutations of three further genes, WT2 (11p15.5), WTX (on the X chromosome), and CTNNB1 account for a further 30% of cases. Lo ss of chromosome 1p and 16q alleles de \201 nes a subgroup with worse prognosis. Stage I Wilms \200\231 tumor (43% of patients) \200\224at least one of the following criteria must be met. - - - Tumor is limited to the kidney and is completely excised. The surface of the renal capsule is intact. The tumor is not ruptured or biopsied (open or needle) prior to removal. No invo lvement of extrarenal or renal sinus lymph \200\223vascular spaces. No residual tumor appar ent beyond the margins of excision. Metastasis of tumor to lymph nodes not identi \201 ed. - Stage II Wilms \200\231 tumor (23% of patients) \200\224at least one of the following crite ria must be met. - - - Tumor extends beyond the kidney, but is completely excised. No residual tumor apparent at o r beyond the margins of excision. Any of the following conditions may also exist. \200 Tumor involvement of the blood vessels of the renal sinus and/or outside the renal parenchy ma. The tumor has been biopsied prior to removal or there is local spillage of tumor during surgery, con \201 ned to the \202 ank. Extensive tumor involvement of renal sinus soft tissue. WILMS \200\231 tumor AND NEUROBLASTOMA 239 Stage III Wilms \200\231 tumor (23% of patients) \200\224at least one of the following crit eria must be met. - - - - Unresectable primary tumor. Lymph node metastasis. Tumor is present at surgical margins. Tu mor spillage involving peritoneal surfaces, either before or during surgery, or transected tumor thrombus. Stage IV Wilms \200\231 tumor (10% of patients) is de \201 ned as the presence of haematog enous metastases (lung, liver, bone, or brain) or lymph node metastases outside the abdomin opelvic region. Stage V Wilms \200\231 tumor (5% of patients) is de \201 ned as bilateral renal involvement at the time of initial diagnosis. Presentation Ninety percent have a mass, 33% complain of abdominal or loin pain, 30 \200 \22350% develop haematuria, 50% are hypertensive. Fifteen percent of patients exhibit other anomalies such as hemihypertrophy/macroglos- sia (Beckwith \200\223Wiedemann syndrome), go nadal dysgenesis/nephropathy (Denys \200\223Drash syndrome) aniridia/retardation (WAGR), an d fetal over- growth (Perlman \200\231s syndrome). Investigations The \201 rst-line investigation for a child with an abdominal mass or haem a- turia is ultrasound which will reveal a renal tumor. Further to diagnostic imaging, stag ing is obtained by CT, including the chest. Needle biopsy is avoided. Treatment and prognosis Children with renal tumors should be managed by a specialist paedia t- ric oncology center. Staging nephrectomy, with or without preoperative or post-operative chemotherapy, remains the mainstay of treatment. The chemotherapy most frequently used is vincristine and doxorubicin. Flank irradiation may be used in higher stage tumors. Survival is generally good at 92% overall, ranging from 55% to 97%, according to stage at presenta- tion and histology. Neuroblastoma The most common extracranial solid tumor of childhood. Eighty percent are dia gnosed <4y old. The tumor is of neural crest origin; 50% occur in the adrenal gland and mos t of the remainder arise along the sympathetic trunks. Presentation Systemic symptoms and signs are common: fever, abdominal pain/disten- sion, ma ss, weight loss, anemia, and bone pain. Retro-orbital metastases may cause proptosis. Imaging and staging Ultrasound initially; CT of chest and abdomen. Calci \201 cation in tu mor helps distinguish neuroblastoma from Wilms \200\231 tumor. MIBG scans are very sensitiv e for detection of neuroblastomas (Table 7.1). CHAPTER 7 Urological neoplasia 240 Table 7.1 Imaging and staging Stage 1 Tumor con \201 ned to organ of origin and grossly complete excision Stage 2 Unilateral tumor with residual disease post-resection or lymphadenopathy Stage 3 Tumor crossing midline or contralateral nodes Stage 4 Metastatic disease beyond regional nodes; survival 6% Stage 4S Unilateral tumor with metastasis limited to liver, skin, or bone marrow; survival 77% Treatment and prognosis Surgical excision; radiotherapy; combination chemotherapy, possibly with autologous bone marrow transplantation. Stage 4S tumors may resolve with little or no treatment. Prognosis is poor, except for stages 1 and 4S disease. This page intentionally left blank CHAPTER 7 Urological neoplasia 242 Radiological assessment of renal masses Abdominal USS is the \201 rst-line investigation for a patient with loin pain or a suspected renal mass. The size resolution for renal masse s is 1.5cm, exhibiting variable echo patterns. Ultrasound may also detect renal cysts, most of which are simple: smooth-walled, round or oval, without internal echoes, and complete t ransmission with a strong acoustic shadow poste- riorly. If the cyst has a solid intracysti c element, septations, an irregular or calci \201 ed wall, further imaging with CT is indi cated. Ten to twenty- \201 ve per- cent of RCC contain cysts. Yale radiologist, Morton Bos niak, developed the following radiological classi \201 cation of renal cysts in Table 7.2. 1 Table 7.2 Radiological classi \201 cation of renal cysts I Uncomplicated simple (see above criteria); benign; no follow-up if asymptomatic II Minimally complicated; septa, calci \201 cation, hyperdense (contain blood); benign, but r equire radiological follow-up III Complicated; irregular margin, thickened septa, thick irregular calci \201 cation; indeter minate, surgical exploration indicated unless there is history of trauma or infection IV Large, irregular cyst margins with solid components internally; cystic renal carcinoma unti l proven otherwise; surgery required If a renal mass is detected by USS, a thin slice or helical CT scan before and after IV con trast is the most important investigation for characteriza- tion and staging. Around 90% of solid-enhancing renal masses will be RCC. Ten percent of RCC will contain calci \201 cati ons or fat. Even relatively avas- cular renal carcinomas enhance by 10 \200\22325* Houns \201 eld units. Occasionally, an isodense, but enhancing, area of kidney is demonstrated: t his is termed \200\230pseudotumour \200\231 and may correspond to a harmless hypertrophied cor- tical column (of Bertin) or dysmorphic segment. CT may mislead with respect to liver invasion (rare) due to \200\230partial volume effect \200\231; real-time ultrasound is mor e accurate. Lymphadenopathy >2cm is invariably indica- tive of metastasis. MRI with gadolinium contrast may be used for imaging the IVC, locally advanced disease, ren al insuf \201 ciency, or for patients allergic to iodinated contrast. Doppler USS may also evaluate IVC tumor thrombus. Renal arteriography is seldom used in the diagnostic setting, but may be helpful to delineate the number and position of renal arteries in preparation f or nephron-sparing surgery or surgery for horseshoe kidneys. Houns \201 eld units are a measure of X-ray attenuation applied to CT scanning: \200\2231 000 units equates with air, 0 units equates with water, and +1000 equates with bone. RADIOLOGICAL ASSESSMENT OF RENAL MASSES 243 Ultrasound or CT-guided \201 ne needle aspiration (FNA) or needle biopsy This is increasi ngly indicated due to the trend in managing small masses with surveillance or minimally inv asive ablative therapies. Also, a histo- logical diagnosis is usually required prior to tre ating inoperable patients with systemic therapies. Needle biopsy is highly speci \201 c, b ut less sensitive for detecting malignancy: 80% of biopsy cores are diagnostic, of which 75 % are RCC. Repeat biopsy is diagnostic in 80%. There are also risks of hemorrhage (5%) and tumor spillage (rare). FNA is useful for aspiration of renal abscess or infected cyst or to diagnose suspected lymphoma or metastatic lesions. Table 7.3 shows a practical radiologica l classi \201 cation of renal masses. Table 7.3 Classi \201 cation of renal masses by radiographic appearance Others (excluding rarities) Simple cyst Complex cyst Fatty mass Cyst Renal carcinoma Angiomyolipoma Renal cell carcinoma Multiple cysts Cystic nephroma Lipoma Metastasis Parapelvic cyst Haemorrhagic cyst Liposarcoma Lymphoma Calyceal diverticulum Metastasis Sarcoma Wilms \200\231 tumor Abscess Infected cyst Tuberculosis Lymphoma Oncocytoma Tuberculosis Xanthogranulomatous pyelonephritis Renal artery aneurysm Phaeochromocytoma (adrenal) Arteriovenous malformation Wilms \200\231 tumor Hydrocalyx Transitional cell carcinoma It has been suggested that abdominal USS could be used as a screen- ing test for early dete ction and treatment of RCC; this has been piloted in Germany and Japan. While there is curr ently no plan for population screening in the UK, it would be appropriate to offer USS to h igh-risk individuals such as relatives of VHL syndrome patients. 1 Bosniak MA (1986) The current radiological approach to renal cysts. Radiology 158:1 \200 \22310. CHAPTER 7 Urological neoplasia 244 Benign renal masses The most common (70%) are simple cysts, present in >50% of those aged > 50y. Rarely symptomatic, treatment by aspiration or laparoscopic de- roo \201 ng is seldom considered. Most benign renal tumors are rare; the two most clinically important are oncocytoma and angiomyolipoma. Oncocytoma This is uncommon, accounting for 3 \200\2237% of renal tumors. Males are twice a s commonly affected as females. They occur simultaneously with RCC in 7 \200\22332% of case s. Pathology Oncocytomas are spherical, capsulated, brown/tan color, mean size 4 \200\2236cm. Half contain a central scar. They may be multifocal and bilateral (4 \200\22313%) and 10 \200\22320% extend into perinephric fat. Histologically, they com- prise aggregates of eosi nophillic cells thought to arise from intercalated cells of the collecting duct. Cells are packed with mitochondria, mitoses are rare, large nucleoli are present; they are considered benign, not known to metastasize. There is often loss of the Y chromosome. Presentation Oncocytomas often (83%) present as an incidental \201 nding or with loin pai n or haematuria. Investigations Oncocytoma cannot often be distinguished radiologically from RCC; they may c oexist with RCC. Rarely, they exhibit a \200\230spoke-wheel \200\231 pattern on CT scannin g, caused by stellate central scar. Percutaneous biopsy is not usu- ally recommended since there is often continuing uncertainty about the diagnosis. The main differential diagnosis of renal oncocytoma is chromo- phobe RCC oncocytic variant which, like the renal oncocytoma , has eosin- ophilic cytoplasm, but has perinuclear clearing and typically, some degree of nuclear atypia. Treatment Radical or partial nephrectomy is indicated as for renal carcinoma. Minimally inv asive techniques such as radiofrequency ablation (RFA) or high intensity focused ultrasound (HIFU) could be considered for smaller tumors. No follow-up is necessary. Angiomyolipoma (AML) Eighty percent of these benign clonal neoplasms (PEComa, formerly cons idered as a hamartoma) occur sporadically, mostly in middle-aged females. Twenty percent ar e in association with tuberous sclerosis (TS), an autosomal dominant syndrome characterized by mental retardation, epilepsy, adenoma sebaceum, and other hamartomas. Up to 80% of TS p atients develop AMLs, mean age 30y, 66% female, frequently multifocal, and bilateral. BENIGN RENAL MASSES 245 Pathology AML is composed of perivascular epithelioid cells (PEC) containing blood vessels, immature smooth muscle, and fat. They are always considered be- nign although extrarenal A MLs have been reported in venous system, hilar lymph nodes, and liver. Macroscopically, it looks like a well circumscribed lump of fat. Solitary AMLs are more frequently found in the right kidney. Presentation AMLs frequently present as incidental \201 ndings (>50%) on USS or CT scans. They may present with \202 ank pain, palpable mass, or painless haema- turia. Massive an d life-threatening retroperitoneal bleeding occurs in up to 10% of cases (Wunderlich \200 \231s syndrome). Investigations Ultrasound re \202 ects from fat, hence a characteristic bright echo patter n. This does not cast an \200\230acoustic shadow \200\231 beyond, helping to distinguish a n AML from a calculus. CT shows fatty tumor as low density (Houns \201 eld units <10) in 8 6% of AMLs. If the proportion of fat is low, a de \201 nite diagno- sis cannot be made as other renal tumors may contain fat. Measurement of the diameter is relevant to treatment. Treatment In studies, 52 \200\22382% of patients with AML >4cm are symptomatic compared wit h only 23% with smaller tumors. Therefore, asymptomatic AMLs can be followed with serial US S if <4cm while those bleeding or >4cm should be treated surgically. Emergency nephrectomy or selective renal artery embolization may be life-saving. Patients with kidney loss should be moni- tored for hypertension (and treated for it if discovered) and avoid neph- rotoxic drugs such as certain pain relievers and IV contrast agents. In patients with TS, in whom multiple bilateral lesions are present, annual renal USS and conservative treatment should be attempted. HIFU could be considered for asymptomatic tumors. CHAPTER 7 Urological neoplasia 246 Renal cell carcinoma: pathology, staging, and prognosis RCC is adenocarcinoma of the renal cortex, believed to arise from the proximal convoluted tubule (although the majority of VHL gene deletions occur in the distal tubule). Usually tan-colored, lobulated, and solid, 7% are multifocal, 1 \200\2232% bilateral, 10 \200\22320% contain calci \201 cation, and 10 \200\22325% contain cysts or are predominantly cystic. There may be zones of haemor- rhage, necrosis, and scarring. Rarely grossly in \201 ltrative, they are usually circumscribed b y a pseudocapsule of compressed tissue. Spread is by: direct extension to adrenal gland (7.5% in tumors >5cm), through the renal ca psule (25%), into renal vein (up to 44%), IVC (5%), right atrium; by lymphatics to hilar an d para-aortic lymph nodes; hae- matogenously to lung (75%), bone (20%), liver (18%), and br ain (8%). Histological classi \201 cation of RCC -