Standard Management of Stage II A versus IIB Disease Thymoma Thymic carcinoma

Relevance of thymoma histotype *

WCLC 2015: P2.15-002: Advanced stage; size >8cm; WHO B3 predict recurrence after R0

Thymoma

Thymic carcinoma (TC)

In Resectable Stage III Disease

Obligatory Radiotherapy in Thymoma and TC

Optional Chemotherapy only in TC

Standard Management of Resectable Stage III Disease: Surgery First!

No minimally invasive surgery!

Treatment Algorithm for Unresectable Stage III-IVa

Thymomas and TCs

ESMO Guidelines 2015

Secondary resectability is of prognostic relevance

Treatment Algorithm for Unresectable Stage III-IVa

Thymomas and TCs

ESMO Guidelines 2015

Secondary resectability is of prognostic relevance

Debulking*?

*Hamaji M et al Eur J Cardiothorac Surg 47(7): 602-607, 2015 (PMID: 25015950) Metaanalysis: HR 0.451 in favor of debulkig

WCLC 2015: P1.15-008 Debulking of no benefit in TC

WCLC 2015: P2.15-005 Debulking is of benefit in TC

ESMO Guidelines 2015

Secondary resectability is of prognostic

relevance

Treatment Algorithm for Metastatic Stage IVB

Thymomas and TCs

Primary Recurrences > Management like newly diagnosed tumors

Resectable recurrences

Upfront surgery (R0 is prognostically favourable)*

Unresectable recurrences

Re-administration of previously effective regimen Alternative: Carbo-Px; CAP-Gem Next line: Pemetrexed Next line: Octretide/Prednisolone (if octreoscan+) WCLC 2015: Mini25.07 Lucitanib (FGFR1-13 …TKI) WCLC 2015: Oral11.05 Amrubicin (better in thymoma)

*WCLC 2015: P1.15-002 Reoperation of resectable recurrent thymoma is assoc. with better outcome

WCLC Mini28.08 Girard N. et al. (Rythmic) (Neo-)adjuvant regimens (A,B - CRT, CT) and regimen for recurrences (C, B)

Management of Refractory Recurrences – Personalized Oncology

• Targeting mutated KIT in TC > Imatinib, Sunitinib, Sorafenib

• Targeting angiogenesis (etc.) in TC > Sunitinib

• Targeting mTOR in thymoma and TC > Everolimus

Effect of sunitinib on metastatic TC with wt KIT

Ströbel P et al. BJC, 2010

TC Thymoma

WCLC 2015: MO03.07 Thomas A. et al. Clinical activity of sunitib in patients with thymic carcinoma Phase II study; chemorefractory thymomas (n=16) and TCs (n=25)

Lancet Oncology, 2015, PMID: 25592632

PR = 26% 6% SD = 65% 75%

WCLC 2015: MTE19.1 Girard N.

Biology and Treatment of Thymoma and Thymic Carcinoma: Role of NGS?

N=647 pts. NSCLC SCLC Thymoma (n=41) Thymic ca (n=48)

CUSTOM Basket Trial Lopez-Chavez A. et al JCO 2015 (PMID: 25667274)

Thymic Tumors 1 x EGFR 2 x HRAS 2 x PIK3CA 4 x KIT in TCs*

235 „cancer related genes“

*PR in 1 of 3 pts

Challenges when Managing Patients with Thymic Tumors

• Distinguishing thymomas and TCs from lymphomas, GCTs and sarcomas (biopsy!)

• Assessing the ‚resectability‘ of a given thymoma or TC (new imaging techniques ?*)

• Whether to resect lymph nodes in thymoma and TCs (poorer prognosis > maybe yes**)

• Whether or not to spare the phrenic nerve in myasthenic patients • Selecting patients for post-operative Rx in stage II disease (WHO histotype?)

• Optimal therapy in stage IVA disease (EPP; pleurectomy; HITHOC; PDT*** ?)

• Primary or secondary debulking in unresectable thymoma (prospective study needed) • Surveillance for autoimmune and immunodeficiency diseases (immunoglobulins!)

• Lack of biomarkers for most „targeted approaches“ (e.g. sunitinib)

• Role of immunotherapy (PD1/PD-L1 inhibitors) in thymoma (?) or TCs (!)

.*Hayes SA et al JTO, 2014 (PMID:24926547); **Weksler B et al. JTCvS 2015 (25595379); JTO, 2015 (PMID: 26317915); ***Photodynamic therapy

Thank you for your attention !

Challenges when Managing Patients with Thymic Tumors

• Distinguishing thymomas and TCs from lymphomas and GCTs (biopsy!)

• Assessing ‚resectability‘ in thymomas or TCs (new imaging techniques ?*)

• Whether to resect lymph nodes in thymoma and TCs (poorer prognosis > maybe yes**) • Optimal therapy in stage IVA disease (EPP; pleurectomy; HITHOC?)

• Debulking in unresectable thymoma (prospective study needed) • Surveillance for autoimmune and immunodeficiency diseases (immunoglobulins!)

• Lack of biomarkers for most „targeted approaches“ (e.g. sunitinib)

• Role of immunotherapy (PD1/PD-L1 inhibitors) in thymoma (?) or TCs (!)

.*Hayes SA et al JTO, 2014 (PMID:24926547); **Weksler B et al. JTCvS 2015 (25595379); JTO, 2015 (PMID: 26317915);

Heidelberg

Take Home Message (1) – New WHO Classification

• To improve diagnostic accuracy immunohistochemical features are

introducted to delineate histological subtypes • Obligatory and optional features for the better separation of type B1, B2

and B3 thymomas are given (e.g. lack of „clustering“ in B1 thymomas)

• Atypical type A thymoma“ is introduced as aggressive type A variant

• H&E morphology dominates over immunohistochemistry in case of difficult-to-classify B3 thymomas versus thymic carcinomas

• Stage (Masaoka-Koga)

• R-Status

• WHO Histology

The most relevant criteria in therapeutic decision making*

* Most relevant predictors of PFS

A AB B1 B2 B3 Carcinoma

Conceptual change #4: Obligatory vs. optional features

Refinements for „borderlands“ between subtypes

Cortex-/medulla-specific IHC markers (b5t, PRSS16, Claudin 4, CD40, Aire)

TdT

MG Risk+ MG Risk+++ No MG Risk

Recognition of „new“ Thymic Neoplasms:

Type A thymoma versus Atypical type A thymoma

3. Edition 4. Edition Type A thymoma Type A thymoma (“benign”) Atypical type A thymoma

Atypical type A thymoma: New variant of type A thymoma with aggressive clinical and histological features (stage III / IV, in- creased mitotic activity (>4 pro 10HPF), comedo-type necrosis)

Treatment Algorithm for Resectable Stage I-III

Thymomas and TCs

ESMO Guidelines 2015

However…

• Type B3 thymomas rarely show – usually focal –

expression of CD5 and CD117

• Thymic squamous cell carcinomas rarely harbour

- usually few - immature TdT+ T cells

In such cases H&E histology “trumps”

immunohistochemical features

TSQCC

Increased epithelial cell content (mostly with „clustering“) is obligatory for the diagnosis of type B2 thymoma

Dense keratin networks with prominent perivascular spaces in B2s

B1 B2