WHO 2017:

New Classification of
Head and Neck Tumours

Ilmo Leivo
Department of Pathology
University of Turku
& Turku University Hospital
FINLAND

Suomen IAP Aulanko 18.05.2018

WHO 2017 ❖ New entities

❖ Simplification of
terminology

❖ Regrouping of
rare entities
WHO 2017

❖ Regrouping of
rare entities

❖ New entities
WHO 2005 WHO 2017
Acinic cell carcinoma Acinic cell carcinoma

Mammary analogue Secretory carcinoma

secretory carcinoma
(Skalova et al AJSP, 2010)
 SECRETORY CARCINOMA OF THE BREAST

• Description: “… a rare type of carcinoma characterized by large amounts of

intra- and extracellular secretory materials...”

• Microscopy: Uniform bland cells, secretions

• IHC: S-100 +, CEA +, ER –
• Genetics: Translocation t(10;15) with ETV6-NTRK3 in 92%

• Clinical course: Generally indolent

Breast: Secretory carcinoma
Parotid gland: Secretory carcinoma
 Secretory Carcinoma

CK7 Mammaglobin
 Secretory Carcinoma

Vimentin S-100
 Secretory Carcinoma of Salivary Glands
- Clinical

• Sites: - Parotid gland

- Submandibular gland
- Minor glands ( most previous cases of minor gland AciCC ! )
- Sinonasal area

• Behavior: Spectrum of behavior similar as in AciCC

 ACINIC CELL CARCINOMA

• IHC: DOG-1 +, SOX10 +

• Mammaglobin -, S-100 -, vimentin (-/+)
• D-PAS + zymogen granules

- Solid pattern - Acinar cells

- Microcystic pattern - Intercalated ductal cells
- Papillary-cystic pattern - Vacuolated cells
- Follicular pattern - Nonspecific glandular cells
- Clear cells

• Unusual in minor salivary glands

 WHO 2005 WHO 2017
Polymorphous low-grade Polymorphous adenocarcinoma
adenocarcinoma (PLGA) (PAC)
PAC
 1999 2011 2014
Cribriform Cribriform Cribriform
adenocarcinoma adenocarcinoma adenocarcinoma
of the tongue of the tongue and of minor salivary
minor salivary glands glands
(CATS) (CAMSG)
CAT Michal paper scans
CAMSG
CAMSG: Glomeruloid structures
 Cribriform Adenocarcinoma of the Minor Salivary Glands

• Poorly circumscribed infiltrative submucosal mass

• Neck lymph node metastases at presentation in 70%

• Outcome: 21 cases with follow-up

- 19/21 alive NED
- 1 alive with disease
- 1 died of other causes
 Gene fusions in CAMSG vs. PAC

• Rearrangements of PRKD1, PRKD2, PRKD3 with partner genes

ARID1A and DDX3X (diacylglycerol and PKC signaling pathway)
in CAMSG (80%) (16/21 cases)

• Overlap cases:
PAC (6%) (1/18 cases)
PRKD1 hotspot mutations encoding p.Glu710Asp in PAC
 WHO 2017

❖ WHO 2017 defines CAMSG/CATS

as a variant of polymorphous
adenocarcinoma (PAC)
 1994 WHO 2005 WHO 2017
Hyalinizing Clear Cell Carcinoma, Clear Cell Carcinoma
Clear Cell Carcinoma NOS
 2004 WHO 2005 WHO 2017
Low-Grade Salivary Low-Grade Cribriform Intraductal Carcinoma
Duct Carcinoma Cystadenocarcinoma (IDC)
(LG-SDC) (LGCCC)
 Low-grade Cribriform Cystadenocarcinoma
IDC IDC SDC
INTRADUCTAL CARCINOMA SALIVARY DUCT CARCINOMA

❖ S-100 +++ S-100 -

❖ Androgen receptor – Androgen receptor ++
❖ HER-2/neu – HER-2/neu ++

S-100
❖ Cystadenocarcinoma
❖ Papillary cystadenocarcinoma
❖ Mucinous adenocarcinoma
❖ Intestinal-type adenocarcinoma
❖ Lesional cells clonal

❖ Sclerosing polycystic adenoma ?

NUT (midline) carcinoma
❖ Mean age 22 years
❖ Nasal cavity, paranasal sinuses, other areas in
upper airways, salivary glands
❖ Generally midline
❖ Overall survival 10 months
Adenoid Cystic Carcinoma (AdCC)
 Adenoid Cystic Carcinoma -
Occurrence of Gene Fusion

t(6;9)(q22-23;p23-24) MYB-NFIB in 90-100% AdCC

❖ Salivary glands, lacrimal glands, ceruminal glands,

sinonasal tract, bronchial glands, larynx, breast, vulva
Mutational landscape of AdCC

• Mean of 22 exonic somatic mutations per tumor

• Low mutation rate, wide mutational diversity

Mutations
• in chromatin regulators SMARCA2, CREBBP, KDM6A
(35% of AdCCs)
• in genes central to DNA-damage and PKA signalling
• MYB-associated genes
• in genes of FGF/IGF/PI3K pathway (30% of AdCCs)
Mucoepidermoid Carcinoma (MEC)
Translocation t(11;19)(q21;p13)

CRTC1-MAML2
❖ CRTC1-MAML2
❖ TP53
❖ POU6F2
 Mutational landscape of MEC

• Mean of 43 exonic somatic mutations per tumor

• Low mutation rate, wide mutational diversity

Mutations
• in tumor suppressor TP53 (LG-MEC 0%, IMG/HG-MEC 56%)
• in transcriptional regulator POU6F2 (only in LG-MEC, in 30%)

• in other genes IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL (very low recurrence)
 Translocations and fusion genes in salivary gland carcinomas

translocation fusion (major) fusion (alternative)

❖ Adenoid cystic carcinoma t(6;9)(q22-23;p23-24) MYB-NFIB
❖ Mucoepidermoid carcinoma t(11;19)(q21;p13) CRTC1-MAML2 CRTC3-MAML2
❖ Acinic cell carcinoma t(4;9)(q13.3;q31.1) HTN3-MSANTD3 PRB3-ZNF217
❖ Secretory carcinoma t(12;15)(p13;q25) ETV6-NTRK3 ETV6- X
❖ Clear cell carcinoma t(12;22)(q12;p13) EWSR1-ATF1
❖ Myoepithelial carcinoma several several
❖ Intraductal carcinoma NCOA4-RET TRIM27-RET
❖ Cribriform adenocarcinoma
of minor salivary glands PRKD1, PRKD2, PRKD3
- ARID1A, DDX3X
❖ Polymorphous
adenocarcinoma PRKD1 Glu710Asp hotspot mutation
 Conclusive comments -
Molecular pathogenesis of SGC

❖ Genomes have no high-frequency CNAs

❖ Mutation rates low, mutational diversity wide

 Tumor type-specific translocations assume

major significance as drivers of pathogenesis

❖ Epigenetic changes are likely to play additional roles

Kiitos !