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Germ Cell Tumors –WHO 2016 Classification Different Pathogenesis of Tgcts

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Germ Cell Tumors –WHO 2016 Classification Different Pathogenesis of Tgcts Joint Session Gynaecological Pathology / Uropathology NON SEMINOMATOUS TUMORS OF THE TESTES. AN UPDATE Pilar González-Peramato Universidad Autónoma de Madrid Hospital Universitario La Paz September 8th-2019 Disclosures No finantial relationships to disclose Whats new after WHO 2016 in non seminomatous TGCT? Updated pathogenetic model → restructuring of classification Two main groups: - Derived from GCNIS tumors - Unrelated to GCNIS tumors Preinvasive lesion: GCNIS Spermatocytic tumor (seminoma) Non-choriocarcinomatous tumors: new entities GCNIS: Germ Cell Neoplasia in Situ Change in nomenclatrure Old terms, neither represents the nature of the lesion Not intraepithelial TIN Unclassified/Undifferentiated Not a carcinoma Confusing Skakkebaek NE. Possible carcinoma-in-situ of the testis. Lancet; 1972; 2; 516–517. Scully, Rosai, Mostofi, Kurman, et al, 1980 Skakkebaek NE. Carcinoma in situ of the testis: frequency and relationship to WHO classification 2004 invasive germ cell tumours in infertile men. Histopathology 1978; 2; 157–170. Reedited: Histopathology 2002; 41; 2–3. GCNIS Gonocyte-like germ cells with ample clear cytoplasm in tubules with / absent spermatogenesis Large angulated hyperchromatic nuclei with coarse chromatin clumps and prominent nucleoli Confined to the basilar aspect of the seminiferous tubule: in the SPERMATOGONIAL NICHE Patchy distribution Single layer Embryonic GC markers OCT3/4 PLAP CD117* D2-40 NANOG SOX17* TSPY * Also marks non neoplastic GC GCNIS Supports the diagnosis of GCT Peritumoral parenchyma in 90% GCT in adults Contralateral testis (2-6%) Cryptorchid testis (2-5%) Infertility biopsies (1%) DSD (25%) Dysgenetic testis with impaired Sertoli cells function GC with delay in maturation Children beyond 6 months of age GCNIS: DD DSD CAIS / PAIS Cryptorchidism Morphology of primordial CG / gonocyte Diffuse distribution Central–parabasal location in the seminiferous tubule Absence of that cells in spermatogonial niche GC with delay in maturation Positive for OCT3/4, CD117+, PLAP + SCF negative Likely give rise to GCNIS, but not invariably, so needs to be separated OCT3/4 PLAP Pre- GCNIS A lesion intermediate between GC maturation delay and GCNIS GCNIS: DD Cells resembling primordial germ cells/gonocytes Location: central, parabasally and in the spermatogonial niche OCT 3/4 and TSPY: heterogeneous expression Expresión de SCF + (KIT ligand) (=GCNIS, ≠ GC with maturation delay) Ulbright TM. Arch Path Lab Med 2019; 143(6):711-721 Specific forms of Intratubular germ cell neoplasia Expanded tubules without residual Sertoli cells Seminoma Embryonal carcinoma Trophoblast cells Necrosis and calcification Germ cell tumors –WHO 2016 Classification Different pathogenesis of TGCTs Testicular Germ Cell Tumors Unrelated to GCNIS Derived from GCNIS Type I Type III Type II Prepubertal-types can occur Prepubertal-type Spermatocytic tumor Postpubertal-type in postpubertal age th rd Pediatric 5-6 decade 2-3 decade Postpubertal-types can occur in prepubertal age (DSD) Oosterhuis JW, Looijenga LH.. Nat Rev Cancer. 2005;5(3):210–222. TGCTs represent the aberrant development of the physiological germ cell towards full spermatogenesis (at different phases of maturation) Type I Type III Epidemiology GCNIS Type II Increased incidence in 20th century Western lifestyle Dysgenetic testicular syndrome Impaired Testicular Maternal hyperstrogenism Sertoli cell dysgenesis Hormonal disruptors function syndrome Disorders of Sex Development Androgen insensitivity syndrome Rajpert-De Meyts E. el al. Lancet 2016; 387: 1752-64 2016 WHO Germ Cell Tumor Classification Occur in a background of dysgenetic testis - Impaired spermatogenesis - Sertoli cell-only pattern - Immature Sertoli cells - Leydig cell hyperplasia - Hyalinized tubules GCNIS-derived - Microlithiasis Testicular Germ Cell Tumors Not GCNIS-derived Normal testicular parenchyma Absence of dysgenetic changes Not associated with cryptorchidism Determines prognosis and treatment Sarcomatoid YST / Somatic Choriocarcinoma / sarcoma NOS malignancy Others trophoblastic tumors Embryonal Yolk sac tumor Teratoma Trophoblastic Seminoma carcinoma Postpubertal-type Postpubertal-type tumors Type II GCNIS-derived Mixed GCT i(12p) Malignant behavior Regressed GCT Germ Cell Tumors Indolent behavior Not GCNIS-derived Type I Type III Spermatocytic Spermatocytic tumor Yolk sac tumor Teratoma Dermoid cyst tumor with sarcoma Epidermoid cyst Prepubertal-type Prepubertal-type Carcinoid tumor Chrom 9 amplification: Gain / losses No genetic DMRT1 gen chromosomes abnormalities Yolk sac tumor Somatic Choriocarcinoma / Adultsmalignancy Others trophoblastic tumors 99% in mixed GCT Yolk sac tumor Teratoma Trophoblastic Seminoma Postpubertal-type Posti(12p pubertal) -type tumors Metastasis (30% in stage I) Malignant GCT that differentiates structures GCNIS-derived Lymphatic based-distribution of metastasis similar to extraembryonic structures (yolk sac, allantoids and extraembryonic mesenchyme) Germ Cell Tumors 98%: AFP > 100 ng/ml In the first 2y of life (48-52%), not congenital Glypican 3 Not GCNIS-derived Most are pure (teratoma) Gain (1q, 3, 8q24, 12 (p13), 20q, 22 ) / losses (1p36, 4, 6q, 16q and 20p) of whole Spermatocytic tumor Yolk sac tumor or portionsTeratoma of several chromosomes Prepubertal-type Prepubertal-type Less apt to metastasize (16% in stage I) Spermatocytic tumor with sarcoma HematogenousDermoid cyst distribution of metastasis Epidermoid cyst Carcinoid tumor Arch Pathol Lab Med. 2019;143:711–721 Pre-pubertal type YST Same morphology Post-pubertal type YST Solid pattern Myxomatous pattern Schiller-Duval or glomeruloid bodies Endodermal sinus pattern: 20% Glandular pattern Macrocystic pattern Hepatoid pattern Yolk sac tumor Pre- and post-pubertal type Microcystic pattern Architectural patterns ❑ Microcystic / Reticular (vacuolated):80% ❑ Solid ❑ Myxomatous ❑ Macrocystic ❑ Glandular / alveolar ❑ Endodermal sinus (feston) ❑ Hepatoid ❑ Papillary Chemo-resistence ❑ Sarcomatoid ❑ Parietal (AFP -) ❑ Polyvesicular vitelline Clues Cuboid cells, intermediate size between seminoma and embryonal carcinoma Mixed patterns Intercellular basement membrane Hyaline globules PAS+ Parietal pattern Yolk sac tumor, postpubertal -type It is the TGCT that most often goes unnoticed 47% of overall errors: failure to diagnose YST Serum AFP Harari SE et al. Urol Oncol Seminars and Original Investigations. 2017; 35: 605.e9–605.e16 Necklace pattern (double layer + EC) (7%) → Mixed GCT Poliembrioma-like → Mixed GCT AE1/AE3 Positive for: AFP (80%) Glypican 3 (100%) CD117 (60% solids) SALL4 GATA 3 AE1/AE3 CDX2 !!!! EC YST Negative for: OCT 3/4 CD30 Inhibin Teratoma Sarcomatoid YST / Somatic AdultsChoriocarcinoma / sarcoma NOS malignancy PureOthers GCT trophoblastic (2.7-7%) tumors Mature elements NOT affect overall Mixed GCT (50%) Teratoma Trophoblastic Immature elements prognosis Malignant Seminoma Postpubertal-type tumors Metastasis (22-37%) GCNIS-derived i(12p) GCT composed elements resembling somatic tissues derived from one or more germinal Germ Cell Tumors layers (endoderm , mesoderm, and ectoderm) Not GCNIS-derived Mostly in children (< 6 y) Also in adults Teratoma Pure neoplasm Prepubertal-type Benign Dermoid cyst No recurrence/ metastasis Epidermoid cyst Conservative treatment Carcinoid tumor Prepubertal-type teratoma Organoid arrangement Cysts Squamous / ciliated epith. Smooth muscle Occasional salivary gland/pancreas acinar cells No necrosis Normal parenchyma Prepubertal-type teratoma in postpubertal patients Postpubertal age: 59 years-old No cytologic atypia Present in childhood ? No immature tisues No scars / dysgenetic changes Diploid → No (i)12p No GCNIS Normal spermatogenesis Prepubertal-type teratoma in postpubertal patients Teratoma Prepubertal-type 10 dermoid cyts 15 non dermoid teratomas Dermoid cyst 23 skin and other elements Epidermoid cyst Carcinoid tumor 18 analyzed: no 12p 17 with follow-up: alive, 11 disease-free University Hospital La Paz for 20 years 72 teratomas- (19 prepubertal-type: 26%) 8 (42%) older 15 y (10 mo-58 y) 12 epidermoid cysts, 2 dermoid cysts, 5 Prepubertal-type T Follow-up (5-19y): No recurrence or metastases Pure primary tumor (65-78%) Primary tumor associated with teratoma, dermoid or epidermoid cysts (26-28%) Metastasis of extratesticular tumor (13%) Prepubertal-type teratoma in postpubertal patients Benign behaviour Lacks atypia No GCNIS Dermoid cyst Epidermoid cyst Unilocular cyst, mural protuberance Unilocular cyst Keratinized squamous epithelium Keratinized squamous epithelium Adnexal structures, Hair No adnexal structures or other tissues Other tissues: glands, muscle, cartílage.. Lipogranulomas Normal spermatogenesis Ye H, Ulbright TM. Difficult differential diagnoses in testicular pathology. Arch Pathol Lab Med. 2012;136:435-46. Well circunscribed nodules GCNIS Teratoma, Postpubertal-type Complex masses, solid-cystic Cartilague, calcification, fibrosis GCNIS and testicular dysgenetic changes in peritumoral parenchyma 16 years-old 33 years-old Dysgenetic changes Epithelium: squamous with / without keratin, gandular, intestinal, respiratory Rangedly distribution Mesenchmal: Fibrous, smooth muscle, adipous, neuroglía, cartílague, bone, retin Organoid arrangement: Less frequent Hypercellular and atypical cartilage not sufficient for sarcoma Teratoma with secondary / somatic-type malignancy Teratoma with malignant transformation Rare Adults with teratomas who develop overgrowth of a secondary malignant somatic-type neoplasm excluding other elements In the testes or
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