Mauro PapottiM. Volante, F.

Maletta, J. Metovic

University of TurinItaly

POORLY DIFFERENTIATED

THYROID CARCINOMA

Veenendaal, April 13, 2018

WHO CLASSIFICATION OF ENDOCRINE TUMORS

June 2017

WHO 2017

Hobnail var.

PD thyroid carcinoma definition

2004 2017

Follicular-cell neoplasm that show limited evidence of structural follicular cell differen-tiation and is both morphologically and beha-viorally an intermediate position between differentiated (follicular & papillary cancers) and undifferentiated (anaplastic) carcinomas.

YES !!

AGGRESSIVE THYROID CARCINOMAS

What are wetalking about?

AGGRESSIVE THYROID CARCINOMAS

-Histotype: PDTC, tall cell, columnar, solid, hobnail PTCs, Hurthle ca…. -High tumor stage: ETE (pT4 vs pT3) -Role of early RAI therapy-Prognostic markers any reliable ? PDGFRa & p-mTor may predict resistanceto RAI -Molecular profiles BRAF mutations, TERT promoter mutations, STRN/ALK fusion, p53

Lopez-Campistrous EBioMed 2016;12:86-97 Tavares. Surgery 2016 Aug

FTC

PTC

Good

ATCClassic

Follicular

Minimallyinvasive

Widelyinvasive POORLY

DIFFERENTIATED CA.

Well diff. Undiff.

Poor

DIFFERENTIATION

PROGNOSIS

Angiosarcoma

AGGRESSIVE THYROID CANCERS

Aggressive variants

TG

•Poorly differentiated carcinoma (1963)

•Insular carcinoma (1984)

•Primordial cell carcinoma (1993)

•Solid / Trabecular carcinoma•Intermediate type carcinoma•Less-well differentiated carcinoma

including extra thyroid ovary locations

Does PD carcinoma exist?

YES, since the WHO 2004 scheme

Proposednames

PD ca • Wuchernde struma

1907 1988

Bern Turin

Any associated condition?

YES (association or transition)

1- Nodular goiter (easy distinction)2- WD carcinoma

PTC (difficult if solid variant PTC) FTC (difficult if solid & few mitoses)

1% US 2% South East Asia6% Italy (Alpine area)

PD ca - Incidence

Varallo Sesia, Italy

Yu. Endocr Metab Seoul 2017 Win. Indian J Pathol Microb 2017

> growth pattern (solid/trabecular/insular)?

PD ca: Diagnostic controversy since 1983

1984

1983

1993

High grade features (mitoses >5 & necrosis) are similarly prognostic as the Turin proposalGnemmi, Aubert. PD thyroid carcinomas: application of the Turin proposal provides prognostic results similar to those from the assessment of high-grade features. Histopathol 2014;64:263-73

2006

> Or high grade features?

> Or both??

PD carcinoma

SOLID

INSULAR

TRABECULAR

Ki67 ≥ 4% predicts survival Histopathology 2014;64:263-73

MIXED

Mitoses & Necrosis

PD ca - Diagnostic clues

NO

A malignant solid trabecular tumor with non-PTC nuclei and mitoticindex >3/10HPF or necrosis, or convoluted (raisin-like) nuclei

Different patterns in different Countries

March 2006The Turinproposal

83 cases x 10 experts

Day 2

PDca

AC & others

FTC

PTC, any variant

EU USA JAP

The Turin proposal

Day 1

Dr Rosai, Turin 2006

Diagnostic algorithm “Turin proposal”

The Turin proposal for PD caclassification was endorsed by

WHO 2017, page 102

PD carcinoma: high grade features

PD carcinoma PDC DM GET EVI

GET: gross extensionbeyond thyroid

Bin Xu et al.

PD carcinoma, oncocytic variant

Oncocytic PDca (“Turin proposal”) made of small/medium size cells follows a more aggressive behavior Asioli. Human Pathol 2014;45:1489

PD carcinoma, oncocytic variant

Worseprognosis

associated components

Hobnail features in AC and PDca

“Hobnail” is a rare variant of PTC associated to a more aggressive behavior. Hobnail features >10% were identified in-PD ca (4/18 cases, 22%), -anaplastic ca (1/26, 3.8%) -only 6 of 478 (1.3%) of PTC (all clinically aggressive variants).Hobnail features may be a manifestation of higher-gradetransformation.

Teng L. Hobnail variant of PTC. Oncotarget 2017;8:22023. Different molecular profile compared to classical PTC, and also to PD ca and ATC.

A- High grade features (atypias, necrosisand mitoses in S/T tumor clusters of cellblock or smears) may point to PDca, if IHC is concordant (TG dots) THY4 (or even 5).

B- A S/T growth of follicular (TG+) cellsleaves several options open

indeterminate category, as for follicularneoplasms THY 3b

Can PDca be diagnosedby FNA cytology?

depending on each case

YES/NO

-High cellularity (solid/trabecular clusters)-Discohesive, small/intermediate size cells

-Rare microfollicles and scant colloid-High mitotic activity -Mild atypia

-Necrosis

PD ca – Main features in FNA cytology

Saglietti … Bongiovanni. FNA diagnosis of PDTC. A review of the recent literature. Cytopathology 2017;28:467-474

Bongiovanni. Cancer Cytopathol 2009;117:185-194

Other solid/trabecular tumors in the thyroid

Is IHC confirmation mandatory? YES

Fetal (follicular) adenomaMedullary carcinomaThyroid ParagangliomaMetastatic NE tumorsTG

Ki67

PDca

HTT/HTASolid trabecularPTC

Parathyroidtumor

How much “poorly differentiated” needed?

Relevance of PDca diagnosis

Relevance of PDca diagnosis

In an independent series, the Turin consensus criteria reliably stratified PDCa cases, with similar overall survival compared to other series. [IMP3 was a further adverse prognostic factor in such PDCa series].

The “Turin proposal” helps to identify thyroid PDca associated to the worst survival.

Ito. World J Surg 2008;32:1535-43

Dettmer. AJSP 2011;35:1866-72 Bongiovanni. Int J Surg Path 2014

Asioli. Mod Pathol 2010;23:1269-78

10%

Rossi, Fadda. AIMM 2015;23:196-201

A minor PDC component (10%) is associated to poor prognosis as cases with extensive PDCa areas.

PD Sakam. PD WHO PD Turin

_______________________________________________

# cases 189 15 5

10 yrs DFS 77% 53.8% 25%

10 yrs survival 94.2% 80% 60%

- Aggressive clinical behavior ++

-Surgery 1st choice then early radio

iodine therapy to obtain persistent results; uptake retained in 80% of PDC. Refractory tumors increasing.

Why is an accurate PDca dx needed?

-Adverse prognostic factors: age >45, size, extrathyroidal extension, distant mets, no post-operative radioiodine therapy.

Hannallah. Int J Endocrinol2013;2013:317487

Asioli. Mod Pathol 2010;23:1269-78 Ibrahimpasic. Thyroid 2013;23:997-1002

-5-yr OS: 60-85%Kazaure. Cancer 2012;118:3260-7Ibrahimpasic. JCEM 2014;99:1245-52

-New therapies? eg somatostatin receptors SSTR5 truncated variant is highlyexpressed in PDca SSA efficacy?

Puig-Domingo. PLoS One 2014;9:e85527

Follicular adenomaRASTSH r, αGTPbp(hyperfunctioning)

HTT: RET/PTC, other?

Follicular carcinomaRAS, PAX8/PPARγ, PI3K, TSHR

Papillary carcinomaRET/PTC, TRK, BRAF, RAS, (APC, CTNNB1)

Anaplastic carcinomaBRAF, PTEN, p16, TP53

BENIGN

MALIGNANT

Molecular alterations in the spectrumof follicular cell-derived tumors

PD carcinomaRAS, PI3K, TP53 (BRAF, RET)

Genetics

Molecular data on 65 PDca classified

according to the Turinproposal

YE NIKIFOROV M VOLANTE

23%

NGS demonstrated mutations in up to 30% of PDCa, mostly in BRAF & RAS (+ PIK3CA, TP53, TSHR & others). Nikiforova. JCEM 2013;98:E1852-60

Genetics in PDca

-Mutually exclusive mutations are found in TP53 (AC: 42%; PDCa: 27%) and RAS(AC: 31%; PDCa: 18%) (p= 0.035). -PIK3CA, PTEN, & CDKI mutations in 14%-20% of PDCa and in 10%-14% of AC. -BRAF, CTNNB1, AXIN1 mutations were rare.

Pita. JCEM 2014;99:E497-507

RET/PTC rearrangements & BRAF mutations in PDca are mostlyassociated with PTC features

Using miR-23b and miR-150 as a separator, 73-79% accuracy was found in taking PDCaapart from WD thyroid cancers.

Dettmer. J Mol Endocrinol 2014;52:181-9

Some miRNAs are down regulated in PDca & AC

Horm Metab Res 2009;41:475-81

Analysis of deregulated miRNAs is helpful to distinguish

poorly differentiated thyroid carcinoma from papillary

thyroid carcinoma.

Schwertheim S, Sheu SY, Worm K, Grabellus F, Schmid KW.

Genetics / epigenetic changes

Dysregulated epigenetic candidates include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex

Sasanakietkul T. Mol Cell Endocrinol 2017

Genetics

Genetics

From WDCa to ATC: BRAF & RAS + p53, mTor, TERT promoter, PI3K, EIF1AX, SWI/ SNF, mismatch repair, ….

PDCa

ATC

Phenotypic, molecular & prognostic features of PD ca

WHO 2017

In other tumor models predictive biomarkers of response to chemotherapy were identified, such as:-Thymid. synthase (TS) response to antifolates-ERCC1 response to cisplatin-RRM1 response to gemcitabine-Topoisomer. 2A response to etoposide (& doxo)

Therapeutic issuesCrouzeix G et al. Unusual short-term complete response to two regimens of

cytotoxic chemotherapy in a patient with PDTC. JCEM 2012;97:3046-50

Rosenbaum MW,… Faquin WC. PD-L1 and IDO1 Are Expressed in Poorly

Differentiated Thyroid Carcinoma. Endocr Pathol 2018;29:59-67.

25% PDTC were PDL1 positive. Almost one third of these also co-expressed IDO1 (indoleamine 2,3-dioxygenase). Immunocheckpoint inhibitors (+ IDO1 inhibitor) should be explored as a novel treatment modality of PDTC.

-53 PD carcinomas (Turin criteria)

-20 anaplastic carcinomas

-BRAF, NRAS and HRAS mutations-TS, ERCC1, RRM1, TOPO2A, VEGFR 1,2,3, PDGF-Rβ gene expression

Predictive gene expressionG

E l

eve

ls

TS ERCC1

PDCAAC PDCAAC

p=0.0092 p=0.0003

p=0.00002

p=0.0055

PDCAAC

PDCAACPD

GFR

βV

EG

FR

2

Gene expressionand genotype

TS RRM1

BR

AF

p=0.088R

AS wt

TOPO2A

BR

AF

RA

S wt

BR

AF

RA

S wt

p=0.087 p=0.115

BRAF: 3/73, all AC, all V600E

RAS: 14/73 (4/20 AC & 10/73

PDca), all N-RAS61

Gen

e e

xp

ress

ion

levels

COMMENTS: 1) genotype (BRAF vs RAS/wt) was associated to specific gene profiles.2) GEP of DNA synthesis/repair enzymes and vasculogenic receptors was different in PDca vs AC different responsiveness to CT & targeted tx ??

Sobrinho- Simoes M, 1990?

FOLLICULARCARCINOMA

PAPILLARYCARCINOMA

POORLYDIFFERENTIATED

CARCINOMA

UNDIFFERENTIATED

CARCINOMA

Rosai J, USCAP 2004

PDca

PTC

FTC

AC

THE STORY OF PD CA

University of Turin

Medical School

Marco Volante

Luisella Righi

Ida Rapa

Simona Vatrano

Federica Massa

Arianna Votta

Jessica Giorcelli

Stefania Izzo

Massimo DiMaio

Silvia Novello

Giorgio Scagliotti

Thank you!!

Luisa Delsedime

Francesca Maletta

Luca Molinaro

Carla Pecchioni

Chiara Musuraca

Francesca Veneziano

Jasna Metovic