• Most common solid malignancy in males aged 15–35 ^[1][2][3].
• Only ~1% of all solid tumours in males ^[2].
• One of the most curable solid neoplasms: 5-year survival > 95%, representing only 0.1% of all male cancer deaths ^[2].
• Global incidence: approximately 10 per 100,000 males/year in Western populations (highest in Scandinavian countries, lowest in Asian and African populations).
• Hong Kong context: Incidence is lower than Western countries (~1–2 per 100,000), but has been rising over recent decades. It remains a relatively uncommon cancer in HK, but awareness is critical because of the young age group affected and the curability.

Risk factors include ^[1][2][3]:

Understanding the anatomy is essential for comprehending spread patterns, surgical approach, and clinical examination.

Testis ^[1][2]:

• Ovoid organ, approximately 3–5 cm long, ~20 mL volume
• Lies within the scrotum, which maintains temperature ~2–4°C below core body temperature (essential for spermatogenesis)
• Covered by:
  • Tunica vaginalis: serous membrane (derivative of the peritoneum from processus vaginalis); covers the anterior and lateral 2/3 of the testis. The potential space between its parietal and visceral layers is where fluid accumulates in hydrocele ^[1].
  • Tunica albuginea: dense fibrous capsule directly investing the testis; sends septa inward to divide the testis into ~250 lobules
  • Each lobule contains 1–4 seminiferous tubules → drain into rete testis → efferent ductules → epididymis

Epididymis ^[1]:

• Tightly coiled tubular structure along the posterolateral surface of the testis
• Has a head (superior pole), body, and tail (inferior pole)
• Functions: sperm storage, maturation, transport
• Tail is continuous with the vas deferens

Appendix testis (hydatid of Morgagni):

• Small vestigial remnant of the Müllerian (paramesonephric) duct, located at the anterosuperior pole of the testis
• Important because torsion of the appendix testis mimics testicular torsion in children

Spermatic cord ^[1]:

• Runs from the tail of the epididymis superiorly through the inguinal canal to the deep inguinal ring
• Contains:
  • Testicular artery (branch of abdominal aorta at L2 level)
  • Pampiniform venous plexus → drains to testicular vein (right → IVC directly; left → left renal vein)
  • Vas deferens and its artery (from superior/inferior vesical artery)
  • Cremasteric artery (from inferior epigastric artery)
  • Lymphatic vessels → drain to para-aortic (retroperitoneal) lymph nodes (NOT inguinal nodes)
  • Genital branch of the genitofemoral nerve (L1-L2)
• Fascial coverings (from outside in): external spermatic fascia, cremasteric fascia + cremaster muscle, internal spermatic fascia

• Right testicular vein → IVC directly
• Left testicular vein → Left renal vein → IVC

This explains why a left varicocele may be a presenting sign of a left renal tumour (left renal vein compression), and also why the left side is more prone to varicocele formation.

All adult-type testicular GCTs (both seminoma and NSGCT) are believed to arise from a common precursor: Germ Cell Neoplasia In Situ (GCNIS), previously called "intratubular germ cell neoplasia unclassified" (ITGCNU) or "carcinoma in situ of the testis."

Pathogenesis of GCNIS:

1. During fetal development, primordial germ cells (PGCs) migrate from the yolk sac to the gonadal ridge
2. Normally, PGCs differentiate into spermatogonia and enter meiosis at puberty
3. In GCNIS, PGCs fail to differentiate properly — they retain embryonic features (expression of OCT3/4, NANOG, KIT, PLAP)
4. These arrested cells remain dormant until puberty, when the hormonal surge (rising gonadotropins and testosterone) stimulates their proliferation
5. Additional genetic hits (gain of 12p — isochromosome 12p — is the hallmark) drive progression to invasive GCT

From GCNIS, two major pathways of differentiation occur:

This branching pathogenesis explains:

• Why embryonal carcinoma is considered the "stem cell" of NSGCT — it can differentiate into any of the other subtypes
• Why mixed GCTs are so common — different regions of the same tumour undergo different differentiation
• Why any GCT containing non-seminomatous elements is treated as NSGCT (more aggressive biology)

Sex cord-stromal tumours arise from Leydig or Sertoli cells, more common in prepubertal males ^[2]:

a) Leydig Cell Tumours ^[2]:

• Most common sex cord-stromal tumour ^[2]
• 20% malignant in adults ^[2]
• 20–30% associated with endocrine symptoms ^[2]
• Can be virilizing (precocious puberty) OR feminizing (gynaecomastia, infertility, loss of libido, erectile dysfunction) ^[2]
• Mechanism of virilisation: Leydig cells produce testosterone → excess androgens → precocious puberty in boys
• Mechanism of feminisation: Excess testosterone → peripheral aromatisation to oestradiol → gynaecomastia, suppressed LH/FSH → infertility
• Reinke crystals on histology (eosinophilic intracytoplasmic rod-shaped crystalloids)

b) Sertoli Cell Tumours ^[2]:

• Less common, can only be feminizing ^[2]
• Mechanism: Sertoli cells produce oestrogen and inhibin → feminization + suppressed FSH

a) Testicular Lymphoma (7%) ^[2]:

• Aggressive extranodal NHL (usually DLBCL) ^[2]
• Commonly bilateral ^[2]
• Propensity for extranodal spread to skin, subcutaneous tissue, CNS, lungs ^[2]
• Most common cause of testicular mass in males > 60 years ^[2]
• This is not a primary testicular tumour but rather lymphoma involving the testis

b) Leukaemia ^[2]:

• Testis involved in 5% of ALL ^[2]
• The blood-testis barrier (formed by tight junctions between Sertoli cells) creates a "sanctuary site" where leukaemic cells can hide from systemic chemotherapy → testicular relapse
• Presents as painless testicular enlargement ^[4]

Classification of testicular tumours ^[1]:

^[1][2]

This is the most important clinical distinction because it determines management:

Testicular cancer staging is unique because it incorporates serum tumour markers (S) into the staging system — it is the only solid tumour that does this.

T — Primary Tumour (based on pathology after orchidectomy):

N — Regional Lymph Nodes (retroperitoneal para-aortic nodes):

M — Distant Metastases:

S — Serum Tumour Markers (post-orchidectomy):

Stage Grouping (simplified):

The International Germ Cell Cancer Collaborative Group (IGCCCG) classifies metastatic GCTs into good, intermediate, and poor prognosis groups — this determines chemotherapy intensity:

Seminoma (no poor-prognosis category):

NSGCT:

From the lecture slides (GC 183, GC 202, Pediatric Urology):

• Testicular cancer is the most common solid malignancy in males aged 15–35 ^[3]
• Germ cell tumours account for 95% of testicular cancers ^[3]
• Ratio of seminoma to NSGCT is approximately 1:1 ^[1]
• Cryptorchidism is the most important and most common risk factor ^[1][3][7]
• Undescended testis has increased chance of malignancy ^[6]
• Orchidopexy ideally before 12 months of age to reduce (not eliminate) cancer risk ^[7]
• Radical inguinal orchidectomy is the initial treatment of all testicular tumours ^[3][8]
• Surgery may cure cancer — surgical oncology principles apply ^[8]

• Testicular cancer and its treatments (surgery, chemotherapy, radiotherapy) can impair fertility
• Sperm cryopreservation (sperm banking) should be offered to all men of reproductive age before starting treatment
• Even at diagnosis, many patients already have impaired spermatogenesis (part of TDS)

• GCTs can rarely arise in extragonadal sites (mediastinum, retroperitoneum, pineal gland) from misplaced primordial germ cells that failed to migrate to the gonad during embryogenesis
• Mediastinal primary NSGCT has the worst prognosis (poor-risk IGCCCG)
• Always perform testicular USS to rule out occult testicular primary before diagnosing an "extragonadal" GCT

When both sides are swollen, think differently:

• Cryptorchidism: history of undescended testis increases risk in both testes, with greater risk in the undescended one ^[1]
• Previous testicular cancer (contralateral)
• Family history (brothers, father)
• History of infertility / subfertility
• Known gonadal dysgenesis or DSD

USG scrotum is the initial imaging modality of choice for evaluating any testicular mass ^[1][2][6][9].

Why ultrasound first?

• Non-invasive, readily available, no radiation
• Extremely sensitive ( > 95%) for detecting intratesticular masses
• Distinguishes between intratesticular vs extratesticular masses (majority of extratesticular masses are benign ^[6])
• Distinguishes solid from cystic lesions
• Screens the contralateral testis for synchronous tumour, microlithiasis, or occult pathology ^[1]

Key USS findings by pathology:

Radical inguinal orchidectomy is both diagnostic and therapeutic ^[1][2][9].

Technique ^[2]:

1. Enter via inguinal incision (NOT scrotal) ^[2][9]
2. Clamp cord early before scrotal manipulation to prevent seeding ^[2] — the testicular vein is clamped and ligated at the level of the deep inguinal ring before the testis is mobilized. This prevents intraoperative shedding of tumour cells into the venous system.
3. Mobilize testis into the incision ^[2]
4. If doubtful, then bisect testis to confirm presence of tumour ^[2] — intraoperative frozen section can be performed if the diagnosis is uncertain (e.g., small lesion, possible benign pathology). If benign, testis-sparing surgery may be considered.
5. If confirmed tumour, then double ligation of cord with division at the level of the inguinal ring + removal of testis ^[2]

Why inguinal approach? ^[2][9]:

• Inguinal approach is preferred as other approaches are associated with scrotal violation → potentially increased risk of recurrence ^[2]
• Scrotal incision would seed tumour into the scrotal skin → drainage to inguinal LNs → changing the staging and treatment field ^[1]

Complications: Usually minimal morbidity, most commonly post-operative scrotal haematoma ^[2]

What does the histopathology report tell you?

The orchidectomy specimen is the definitive staging tool for the T-component of TNM. The pathologist reports:

• Tumour type (seminoma, NSGCT subtypes, mixed)
• Tumour size
• Invasion of tunica albuginea, tunica vaginalis, rete testis, epididymis, spermatic cord, scrotal wall
• Lymphovascular invasion (LVI) — critical for risk stratification of Stage I disease
• Margins (particularly cord margin)
• Presence of GCNIS in adjacent tissue
• Immunohistochemistry: OCT3/4, PLAP (seminoma), CD30 (embryonal carcinoma), AFP (yolk sac), β-hCG (trophoblastic elements), CD117/KIT (GCNIS, seminoma)

Cryopreservation of sperm ^[1][9]:

• Should be made available to all men diagnosed with testicular cancer prior to instituting therapy if they wish to preserve fertility ^[1]
• Baseline sperm count and sperm banking should be performed prior to radiographic diagnostic evaluation to avoid radiation exposure of sperm ^[1]
• Note that testicular tumours are associated with gonadal dysgenesis and ~50% of men have some degree of underlying impairment of spermatogenesis, and semen quality may further deteriorate following removal of affected testis ^[1]

Timing: Ideally before orchidectomy (if possible and not delaying treatment) or at minimum before chemotherapy/radiotherapy begins.

Occasionally, a patient presents with metastatic GCT (e.g., large retroperitoneal mass, elevated markers) but the testicular primary has spontaneously regressed. On USS, the testis may show a scar, calcification, or GCNIS but no visible mass. This is called a "burned-out" tumour. The orchidectomy should still be performed because:

• There may be residual viable tumour not visible on USS
• GCNIS remains as a precursor for second tumours
• Histological subtyping may still be possible from the residual scar

• Synchronous (simultaneous) bilateral GCTs occur in ~1–2%
• Metachronous (sequential) bilateral GCTs in ~2–5% over a lifetime
• If bilateral, testis-sparing surgery (partial orchidectomy) should be considered for the smaller tumour to preserve testosterone production and avoid lifelong androgen replacement
• Always screen the contralateral testis with USS at diagnosis

• Different biology from adult GCTs
• Yolk sac tumour is the most common (pure form, not mixed)
• Mature teratoma in children is benign (unlike in adults)
• Testis-sparing surgery may be considered in children with small tumours and normal markers
• Do NOT assume adult staging/management rules apply to prepubertal tumours

This is the most common presentation (~70–80% of seminomas). The cure rate is > 99% regardless of which option is chosen. The debate is about minimising overtreatment while maintaining cure.

Three options ^[1][2]:

Risk factors for relapse in Stage I seminoma (guide shared decision-making):

• Tumour size > 4 cm
• Rete testis invasion
• Lymphovascular invasion (LVI)
• (These are not absolute indications for adjuvant treatment — they inform the discussion)

Adjuvant RT for stage II seminomas (exquisitely radiosensitive) ^[2]:

Why does RT work so well for seminoma? Seminoma cells have a high sensitivity to DNA damage from ionising radiation. They have limited DNA repair capacity compared to NSGCT cells, possibly related to their germ cell origin (germ cells normally undergo apoptosis readily when DNA is damaged — a protective mechanism for genetic integrity).

Cisplatin-based chemotherapy for more advanced tumours ^[2]:

Note: There is no "poor prognosis" category for seminoma in the IGCCCG system — even metastatic seminoma has relatively favourable outcomes.

Post-chemotherapy management of residual masses in seminoma:

• If residual mass < 3 cm → surveillance (most are fibrosis/necrosis)
• If residual mass ≥ 3 cm → PET-CT at 6–8 weeks post-chemo
  • PET-negative → surveillance
  • PET-positive → further treatment (surgical resection or salvage chemotherapy)

Risk stratification is based on lymphovascular invasion (LVI):

No treatment if early (stage I) — this refers to the surveillance option ^[2].

RPLND for high-risk early (stage I) NSGCTs ^[2]:

• Primary nerve-sparing RPLND is an option for Stage I NSGCT (especially in centres with expertise)
• Advantage: definitive pathological staging of the retroperitoneum; avoids chemotherapy in patients with pN0 disease
• Disadvantage: morbidity (see below); does not address potential distant micrometastases

This is a unique situation: markers are rising/not normalising after orchidectomy, but imaging shows no visible disease. The tumour is producing markers from somewhere — there must be micrometastatic disease.

Cisplatin-based chemotherapy for other more advanced tumours. Regimen depends on risk stratification and extent of tumour ^[2].

Post-chemotherapy assessment for NSGCT (critical decision point):

Why is post-chemo RPLND mandatory in NSGCT but not seminoma?

The histology of post-chemo residual masses differs fundamentally between the two:

The key issue is teratoma. In NSGCT, post-chemo residual masses contain teratoma in ~40–50% of cases. Teratoma is chemoresistant (it doesn't respond to further cycles), can grow progressively ("growing teratoma syndrome"), and can undergo malignant transformation into non-germ-cell cancers (sarcoma, adenocarcinoma). The only way to deal with teratoma is surgical resection. In seminoma, teratoma is exceedingly rare in residual masses, so PET-CT can reliably distinguish fibrosis from viable tumour.

Seminoma is exquisitely sensitive to radiation therapy ^[1][9]. Non-seminomatous germ cell tumours are more radio-resistant ^[1].

Risk of secondary radiotherapy-induced malignancies ^[1]: This is the major concern with RT in young patients. Radiation fields to the para-aortic region expose the stomach, pancreas, kidney, bowel, and remaining testis to scatter. Long-term follow-up studies show increased rates of:

• Second solid cancers (GI cancers, sarcomas) — risk increases over decades
• Contralateral testicular cancer (from scatter)
• Cardiovascular disease (mediastinal irradiation)

This is why there has been a strong shift towards surveillance and carboplatin over RT for Stage I seminoma.

RPLND ^[1][2]:

What it is: Surgical removal of the retroperitoneal lymph node-bearing tissue (fat pad) along the great vessels from the renal hilum to the bifurcation of the common iliac arteries.

Indications:

Key points about RPLND ^[1]:

• Requires expertise and has high risk of complications ^[1]
• Only reliable method to identify nodal micrometastasis given the high false-negative rate with CT ^[1]
• GOLD standard for providing accurate pathological staging of the retroperitoneum ^[1]

Surgical templates:

• Right-sided tumour: right-sided modified template (right paracaval, interaortocaval, preaortic)
• Left-sided tumour: left-sided modified template (left para-aortic, preaortic, interaortocaval)
• Full bilateral template: used for post-chemotherapy RPLND when disease is bilateral

Nerve-sparing technique:

• The sympathetic postganglionic fibres (from the hypogastric plexus, T12-L3) that control antegrade ejaculation run along the aorta and cross anterior to the common iliac arteries
• Damage to these fibres → retrograde ejaculation (semen goes backward into the bladder instead of forward through the urethra) → effective infertility despite normal sperm production
• Nerve-sparing RPLND carefully identifies and preserves these fibres, reducing the rate of retrograde ejaculation from ~75% (non-nerve-sparing) to < 5% (nerve-sparing)

Complications of RPLND:

For patients who relapse after first-line BEP or have refractory disease:

• If synchronous or metachronous bilateral tumours, testis-sparing surgery (partial orchidectomy) should be considered for the second tumour (to preserve testosterone production and avoid bilateral orchidectomy → lifelong androgen replacement)
• Criteria for testis-sparing: tumour < 2 cm, AFP normal, adequate residual testicular volume, patient reliable for surveillance
• Multiple biopsies of surrounding parenchyma for GCNIS

• Some patients present with respiratory failure from massive pulmonary metastases or intracranial haemorrhage from brain metastases (choriocarcinoma)
• Start emergency chemotherapy BEFORE orchidectomy in these cases — orchidectomy is deferred until the patient is stabilised
• Very high β-hCG ( > 50,000 mIU/mL) + characteristic imaging is sufficient for diagnosis without histology in emergencies

• Enlarging masses during or after chemotherapy with normalising or normal markers
• Indicates mature teratoma growth (chemoresistant, marker-negative) despite effective treatment of other GCT components
• Management: Surgical resection of all growing masses — chemotherapy will not help

• Radical inguinal orchidectomy — same as for GCTs
• No established role for chemotherapy or RT (these tumours are generally chemo/radioresistant)
• If malignant (metastatic): RPLND ± mitotane (for Leydig cell tumour) or clinical trial
• If benign and small: testis-sparing surgery may be considered

• Not managed as a testicular tumour — managed as systemic lymphoma
• Orchidectomy for local control + R-CHOP (rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone) × 6–8 cycles
• CNS prophylaxis (intrathecal methotrexate or high-dose systemic methotrexate) — due to high propensity for CNS relapse
• Contralateral testicular RT (scrotal irradiation) — due to high rate of bilateral involvement and testicular relapse
• Prognosis worse than GCTs (5-year OS ~50–60%)

Non-seminoma is more likely to spread to retroperitoneal LNs and to distant areas such as the liver, lung, bone and brain via the bloodstream ^[1].

Complications: usually minimal morbidity, most commonly post-operative scrotal haematoma ^[2].

RPLND requires expertise and has high risk of complications ^[1].

Cardiovascular disease is the leading non-cancer cause of death in testicular cancer survivors. This is why lifestyle counselling (smoking cessation, exercise, healthy diet) and monitoring of cardiovascular risk factors are essential components of survivorship care.

Testicular cancer survivors treated with cisplatin-based chemotherapy have a significantly increased risk of metabolic syndrome (central obesity + dyslipidaemia + hypertension + insulin resistance):

Prevalence of metabolic syndrome in testicular cancer survivors is approximately 20–30%, compared to ~10% in age-matched controls. Annual screening and aggressive risk factor management are essential.