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. This page intentionally left blank CHAPTER 7 Urological neoplasia 374 Penile cancer: clinical management Clinical presentation A hard painless lump on the glans penis or inner prepuce is the most common presentation. Up to 15 \200\22350% of patients de lay presentation for >1y due to embarrassment, personal neglect, fear, or ignorance. A bloo dy discharge may be confused with haematuria. Rarely, a groin mass or uri- nary retention a re presenting symptoms. Examination reveals a solid non- tender mass or ulcer beneath or in volving the foreskin. There is usually evidence of local infection. In more advanced diseas e, the genitalia and even perineum are replaced by a fungating tumor. Examination A thorough examination of the abdomen, external genitalia, and inguinal lymph n odes is necessary. Investigations A biopsy is usually indicated. Chest, abdomen, and pelvic CT scan is ob- tai ned in advanced cases to assess stage and tumor depth of invasion. Penile MRI may be useful when tumor depth is dif \201 cult to assess. Treatment Following histological diagnosis, management of penile cancer should take place i n supraregional centers that can provide multidisciplinary surgical and oncological experti se for this rare disease. The primary tumor The \201 rst-line treatment of penile cancer, regardless of the inguina l node status, is surgery. Circumcision is appropriate for preputial lesions. Penis- preser ving surgery such as glans resurfacing and wide excision of glanular lesions with extrageni tal split skin graft glanular reconstruction is recom- mended for penile intraepithelial ne oplasia (PIN), Ta \200\2231 G1 \200\2232, and care- fully selected small T1G3 or T2 tumors, giving safe oncological and good cosmetic and functional results. Alternatives to surgery include topical 5- \202 uorouracil (PIN only), laser ablation, cryoablation, external beam radio- therapy, or brachytherapy.1 For tumors con \201 ned to the glans and distal corpora, a glansectomy 9 corporal resectio n is performed and a neoglans may be reconstructed and covered with extragenital split skin graft with good cosmetic, functional, and oncological outcomes. Total penile amputation with formation of a perineal urethrostomy is indi- cated in patient s with more extensive lesions. The patient must be psycho- logically prepared for the inabi lity to have sexual intercourse and need to sit to void urine. Local recurrence occurs in < 5% if the excision margins are clear by 1 \200\2232mm. The most common complication is uret hral meatal ste- nosis. Radiotherapy or brachytherapy are non-surgical alternatives, though local recurrence rates of 30 \200\22350% are reported; tissue necrosis/damage leads to mea tal stenosis (15 \200\22330%), urethral stricture (20 \200\22335%), \201 stula, and pain. The use of neoadjuvant chemotherapy is under investigation. PENILE CANCER: CLINICAL MANAGEMENT 375 Lymphadenopathy There is controversy regarding the management of patients with initially no n-palpable nodes. While the majority overall will not harbor metastat- ic disease, it is ar gued that delayed lymphadenectomy could reduce the chance of cure. Prophylactic inguinal ly mphadenectomy can be offered for high-risk G3 or pT2 \200\2234 tumors (risk of N+ disease i s 30%), but it has a reported morbidity rate of 30 \200\22350%. Dynamic sentinel lymph node biopsy is currently being evaluated as an alternative with less morbidity. For patients with persistent inguinal lymphadenopathy or positive inguinal nodes on dynamic sentinel lymph node biopsy, in the absence of demonstrable pelvic or metastatic disease, r adical inguinal lymphadenec- tomy should be undertaken on the appropriate side. The boundar ies of the dissection are the inguinal ligament, the adductors and sartorius, with the femo ral vessels in the \202 oor. Fine needle aspiration cytology is recom- mended as 20% of p alpable inguinal nodes will be reactive at the time of diagnosis of penile cancer for conco mitant infection. Radiotherapy and che- motherapy are alternative or adjuvant treatments fo r metastatic nodal dis- ease in un \201 t, elderly, or inoperable patients; 5y survival 25 % (Table 7.26).2 Pelvic lymphadenectomy should be considered when two or more posi- tive in guinal nodes are identi \201 ed at dynamic sentinel lymph node biopsy or inguinal lymphade nectomy or if CT scan has shown enlarged pelvic lymph nodes by CT criteria; here, the likel ihood of pelvic node metastasis is 23 \200\22356% and cure rates of 14 \200\22354% are repo rted. Fixed inguinal masses may be considered for salvage surgery following neoadjuvant chemother apy (response rates 20 \200\22360%), ideally within a clini- cal trial. Rarely, lymphadenop athy ulcerates the skin, may encase the fem- oral vessels, and invade the deeper musculatur e. In these circumstances, collaboration with plastic and vascular surgeons is necessary if surgery is considered appropriate. Distant metastatic disease is treated in a palliative setting using systemic chemotherapy w ith cisplatin-based chemotherapy. Responses are partial and short-lived. Patients with M1 d isease are offered palliative surgery for their primary tumor as prognosis in this group of patients is extremely poor. Follow-up Careful follow-up, initially every 2 \200\2234 months, is essential after primary tu- mour surgery to detect and treat local recurrence early. Groin evaluations of patients with initially non-palpable nodes at similar intervals is necessary since late diagnosis a nd treatment is a negative prognostic factor. Pelvic, abdominal, and chest CT imaging is ju sti \201 ed for those patients who have undergone inguinal lymphadenectomy for metastatic disease. CHAPTER 7 Urological neoplasia 376 Table 7.26 5y cancer-speci \201 c survival N0 90 \200\223100% N1 80 \200\22395% N2 60 \200\22380% N3 10 \200\22320% M1 0% 1 Solsona E, Bahl A, Brandes SB, et al. (2010) New developments in the treatment of localiz ed penile cancer. Urology 76 Suppl 1:S36 \200\22342. 2 Pizzocaro G, Algaba F, Horenblas S, et al. (2010) European Association of Urology (EAU) G uidelines Group on Penile Cancer. Eur Urol 57:1002 \200\22312. SCROTAL AND PARATESTICULAR tumors 377 Scrotal and paratesticular tumors Carcinoma of the scrotum Squamous cell carcinoma was orig inally described in 1775 by London sur- geon, Percivall Pott, as \200\230chimney sweepers \200\231 cancer \200\231. Called by the unfortu- nate individuals \200\230the soot wart \200\231, it was the \201 rst cancer to be associated with an occupation. Pott wrote \200\230It is a disease which always makes its \201 rst attack on and its \201 rst appe arance in the inferior part of the scrotum; where it produces a super \201 cial, painful, ragged, ill-looking sore, with hard and rising edges. In no great length of time, it pervad es the skin, dartos, and mem- branes of the scrotum, and seizes the testicle, which it inla rges, hardens, and renders truly and thoroughly distempered; from whence it makes its way u p the spermatic process into the abdomen, most frequently indurating and spoiling the ingui nal glands: when arrived within the abdomen, it affects some of the viscera and then very s oon becomes painfully destructive \200\231. Nowadays, a rare disease, chronic exposure of the scrotal skin to soot, tar, or oil was the cause. It presents as a painless lump or ulcer, often purulent, on the anterior or posteri or scrotal wall. If posterior, the lesion is concealed from view if the patient is lying or sitting. Inguinal lymphade- nopathy may suggest metastasis or reaction to infection. Treatment of a mass or ulcer on the scrotum is wide local excision. Antimicrobials are admi nistered for 6 weeks if there is lymphadenopa- thy, after which the groins are re-evaluated . Inguinal lymphadenectomy is considered if lymphadenopathy persists, with adjuvant chemoth erapy. Supraclavicular lymphadenopathy, haematogenous visceral, and bony metastasis are rar e and carry a poor prognosis. Tumors of the testicular adnexa Epithelial tumors arising from the epididymis and paratesti cular tissues are rare. They are mostly of mesenchymal origin, Adenomatoid tumors: small solid tumors arising in the epididymis or on the surface of the t unica albuginea; usually present without change for severaly; benign vacuolated epithelial and stromal cells, origin unknown, treatment is local excision. Cystadenoma of the epididymis: benign epithelial hyperplasia; young adults; often asymptoma tic; one third bilateral and associated with VHL syndrome. Mesothelioma: presents as a \201 rm painless scrotal mass associated with hydrocele which gradually enlarges; any age group; 15% metastatic to inguinal nodes; treated with orchidec tomy and follow-up. Paratesticular tumors Rhabdomyosarcoma: scrotal mass in \201 rst/second decade; in sperma tic cord, compresses testis and epididymis; lymphatic spread to para-aortic nodes; treatmen t is multimodal radical orchidectomy with radiotherapy and chemotherapy; 5y survival, 75%. Leiomyoma/sarcoma: scrotal mass age 40 \200\22370y; in spermatic cord; 30% are malignant, 7 0% are benign; haematogenous distant spread; treatment is wide excision or radical orchidec tomy. Liposarcoma: spermatic cord tumor; 70% are malignant. CHAPTER 7 Urological neoplasia 378 Testicular cancer: incidence, mortality, epidemiology, and etiology Incidence and mortality Primary testicular cancer (TC) is the most common solid cancer in men aged 20 \200\22345, rare below 15y and above 60y. Constituting 1 \200\2232% of all male cancers and 5% of all u rological tumors, it is considered the most curable cancer. The incidence is increasing in most European countries (although recently it has fallen slightly in UK) while the mortalit y has fallen steadi- ly since the introduction of platinum-based chemotherapy in the 1980 \200\231s. Lifetime risk of developing TC is estimated at 1 in 210: 1990 new cases, but onl y 70 deaths occurring in the UK (2008). Public health campaigns en- couraging testicular se lf-examination (TSE) for young men are ongoing. Epidemiology and etiology - Age: the commonest affected age group is 20 \200\22345y, with germ cell tumors. Half of all cases occur in men <35y. Non-seminomatous germ cell tumors (NSGCT) are more common at ages 20 \200\22335, while seminoma is more common at age 35 \200\22345y. Rarely, infants and bo ys below 10y develop yolk sac tumors and 50% men >60y with TC have lymphoma. Race: highest risk. Whites are three times more likely to develop TC than blacks in the USA. With the exc eption of the New Zealand Maoris, TC is rare in non-Caucasian races. Previous Bilateral TC occurs in 1 \200\2232% of cases. Cryptorchidism: cryptorchidism. Ultrastructural changes ar e present in these testes by age 3y, although earlier orchidopexy does not completely elimi nate the risk of developing TC. According to a large Swedish study, cryptorchidism is assoc iated with a two-fold increased risk of TC in men who underwent orchiopexy <13y old, but ri sk is increased 5-fold in men who underwent orchiopexy >13y. A meta-analysis showed risk of contralateral TC almost doubles while ipsilateral TC risk is increased 6-fold in men with unilateral cryptorchidism. Intratubular germ cell neoplasia (testicular intraepithelial neo plasia, TIN): synonymous with carcinoma in situ, although the disease arises from malignant change in spermatogonia; 50% of cases develop invasive germ cell TC within 5y. The populat ion incidence is 0.8%. Risk factors include cryptorchidism, extragonadal germ cell tumor, a trophic contralateral testis, 45XO karyotype, Klinefelter \200\231s syndrome, previous or c ontralateral TC (5%), and infertility. Human immunode \201 ciency virus 35% more frequentl y than expected. white Caucasian people living in Europe and USA have the TC: confers a 12-fold increased risk of metachronous TC. 5 \200\22310% of TC patients have a history of (HIV): patients develop seminoma TESTICULAR CANCER 379 Genetic factors: appear to play a role, given that \201 rst-degree relatives are at highe r risk by 4 \200\2239-fold, but a de \201 ned familial inheritance pattern is not apparent . Maternal estrogen exposure: pregnancy appears to increase risk of cryptorchidism, urethra l anomalies, and TC in male offspring. at higher than usual levels during Trauma and viral-induced atrophy have not been convincingly implicated as risk factors for TC. CHAPTER 7 Urological neoplasia 380 Testicular cancer: pathology and staging Ninety percent of TC are malignant germ cell tumor s (GCT), split into seminomatous and non-seminomatous GCTs for clinical purposes (Table 7.2 7). Seminoma, the most common germ cell tumor, appears pale and homogeneous. Teratomas are heterogeneous and sometimes contain bizarre tissues such as cartilage or hair. Metastases t o the testis are rare, notably from the prostate (35%), lung (19%), colon (9%), and kidney (7%). Table 7.27 The WHO histopathological classi \201 cation of testicular tumors Germ cell tumors (90%) Other Tumors (7%) Epidermoid cyst (benign) Adenomatoid tumor Adenocarcinoma of the rete testis Carcinoid Lymp homa (5%) Metastatic, from another site (1%) Seminoma (48%) Spermatocytic, classical, and anaplastic subtypes Non-seminomatous GCT (42%) Teratoma: differentiated/ mature, intermediate/immature, undiffe rentiated/malignant Yolk sac tumor Choriocarcinoma Mixed Mixed GCT (10%) Sex cord stromal tumors (3% ; 10% malignant) Leydig cell Sertoli cell Mixed or unclassi \201 ed Mixed germ cell/sex cord tumors (rare) The right testis is affected slightly more commonly than the left; synchro- nous bilateral TC occurs in 2.5% of cases. TC spreads by local extension into the epididymis, spermatic co rd, and rarely, the scrotal wall. Lymphatic spread occurs via the testicular vessels, initi ally to the para-aortic nodes. Involvement of the epididymis, spermatic cord, or scrotum ma y lead to pelvic and ingui- nal node metastasis. Bloodborne metastasis to the lungs, liver, and bones is more likely once the disease has breached the tunica albuginea. TC is staged using various classi \201 cations, most recently the UICC TNM (2009) system ( Table 7.28 and Fig. 7.13). Herein, T stage is patho- logical, N stage is clinical (physical examination, imaging with CT abdomen and chest) or pathological; M stage involves physical examination, imag- ing (with CT), and biochemical investigations. An additional S category is appended for serum tumor markers (see b p. 386). TESTICULAR CANCER: PATHOLOGY AND STAGING 381 Table 7.28 TNM staging of testicular germ cell tumors (UICC 2009, 7th edition) Tx Primary tumor has not been assessed (no radical orchidectomy) T0 No evidence of primary tumor Tis Intratubular germ cell neoplasia, testicular intraepithelial neoplasia (carcinoma in situ) T1 Tumor limited to testis and epididymis without vascular/lymphatic invasion; may invade tuni ca albuginea, but not tunica vaginalis T2 Tumor limited to testis and epididymis with vascular/lymphatic invasion or tumor involving tunica vaginalis T3 Tumor invades spermatic cord with or without vascular/lymphatic invasion T4 Tumor invades scrotum with or without vascular/lymphatic invasion Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis with a lymph node mass (cid:100)2cm and (cid:100)5 lymph nodes, none >2cm N2 Metastasis with a lymph node mass 2 \200\2235cm, or >5 lymph nodes together size 2 \200\223 5cm, or evidence of extranodal extension N3 Metastasis with a lymph node mass >5cm Mx Distant metastasis cannot be assessed M0 No distant metastasis M1a Non-regional lymph node or pulmonary metastasis M1b Distant metastasis other than to non-regional lymph node or lungs Intratubular germ cell neoplasia (testicular intraepithelial neoplasia, TIN) The precursor lesion for most testicular GCTs, TIN may be observed adjacent to TC. It is present in the c ontralateral testis of up to 5% of TC patients. Controversy exists as to whether to biopsy the contralateral testis in all cases to diagnose TIN. At particularly high risk of TIN are patients with small (<12mL) testis, a history of cryptorchidism, and age <30y. If TIN is d iagnosed, treatment is with radiotherapy. Consequently, the issues of infertility and hormo ne replacement need to be discussed with these patients. CHAPTER 7 Urological neoplasia 382 (a) T1 T2 Vas deferens, spermatic cord Scrotal wall Epididymis Tunica vaginalis Testis T3 T (b) T1 \200\2234 N0M0 T1 \200\2234 N1 \200\2233 M0 T1 \200\2234 N1 \200\2233 M1 Fig. 7.13 Pathological staging of testicular cancer. (a) Primary tumors T1 \200\2234. If ra dical orchidectomy has not been used, Tx is used. (b) Node/metastasis: para-aortic lymphade nopathy measured in long axis on CT scan (upper \201 gure); supraclavicular lymphadenopat hy and/or pulmonary metastases \200\224M1a, other distant metastases (e.g. liver, brain); M 1b lower \201 gure. This page intentionally left blank CHAPTER 7 Urological neoplasia 384 Testicular cancer: clinical presentation, investigation, and primary treatment Symptoms Mos t patients present with a scrotal lump, usually painless. Delay in pres- entation is not un common, particularly those with metastatic disease. This may be due to patient factors (fea r, self-neglect, ignorance, denial) or ear- lier misdiagnosis. Five percent of patients dev elop acute scrotal pain due to intratumoural hemorrhage, causing diagnostic confusion. The lump may have been noted by the patient, sometimes after minor trauma, or by his partner. T en percent of patients develop symptoms suggestive of ad- vanced disease, including weight loss, lumps in the neck, chest symptoms, or bone pain. Signs Examination of the genitalia should be carried out in a warm room with the patient re laxed. Observation may reveal asymmetry or slight scrotal skin discoloration. Using careful bimanual palpation, the normal side is \201 rst examined, followed by the abnormal side. This will reveal a hard, non-tender, irregular, non-transilluminable mass in the testis or replac- ing the testis. Care should be taken to assess the epididymis, spermat- ic cord, a nd overlying scrotal wall, which may be normal or involved in 10 \200\22315% of cases. Rare ly, a secondary hydrocele may be present if the tunica albuginea has been breached. General examination may reveal ca- chexia, supraclavicular lymphadenopathy, chest signs, hepatomeg aly, low- er limb oedema, or abdominal mass, all suggestive of metastatic disease. Gynaecom astia is seen in about 5% of patients with TC due to endocrine manifestations of some tumor s. Differential diagnoses Hydrocele, epididymal cyst (spermatocoele), indirect inguinal hernia , TB, or syphilitic gumma (both exceedingly rare nowadays in developed coun- tries) are cau ses of painless scrotal swellings. Varicocele is normally ap- parent only when the patient is standing. Epididymal \200\230sperm granuloma \200\231, testicular torsion, and acute ep ididymo-orchitis account for most presen- tations of acute scrotal pain. Every patient who is concerned should be examined and if any doubt persists, further investigated. Investigations Ultrasound is the \201 rst-line investigation of any scrotal lump and will con- \201 rm whether the palpable lesion is within the testis, distorting its normally r egular outline and internal echo pattern. The sensitivity of USS for de- tecting a testicul ar tumor is almost 100%, including impalpable lesions of 1 \200\2232mm and \200\230occult \200\231 primary tumors in patients presenting with system- ic symptoms and signs. Any hypo echoic area within the tunica albuginea should be regarded with suspicion. USS may also dis tinguish a primary from a secondary hydrocele. Testicular microlithiasis is occasionally re - ported in association with TC. There has been uncertainty regarding the signi \201 cance of this anomaly in otherwise normal testes; the few prospec- CLINICAL PRESENTATION, INVESTIGATION, PRIMARY TREATMENT 385 tive studies have failed to demonstrate any increased risk of TC develop- ment. Consequentl y, there is no rationale for recommending serial ultra- sound scans to these individuals. Abdominal and chest CT scans are usually obtained for staging purposes if the diagnosis of TC is con \201 rmed or considered likely. Other imaging (such as CT of brain, spine, or bo ne scan) is performed if clinically indicated. Serum tumor markers (AFP, LDH, and hCG) are measured prior to any treatment of a suspected TC (see b p. 386). Treatment Radical inguinal orchidectomy is both the de \201 nitive diagnostic investigatio n and primary treatment for most testicular tumors, unless tissue diagnosis has been made f rom biopsy of a metastasis. Radical orchidectomy is cur- ative in approximately 75% of pati ents. Fertility assessment, semen analy- sis, and cryopreservation should be offered to pat ients without a normal contralateral testis. The testis, epididymis, and spermatic cord are excised en bloc through a groin incision. The cord is mobilized within the inguinal canal, clamped, trans \201 xed, and divided 1 \200\2232cm from the internal inguinal ring before the testis is manipulated into the wound, preventing inadvert- ent metastasis. A silicone prosthesis may be inserted at the time or at a later date. Contralateral testis biopsy shou ld be considered in patients at high risk for intratubular germ cell neoplasia (see b p. 37 8 Etiology). CHAPTER 7 Urological neoplasia 386 Testicular cancer: serum markers Germ cell tumors may express and secrete into the bloodstr eam rel- atively speci \201 c and readily measurable proteins. These tumor markers (with t he exception of PLAP) are useful in diagnosis, staging, prognostica- tion (see b p. 388), a nd monitoring of response to treatment. Oncofetal proteins Alpha-fetoprotein (AFP): is expressed by trophoblastic elements within 50 \200\22370% of te ratomas and yolk sac tumors. With respect to seminoma, the presence of elevated serum AFP s trongly suggests a non-seminoma- tous element. Serum half-life is 3 \200\2235 days; normal <10ng/mL. Human chorionic gonadotrophin (hCG): is expressed by syncytiotrophob- lastic elements of ch oriocarcinomas (100%), teratomas (40%), and semi- nomas (10%). Serum half-life is 24 \200 \22336h. Laboratory assays measure the B-subunit; normal <5mIU/mL. When used together, 90% of patients have elevation of one or both markers; less among patients with low-stage tumors. Cellular enzymes Lactate dehydrogenase (LDH): is a ubiquitous enzyme, elevated in serum for various causes, therefore, less speci \201 c. It is elevated in 10 \200\22320% of semi- n omas, correlating with tumor burden and is most useful in monitoring treatment response in advanced seminoma. Placental alkaline phosphatase (PLAP): is a fetal isoenzyme, elevated in up to 40% of patie nts with advanced germ cell tumors. It is not widely used as it is non-speci \201 c, may b e elevated in smokers. Clinical use These markers are measured at presentation, 1 \200\2232 weeks after radical or - chidectomy and during follow-up to assess response to treatment and residual disease (Tab le 7.29). Normal markers prior to orchidectomy do not exclude metastatic disease; normalization of ma rkers post-orchidectomy cannot be equated with absence of disease; and persistent elevation s of markers post-orchi- dectomy may occur with liver dysfunction and hypogonadotrophism, b ut usually indicate metastatic disease. TESTICULAR CANCER: SERUM MARKERS 387 Table 7.29 S staging (part of the UICC (2006) TNM classi \201 cation) Sx Markers not available S0 Markers normal S1 LDH <1.5 times normal upper limit; hCG <5000mIU/mL; and AFP <1000ng/mL S2 LDH 1.5 \200\22310 times normal; hCG 5000 \200\22350 000 mIU/mL; and AFP 1000 \200\22310 00 0ng/mL S3 LDH >10 times normal; hCG >50 000mIU/mL; and AFP >10 000ng/mL CHAPTER 7 Urological neoplasia 388 Testicular cancer: prognostic staging system for metastatic germ cell tumors (GCT) The Inte rnational Germ Cell Cancer Collaborative Group (IGCCCG)* devised a prognostic factor-based staging system for metastatic germ cell cancer that includes good and intermediate prognosi s seminoma and good, intermediate, and poor prognosis non-seminomatous germ cell tumors (NS GCT) (Table 7.30). See b p. 386 for discussion on testicular tumor markers, including S sta ging. PROGNOSTIC STAGING SYSTEM FOR METASTATIC GCT 389 Table 7.30 IGCCCG prognostic factor-based staging system for metastatic germ cell cancer* Prognostic Group Seminoma NSGCT Good 90% of patients 56% of patients 5y progression-free survival (%) 86 92 All factors listed present Any primary site; Testis or retroperitoneal primary site; no non-pulmonary visceral metastases; no non-pulmonary visceral metastases; normal AFP; AFP <1000ng/mL; any hCG or LDH HCG <5000mIU/L; and LDH <1.5 times normal upper limit (S1) Intermediate 10% of patients 28% of patients 5y progression-free survival (%) 73 80 All factors listed present Any primary site; Testis or retroperitoneal primary site; non-pulmonary visceral metastases present; no non-pulmonary visceral metastases; normal AFP; AFP 1000 \200\2239999ng/Ml; or any hCG or LDH HCG 5000 \200\22349 999mIU/L; LDH 1.5 \200\22310 times normal upper limit (S2) Poor 16% of patients 5y progression-free survival (%) No patients classi \201 ed as poor prognosis 48 All factors listed present Mediastinal primary; non-pulmonary visceral metastases present; AFP >10 000ng/mL or HCG >50 000mIU/L; LDH >10 times normal upper limit (S3) International Germ Cell Cancer Collaborative Group (IGCCCG) (1997) International Germ Cell Consensus Classi \201 cation: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15 (2): 594 \200\223603. CHAPTER 7 Urological neoplasia 390 Testicular cancer: management of non-seminomatous germ cell tumors (NSGCT) Following radica l orchidectomy and formal staging, the patient is normally managed by the oncologist, thoug h the urological surgeon may perform retroperitoneal lymph node dissection (RPLND) in selec ted cases based on multidisciplinary team discussion. In the presence of elevated AFP, a se minoma would be managed as for teratoma. Combination chemother- apy introduced in the 1970 \200\231s revolutionized the treatment of metastatic testicular teratoma which was hitherto virtually untreatable. Treatment and follow-up varies between the UK and USA. In the UK, it depends largely on the IGCCCG prognostic staging (see b p. 388), as follows. Localized disease pT1-4N0M0S0 (often referred to as stage I) Surveillance results in 30% re lapse rate, mostly <1y post-orchidectomy. Salvage chemotherapy produces excellent responses , with disease-specif- ic survival >99%. Hence, a risk-adapted management is recommended to minimize the risk of toxicity: - Surveillance for pT1 disease without vascular invasion (only 15% relapse). x 2 cycles for t hose unwilling or unsuitable Adjuvant chemotherapy for surveillance, for pT1 disease with v ascular invasion, or for pT2 \200\2234 disease. Metastatic disease - x 3 Good prognosis: chemotherapy (bleomycin, etoposide, cisplatin cycles); RPLND for residual o r recurrent mass; salvage chemotherapy for relapse. Intermediate and poor prognosis: chemot herapy (bleomycin, etoposide, cisplatin x 4 cycles); RPLND for residual or recurrent mass; occasionally, salvage chemotherapy or radiotherapy if histology con \201 rms tumor; salvag e high-dose chemotherapy with autologous stem cells for relapse. Surveillance and follow-up after treatment Surveillance requires the following: - Year 1: CT \200\224months 3 and 12. Year 2: abdominal CT \200\224month 24. Years 3, 4, and 5: X-ray. Annual clinic visit, serum markers, and chest X-ray thereafter to 10y. monthly clinic visit, serum markers and chest X-ray, abdominal 2-monthly clinic visit with serum markers and chest X-ray, 3-monthly clinic visit, serum markers, and chest MANAGEMENT OF NSGCT 391 Follow-up after treatment is slightly less intensive, also to 10y. The risk of relapse is h ighest in the \201 rst 2y. RPLND - Retroperitoneal lymphadenopathy is usually the \201 rst and only evidence of extragonadal metastasis of NSGCT. In the post-chemotherapy. RPLND aortic nodes up to the origin of the superior mesenteric artery and down to the iliac bifurcation. Complications: pancreatitis, ileus, and ejaculatory failure. Modi \201 ed techniques reduce the risk of ejaculatory dis turbance by taking nodes on the unaffected side only down to the inferior mesenteric artery . In the following radical orchidectomy. UK, RPLND is used only to remove or debulk residual mass may remove viable tumor in 10 \200\22330% of patients, taking para- 1% mortality and 25% morbidity includes lymphocele, USA, RPLND remains the gold standard staging investigation CHAPTER 7 Urological neoplasia 392 Testicular cancer: management of seminoma, IGCN, and lymphoma Of all seminomas, 75% are con \201 ned to the testis at presentation and are cured by radical orchidectomy; 10 \200\223 15% of patients harbor regional node metastasis while 5 \200\22310% have more advanced dise ase. Following radical orchidectomy and formal staging, the patient is man- aged by the oncologi st. Treatment and follow-up depends largely on dis- ease stage according to presence of met astases and size of nodal disease as in Table 7.31. Table 7.31 Treatment and follow-up Non-metastatic disease T1N0M0S0 \200\2231 Risk of subsequent para-aortic node relapse is 20%. Adjuvant treatment reduces the risk of recurrence to <1%. Standard treatment for stage 1 disease is either surveillance or single agent carboplatin (some centers use this for those patients with tumors >4cm and/or rete te stis involvement. A randomized MRC study compared one cycle of carboplatin with radiotherap y (RT; results suggested equivalence. If RT is used, 20Gy is delivered in 10 fractions, inc luding para-aortic nodes. Spermatocytic subtype usually warrants surveillance. Metastatic disease T1 \200\2233 N1 M0S0 \200\2231 RT T1 \200\2233 N2 M0 S0 \200\2231 RT; chemotherapy if nodes near kidneys T1 \200\2234 N3 M0 S0 \200\2231 Chemotherapy (either bleomycin, etoposide and cisplatin or etoposide and cisplatin); if res idual node mass >3cm (rare), retroperitoneal lymph node dissection (RPLND) considered altho ugh not usually necessary or performed with pure seminomas T1 \200\2234N0 \200\2233M1 \200\2232S0 \200\2233 Chemotherapy with etoposide and cisplatin 9 bleomycin; if residual node mass (rare), RPLND considered although not usually necessary or performed with pure seminomas Patients should also be classi \201 ed into prognostic grouping classi \201 ca- tion (IGC CCG; see b p. 388) as this provides an overall prognosis for patients. These patients requi re careful long-term follow-up, according to national guidance. MANAGEMENT OF SEMINOMA, IGCN, AND LYMPHOMA 393 Management of intratubular germ cell neoplasia - Observation or orchidectomy for unilateral disease. - Radiotherapy for unilateral disease in the presence of a contralateral tumor. R adiotherapy for bilateral disease to preserve Sertoli cells. Systemic chemotherapy (e.g. ci splatin) controversial, not currently adopted in UK. Sperm storage must be offered. Management of testicular lymphoma This may be a primary disease or a manifestation of disse minated nodal lymphoma. The median age of incidence is 60y, but has been reported in childr en. Twenty- \201 ve percent of patients present with systemic symptoms, 10% have bilateral testicular tumors. These patients have a poorer prog- nosis following radical orchidectomy and chemotherapy, while those with localized disease may enjoy long-term survival. This page intentionally left blank 395 Chapter 8 Miscellaneous urological diseases of the kidney