IAP / SGPath Switzerland

Bern 2017: Salivary glands

Stephan Ihrler
Labor für Dermatohistologie und Oralpathologie, München
In cooperation with: Pathologisches Institut, LMU München
Case 1: Tumour right parotid
gland, 56 y., female
Intracapsular / intraductal
Carcinoma ex PA

CK18

Ki67

CK14
 Intraductal carcinoma in CEPA
• Intraductal component in 57 of 82 cases (71 %)
• Obligate precursor in (non-myoepithelial) CEPA
• 25 of our 86 cases (29 %) are purely intraductal
• purely intraductal CEPA do not metastazise
• supports correct diagnosis in difficult cases
• Distinction intraductal / intracapsular CEPA not
absolutely necessary

Diagnoses
CEPA 25
Pleomorphic adenoma 14
Oncocytoma 16
Oncocytic Ca 11
CK14 Acinar cell Ca 6
Myoepithelioma 5
Androgen receptor Myoepithelial Ca 3
Salivary duct Ca 3

Allthogether benign 35/94

„oncocytic“ 34/94
Her2neu 2+ (FISH -)
 CEPA: historically very aggressive carcinoma

Intracapsular CEPA (Li Volsi 1976) classical extracapsular CEPA

(WHO 2005)

„benign“ LG LG HG

Intraductal Intracapsular Minor Widely

CEPA invasive extracapsular extracapsular
CEPA invasive CEPA invasive CEPA
4-6 mm
(WHO 2017)
(confusing terms: In situ / non-invasive / early CEPA)

Multistep carcinogenesis from PA to CEPA

Largely accepted in the new WHO-classification 2017
Multistep carcinogenesis in Ca ex pleomorphic adenoma
Luminal cell of PA (+ CK7, CK18)
Malignantly transformed luminal cell
relatively quick ?
(+ CK7, CK18, some +p53)
Abluminal cell of PA (+ CK14, p63, actin) 3b.
Nuclear Ki67 (MIB I) 3a.
slow quick ?
2.

PA
1.

1. Intraductal carcinoma developing from luminal cells of the tubuli of PA (in

about 40% with mutation of p53 gene, very good prognosis)
2. Transformation into invasive CEPA within capsule of PA
3. Invasion beyond capsule of PA: extracapsular invasive CEPA
Ihrler et al., Weiler et al. Histopathology, 2007 + 2011
CEPA in the new WHO-cassification 2017

75-80%
In situ Ca

20-25%
No in situ
Ca in
myoep. Ca
3mm

*
* minor extracapsular invasive
CEPA (up to 6 mm):

* 14 of our 86 cases (16 %)

no death in our study
 stages of progression conventional pT-classification

• distinction between minor versus

5-8 mm
Weiler C, Guntinas-Lichius O, Schwarz S, ..., Ihrler S,
Histopathology 59(2011)741-750
extensively invasive CEPA is
prognostically more relevant than
conventional pT-classification
• area of distinction: 5-8 mm in our
study; 3 other studies with a similar
threshold (Tortoledo et al., Olsen et al.,
Katabi et al.)
• (WHO 2005: 1.5 mm)
• WHO 2017: 4-6 mm (provisional)
 Complex relationship CEPA – salivary duct ca
causing major terminological confusion
(not solved in the new WHO-classification )

?
CEPA, type
CEPA, salivary duct Salivary
„not ca (30% - 60%) duct ca,
salivary or
de novo
duct type“ Salivary duct (40-60%)
(40 – 70%) ca (type CEPA)
(40 – 60%)

PA

Myoepithelial type CEPA

Case 2: Tumour right
parotid gland, 64 y., male

sofar mostly: „unusual acinar cell ca“

PAS
 DOG-1 -

CK7 + (CK14, p63 -)

t(12;15)(p13;q25) ETV6/NTRK3-
Translocation
S100 + (Mammaglobin +)
(Mammary analogue)
Secretory Carcinoma
of salivary glands
pT3, pN2b, L1

Vimentin (+) Ki67

WHO 2017: new entity Am J Surg Pathol 2010;34:599-608
(---------------------------- )

• Major analogy to secretory

carcinoma of mammary gland
• Sofar mostly classified as
„unusual acinar cell carcinoma“
Diagnoses • Typical IH: CK18/7 +, CK14/p63
Mukoepidermoid Ca 37 -, S100 +, Vimentin +, Mamma-
Secretory Ca 12 globin +, DOG1 -, Ki67: 5-20%
Adeno Ca NOS 10
Acinar cell Ca 10 • Obligate Translocation ETV6-
Oncocytic Ca 4 NTRK3 (infantile fibrosarcoma)
Myoepithelial Ca 4
Polym. LG Adeno Ca 4 • Intermediate prognosis
• sofar 18 own cases, the
Allthogether benign 9/94
tumour is not so rare!
 (Mammary Analogue) Secretory Carcinoma:
t(12;15)(p13;q25) ETV6/NTRK3-Translocation
Detection of ETV6/NTRK3-Translocation by RT-PCR

1 2 3 4 5

▬ 223 bp 1 ETV/NTRK1 Sample

110 bp ▬ 2 Negative Control
3 Blank
4 RT-PCR Control Sample
5 Blank

• Detectable in almost all cases

• In rare cases other translocation partners
• FISH seems to be more sensitive than PCR (new study: 10 cases,
10 + in FISH, 7 + in PCR)
• Molecular testing is suggested for all cases, where diagnosis is
not straightforward with routine and IH staining
 Molecular pathology in salivary tumours
Mucoepidermoid ca t(11;19)(q21;p13) CRTC1-MAML2
Clear cell myoepithelial ca t(12;22)(q13;q12) EWSR1
Clear cell ca t(12;22)(q13;q12) EWSR1
Adenoidcystic ca t(6;9)(q22-23;p23-24) MYB-NFIB
(Mamma analogue) secretory ca t(12;15)(t13;q25) ETV6-NTRK3
Pleomorphic adenoma t(3;8)(q21;q12) PLAG1

Carcinoma ex PA p53, many others

Salivary duct ca Her2-neu, Androgen receptor
……………

• Far later than in other organs – strong progress in the last years
• Still predominantly scientific and diagnostic – theurapeutic in the future
• Predilection for translocations , unusual for carcinomas
• Contributes to an interesting overlap of some salivary tumours with certain
tumours of cutaneous adnexae, of mammary gland, and of soft tissue
 Speicheldrüsen Hautadnexe

Schaltstück
Azinus Streifenstück / Ausführungsgang

CK14 (+ CK Ks8.12, Bcl-2, p63)

CK18
CK7 (+CK18)
-Aktin (+CK14) ekkrin apokrin
Ki-67
DD Infiltration ?
• Adenomatous mucous hyperplasia ?
• Mucinous cystadenoma ?
• Mucinous adeno Ca ?
• Mucoepidermoid Ca ?

Case 3:
Tumour of the lateral border of the
tongue (2.5 mm), female, 83 years,
KS Aarau,
clinically suspicious of squamous cell ca,
Biopsy: ?, „no malignancy“
 • cN0
• wait and see

Diagnoses CK14: -
Mucoepidermoid Ca (esp. LG) 28
Adenomatous/mucous Hpl. 21
Mucinous (Cyst)-adenoma 21
Mucinous adeno Ca 8
Clear cell Ca 5

Alltogether benign 57/94

DD
• Adenomatous mucous hpl. ?
• Mucinous cystadenoma ? p63: +
• Mucinous adeno ca ?
• Mucoepidermoid ca ?

Mucoepidermoid Ca, G1
MAML2-rearrangement +
CRTC1-MAML2 fusion transcript
 Prognostic criteria of proliferative / tumorous
lesions of salivary glands

Reactive / Benign tumour Low-grade High-grade

metaplasia carcinoma (G1) carcinoma (G3)
No (low grade) No (low grade) cellular Low grade (or no) Usually high grade
cellular atypia atypia cellular atypia cellular atypia
Not infiltrative Not infiltrative, (or Mostly, not always Usually severely
pseudo-infiltrative) infiltrative infiltrative

Mucinous or Pleomorphic Azinar cell carcinoma Salivary duct

squamous adenoma carcinoma /
metaplasia metastasis
Rarely danger of Rarely recurrence Frequently local Frequently
misdiagnosis as (or progression) recurrence, rarely recurrences and
tumour metastases metastases

Wide and difficult overlap between certain benign tumours and many types
of low-grade carcinoma: this overlap is much larger in salivary glands
than in many other organ systems
Strategy in a difficult salivary tumour:
- Not dignity first (wrong, like America first)
- But entity ! (entity identifies dignity !)
 Peculiarities of tumours of the small salivary glands
• Tumours of the small salivary glands are more frequently malignant (ca. 45%) than
tumours of the parotid gland (ca. 20 %).
• Carcinoma of the parotid gland are frequently high-grade, while carcinoma of the small
glands are more often low-grade (rendering DD more difficult).
• Some rare entities are restricted to the small glands: canalicular adenoma, sialadenoma
papilliferum, polymorphous low-grade adeno-carcinoma, ect.
• Benign tumours of small glands are often devoid of a tumour capsule, this may cause the
impression of (pseudo-)infiltration.
• Ulceration and necrosis may manifest both in malignant and benign tumours of small
glands (esp. in the palate). Consecutive inflammation with squamous metaplasia may
simulate malignancy.
• In tumours of small glands the diagnostic strategy frequently starts with a biopsy (instead
of total tumour resection used in parotid glands). This may severely limit the diagnotic
accuracy and may induce major inflammation and necrosis, obliterating a tumour rest in a
subsequent resection. Beware of „kein Anhalt für Malignität“ in a biopsy!!!
Case 4: Tumour right
parotid gland, 55 y., female
 p63

CK18

Smaller part:
Adenoid cystic Ca

CK14

Ki67
 Aktin +
(CK14, S100, p63 +)

Ki67

Larger, mono-
morphous part:

Myoepithelioma
or
LG myoepithelial Ca ?

CK7: no tubules with lumen

 Concept of pluriform differentiation of pleomorphic adenoma
schwannoma-
like
Myoepithelial
ca
myoepi-
Myoepithelioma thelial

mucinous
lipo-
matous

onko- myxoid
squamous cytic
• „Monomorphic-tubular
variant of PA“
• Adenoid cystic Ca
• Epithelial-myoepithelial Ca
osteoid
chondroid

S. Ihrler et al., Pathologe 2009

 • Adenoid cyst Ca ex
myoepithelioma
Diagnoses • Malignant hybrid tumour
Adenoid cystic Ca (4x with Dediff.) 28
Epithelial-myoepithelial Ca 15 (Adenoid cyst Ca + LG Myo Ca)
Ca ex PA 6
Myoepithelial Ca 11
Myoepithelioma 5
Pleomorphic adenoma 4
Adenomyoepithelioma 1
„Biphasic Ca“ 1

Alltogether benign 10/94

CK18
CK18
 Salivary tumours
with two distinct components
• Benign tumour – malignant Tx Ca ex PA (case 1)

• LG malignant tumour – HG Tx Acinar cell Ca with high grade Tx

• Malignant hybrid tumour Myo Ca + AdcystCa (case 4)

• Benign hybrid tumour PA + canalicular adenoma

• Collision of 2 different salivary tumours

*
*
Benign hybrid tumour: PA + canalicular adenoma