Classification of GCT Germ Cell Tumours . British Testicular Tumour Panel (BTTP) of Testis •Seminoma; spermatocytic seminoma •Yolk sac tumour (only infantile) Murali Varma Cardiff, UK •Malignant teratoma differentiated (MTD) [email protected] •Malignant teratoma undifferentiated (MTU) •Malignant teratoma intermediate (MTI) •Malignant teratoma trophoblastic (MTT) Sarajevo Nov 2013 Classification of GCT BTTP vs. WHO . WHO . Proportion of components in mixed tumours • WHO: recommends determination of •Seminoma, spermatocytic seminoma proportions •Teratoma: . eg. 75% EC, 10% YST, 10% seminoma, 5% teratoma • Mature/immature/overtly malignant • BTTP: purely descriptive •Embryonal carcinoma . MTI may be 95% MTD or 95% MTU . MTT may be <5% choriocarcinoma •Yolk sac tumour . Focal choriocarcinoma in EC has good prognosis •Choriocarcinoma . Meaning of the term Teratoma •Malignant mixed germ cell tumour • Different in BTTP and WHO Testicular Teratoma Teratoma (WHO) . WHO: . In contrast to ovarian teratomas • Only tumours analogous to ovarian • Most are solid (cf benign cystic teratoma teratoma of ovary) . BTTP • All testicular teratomas in post-pubertal males potentially malignant • All non-seminomatous germ cell tumours • Pure mature teratoma in post-pubertal • Embryonal carcinoma = malignant males has metastatic potential teratoma undifferentiated • Pure mature teratoma in pre-pubertal males is benign 1 Testicular Teratoma Epidermoid cyst . Presence and extent of immaturity . Unilocular, squamous epithelium lined cyst generally not important • Keratinous contents • Do not report “immature teratoma” . No other components . PNET: area greater than 1 low-power . Testis away from cyst normal field of pure immature neuroepithelium • No atrophy • Presence in testis does not alter prognosis • No ITGCN • Presence in metastasis very poor outcome . Adjacent testis may show pressure effects • Chemoresistant • Atrophy, fibrosis Dermoid cyst Dermoid cyst vs. “Mature” Teratoma . Similar criteria for diagnosis as epidermoid Dermoid Cyst Teratoma cyst but more organised and includes other Age Almost always prepubertal Generally adults components Architecture Unilocular cyst Multlocular solid/cystic Cytological atypia No Yes • Skin adnexae: hair follicles, sebaceous glands, Associated ITGCN No Yes sweat glands Other germ cell Absent May be present • Cartilage tumour elements Neuroepithelium Absent May be present • Intestinal or ciliated epithelium Background testis May be atrophic with Normal . Benign (away from lesion) impaired spermatogenesis Yes (as Teratoma or non- None Metastatic potential teratomatous GCT) Intratubular Germ Cell Neoplasia (ITGCN) ITGCN . Also referred to as IGCNU (intratubular germ cell . Morphology and immunoprofile similar to neoplasia unclassified) seminoma . Precursor of all invasive germ cell tumours except . Located along basement membrane spermatocytic seminoma and prepubertal germ cell tumours (yolk sac tumour and mature teratoma in . Differential diagnosis: vacuolated young children) seminiferous cells mimicking ITGCN . NOT associated with epidermoid cyst/dermoid cyst • Lack cytology of ITGCN . Untreated progresses to invasive GCT in 50% over 5 . Don’t use c-kit to confirm ITGCN years (probably 100% lifetime risk) • Spermatogonia may be positive 2 Vacuolated seminiferous cells Intratubular seminoma mimicking ITGCN . Must not be confused with ITGCN . Lacks cytology of ITGCN . Tumour cells fill lumens of seminiferous • No cytological atypia tubules • No prominent nucleoli • The tubules may show spermatogenesis . Negative for PLAP, c-KIT and OCT 3/4 . Intratubular spread may be seen in many germ cell tumours • Classical seminoma • Spermatocytic seminoma • Embryonal carcinoma Classical Seminoma Seminoma: immunoprofile . 50% of all germ cell tumours . Positive . Age incidence: • Peak 30 - 40 yrs (10 years later than non-seminoma GCT) • PLAP, c-KIT, OCT 3/4 . Typical histology: . Negative • Clear cytoplasm, central nucleus, prominent nucleoli . Atypical histologies: • AE1/AE3, CD30 • Intertubular, tubular, microcystic, signet ring • AE1/AE3 positivity may suggest . Overall survival >95% transformation to EC Spermatocytic Seminoma Classical vs. Spermatocytic Seminoma . Rare (1-2% of testicular GCTs) CLASSICAL SEMINOMA SPERMATOCYTIC Age Peak incidence: 30-40 Generally older (>55) but can . Bilateral in up to 9% occur in younger men . Peak incidence 55 years, rare below 30 years Bilateral More common (up to 9%) Ovarian counterpart Dysgerminoma None . Only in testis (no ovarian counterpart, not in Extra-testicular sites Yes No mediastinum or retroperitoneum) Associated ITGCN Almost always No . Serum markers normal PLAP Present Generally absent . No association with cryptorchidism, ITGCN or Isochromosome 12p Present Absent i(12p) Tumour cells Monomorphous Polymorphous (3 sizes) Fibrous septae with Present Absent . Excellent prognosis lymphoid infiltration Risk of metastasis Present Almost never (exception: • Except following sarcomatous change (about 6% cases) sarcomatous change) 3 Embryonal Carcinoma EC: immunoprofile . Undifferentiated malignant GCT . OCT 3/4 (+) . Most common component of mixed GCT • Post-chemo embryonal carcinoma may be . Pure EC rare OCT 3/4 (-) . Peak incidence at about 30 years AE1/AE3 (+), Cam5.2 (+) . CD30 (+) . <40% present as stage I disease . EMA (-)- • Unlike somatic carcinomas Seminoma vs. Embryonal Carcinoma Unusual features in Seminoma Mimicking Embryonal Carcinoma Seminoma EC . Radiotherapy Sensitive Resistant Cytological atypia (anaplastic seminoma) Peak age group 30-40 20-30 • Nuclear atypia, cellular crowding, darker Cytology Uniform cells Anaplastic cytoplasm Cell membranes distinct Less distinct Cytoplasm Pale to clear More dense amphophilic . Tubular differentiation Fibrous bands Common Rare • Pseudoglandular rather than true gland lumina Lymphocytic reaction Prominent Generally absent Granulomatous reaction Present Absent . Cytokeratin immunoreactivity Positive Negative (may be focally +) C-Kt • Generally very focal AE1/AE3, Cam 5.2 Negative (may be focally +) Strongly + CD30 Negative (may be focally +) Positive • More AE1/AE3 positivity in otherwise typical seminoma would suggest transformation to EC Yolk Sac Tumour Yolk Sac Tumour . Part of mixed GCT in 40% . May resemble seminoma • More common in younger patients . YST as part of mixed GCT • Solid sheets with clear cytoplasm and • Pure YST very rare in adults well defined cytoplasmic membranes • Presence in primary: good prognosis (better staging?) • Usually associated with more typical areas • Presence in metastasis: poor prognosis (chemoresistant) of YST . Paediatric pure YST • Most common childhood testis tumour, usually <4yrs old • No association with cryptorchidism and ITGCN • Good prognosis 4 Unusual Patterns of YST Seminoma vs. YST . Solid, hepatoid, parietal, endometroid Seminoma Solid pattern . Generally in post chemoRx late recurrences of YST Eosinophilic hyaline Rare Common . Chemoresistantsy globules . May be treated effectively with surgery Lymphocytic reaction Common Unusual Granuloma Common Rare OCT 3/4 Positive Negative AE1/AE3 Negative Diffusely + (may be focally +) Glypican-3 Negative Positive Differential Diagnosis of GCT Differential Diagnosis of GCT . CRITICAL . LESS IMPORTANT • Germ cell vs. non-germ cell tumour • Seminoma vs. non-seminoma (if serum AFP high) • Treated as non-seminoma if no other explanation for • Seminoma vs. non-seminoma GCT (if serum AFP level markers normal) • Presence of seminoma in non-seminoma GCT • Classical seminoma vs. spermatocytic • Focal choriocarcinoma in non-seminoma GCT seminoma • Embryonal carcinoma vs. Yolk Sac Tumour • Dermoid/epidermoid cyst vs. monodermal • ITGCN in background testis teratoma • Absence suggests non-germ cell tumour Differential Diagnosis of GCT Critical Differential Diagnosis GCT vs. Non-GCT . LEAST IMPORTANT . Non-germ cell tumours • Mature vs. immature teratoma • Non-Hodgkin’s lymphoma • No clinical significance • Sex cord stromal tumours • Vascular invasion in seminoma • Seminoma-like Sertoli cell tumour • Isolated syncitiotrophoblasts in seminoma and EC • Metastasis into testis • Could explain raised serum HCG • Most common is prostate cancer 5 Critical Differential Diagnosis Seminoma vs. Clear Cell Sex Cord Tumours GCT vs. Non-GCT Seminoma Clear cell SCT . Importance Response to RadioRx Excellent Resistant • and ChemoRx Therapy: GCT very responsive to BEP Nuclei Polygonal Round/irregular chemoRx Cytology Uniform Polymorphic Intranuclear Absent May be present • Prognosis: GCT much better than cytoplasmic inclusions non-GCT even following metastasis Associated ITGCN Present in >90% Absent Immunohistochemistry Oct3/4+, c-KIT+ Melan A+, calretinin+, inhibin + (Sertoli cell tumours often inhibin-) GCT Immunohistochemistry Seminoma EC Spermatocytic YST ChorioCa (and ITGCN) Seminoma PLAP + +/- - (or focal) +/- +/- OCT4 + + - - - SALL4 + + -/+ + + C-KIT + - +/- -/+ - AE1/AE3, Cam 5.2 - (or focal) + - (or focal) + + CD30 - + - - - AFP - - - + - SALL4 + + - + +/- Alpha-Inhibin - - - - + Calretinin - - - - - 6 .