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Im Improvement of

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João

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Lobo Hans ns Stoo

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Ad Gi Gillis, Le Leend nder ert HJ Looi Looije jeng nga, J.

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No conflicts of interest 8th September 2019

Lobo et al. Hum Pathol 2018

TGCTs: heterogeneity & challenges

Lobo et al. Int J Mol Sci 2019

TGCTs: heterogeneity & challenges

“Germ cell tumors are at the crossroads between developmental biology and cancer"

1% male cancer Decreasing mortality Most curable solid neoplasms Same cytogenetic background (i12p) and low mutational burden Most common cancer in Caucasian men 15—44yo Rising incidence 15-20% disseminated disease recurs (poor prognosis) Cisplatin resistance Iatrogeny (young patients) Better disease biomarkers urgently needed

Why focusing on TGCTs?

1% male cancer Decreasing mortality Most curable solid neoplasms Same cytogenetic background (i12p) and low mutational burden Most common cancer in Caucasian men 15—44yo Rising incidence 15-20% disseminated disease recurs (poor prognosis) Cisplatin resistance Iatrogeny (young patients) Better disease biomarkers needed

Why focusing on TGCTs?

Costa and Lobo et al. Epigenomics 2017

Vascular invasion as a biomarker

Prognostic marker

Metastases, recurrence TNM (pT2, stage IA) Patient stratification

Inter-observer agreement in reporting

Not ideal Most common disagreement upon centralized review Subjectivity, artifacts, criteria…

Immunohistochemistry and type of vessel

No formal recommendation (ISUP) Lack of data

Aims and Methodology

1

• Inter-observer

agreement in VI scoring on H&E

2

• Additional value of

adding IHC for vascular markers

3

• Additional value of

characterizing the type of vessel invaded

“Clean” cohort Strict inclusion criteria H&E + IHC panel (D2-40, CD31, FVIII) Scoring by 3 independent

• bservers

✓ Consecutively diagnosed NS patients ✓ Stage I ✓ Only surveillance after orchiectomy ✓ 2 FFPE samples ✓ >1cm2 tumor ✓ Tumor-parenchyma interface ✓ Dedicated to TGCT pathology ✓ D2-40: lymph vessels ✓ CD31, FVIII: blood vessels

Cohort characterization

Variables Patient cohort (n=52) Age [years (median, IQR)] 31 (24-35) Laterality (n, %) Right 21/52 (40.4) Left 31/52 (59.6) Pre-operative serum tumor markers (n, %) Within normal range 20/52 (38.5) Elevated 32/52 (61.5) Histologic subtypes (n, %) Pure embryonal carcinoma 5/52 (9.6) Pure postpubertal-type teratoma 2/52 (3.8) Mixed tumor, without seminoma 21/52 (40.4) Mixed tumor, with seminoma 24/52 (46.2) Multifocality (n, %) Absent 50/52 (96.2) Present 2/52 (3.8) Largest tumor size [cm (median, IQR)] 3.5 (2.5-5.4) Rete testis invasion (n, %) Absent 30/42 (71.4) Present, stromal 9/42 (21.4) Only pagetoid spread of GCNIS 3/42 (7.1) Vascular invasion (n, %) Absent 25/50 (50.0) Present 25/50 (50.0) Variables Patient cohort (n=52) Relapse (n, %) No 21/52 (40.4) Yes 31/52 (59.6) Type of relapse (n, %) Early 28/31 (90.3) Late 3/31 (9.7) Site of relapse (n, %) Only serum markers 6/31 (19.4) Serum markers + PAoLN 14/31 (45.2) Only PAoLN 4/31 (12.9) Only Lung 2/31 (6.5) Serum markers + Lung + PAoLN 4/31 (12.9) Serum markers + Liver + Lung + PAoLN 1/31 (3.2) Treatment performed for relapses (n, %) Only chemotherapy 26/31 (83.9) Chemotherapy + RPLND 5/31 (16.1) Vital status at last follow-up (n, %) A-NED 50/52 (96.2) D-NED 1/52 (1.9) DFD 1/52 (1.9)

Prognostic value

On multivariable analysis (age, tumor size, serum tumor markers, rete testis invasion) VI showed an independent impact in predicting disease relapse (HR 3.163, 95% CI 1.31-7.63)

Inter-observer agreement

Testicular germ cell tumor-dedicated pathologists’ assessment of vascular invasion Agreement Cohen’s Kappa = 0.54 (p<0.001) Pathologist 3 Absent Present Pathologist 1 Absent 23 4 Present 8 17 Agreement Cohen’s Kappa = 0.50 (p<0.001) Pathologist 2 Absent Present Pathologist 1 Absent 22 5 Present 8 17 Agreement Cohen’s Kappa = 0.49 (p<0.001) Pathologist 2 Absent Present Pathologist 3 Absent 24 7 Present 6 15

Agreement among TGCT-dedicated pathologists was moderate, as reported (κ 0.49-0.54)

Performance in predicting relapse

Vascular invasion scoring Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) H&E (consensus) 61.3 85.7 86.4 60.0 71.2 Immunohistochemistry (D2-40 + FVIII + CD31) 71.0 71.4 78.6 62.5 71.2

IHC resulted in increase in sensitivity and decrease in specificity IHC upgraded 8 cases of “absent VI

• n H&E” → 3 of them developed

relapse IHC downgraded 2 cases of “present VI on H&E” → both did not develop relapse

Vascular invasion: challenges

Missed cases on H&E assessment Vascular invasion mimickers

H&E D2-40 CD31 FVIII H&E D2-40 CD31 FVIII

Type of vessel

Vascular invasion scoring No relapse (n) Relapse (n) IHC showing LVI only 3 12 IHC showing BVI only 3 2 IHC showing LVI + BVI 8

“Double vascular invasion patients”: 100% accuracy in predicting disease relapse Active selection for adjuvant treatment instead of surveillance?

Conclusions

1

• Inter-observer

agreement in VI scoring on H&E

2

• Additional value of

adding IHC for vascular markers

3

• Additional value of

characterizing the type of vessel invaded Moderate among TGCT-dedicated pathologists, but can be improved Increase in sensitivity for predicting disease relapse Identification of high-risk patients (both LVI and BVI)

Conclusions

Indication for routine IHC use? Endpoint: relapse-free survival Large, prospective studies, with IHC

FUTURE

Supervising team: Rui Henrique Carmen Jerónimo Leendert Looijenga

Department of Pathology Ângelo Rodrigues Paula Lopes Mariana Cantante Rita Guimarães Cancer Biology & Epigenetics Group Vera Gonçalves Daniela Barros Silva Sandra Nunes

Ethics approval: CES IPO 1/2018

IPO Porto The Netherlands

Project Funding: POCI-01-0145-FEDER-29043 Doctoral Grant: SFRH/BD/132751/2017

Urology Clinic Jorge Oliveira Joaquina Maurício Isaac Braga Department of Epidemiology Luís Antunes PMC Utrecht (Group Looijenga) Ad Gillis Annette van den Berg Rachita Lahri Dennis Timmerman Erasmus MC Rotterdam & LEPO

Wolter Oosterhuis

Lambert Dorssers Hans Stoop Willem Boellaard

Thank you for your attention!