Adrian Clubb

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Testicular Cancer

• Adrian Clubb
• Greenslopes Hospital

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References

• Smiths General Urology
• Campbells Urology
• European Urology (March 08)
• European Consensus Conference on Diagnosis and
  Treatment of Germ Cell Cancer A Report of the
  Second Meeting of the European Germ Cell Cancer
  Consensus group (EGCCCG) Part I

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Overview

• Most common solid tumour in men 15 30 years
• Incidence 1/1,600 (exact figure varies on
  source)
• Right gt left (cryptochidism more common on right)
• Bilateral in 1-2

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Aetiology

• Cryptochidism represents 10 of cases
• Risk 1/20 intra-abdominal, 1/80 inguinal
• Exogenous estrogens to mother
• Atrophy (nonspecific or Mumps related)
• Trauma/infection not proven

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Staging - TNM

• T
• 1 limited to testis and epididymis, no vascular
  invasion
• 2 invades beyond tunica albuginea or has
  vascular invasion
• 3 invades spermatic cord
• 4 invades scrotum

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• N
• 1 - lymph node metastasis lt2cm and lt5 nodes
• 2 metastasis in gt5 nodes, nodal mass 2-5cm
• 3 nodal mass gt5cm
• M
• 1 distant metastasis present

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Staging AJCC (American Joint Comittee on Cancer)

• Stage 0 CIS
• Stage I T1-4/N0/M0
• IA T1
• IB T2-4
• IS ANY T, S1-3
• Stage II T1-4/N1-3/M0
• IIA N1
• IIB N2
• IIC N3
• Stage III T1-4/N1-3/M1

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Presentation

• Painless enlargement/mass of testis
• Acute pain 10 (intratesticular haemorrhage or
  infarction)
• Metastatic disease 10
• Following trauma (incidentaloma)

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• Firm, nontender mass
• Hydrocoele
• Abdominal mass with advanced retroperitoneal
  disease
• Gynaecomastia 5 GCT (but 30-50 Sertoli/Leydig
  tumours)

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Initial Investigations

• Tumour Markers (ensure prior to surgery)
• CT Abdomen/Pelvis
• CXR
• Testicular US (often done but should never delay
  surgery)

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Tumour Markers

• Alpha-fetoprotein
• Trophoblasts
• Major serum binding protein produced by foetal
  yolk sac, liver, GIT
• Negligible amounts after 1 year of age
• Half life 4-6 days
• Beta-human chorionic gonadotrophin
• Syncytiotrophoblasts
• Secreted by placenta for maintanence of corpus
  luteum
• Half life 24 hours
• LDH
• Correlates with tumour burden

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Surgery

• Inguinal orchidectomy
• High vascular ligation (internal ring)
• Frozen section only if diagnosis in doubt or for
  organ sparing
• Prolene stitch tie to cord with long tail (in
  order to find later if RPLND necessary)

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Surgical Pitfalls

• Dont forget fertility issues sperm banking an
  option
• Haemorrhage most common complication
• Acute painful scrotal swelling
• Retroperitoneal bleed
• Bleeding
• Testicular artery
• Cremesteric branch
• Scrotal (gubernaculum)

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• Scrotal approach
• Cannot ligate the cord high enough
• Higher local recurrence rate
• Never biopsy

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Fertility Issues

• 25 have fertility issues at time of
  presentation
• High concentrations of anti-sperm antibodies than
  general population
• 50 subfertile post-orchidectomy
• Further attacks on fertility common (RPLND,
  chemo, radio)
• 35 pregnancy rate in one US study
• Offer sperm banking prior to chemotherapy
  (Europeans recommend offering prior to
  orchidectomy)

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Pathology

• GCT
• Seminoma
• Classical
• Anaplastic
• Spermatocytic
• Non-Seminoma
• Embryonal
• Yolk sac
• Teratoma
• Choriocarcinoma
• Mixed

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• CIS
• Non GCT
• Leydig
• Sertoli
• Gonadoblastomas
• Secondary
• Lymphoma (most common testicular malignancy in
  gt50 year olds)
• Leukemic infiltration
• Metastatic

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Germ Cell Tumours
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Seminoma

• Three histologic subtypes
• Classical 85 (3rd decade)
• Anaplastic 5-10, metastasis early
• Spermatocytic 5-10 (gt50 year olds), v. Good
  prognosis
• Tumour markers often normal, B-HCG can be raised
  (but lt500)
• Overall survival gt99

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Prognostic Indicators

• Size of tumour (gt4cm)
• Infiltration of the rete testis
• Any positive tumour markers

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Treatment

• Stage I (T1-4/N0/M0)
• 32 will relapse if 2 or more risk factors
• 12 relapse with no risk factors
• 97 of relapses in retroperitoneal and iliac
  lymph nodes
• Relapse can occur as late as 10 years

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• Surveillance
• Radiotherapy
• Retroperitoneum
• Retroperitoneum and iliac nodes
• Chemotherapy (not favoured in Australia)

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Surveillance

• Up to 88 cured by orchidectomy alone
• Patient needs to be reliable
• Psychological stress potential negative
  (difficult to qualify)
• Difficult for patients living out of town

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Radiotherapy

• Relapse rate 3-4 at 5 years (almost always
  outside radiation field)
• Irradiation field involves infradiaphragmatic
  paraaortic and paracaval lymphatics
• Traditionally iliac nodes included (15 of LN
  metastases) called dog leg pattern
• Total dose 20-30Gray
• Shielding of contralateral testicle (scatter
  radiation)
• Well tolerated (gastro SEs most common)
• Theoretical but poorly documented risk of
  secondary malignancies

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Chemotherapy

• Adjuvant carboplatin
• Similar results to radiotherapy (Oliver RT, Mason
  MD, Mead GM, et al. Radiotherapy versus
  single-dose carboplatin in adjuvant treatment of
  stage I seminoma a randomized trial. Lancet
  2005366293300 (EBM IB))
• Not commonly used in Australia
• Fertility concerns

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• Stage IIA/B (T1-4/N1-2/M0)
• Chemotherapy
• 3 cycles of BEP (bleomycin, etoposide, cisplatin)
• Cisplatin is not adequate as a sole agent
• Radiotherapy
• Stage IIC/III
• Long term survival 30-40 (Lance Armstrong)
• Chemotherapy
• 3 cycles of BEP (ototoxicity, peripheral
  neuropathies, Raynaud syndrome, lung fibrosis)

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Follow Up - Seminoma
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Relapses

• Surveillance/Radiotherapy
• BEP x 3
• Chemotherapy cohort
• VIP x 4 (vinblastine, ifosfamide and cisplatin)
  or
• TIP x 4 (paclitaxol, ifosfamide and cisplatin)

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NSGCT

• Embryonal (20)
• Yolk Sac Tumour
• Teratoma (5)
• Choriocarcinoma (lt1)
• Mixed (40)
• Treat as NSGCT (seminoma component does not
  influence)

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Embryonal Cell Carcinoma

• 20 overall
• Yolk sac tumour represents infantile variant of
  this subtype (aka endodermal sinus tumour)
• Histology
• Marked pleomorphism
• Indistinct cellular borders
• Mitotic figures and giant cells common
• Extensive haemorrhage/necrosis not uncommon

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Yolk Sac Tumour

• Infantile version of embryonal
• Component of mixed type that accounts for afp
  production
• Histology
• Vacuolated cytoplasm secondary to fat and
  glycogen deposition
• Arranged in a loose network with intervening
  cystic spaces
• Embryoid bodies are commonly seen and resemble
  1-2 week old embryos consisting of a cavity
  surrounded by syncytio- and cytiotrophoblasts

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Teratoma

• 5 all tumours
• Children and adults
• Contain more than one germ cell layer in various
  stages of maturation and differentiation
• Tumour appears lobulated with cysts filled with
  mucinous/gelatinous filling

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Teratoma (cont)

• Mature
• Benign structures derived from ectoderm, mesoderm
  and endoderm
• Immature
• Undifferentiated primitive tissue
• Less differentiated than its ovarian counterpart

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• Varying histological appearance depending on
  which germ cell layer
• Ectoderm squamous epithelium, neural tissue
• Endoderm intestinal, pancreatic, or respiratory
  tissue
• Mesoderm smooth or skeletal muscle, cartilage,
  bone

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Choriocarcinoma

• lt 1
• Very aggressive
• Metastasises early (even with small primaries)
• Central haemorrhage common
• Syncytiotrophoblasts and cytotrophoblasts both
  present

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Prognostic Indicators NSGCT

• Vascular invasion
• 48 with vascular invasion will develop
  metastases
• Percentage of embryonal carcinoma
• gt40 a risk factor

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NSGCT Stage I

• Cure rate gt99
• Relapse rate 27-30 (overall)
• 54-78 retroperitoneum
• 13-31 lung

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Treatment NSGCT Stage I

• No vascular invasion
• Surveillance preferred Europeans
• Chemotherapy
• RPLND
• Vascular invasion
• Chemotherapy 2 x BEP
• RPLND
• Surveillance (accept 50 failure)

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Follow Up Surveillance Stage I NSGCT
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NSGCT Stage IIA/B

• Cure rate 98
• Tumour markers raised treat as for advanced
  disease

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NSGCT Advanced Disease

• Cure rate 80
• BEP x 3 if medically well
• No evidence adding G-CSF helps with recovery
• Brain metastases controversial - ?role of
  surgery/chemo/radio

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Monitoring Treatments

• Residual masses (CT)
• Small lt3cm can be observed
• Greater than 3cm consider RPLND
• Tumour markers
• Be aware of half lives
• Can rise due to tumour lysis
• Rising tumour markers beyond 3 half lives
  failure and need to consider salvage treatments

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Patterns of Metastatic Spread

• GCT spread in stepwise progression (exc.
  Choriocarcinoma spreads early haematogenously)
• LNs around renal hilum most common site due to
  embryological origin of testes
• Right testis
• Interaortocaval area at level of right renal
  hilum
• Stepwise precaval, preaortic, paracaval, right
  common iliac and right external iliac lymph nodes
• Left testis
• Paraaortic area at level of left renal hilum
• Stepwise preaortic, left common iliac and left
  external iliac

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• No crossover occurs from left to right
• Crossover is common from right to left
• Important for RPLND planning
• Invasion of epididymis or spermatic cord distal
  external iliac or obturator LNs
• Scrotal violation or invasion of tunica albuginea
  inguinal mets
• Extraretroperitoneal spread lung, liver, brain,
  bone, kidney, adrenal, GIT and spleen

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Retroperitoneal Lymph Node Dissection

• Indications vary internationally
• Role remains controversial
• Not indicated in Australia for seminoma
• Post-chemotherapy NSGCT failures main indication
• Indication in US positive health insurance
  serology
• Laparoscopic approach has been described

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RPLND

• Morbidity
• Short-term
• Lymph leak (can be large thoracic duct)
• 20
• Bowel injury
• Vascular injury
• Long-term
• Loss of ejaculation
• S2-4 fibres transected
• Relative infertility

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Carcinoma In Situ

• Precancerous for all GCT except spermatocytic
  seminoma
• 50 invasive disease at 5 years
• Incidence of CIS estimated at 0.4
• Similar aetiology/risk factors as for GCTs

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CIS Treatment

• Difficult management
• Factors unilateral vs bilateral, fertility,
  patient age
• Options
• Radiotherapy
• Surgery
• Observation
• (Chemotherapy not currently recommended)

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Non Germ Cell Tumours
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Non-Germ Cell Tumours

• Leydig cells tumours
• Sertoli cell tumours
• Gonadoblastomas
• Secondary tumours
• Lymphoma
• Leukemic infiltration
• Metastasis

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Leydig Cell Tumours

• 1-3 of testicular tumours overall
• Bimodal age distribution
• 5-9 year olds
• 25-35 year olds
• Bilateral in 5-10
• No association with cryptochidism
• Small, yellow, well circumscribed lesion devoid
  of any haemorrhage or necrosis
• Reinke crystals are fusiform-shaped cytoplasmic
  inclusions that are pathognomonic for Leydig cell

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• Prepubertal presentation virilisation
• Tumours benign
• Adults usually asymptomatic
• Gynaecomastia in 20-25
• 10 malignant in adults
• Staging as per GCT
• 17-ketosteroids help distiguish benign vs. mal.

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Sertoli Cell Tumours

• Rare
• Bimodal
• lt1 year of age
• 20-45 years old
• 10 malignant
• Yellow or grey-white lesion with cystic
  components
• Virilisation or kids and gynaecomastia (30)

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Gonadoblastomas

• Rare
• Only seen in patients with gonadal dysgenesis
• Any age but usually lt30
• 80 phenotypic females
• Bilateral orchidectomy (50 bilateral)

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Lymphoma

• Lymphoma of the testicle is the most common
  testicular malignancy in men gt50 years
• 5 of all tumours
• Grey or pink lesion
• Haemorrhage/necrosis common
• Diffuse histiocytic lymphoma most common type
• 50 bilateral (systemic disease)

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Leukemic Infiltration

• Common site of relapse in children with ALL
• Sanctuary site
• 50 bilateral
• Biopsy for diagnosis
• Radiotherapy to both testicles

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Metastatic Disease

• Very rare
• Prostate carcinoma most common primary