professor of pathology charles university, faculty of

Salivary glandcarcinomas-update

Alena Skalova, MD, PhD

Professor of Pathology

Charles University, Faculty of Medicine in Plzen, Czech Republic

An update on Histopathology of Salivary Gland Tumors, La Spezia, Italy, Oct 18-20, 2017

Salivary gland carcinomas• Rare tumors with heterogenous morphology

• Newly described entities and reclassification

of other salivary gland ca

• Genetic alterations, some of them specific

oCRTC1/MAML2, ETV6/NTRK3, PLAG1,etc

• Immunohistochemistry

oMIB1 and prognosis (AciCC, MEC,

AdCCa)

• Chalenging both for pathologists and

clinicians

Incidence, etiology and risk factors

• about 0.5% of all malignancies and less that

5% of all head and neck cancers

• Risk factors are largely unknown

o Ionising radiation

o Endogenous hormones (AR in SDC)

o Hereditary origin in basal cell carcinoma

and acinic cell carcinoma

Grading• different concepts of grading the heterogenous

group of SG tumors have been proposed but there is no consensus to date

• grading of SG cancers is an important predictor of survival

• Carcinoma types for which grading systems exist and are relevant are incorporated into histologic type.

• amenable to grading include o adenoid cystic carcinoma,

o mucoepidermoid carcinoma, and adenocarcinoma, not otherwise specified.

o polymorphous adenocarcinoma

Low-risk category• LG mucoepidermoid carcinoma

• Acinic cell carcinoma

• Basal cell adenocarcinoma

• PLGA

• MASC

• Cystadenocarcinoma

• Clear cell carcinoma

• Epithelial-myoepithelial carcinoma

Intermediate-risk category

• Grade 2 mucoepidermoid carcinoma

• Tubular and cribriform adenoid cystic

carcinoma

• Myoepithelial carcinoma

• Mucinous adenocarcinoma

High-risk category• High grade mucoepidermoid carcinoma

• Solid (basaloid) adenoid cystic carcinoma

• SDC

• Carcinoma ex pleomorphic adenoma

• Carcinosarcoma

• HG clear cell myoepithelial carcinoma

High-grade transformation

• Acinic cell carcinoma

• MASC

• Adenoid cystic carcinoma



• PLGA, etc.

High-grade transformation

• High grade transformation (originally called

“dedifferentiation”) is defined as the histologic

progression of a low grade malignant neoplasm to

a high grade one, within which the original line of

differentiation is lost

• always associated with tumor progression

• Aggressive behavior and poor outcome

HG transformation of MASC

MIB1

HG transformation of MASC

Staging

• SG carcinomas are staged according to the

recommendation of the Am Joint Committee on

Cancer (AJCC) or the UICC (International Union

against Cancer)

• distinct TNM classification exists for major salivary

glands

• minor salivary gland tumors are staged as oral

squamous cell carcinoma

Prognosis• Histologic type

• Age (high age is worse)

• Stage and grade

• Gender (male worse)

• Site (submandibular gland worse)

• facial nerve involvement

• MIB1 proliferation activity

• CRTC1/MAML2 translocation (better)

"Molecular classification" of salivary gland carcinomas

• Mammary analogue secretory carcinoma

(MASC)

• adenoid cystic carcinoma

• mucoepidermoid carcinoma

• hyalinizing clear cell carcinoma

• CATS versus PLGA


• Intraductal carcinoma

Key molecular alterations in

salivary gland carcinomasTumor type Chromosomal

alterationGene fusion/rearrangement

Prevalence (%)

(Mammary analogue) secretory carcinoma

t(12;15)(p13;q25)t(12;X)

ETV6-NTRK3ETV6-RET

95-982-5

Mucoepidermoidcarcinoma

t(11;19)(q21;p13)t(11;15)(q21;q26)

CRTC1-MAML2CRTC3-MAML2

40-805

Hyalinizing clear cell carcinoma

t(12;22)(q21;q12) EWSR1-ATF1 80-90

Adenoid cystic carcinoma

t(6;9)(q22-23;p23-24)t(8;9)

MYB-NFIB

MYBL1-NFIB

25-8010-20

Polymorphous adenocarcinoma

14q12 Hotspot activating PRKD1somatic point mutation (E710D)

20

Cribriform adenocarcinoma of minor salivary glands

t(1;14)(p36.11;q12)t(X;14)(p11.4;q12)

ARID1A-PRKD1DDX3X-PRKD1PRKD2 and PRKD3 rearrangements

241316

Salivary duct carcinoma/ IC

17q21.13q26.32inv(10)(q11.21q11.22)

HER2 amplificationPIK3CA mutationNCOA4-RET

20-4020<5

Mucoepidermoidcarcinoma

Mucoepidermoid carcinoma

• common salivary gland tumor

• occurs in broad age range and can appear both in major and minor glands

• translocation t(11;19) fuses MECT1 (mucoepidermoid carcinoma translocated-1) at19p13 with MAML2 (mastermind-like gene

family) at 11q21

• also known as CRTC1/MAML2

Tonon et al. 2003. Nat Genet 33:208-213.

Behboudi et al. 2006. Genes Chromosomes Cancer 45:470-481

Low grade mucoepidermoid

carcinoma- prognosis

• Proportion of cystic

and solid growth

patterns

• MIB1 index

• Invasion

• CRTC1/CRTC3–MAML2

translocation

Mucoepidermoid carcinoma

• Highly variable clinical prognosis

• Grading of MEC o WHO 2005, AFIP, Brandwein-Gensler system, modified

Healey grading system, etc.

• CRTC1/MAML2 t(11;19) fusion positive

patients have better outcomeso Less local recurrences, metastases and tumor-related

deaths

Adenoid cystic carcinoma

Adenoid cystic carcinoma• both minor and major SG

• relentless clinical course with late recurrences and

distant metastases

• causes significant morbidity

• Perineural infiltration

• intracranial invasion

Adenoid cystic carcinoma• Recurrent t(6;9) translocation in AdCC

of both head and neck (salivary,

lacrimal, ceruminal glands) and breast

• Translocation fuses MYB oncogene

with transcription factor gene NFIB

o Leads to chimeric MYB-NFIB fusion

transcript

oMYB activation through gene fusion is a

major oncogenic event in AdCCa of

many sites

Adenoid cystic carcinoma• Differential diagnosis

oMYB-NFIB fusion- in 30-100% caseso All anatomic locations

• prognosis

oMYB-NFIB fusion- positive cases show

tendency toward higher local relapse rate

• MYB-NFIB fusion is a candidate therapeutic

target

Mammary analoguesecretory carcinoma

(MASC)

Mammary analoguesecretory carcinoma (MASC)

Mammary analogue secretory

carcinoma (MASC)• akin to secretory carcinoma of the breast,

MASC expresses S-100 protein and

mammaglobin and harbours a

t(12;15)(p13;q25) translocation that results in

an ETV6/NTRK3 fusion product

• presence of t(12;15) has not been

demonstrated in any other salivary gland

tumour so far

Mammary analogue secretory carcinoma of salivary glands

1 2 3 4 5 6

ETV6 NTRK3

Mammary analogue secretory carcinoma of salivary glands

Hyalinizing clear cell carcinoma of minor salivary

glands


of minor salivary glands


of minor salivary glands• considered a diagnosis of exclusion

• Despite its very distinctive appearance it

was labeled as “not otherwise specified “ by

WHO 2005

• Dif. Dg.

o clear epithelial-myoepithelial ca,

mucoepidermoid carcinoma, myoepithelial ca

o metastatic renal cell ca

o clear cell odontogenic ca

Simpson et al: Histopathology 1990: 17:433-438Milchgrub et al. Am J Surg Pathol 1994:18:74-92

EWSR1-ATF1 fusion is a novel and consistent finding in hyalinizing clear-cell

carcinoma of salivary gland

Cristina Antonescu, et al, and Ilan Weinreb.

Genes Chromosomes Cancer 2011: 50:559-70.

EWSR1-ATF1 translocation

• EWSR1-ATF1 fusion gene in soft tissue tumors (alsowith other fusion partners, such as CREB1, etc.)

• EWSR1-ATF1 fusion has been characterized by Antonescu et al. as a consistent finding in HCCCa

• Recently seen in clear cell odontogeniccarcinoma (CCOCa)

• HCCC can be distinguished from its mimics, such as epithelial-myoepithelial carcinoma and mucoepidermoid carcinoma

• Molecular and biological link between HCCCaand CCOCa

EWSR1 positive clear cell myoepithelial carcinoma

FISH analysis using EWSR1 dual color, break apart probe. Visualization under Triple Band Pass filter. Yellow signals indicate intact EWSR1 gene region, separated green and red signals represent rearrangered EWSR1 gene region. Several nucleipositive for EWSR1 break are shown.

EWSR1 positive clear cell myoepithelial carcinoma

Clear cell myoepithelialcarcinoma EWSR1 positive

• arranged in nodules composed of compact nests

of large polyhedral cells with abundant clear

cytoplasm

• Necrosis, areas of squamous metaplasia, and

hyalinization

• IHC- tumors expressed p63 (96%), cytokeratin CK14

(96%), and S-100 protein (88%)

• MIB1 index varied from 10-100% with most cases in

20-40% range

Clear cell variant HG myoepithelial carcinoma

MIB1 40%

Clinical follow-up of CCMC

• available in 21 cases (84%), and ranged from 3

months to 15 years (mean 5.2 years)

• 10 patients - alive NED in follow up period from 3

months to 15 years (mean 5 years)

• 3 patients - alive with recurrent/metastatic disease

• 8 died of disseminated cancer 9 months to 16 years

after diagnosis (mean 6 years)

• LN mets - 5 patients within 5 months to 4 years after

diagnosis (mean 22 months)

• distant mets - 7 patients o orbit (2 cases), one case each neck soft tissues, liver, lungs, mediastinum,

and thoracic vertebra

Conclusions: CCMC• We describe for the first time EWSR1 gene

rearrangement in a subset of MC arising in minor

and major salivary glands

• The EWSR1 rearranged CCMC represents distinctive

aggressive variant composed predominantly of

clear cells with frequent necrosis

• Most EWSR1-rearranged CCMC of salivary glands

are characterized by poor clinical outcomes

Conventional“ classificationof salivary gland

carcinomas

„Conventional“ classificationof salivary gland carcinomas• Acinic cell carcinoma

• PAC/PLGA


• Oncocytic carcinoma

• Salivary duct carcinoma

• Carcinoma ex pleomorphic adenoma (PA)

• Metastasizing PA

• Hybrid and metastic tumors

Acinic cell carcinoma

Acinic Cell Carcinoma

Acinic Cell Carcinoma• Accounts for 18% of malignant SG tu

• Parotis (80%), minor SG, subm gland

• Women affected more commonly

• Age: evenly distributed 3-7th decades

• 2nd most common malignant SG tumor in children

• 3rd most common bilateral tumor (3 %), after Warthin’s tumor (5-10%) and PA

• Multifocal, familiar occurrence

Well differentiated

AciCCa with lymphoid

stroma

Acinic Cell Carcinoma

Notoriously protracted clinical course

Expected rates:

Recurrence: 30-50%, often multiple

Metastasis : 13%

Mortality : 30%

Death of progressive loco-regional or

metastatic disease

Metastasis: lymphatic and/or hematogenous

(lung, bone)

Acinic Cell Carcinoma: Disease course

Polymorphous (low-grade) adenocarcinoma (PLGA)

Polymorphous low grade

adenocarcinoma PLGA

Perineural infiltrationTumour cells show bland cytonuclear abnormalityIndian filing appearance resembling lobular carcinoma of the breast

Minor glands only

Salivary duct carcinoma

Salivary duct carcinoma• about 10% of malignant salivary gland tumors

• Male to female ratio 4:1

• Most patients older than 50 years

• Parotid gland most commonly involved

• Pain and facial nerve paralysis

• Perineural invasion 60%

• Intravascular tumor emboli 31%

• Most patients present with stage III and IV

• Lymph nodes positive in 50% (range 40-72%)

Luminal type SDC

AR

HER2

HER2 type SDC

Rare salivary glandcarcinomas


• carcinosarcoma

• Cystadenocarcinoma

• Mucinous adenocarcinoma


• Cribriform adenocarcinoma of tongue and other

minor salivary glands (CATS)

Myoepithelial carcinoma

• Most cases arise in parotid gland

• but they also occur in submandibular and minor

glands, usually the palate

• they rarely may arise in the base of tongue,

maxillary sinus and larynx

• may arise de novo, but at least half of them

develop in pre-existing pleomorphic adenomas

(PA) or benign myoepitheliomas

• mean age of patients at presentation is about 55

years (range 14-86 years)

Macroscopy• unencapsulated but may be well-defined with

nodular surfaces

• cut surface is grey-white and can be glassy

• some tumors reveal areas of hemorrhage, necrosis

and pseudocystic degeneration

ASMAp63 protein

Prognosis of myoepithelial carcinoma

• one third of patients die of disease

• another third have multiple recurrence

• remaining third are disease free

• Myoepithelial carcinomas ex recurrent PAs may

persue a prolonged clinical course

• marked cellular pleomorphism, high mitotic rate

and high proliferative activity (MIB1 index) correlate

with poor prognosis

Differential diagnosis• salivary duct carcinoma

• spectrum of clear cell tumors

• mucoepidermoid carcinoma

• soft tissue sarcomas

• variety of clear cell neoplasms primary and

metastatic, including epithelial-myoepithelial

carcinoma, clear cell carcinoma NOS, hyalinizing

clear cell carcinoma and metastatic renal cell

carcinoma

• immunohistochemistry is helpful in excluding these

neoplasms

Carcinosarcoma

Carcinosarcoma• Very rare biphasic salivary gland tumor

composed of sarcomatous and

carcinomatous component

• Variable histomorphology

• Arise ex pleomorphic adenoma or de novo

• Aggressive, high grade malignancy

AR

HER-2/neu

MIB1 proliferative activity

Cystadenocarcinoma

Cystadenocarcinoma• rare malignant tumor of salivary glands

characterized by invasive growth and multiple cystic structures lined with epithelium

• accounting for 0.5 to 2.0% of malignant salivary gland tumors

• Although the age range is broad (5 to 87 years), more than 70 % of patients are over 50 years of age

• grossly, the tumours are cystic or multicystic, well circumscribed unencapsulated lesions that usually range in size from 0.4 to 10 cm in greatest dimension

• cystadenocarcinoma represents malignant counterpart of cystadenoma

Site and treatment• In AFIP series about 60 percent occur in major

salivary glands, most of these were located in

parotid gland

• minor glands are affected in descending order in

frequency in palate, buccal mucosa, lips, floor of

mouth and tongue

• majority are low-grade or intermediate-grade

neoplasms

• treatment should be relevant to grade and stage of

the tumor

Mucinous adenocarcinoma

Mucinousadenocarcinoma

• a malignant epithelial tumor composed of epithelial

clusters within large pools of extracellular mucin

• mucin component occupies the majority of the

tumor

• Signet-ring cell carcinoma - characterized by

presence of isolated tumor cells with

intracytoplasmic mucus vacuoles

• Mucinous (colloid) adenocarcinoma of major and

minor salivary glands is an extremely rare neoplasm

• Most tumors arise in minor salivary glandso namely in the glands of palate

o buccal mucosa

o floor of the mouth, and base of the tongue

o few cases have been described in the parotid gland

• tumor is often nodular and ill defined

• cut surface is whitish-grey with multiple cystic

spaces containing gelatinous secretory material

• Mucinous (colloid) adenocarcinoma of salivary

glands is histologically identical with breast and

colorectal analogues

Differential diagnosis• mucinous cystadenoma

• mucinous cystadenocarcinoma

• mucoepidermoid carcinoma (MEC)

• mucin-rich salivary duct carcinoma

• metastic tumors

• mucin extravasation phenomenon

Basal cell adenocarcinoma

Basal cell adenocarcinoma• rare malignant epithelial tumor of major and minor

salivary glands composed of predominantly

basaloid cells

• cytologically and morphologically similar to basal

cell adenoma

• but has invasive growth and potential to develop

metastases

Site and gross appearance• Over 90% of BCAC occur in parotid gland

• occurs over a wide age range with average age of

60

• most are well defined nonencapsulated lesions

• on cut section, they are mostly homogenous, some

of them partly cystic

Microscopy• 4 main growth patterns – tubular, trabecular, solid,

and membranous

• BCAC is composed of basaloid cells with large

round to oval nuclei and little cytoplasm

• most tumors have a limited mitotic activity and

nuclear and celllular polymorphism

• diagnosis of BCAC is based on invasive growth into

the adjacent tissues and identification of perineural

or vascular invasion

Vážený pane docente, chtěla bych Vás požádat o přidání termínů na zkoušky z Farmakologie. Ve zkouškovém období byl vypsán sice dostatečný počet míst pro studenty 4. ročníku, bohužel tyto termíny pro studenty nestaVážený pane docente, chtěla bych Vás požádat o přidání termínů na zkoušky z Farmakologie. Ve zkouškovém období byl vypsán sice dostatečný počet míst pro studenty 4. ročníku, bohužel tyto termíny pro studenty nesta

Treatment and prognosis• low-grade malignancy

• cumulative data from the literature reveal a local

recurrence rate of about 37%, locoregional

metastatic rate of 8% and very low risk of distant

metastasis

• Optimal treatment includes wide surgical resection

with free margins, additional radiotherapy or

elective neck dissection are not warranted

Sialoblastoma

Sialoblastoma-definiton• low-grade malignant neoplasm usually present at

birth or shortly thereafter

• composed of epithelial basaloid and myoepithelial

cells that recapitulate primitive salivary gland

anlage

• Sialoblastoma was first reported in 1996 by Vawter

and Tefft who used the term embryoma

• approximately 40 tumors, that fit into a definition of

sialoblastoma, were reported under different nameso congenital basal cell adenoma

o congenital hybrid basal cell adenoma/adenoid cystic carcinoma

o sialoblastoma

Sialoblastoma-grossly• arises almost exclusively in perinatal period with rare

cases presenting after 2 years of age

• tumors range up to 15 cm in greatest dimension

and are well circumscribed and even partly

encapsulated

• they may be locally invasive with extension to

adjacent soft tissues and bone

Sialoblastoma-microscopy• It recapitulates embryonic development of major

salivary glands

• variable histological patterns, composed of variably sized nests and solid sheets of basaloid cells with focal ductal differentiation and cystic and microcystic change

• cells are fairly uniform with minimal cytoplasm and round to oval nuclei with only slight polymorphism

• Mitoses are frequently found and may be numerous, atypical mitoses are not present

• Neural and occasionally vascular invasion may be found

Cribriform carcinoma of minor salivary glands

• 23 patients/15x cervical LN meta• In 3 patietns original dg was metastasis of PTC

Ground-glass nuclei („Orhan Annie eyes“)-resemble papillary ca of thyroid

Papillary growth pattern, ground-glass nucleiCK7, S-100, actin+

TTF1, Thyreoglobulin neg

Ground glass nuclei in LN metastasis

D2-40

LVI

CATS versus PLGA• extensive nuclear ground-glass change in CATS with

overlapping clear “Orphan Annie eye–like nuclei”

• a novel and recurrent ARID1A-PRKD1 fusion in CATS

was recently detected

• CATS had lymph node metastases in most cases

already at the time of the presentation of the

primary tumor

Conclusions• Morphology and immunoprofile

• unique oncogenic translocations

o Diagnostic markers (HCCC, MASC)

o Identify as yet not discovered tumor types or

reclassify (MASC)

o Some may be prognostic (MAML2 in MEC)

o May serve as targets for therapy (MYB-NFIB?

ETV6/NTRK3?)

o Many others wait for identification (CCMC,

PLGA, CATS, etc.)

Thank you for attention

An update on Histopathology of Salivary Gland Tumors, La Spezia, Italy, Oct 18-20, 2017

professor of pathology charles university, faculty of

Documents