TESTICULAR MALIGNANCIES

1. TESTICULAR MALIGNANCIES Dr Imogen Patterson April 2010

2. Histologic classification • Germ cell tumours – 90-95% • Seminoma • Embryonal cell carcinoma • Yolk sac tumour • Choriocarcinoma • Teratoma • Non-germ cell tumours – 5-10%

3. Seminoma • Seminomas account for about 45% of GCT • Three subtypes of pure seminomas: • Classic • Anaplastic • spermatocytic

4. Classical seminoma • Classic seminoma accounts for 80-85% of seminomas • Macroscopic: testicle usually enlarged, and when cut has a bulging homogeneous gray-white appearance • Microscopic: relatively large cells, with clear cytoplasm arranged in uniform sheets, lobules or columns • Supporting stroma shows varying amounts of lymphocytic infiltrate (20%) or granulomatous reaction • Occasional mitoses • Syncytiotrophoblastic elements occur in 10-20% and corresponds to the frequency of bHCG production

5. Anaplastic seminoma • Also referred to seminoma with high mitotic index • Accounts for 5-10% of all seminomas • Several features suggest anaplastic seminoma is more aggressive and potentially more lethal • Greater mitotic activity (avg 3 mitoses/hpf) • Higher rate of local invasion • Increased rate of metastatic spread • Higher rate of bHCG production

6. Spermatocytic seminoma • Accounts for <5% of all seminomas • Occur in men >40yrs (50% of pts are over 50yo) • approx 5% patients have bilateral disease • Macroscopic: tumours are large with yellowish, soft, mucoid appearance to the cut surface. • Microscopic: Cells vary in size and have deeply pigmented cytoplasm and closely resemble different phases of maturing spermatogonia • Nuclei have characteristic filamentous chromatin • Metastatic potential is low and once diagnosed via radical orchidectomy, no further treatment is required.

7. Embryonal carcinoma • Pure EC comprises only 3-4% of GCT • EC cells present in variable amounts in up to 40% of mixed tumours • Most common in 3rd decade • EC elements have not been described in pre-pubertal testes • Macroscopic: small, round, irregular mass invading tunica vaginalis. • Cut surface appears greyish-white with areas of haemorrhage and necrosis • Microscopic: malignant appearing epithelioid cells arranged in glands or tubules • Cell borders are indistinct • Cytoplasm pale and vacuolated • Nuclei have see-through appearance with prominent nucleoli and numerous mitoses • Lymphovascular invasion and involvement of epididymal and paratesticular structure are common • Prognostic importance • Pure EC may be associated with elevated AFP • Syncytiotrophoblastic cells are scattered throughout the tumour and are responsible for bHCG elevation

8. Yolk sac tumour • Predominant tumour in infants and children • In adults, pure yolk sac tumours account for a very small percentage – 2% • Present in up to 40% of mixed GCT • Responsible for the production of AFP in these tumours • Macroscopic: soft, homogeneous, grey-yellow and greasy. • Poorly encapsulated • Microscopically: at least 10 different patterns of yolk sac elements. • Epithelioid cells forming glands or ductal structures within a primitive mesenchymal stroma • Individual cells are small, varying shape, poorly defined borders • Vacuolated cytoplasm of glycogen and fat • Nuclei of varying sizes with frequent mitosis and prominent nucleoli

9. Choriocarcinoma • Pure choriocarcinoma account for <1% of GCT • May present with distant metastasis and small intratesticular lesion • May present as palpable nodule, the size depends on extent of local haemorrhage • Macroscopic: cut surface may show central haemorrhage with viable, greyish-white tumour at the periphery • Microscopic: two cell types must be demonstrate to satisfy diagnosis of choriocarcinoma: • Syncytiotrophoblasts – large multinucleated cells, abundant + vacuolated cytoplasm, large hyperchromatic irregular nuclei • Produce bHCG • Cytotrophoblasts – closely packed, intermediate-sized, uniform cells with distinct cell border, clear cytoplasm, single vesicular nucleus

10. Teratoma • Comprise 2-7% of adult tumours in pure form • 45-50% of mixed GCT contain teratoma • Contain more than one germ cell layer in various stages of maturation and differentiation • Mature elements resemble benign structures derived from normal ectoderm, endoderm, and mesoderm • Immature elements consist of undifferentiated primitive tissues from the three germ cell layers • Macroscopic: tumours are large, lobulated and nonhomogeneous in consistency • Cut surface: variably sized cysts containing gelatinous, mucinous or hyalinised material, interspersed with islands of solid tissue often containing cartilage or bone • Microscopic: cysts may be lined by squamous, cuboidal, columnar or transitional epithelium , solid element may contain anything! • Malignant changes may be recognised in such differentiated tissues, justifying the designation malignant teratoma

11. Mixed tumours • Approx 60% of GCT contain >1 histologic pattern • Most frequent combination is EC, yolk sac, teratoma with syncytiotrophoblast cells, with or without seminoma • Pluripotential nature of GCT evident from the varied histologic patterns of metastasis • More than half display different morphologies in primary versus metastatic sites • 30-45% of patients dying with seminoma harbour nonseminomatous metastases • Converse rarely documented

12. Intratubular germ cell neoplasia • Testicular carcinoma in situ (CIS) is widely regarded as the preinvasive precursor of all GCTs except spermatocytic seminoma • Early studies in infertile men and pts with testicular GCTs showed that 50% of men in whom CIS was found on biopsy developed “invasive” within 5 years if left untreated • ITGCN microscopic: large with abundant pale cytoplasm, irregularly outlined nuclei and located at the periphery of the seminiferous tubules between normal appearing sertoli cells • Well studied in Scandinavian studies – reported incidence is 0.8% • Corresponds to lifetime risk of developing invasive testis ca in this population • Groups of patients at risk for development of CIS: • History of contralateral testicular cancer: 5-6% • Cryptorchidism: 3-5% • An atrophic contralateral testis with unilateral testis cancer: 30% • Extragonadal germ cell tumour: 40% • Intersex or sexual ambiguity: 25-100%

13. ITGCN • Open testicular biopsy remains gold standard for diagnosing CIS • Management depends on: • Patient age • Bilateral or unilateral CIS • Associated testicular atrophy • Physician philosophy • Treatment options include: • Observation • Radiation • Chemotherapy • orchidectomy

14. Epidemiology • 2008: 8000 new testis cancer cases in US • 370 deaths • Most common solid organ tumour in men aged 20-34 • Second most common tumour in men aged 35-40 • Lifetime probability of developing testicular cancer is 1 in 300 and risk of dying is 1 in 5000 • Age-adjusted incidence is highest in Scandinavian countries (9.3 cases per 100,000men) • Intermediate in USA: 5.4 per 100,000 men • Lowest in Africa and Asia: 0.9 per 100,000 men

15. Other factors • Racial factors: • Incidence of testicular tumours in American blacks is approx 1/3 that in American whites, but 10 times that of African blacks • In Israel, Jewish people have 8x higher incidence than non-Jewish • Higher incidence in upper and middle socioeconomic classes of whites in LA • Genetic factors: • Relatively higher incidence of testicular tumours in twins, brothers and family members but not overwhelming • Laterality and bilaterality: • Slightly more common in right than left • 2-3% are bilateral • Synchronous 17-30% • Metachronous 70-83%

16. Risk factors • Cryptorchidism – 3-14x • Metachronous testis cancer – 2-4x • Positive family history – 5x • Diethylstilbestrol exposure – 2.5-5x • Gonadal dysgenesis – 50x • Androgen insensitivity syndrome – 15x

17. Patterns of spread • GCT spreads in predictable and stepwise fashion, except choriocarcinoma • Primary landing zone for right-sided testicular tumours is interaortocaval region beneath left renal vein, then paracaval and preaortic region • In many cases, lymphatic drainage crossed from right to left • Primary landing zone for left testicular malignancies is para-aortic region bounded by left ureter, left renal vein , aorta and IMA origin • Subsequent cephalad drainage is to cysterna chyli, thoracic duct, and supraclavicular nodes • Lymphatics of epididymis drain into the external iliac chain, affording locally extensive tumours access to pelvic LN • Inguinal LN metastasis may result from scrotal involvement or retrograde lymphatic spread, or prior scrotal or inguinal surgery or massive retroperitoneal deposits • Extranodal distal metastasis results from direct vascular invasion or tumour emboli • Despite surgical excision of negative RP LN, distant failure rate is around 5%

18. Presentation • Usual presentation is of a nodule of painless swelling of one gonad • 10% of patients may present due to metastases • Neck mass • Respiratory symptoms • GIT disturbances • Lumbar back pain • Bone pain • Peripheral nervous system manifestations

19. Tumour markers • GCT markers belong to two main classes: • Oncofoetal substances – AFP and bHCG • Cellular enzymes – LDH and PLAP

20. AFP • 70kDalton single chain glycoprotein • Predominant serum-binding protein in foetus • Synthesized in foetal yolk sac, liver and intestine • Peak gestational levels are between weeks 12-14 • Gradually decline after birth • Serum half life is 5-7 days • AFP may be produced by: • Pure EC • Teratocarcinoma • Yolk sac tumour • Combined tumours • AFP levels are normal in pure seminoma and pure choriocarcinoma

21. bHCG • 38kDalton protein secreted by placental syncytiotrophoblasts to maintain viability of corpus luteum • Two subunits of HCG • aHCG: homologous with pituitary glycoprotein hormones (LH, FSH, TSH) • bHCG: 70% homologous with LH beta chain • Serum half life bHCG: 24-36hrs • Can be falsely elevated in some conditions

22. LDH • 134 kDalton cellular enzyme produced by muscles, liver and numerous other organs • Elevation is non-specific, but evidence suggests it can be used as a marker of tumour volume or advanced disease

23. PLAP and GGTP • Placental alkaline phosphatase – a foetal isoenzyme • Elevated in 40% of patients with advanced disease • Gamma-glutamyl-transpepidase – a hepatocellular enzyme frequently elevated in benign or malignant diseases of the liver

24. Clinical applications of tumour markers • Among patients with NSGCT: • 50-70% have elevated AFP • 40-60% have elevates bHCG • 90% patients have elevations of one or both • Additionally, 10-15% of patients with advanced disease can have normal tumour markers • Normalisation of markers after treatment do not exclude the presence of residual disease • 10-20% of patients undergoing chemotherapy and then RPLND have viable tumour despite normal tumour markers

25. Radiographic studies • Scrotal USS – extension of physical examination • Any hypoechoic area within tunica albuginea is markedly suspicious for testicular cancer • CXR – in clinical stage I disease, risk of chest involvement is <5% • CT – most effective means to identify RPLN • Cannot distinguish benign lesions (fibrosis) from teratoma • Unable to detect micrometastases • Understages disease • MRI – no distinct advantage over CT

26. PET • PET has a limited role in staging and evaluation of patients with metastatic disease • Can detect malignant cells, but cannot distinguish between teratoma and fibrosis • PET therefore not recommended in NSGCT • PET scan however is highly predictive for residual tumour following chemotherapy in patients with stage II or III seminoma • Helps clarify which patients may benefit from RPLND

27. PET scan

28. Staging system

30. Prognostic classification system

31. Treatment of primary tumour • Radical orchidectomy – inguinal exploration and en bloc removal of testis, tunica albuginea and spermatic cord • Partial orchidectomy – may be attempted in special cases (bilateral tumour or solitary testis) • Post orchidectomy tumour markers – presence of elevated tumour markers 3 weeks post orchidectomy may indicate presence of metastatic disease • Treatment of scrotal violation • May be present if pT4 tumour, previous scrotal surgery, or previous inguinal surgery • After trans-scrotal bx – radical inguinal orchidectomy, excision of ipsilateral hemiscrotum including scar • Follow up with examination of inguinal lymph nodes

32. Treatment: Seminoma Stage I • Surveillance • Rationale: over 80% with clinical stage N0 will have pathological stage N0 • Disadvantages: higher relapse rate than treatment • Strict compliance and intensive follow up required • Patients may have more psychological stress • Indicated for compliant stage I with normal post-orchidectomy markers • Relapse appears more likely for tumours>4-6cm, rete testis invasion and age> 34yrs • Usually occurs in RP • 20% are more than four years post orchidectomy • Radiation • Rationale: very low morbidity and mortality • Disadvantages: increases risk of death (2x) from cardiac disease and secondary malignancy starting at 15 yrs post XRT • Relapses occur outside RP – treat with chemo • 5 year OS >95% • Chemotherapy • Rationale: may have lower mortality than XRT • Disadvantages: myelosuppression, nausea, fatigue • 1-2 cycles of AUC 7 carboplatin appear to be as effective as XRT • Relapses occur in RP

33. Seminoma stage IIa and IIb • Traditionally, seminoma patients with bulky RP disease received XRT • More recently, adjuvant chemotherapy has been preferred • XRT – ipsilateral external iliac, bilateral common iliac, paracaval and paraaortic nodes, including cysterna chyli • N1 disease: 30Gy • N2 disease: 35Gy • BEP x 3

34. Seminoma stage IIc and III • Cisplatin-based chemo has been found to be highly effective against disseminated testicular seminoma (as well as nonseminomatous tumours) • More than 90% of patients who present with stage III disease achieve complete response to chemotherapy alone • More than 90% of responders remain disease free during follow up of 4 years • Response rates seen better if no prior XRT is given • Management of post chemo residual mass • RPLND for seminoma is difficult as seminoma involves the RP in a fibrotic process that is similar to RPF • In most patients explored after chemotherapy, only residual necrosis or fibrosis is found

35. Treatment: Nonseminoma Stage I • Surveillance • Rationale: 70% of clinical stage N0 have pathologic N0 • Disadvantages: has higher relapse rate than treatment • Strict compliance and intensive follow up are required • Relapse more likely when: • Lymphatic invasion, vascular invasion, stage pT2 or higher, predominance of EC, absence of yolk sac • Indicated for compliant stage I men • 60% relapses in RP, 40% outside RP • 80% develop within 1 year • RPLND • Rationale: treats RP metastases, permits more accurate staging, requires less intensive follow up. • CT understages around 25% of stage I disease • Disadvantages: invasive, may treat up to 70% unnecessarily, can cause ejaculatory dysfunction etc • Indicated for stage I men with normal post-orchidectomy tumour markers • Relapses occur in 10% of men who are pN0, usually outside RP • Treat with chemotherapy • Chemotherapy • Rationale: treats metastases inside and outside RP, less invasive than RPLND, requires less intensive surveillance and lower relapse rate than RPLND or surveillance • Disadvantage: treats 70% unnecessarily and will not adequately treat teratoma • Usually consists in this setting of 2 cycles of BEP • Relapses in RP, usually containing teratoma and should be treated with RPLND or salvage chemo

36. Low volume metastatic NSGCT • Option of RPLND or primary chemotherapy • Similarly effective for Stage II disease • Chemotherapy consists of 3 or 4 cycles of BEP

37. Stage IIc and III NSGCT • Divided into good prognosis and poor prognosis • Good prognosis patients receive standard chemotherapy regimens (3 x BEP) • Poor prognosis patients should start chemotherapy quickly – 4 x BEP • Majority achieve durable complete remission • 20-30% relapse or fail to achieve complete response and eventually die • Salvage chemo indicated for men who progress on primary chemo or who relapse • VIP x 4 • 50% obtain complete response • Post chemotherapy residual mass • 45-50% contain teratoma after primary chemotherapy for NSGCT

38. Non germ cell tumours • Leydig cell tumours • 1-3% of all testicular tumours and most common of non-germ cell tumours • Patients generally aged between 20 and 60 • 20% of Leydig tumours that occur in prepubertal patients are considered benign • Aetiology unknown • Macroscopically: small, yellow to brown and well circumscribed • Histology: eosinophilic cells, extracellular Reinke’s crystals • May produce testosterone and 17-ketosteroid, therefore may present with virilisation or gynaecomastia or low libido • Sertoli cell tumours • <1% testicular tumours • Generally present before age 20 and up to 1/3 have gynaecomastia • Large-cell calcifying type occurs most commonly in paediatric population and can be associated with Peutz Jeghers syndrome or Carney syndrome • 10% of these tumours are malignant, only reliable indicator is presence of metastasis • Gonadoblastoma • Occur almost exclusively in patients with intersex disorder (complete androgen insensitivity, male pseudohermaphroditism and Turner syndrome) and gonadal dysgenesis (45x, 46XY) • Less than 0.5% all testicular tumours • 80% patients are phenotypically female

39. Other tumours • Lymphoma • Can occur as primary tumour or recurrence • Most common testicular neoplasm in patients >60yrs • Metachronous or synchronous development in 38% • Diffuse painless enlargement of testis • 30% patients have systemic constitutional symptoms including weight loss, anorexia or fever • Prognosis is poor: 50% 5 year survival • Leukaemia • Common site of recurrence, mainly in children (ALL) • Bilateral involvement occurs in 50% • Biopsy is diagnostic • Treated with testicular irradiation and chemotherapy • Metastatic tumours • Rare, but include prostate, lung, GIT, melanoma and kidney