Testicular Germ Cell Tumours

Overview

~1% of cancer deaths. More in white men, less in Africans/Asians. TRIMODAL age (infancy, late adolescence/early adult, >60yr). Germ cell tumours (95%) >> sex cord-stromal (<5%) >> mixed. Clinical split: SEMINOMATOUS (SGCT) vs NON-SEMINOMATOUS (NSGCT) — drives management more than exact subtype.

Etiology

1. Cryptorchidism — 30-50x risk, ~10% of GCTs cryptorchidism-associated. Temperature exposure theory. Intra-abdominal>inguinal risk. CONTRALATERAL normal testis also ↑risk.
2. Other developmental — dysgenetic gonads, androgen insensitivity syndrome
3. Genetic — familial, twin concordance, white>>Black African, no defined inheritance
4. Other — mumps orchitis, trauma (likely detection trigger not cause), carcinogens/radiation

Histogenesis

1. Shared molecular features (nearly all testicular GCTs): hyperdiploidy (near-universal), ISOCHROMOSOME 12p [i(12p)] >90% (also ovarian GCTs), 12q deletion, universal telomerase activity, p53/cyclin E/FAS mutations
2. ITGCN/CIS — preinvasive precursor for MOST adult GCTs (from spermatogenic elements). Found near most seminomas/embryonal carcinomas/mixed GCTs. ABSENT near childhood yolk sac tumour, paediatric teratoma, spermatocytic seminoma — different pathogenetic route
3. “Three-hit” model (seminomatous): activation (hit 1) → CIS/intratubular malignant transformation (hit 2) → invasion via epigenetic change (hit 3). Unclear if NSGCT follows same route.

SGCT vs NSGCT (key clinical split)

Individual types

Classic seminoma (~45%, commonest) — peak 4th decade, rare pre-puberty; female counterpart = dysgerminoma. Gross: enlarged (up to 10x), CONTOUR PRESERVED, homogeneous grey-white, rare necrosis/haemorrhage. Micro: uniform cells, clear glycogen-rich (PAS+) cytoplasm, central nuclei+1-2 nucleoli; delicate stroma with LYMPHOCYTIC infiltration ±granulomas (20%). ~10% → anaplastic seminoma (more aggressive). Radiosensitive, good prognosis.

Spermatocytic seminoma (~5%) — distinct entity, OLDER patients (6th decade), 10% bilateral. Gross: softer/yellowish. Micro: highly variable cell size (lymphocyte-like to giant), eosinophilic cytoplasm NO glycogen, filamentous chromatin, frequent mitoses, NO lymphocytic/granulomatous reaction (contrast classic). Slow-growing, rarely metastasises, EXCELLENT prognosis (better than classic).

Embryonal carcinoma (~30% pure, 40% component) — 2nd-3rd decade, ~90% AFP/hCG+, more aggressive. Gross: small but INVADES tunica/epididymis, distorts contour, haemorrhagic/necrotic. Micro: glandular/tubular/papillary/solid, highly anaplastic, marked size variation, frequent mitoses/giant cells. Less radiosensitive; chemo more effective.

Yolk sac tumour (endodermal sinus tumour) — COMMONEST testicular tumour in infants/young children (<4yr) pure; adult = component (40% of mixed). AFP 100% elevated — most reliable marker. Micro: reticular/papillary/tubular/solid, clear vacuolated cytoplasm, SCHILLER-DUVAL BODIES (perivascular structures), PAS+ hyaline globules (AFP-containing).

Polyembryoma — extremely rare, EMBRYOID BODIES (2-week-embryo-like structures); usually component of embryonal carcinoma/teratoma.

Choriocarcinoma — highly malignant, pure form extremely rare. 2nd decade, small primary + METASTATIC presentation. hCG 100% massively elevated. Micro: syncytiotrophoblast (large, bizarre multinucleated, hCG+) + cytotrophoblast (regular polyhedral) admixed WITHOUT true placental villi (key distinguishing negative).

Teratoma — tissue from >1 germ layer. Common in infants (40% of infantile testicular tumours), only 5% pure in adults but 45% component (usually with embryonal carcinoma). ~half hCG/AFP+. 3 types: Mature (well-differentiated tissue mix — cartilage, muscle, GI/resp epithelium, mucous glands, cysts, neural, fat, bone), Immature (incompletely differentiated), Malignant transformation (one component turns frankly malignant). Gross: large, VARIEGATED (solid+cystic/honeycombed+cartilage/bone foci).

Clinical features/spread/diagnosis

Gradual painless enlargement, dragging sensation. Mets: pain, lymphadenopathy, haemoptysis, urinary obstruction. TOTIPOTENT origin → metastases may show DIFFERENT histologic type from primary.

Spread: lymphatic (retroperitoneal para-aortic→mediastinal→supraclavicular) + haematogenous (lungs, liver, brain, bone).

Markers: hCG (syncytiotrophoblast differentiation — choriocarcinoma, yolk sac, embryonal carcinoma; ectopic hCG also elsewhere), AFP (yolk sac differentiation; also ↑in HCC). Also: CEA, HPL, placental ALP, testosterone, oestrogen, LH.

Staging/prognosis

Stage I (testis-confined) → II (retroperitoneal nodes, below diaphragm) → III (beyond retroperitoneal nodes). Seminomas mostly Stage I, radiosensitive, ~90% cure. NSGCT more advanced at presentation, radioresistant, more aggressive.

Clinical relevance

SGCT/NSGCT split matters MORE than exact subtype — determines radiosensitivity/spread/prognosis, managed as binary decision not 5-6-way classification exercise. hCG+AFP together = near-complete histologic fingerprint WITHOUT tissue — hCG=syncytiotrophoblast, AFP=yolk sac, both-negative=likely pure seminoma — genuinely diagnostically actionable. ITGCN absence near childhood yolk sac/paediatric teratoma/spermatocytic seminoma (vs presence near virtually all other adult GCTs) = key evidence these 3 arise via DIFFERENT pathogenetic mechanism — why spermatocytic seminoma is classified entirely separately despite similar name. Metastases showing DIFFERENT histology from primary = direct logical consequence of totipotent cell of origin — thorough primary sampling + marker correlation both matter for management.

Overview

Testicular tumours cause ~1% of all cancer deaths; more frequent in white men, less common in Africans/Asians. Trimodal age distribution — infancy, late adolescence/early adulthood, and after 60. Classified into germ cell tumours (95%), sex cord-stromal tumours (<5%), and mixed forms. Germ cell tumours are further split clinically into seminomatous (SGCT) and non-seminomatous (NSGCT) — a distinction that drives management more than exact histologic subtype.

Etiologic Factors

1. Cryptorchidism — 30–50× increased risk (see Cryptorchidism and Male Infertility); ~10% of germ cell tumours are cryptorchidism-associated; attributed to higher scrotal-versus-abdominal temperature exposure; intra-abdominal testis at greater risk than inguinal; contralateral normally-descended testis also carries increased risk.
2. Other developmental disorders — dysgenetic gonads, androgen insensitivity syndrome.
3. Genetic factors — familial clustering, twin concordance, marked racial variation (white >> Black African) — no defined inheritance pattern.
4. Other — prior orchitis (mumps), trauma (likely a detection trigger rather than cause), carcinogen exposure (certain drugs, radiation).

Histogenesis

1. Molecular features common to nearly all testicular GCTs (a shared pathogenesis regardless of final histologic type): near-universal hyperdiploidy; isochromosome 12p [i(12p)] in >90% of cases (also seen in ovarian GCTs); 12q deletion; universal telomerase activity; p53/cyclin E/FAS mutations.
2. Intratubular germ cell neoplasia (ITGCN)/CIS — the preinvasive precursor stage for most adult testicular GCTs, arising from spermatogenic elements within seminiferous tubules; found adjacent to most seminomas, embryonal carcinomas, and mixed GCTs, but notably absent adjacent to childhood yolk sac tumour, paediatric/adolescent benign teratoma, and spermatocytic seminoma — implying these follow a genuinely different pathogenetic route.
3. The “three-hit” model (for seminomatous tumorigenesis specifically): germ cell activation (“first hit”) → malignant transformation confined within the tubule as CIS (“second hit”) → invasion via epigenetic change (“third hit”). Whether NSGCTs follow this same staged route or arise more directly remains unclear.

Seminomatous vs Non-Seminomatous — the Key Clinical Split

Individual Tumour Types

Classic Seminoma (~45% of GCTs — commonest)

Peak 4th decade, rare before puberty; female counterpart is dysgerminoma. Gross: enlarged (up to 10×) but contour typically preserved (rarely invades tunica); homogeneous grey-white lobulated cut surface; necrosis/haemorrhage rare. Micro: uniform cells in cords/sheets/lobules, clear glycogen-rich (PAS+) cytoplasm, well-defined borders, central hyperchromatic nuclei with 1–2 prominent nucleoli; delicate fibrous stroma with characteristic lymphocytic infiltration (host immune response) ± granulomatous reaction (~20%). ~10% show increased mitotic activity → anaplastic seminoma (more aggressive). Highly radiosensitive, good prognosis.

Spermatocytic Seminoma (~5% of GCTs)

Distinct entity — older patients (6th decade), 10% bilateral. Gross: softer, more yellowish/gelatinous than classic seminoma. Micro: cells vary widely in size (lymphocyte-like to giant multinucleate), eosinophilic cytoplasm without glycogen, filamentous nuclear chromatin; frequent mitoses; no lymphocytic/granulomatous stromal reaction (contrast with classic seminoma). Slow-growing, rarely metastasises, excellent prognosis — better even than classic seminoma.

Embryonal Carcinoma (~30% pure; component in 40% of mixed GCTs)

2nd–3rd decade; ~90% show elevated AFP and/or hCG; more aggressive than seminoma. Gross: small but frequently invades tunica/epididymis, distorting contour; grey-white, soft, haemorrhagic/necrotic. Micro: glandular/tubular/papillary/solid patterns; highly anaplastic cells, large, indistinct borders, amphophilic cytoplasm, marked nuclear size variation, frequent mitoses/giant cells. Less radiosensitive than seminoma; chemotherapy more effective.

Yolk Sac Tumour (Endodermal Sinus Tumour)

The commonest testicular tumour of infants/young children (<4 years) in pure form; in adults, usually a component within mixed GCTs (40%). AFP elevated in 100% — the single most reliable marker for this component. Micro: reticular/papillary/tubular/solid patterns; flattened-to-cuboidal cells with clear vacuolated cytoplasm; characteristic Schiller-Duval bodies (perivascular structures resembling yolk sac/endodermal sinuses); intra-/extracellular PAS+ hyaline globules (many AFP-containing).

Polyembryoma

Extremely rare; composed predominantly of embryoid bodies (disc-and-cavity structures resembling a ~2-week embryo); more often seen as a component within embryonal carcinoma/teratoma than as a pure tumour.

Choriocarcinoma

Highly malignant; pure form extremely rare, more often a component of mixed GCTs. 2nd decade; primary tumour often small, presenting instead with metastatic symptoms; hCG massively elevated in 100%. Micro: intimately admixed syncytiotrophoblast (large, bizarre multinucleated, hCG+) and cytotrophoblast (regular polyhedral cells) — without forming true placental villi (the key distinguishing negative feature from normal placental tissue).

Teratoma

Contains tissue from more than one germ layer (endoderm, mesoderm, ectoderm). Common in infants/children (~40% of infantile testicular tumours); only ~5% of adult GCTs pure, but a component in ~45% of mixed GCTs (most often with embryonal carcinoma). About half show elevated hCG/AFP.

Three types:

1. Mature (differentiated) — disorderly mix of well-differentiated tissues (cartilage, smooth muscle, GI/respiratory epithelium, mucous glands, squamous/transitional-lined cysts, neural tissue, fat, bone). Testicular dermoid cysts (common in ovary) are rare here.
2. Immature — incompletely differentiated tissue elements.
3. Teratoma with malignant transformation — one component undergoes frank malignant change.

Gross: large, grey-white, characteristically variegated — solid grey-white areas, cystic/honeycombed regions, cartilage/bone foci.

Clinical Features, Spread, and Diagnosis

Presents with gradual painless gonadal enlargement, a dragging sensation; metastatic disease can produce pain, lymphadenopathy, haemoptysis, urinary obstruction. Because these arise from totipotent germ cells, metastases can show a different histologic type from the primary tumour.

Spread: lymphatic (retroperitoneal para-aortic → mediastinal → supraclavicular nodes) and haematogenous (lungs, liver, brain, bone).

Tumour markers: hCG (syncytiotrophoblastic differentiation — choriocarcinoma, yolk sac tumour, embryonal carcinoma; note ectopic hCG also occurs in non-germ-cell tumours elsewhere) and AFP (foetal liver/yolk sac/gut origin — elevated with yolk sac tumour component; also elevated in hepatocellular carcinoma). Also potentially raised: CEA, HPL, placental alkaline phosphatase, testosterone, oestrogen, LH.

Staging and Prognosis

• Stage I — confined to testis.
• Stage II — retroperitoneal nodal spread (below diaphragm).
• Stage III — metastases beyond retroperitoneal nodes.

Seminomas tend to present at stage I (localised) and are highly radiosensitive with ~90% cure; NSGCTs more often present with advanced disease, are radioresistant, and behave more aggressively.

Clinical Relevance

• The seminomatous-versus-non-seminomatous split matters more clinically than the exact histologic subtype within each group, since it directly determines radiosensitivity, typical spread pattern, and prognosis — this is why testicular GCTs are managed as a binary clinical decision more than a five-or-six-way histologic classification exercise.
• hCG and AFP together function as a near-complete histologic fingerprint of a germ cell tumour’s composition without needing tissue at all — hCG signals syncytiotrophoblastic differentiation (choriocarcinoma, embryonal carcinoma, some yolk sac tumours), AFP signals yolk sac differentiation, and a tumour negative for both is far more likely pure seminoma — this is genuinely diagnostically actionable, not just descriptive.
• The absence of ITGCN/CIS adjacent to childhood yolk sac tumour, paediatric teratoma, and spermatocytic seminoma — in contrast to its presence adjacent to virtually all other adult GCTs — is a key piece of evidence that these three entities arise through a fundamentally different pathogenetic mechanism, which is exactly why spermatocytic seminoma is classified entirely separately from classic seminoma despite the similar name.
• Metastases showing a different histologic type from the primary tumour is a direct, logical consequence of germ cell tumours’ totipotent cell of origin — a primary that looks like pure seminoma can still metastasise as choriocarcinoma or yolk sac tumour if a minor, unsampled component of that lineage was present, which is why thorough sampling of the primary tumour and correlation with serum markers both matter for accurate management.

• Germ cell tumour histogenesis: ITGCN as the shared precursor, with the three exceptions that bypass it
• hCG/AFP marker fingerprint mapped to each germ cell tumour type
• SGCT vs NSGCT compared across primary tumour, spread, radiosensitivity, and prognosis

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