Germ Cell Tumours of the Testis and Ovary

Hong Kong 2021

Dan Berney

Testis tumour classification

• BTTP • WHO 2004 • Now WHO 2016 • New Classification planned 2020/21 • Paediatric WHO WHO Book 2020/21 Type Grade Stage The Importance of Tumour Type • Seminoma v NSGCT v Mixed – Different tx and follow up imaging • Risk of recurrence • Correlation with tumour markers • Intersex or other inherited conditions WHO Zurich March 2015 WHY BOTHER?

• AVOID MISUNDERSTANDINGS • REFINE TREATMENTS. • UNLOCK PATHOGENESIS. Purshouse K, Watson RA, Church DN, et al. Value of Supraregional Multidisciplinary Review for the Contemporary Management of Testicular Tumors. Clin Genitourin Cancer. 2017;15(1):152‐156. doi:10.1016/j.clgc.2016.05.005 AVOID MISUNDERSTANDINGS! • CIS – Not a carcinoma • TIN – Not intraepithelial • IGCNU – Unclassified/Undifferentiated… – The spermatogonial niche GCNIS GERM CELL NEOPLASIA IN SITU PLAP WHO 2016 Germ cell tumours

• Tumours derived from GCNIS of one type • Seminoma • Embryonal carcinoma • Yolk Sac Tumour, post pubertal type • Trophoblastic tumours • Teratoma, post pubertal type • Teratoma with somatic type malignancy

OCT3/4

hCG

I am not a choriocarcinoma Embryonal carcinoma YST: histologic patterns

• Reticular or microcystic (most common) • Endodermal sinus (most distinctive) • Macrocystic • Solid • Glandular / alveolar • Papillary • Myxomatous (magma reticulare) • Spindle cell • Polyvesicular vitelline • Hepatoid • Enteric (primitive intestinal) • Parietal • sarcomatoid YST: Schiller-Duvall bodies Hyaline globules Hepatoid YST Glandular YST

Parietal Solid YST Trophoblastic tumours

• Choriocarcioma • Non-choriocarcinomatous trophoblastic tumours – Placental site trophoblastic tumour – Epithelioid trophoblastic tumour – Cystic trophoblastic tumour Choriocarcinoma Teratoma, post pubertal type • Immaturity • Atrophy • GCNIS Teratoma with somatic type malignancy (WE WILL REVISIT THIS!) Non-seminomatous germ cell tumours of more than one histological type

- Mixed germ cell tumours

Germ cell tumours of unknown type - Regressed germ cell tumours

OCT3/4 AFP

Regressed germ cell tumours Germ cell tumours unrelated to GCNIS

• Spermatocytic tumour • Teratoma, prepubertal type – Dermoid cyst – Epidermoid cyst – Well-differentiated neuroendocrine tumour (monodermal teratoma) • Yolk sac tumour, prepubertal-type • Mixed teratoma and yolk sac tumour, prepubertal-type Spermatocytic tumour

• Danger of inappropriate chemotherapy

Prospective Molecular and Morphological Assessment of Testicular Prepubertal-Type Teratomas in Postpubertal Men Mod Pathol 2020 Apr;33(4):713-721. Wagner et al

• Prospective cases of prepubertal type teratoma in adults • Morphology and correlation with isochromospme 12p • Comparison with post pubertal type teratomas Cas Age Size Histologic findings GCNI Regressi Abnormal Clinical Treatment F/U (date) Disease status e (mm) S on 12p stage on last f/u no. (duration in months)

1 40 18 Smooth muscle, glands, cartilage, 2 No No Negative I RO, A&W NED (6) mm well differentiated NET with Ki67 surveillance (January 2018) <2% 2 24 12 Smooth muscle, bone, glands No No Failed test NA RO, NA NA NA 3 26 28 Smooth muscle, glands, 1 mm well No No Negative I RO, Discharged NED (2) differentiated NET with Ki67 < 2% surveillance (May 2017)

4 64 20 Glands, 2 mm well differentiated NET No No Negative NA RO, NA NA NA with Ki67< 2%

5 42 15 Naevus glands, adnexa, fat tissues No No Negative II RO, BEP A&W NED (18) due to (February 2018) contralateral seminoma

6 27 7 Glands and smooth muscle No No Negative I RO, A&W NED (26) surveillance (January 2018)

7 28 15 Squamous epithelium and bone No No Negative I RO, Discharged (2016) NED (12) surveillance 8 58 20 Squamous epithelium and glands No No Negative NA RO, NA NA NA 9 46 12 Glands and smooth muscle No No Negative I RO, Lost to f/u NED (1) surveillance (February 2014)

10 31 10 Mature bone and fibrous tissue No No Failed test I RO, Discharged NED (55) surveillance (April 2018)

11 33 19 Bone, colonic gland, smooth muscle No No Negative NA RO, NA NA NA 12 19 17 Squamous, smooth muscle, 2 mm well No No Negative I RO, A&W NED (12) differentiated NET with Ki67 of 1% surveillance (January 2019)

13 26 9 Bone, gland No No Negative Imaging not RO Discharged without NED (10) performed F/U (October 2018)

14 70 25 Squamous, gland, smooth muscle No No Negative I RO, Discharged NED (7) surveillance (October 2018) Case Age Size (mm) Histologic findings GCNIS Regression Remarks no.

15 19 10 Cartilage, glands Yes Yes 16 27 45 Squamous epithelium and glands Yes Yes 17 38 6 Squamous epithelium, immature glands and No Yes cartilage 18 23 45 Squamous epithelium, glands, cartilage and Yes Yes smooth muscle

19 21 18 Glands, cartilage Yes Yes 20 52 75 PNET 75%, glands and smooth muscle No Yes 21 26 55 Glands, squamous epithelium, smooth muscle NA NA Presentation with metastasis 22 43 13 Glands, smooth muscle, cartilage No Yes 23 28 90 Cartilage NA NA Presentation with metastasis 24 67 14 Squamous epithelium, glands and cartilage Yes Yes 25 54 60 Squamous epithelium and glands No Yes 26 29 46 Cartilage, glands, bone and smooth muscle Yes Yes 27 27 NA Glands and smooth muscle Yes Yes Partial orchiectomy 28 33 42 Glands, squamous epithelium, glia, cartilage No Yes 29 32 12 Squamous epithelium No Yes 30 35 13 Squamous epithelium, glands and smooth muscle Yes Yes 31 28 70 Glands, smooth muscle, squamous epithelium Yes Yes Presentation with metastasis 32 22 75 Glands and necrotic areas No No Widespread necrosis 33 59 NA Glands, smooth muscle No Yes 34 30 60 PNET Yes Yes 35 46 7 Skeletal muscle only Yes No 12p amplification Prepubertal type teratoma and variants, Epidermoid and dermoid cyst

• No GCNIS • No immature areas • No evidence of regression • i12p? Yolk sac tumour, prepubertal-type Mixed teratoma and yolk sac tumour, prepubertal-type

• V rare • No GCNIS • Metastatic disease does occur • Survival approaches 100% Somatic malignancy in GCT

• 3-6% of patients with metastatic GCT • May strongly affect disease course – Increased number recurrences – Decreased relapse-free survival – Decreased overall survival SOMATIC TRANSFORMATION • Stromal invasion – Useful in epithelial malignancies • Overgrowth of GCT – Nodule of malignant cells equivalent to area seen by 4X objective and overgrowing other GCT elements – Useful for sarcomas and other tumours Histology of PNET in GCT

• Small round blue cell tumors usually resemble pediatric type CNS embryonal neoplasms – Neuroblastoma – Medulloepithelioma – Medulloblastoma – Ependymoblastoma • Most lack evidence of chromosome 22 translocation of peripheral PNET PNET in GCT: prognosis • If limited to testis, does not affect prognosis of GCT • Very poor prognosis in metastatic sites – All 19 patients in largest series (Michael et. al. were DOD (13), AWD (4) or alive (2) with short follow-up) • Do not respond to GCT chemotherapy • Treatment is surgical PNET PNET with tubules

PNET with rosettes Homer Wright rosettes Undiff. Sarcoma Rhabdomyosarcoma

Pleomorphic undiff. Osteosarcoma Nephroblastoma Brain metastasis IN TESTIS THE NATURE OF THE IMMATURITY/SOMATIC TX IS VITAL TO UNDERSTAND PROGNSIS Adjuvant treatment for stage 1Testicular GCTS • Seminoma: Rx or carboplatin (don’t faint!) • NSGCTs: BEP chemotherapy

• Nearly everybody lives! • Recurrence reduction. • Morbidity of the treatment When do oncologists give adjuvant treatment? • Patient choice • Variations in international practice • Based on risk factors Risk factors • Seminoma – Tumor size – Rete invasion – Soft Tissue invasion – Other structure invasion • NSGCT – All the above – % of EC Studies on pathology are difficult!

• Variations of Tx given • No review of path (from notes) • Relapse endpoints make powering study tricky • Insufficient centralization in many centres • Changes/inconsistency in TNM UICC/AJCC: epididymis/soft tissue Scandura G, Wagner T, Beltran L, Alifrangis C, Shamash J, Berney DM. Pathological risk factors for metastatic disease at presentation in testicular seminomas with focus on the recent pT changes in AJCC TNM eighth edition. Hum Pathol. 2019 Dec;94:16-22

• 290 (87%) tumors were CS 1 and 42 (13%) were CS 2/3

• On univariate analysis, lymphovascular invasion, epididymal invasion and tumor size associated with CS • On multivariate analysis, tumor size (P = .0001) and epididymis invasion (P = .023) remained significant. Optimal tumor size cutoff was 4.25 cm Fig.1 Receiver operating characteristic (ROC) curve for tumour size cut-off of 4.25 cm Pathological Predictors of Clinical Stage in Non-Seminomatous Germ Cell Tumours: which TNM staging system ? Glenda Scandura, Thomas Wagner Nielsen, Luis Beltran, Constantine Alifrangis, Jonathan Shamash, Daniel M Berney Modern Pathology (In Press)

• 219 NSGCTs, 151 (69%) were CS 1 & 68 (31%) were CS 2/3. • Mean tumour size of CS 1 was 37 mm (5 - 95), of CS 2/3 was 43 mm (8-95). • On univariate analysis, LVI (P=0.0001), hilar fat invasion (P= 0.009), rete testis (P=0.001), epididymal invasion (P=0.010), spermatic cord invasion (P=0.001), tumour at spermatic cord margins (P=0.002), tumour size (P=0.028), percentage of EC (P=0.004) were all associated with higher CS. • On multivariate analysis LVI (P=0.002), spermatic cord invasion (P=0.018), percentage of EC (P=0.003) and tumour size (P=0.001) were significant. • Our results validate the changes in the AJCC TNM 8th edition as invasion of the epididymis and hilar fat were both univariately significant. The multivariate significance of tumour size and %EC suggests they should be included in any future TNM revision. WE NEED: Large Cohort seminoma/NSGCT Centralised Follow up for relapse No Adjuvant treatment Pathology review Assessment of all known risk factors

Wagner T, Toft BG, Engvad B, et al. Prognostic factors for relapse in patients with clinical stage I testicular cancer: protocol for a Danish nationwide cohort study [published correction appears in BMJ Open. 2019 Dec 11;9(12):e033713corr1]. BMJ Open. 2019;9(10):e033713. Published 2019 Oct 31. doi:10.1136/bmjopen-2019-033713 OVARY WHO 2014/20

1. Germ cell Tumours 2. Monodermal teratoma and somatic type tumours arising from a dermoid cyst 3. Germ cell-sex cord stromal tumours Mature teratoma

• 20% of all ovarian neoplasms • NO i(12p) Germ Cell tumours • Dysgerminoma • Yolk sac tumour • Embryonal carcinoma • Non-gestational choriocarcinoma • Mature teratoma • Immature teratoma • Mixed germ cell tumour.

Immature teratoma

• Second most common malignant ovarian GCT. • No i(12p) • Based almost exclusively on PNET

Grading

• Based on aggregate low power fields • Somewhat out of date – <1LPF in any slide G1 – 1-3LPFs in any slide G2 – >3 LPFs in any slide G3 Gliomatosis • Spread through peritoneum: favourable prognosis. Issues

• Grading not v well standardised • What is immature neuroepithelium? • Embryoid bodies/Yolk sac mentioned in text of WHO as part of IT! • Few validating series. GRADE AND SOMATIC TX

A Grand Unified Theory of Germ cell Tumours! Germ cell Description Tumour type 1 Testis: Pre-pubertal type teratomas and prepubertal yolk sac tumour.

Ovary: May form a subset of some ovarian teratomas and yolk sac tumours

2 Testis: Post-pubertal Type adult Teratomas, seminoma and other non seminomatous‘malignant’ germ cell tumours.

Ovary: Dysgeminoma and other ‘malignant’ ovarian tumours (yolk sac, embryonal carcinoma ) and possibly ‘immature teratomas’ of the ovary. 3 Testis: Spermatocytic Tumour

Ovary: No counterpart exists

4 Ovarian ‘Dermoid Cysts’ also known as benign cystic teratomas. May include some ‘immature teratomas’ 5 Gestational trophoblastic neoplasia 6 Somatic tumours showing transdifferentiation to elements with characteristic germ cell features. • IF IT IS A MIXED GCT THEN CALL IT THAT NO MATTER HOW SMALL THE SECONDARY ELEMENT • CALL IMMATURE TERATOMAS, TERATOMA WITH IMMATURE NEUROEPITHELIUM. IF IMMATURITY IS ANOTHER ELEMENT THEN TELL US WHAT IT IS • GRADING NEEDS STRICTER DEFINITIONS AND CONSIDER SOMATID TRANSFORMATION AS IN TESTIS. Thoughts of an adult testicular pathologist!

• Priorities for gynae pathologists. • Suboptimal esp for IT • Old series. • Optimisation of therapy choices compromised. • Accurate typing is by far the most important factor in a testicular tumour. WHO 2016 is an advance. • Often this is about giving less treatment and scanning • Central review is necessary for any study • Other germ cell tumour sites may benefit by a unified classification which will be more comprehensible to clinicians.