SALIVARY GLAND

TUMORS

Prof S. Subbiah et al 1
• Major (parotid, submandibular, sublingual)- paired
• Minor – 800, submucosa of upper aerodigestive tract from
nasal cavity to esophagus & trachea.
• Tubuloacinar structures – somatoderm(ectodermal) & foregut
(endodermal). Major SG- ectodermal, Minor SG- both
ectodermal & endodermal. Stroma (capsule, septae)- cranial
neural crest cells
• Type of secretions: serous, mucinous or mixed
• Parotid: serous
• Submandibular: serous > mucinous
Prof S. Subbiah et al 2
• Sublingual: mucinous > serous
 SALIVARY NEOPLASMS

• 3-6% of all tumors of head & neck

• Risk factors:
• Low dose radiation
• Chronic wood dust/soft wood exposure
• Tanning industry
• Rubber & nickel industry

Prof S. Subbiah et al 3
• Incidence of malignancy in tumors of

• Parotid 25%,
• Submandibular 50%
• Minor SG 80%

• Overall salivary gland cancer affects

• Parotid 65%
• Submandibular 8%

Prof• S. Minor
Subbiah et SG
al 27% 4
 WHO- HISTOLOGIC
CLASSIFICATION

Prof S. Subbiah et al 5
 THEORIES OF HISTOGENESIS

• MULTICELLULAR THEORY:
• Each cancer arises from particular cell type
within the secretory unit
• Eg: acinic cell carcinoma from acinus, warthin
& oncocytic from striated ductal cells

• BICELLULAR RESERVE CELL THEORY:

• Tumor arises from basal cells of either
excretory duct reserve cells(epidermoid
tumors) or intercalated duct basal cells
(adenomatoid
Prof S. Subbiah et al tumors) 6
 PLEOMORPHIC ADENOMA

• Most common benign tumor, mixed tumor

• M/C site: superficial lobe of parotid, 5 th & 6th decades, women
• Asymptomatic, slow growing
• Admixture of epithelial, myoepithelial & stromal elements
with architectural pleomorphism
• CARCINOMA EX PLEOMORPHIC ADENOMA:
• High grade
• Malignant part: salivary duct carcinoma, myoepithelial
carcinoma
Prof S. Subbiah et al 7
• Classification: intracapsular, minimally invasive, invasive
 WARTHIN’S TUMOR

• 2nd M/C
• Papillary cystadenoma lymphomatosum
• M/C site: tail of parotid
• Tobacco- smokers -5-10 times, older white men
• B/L in 10%

Prof S. Subbiah et al 8
 MUCOEPIDERMOID CARCINOMA

• M/C in both adults & children

• M/C site: parotid gland
• Low, intermediate & high grade (based on cystic component, neural
invasion, degree of anaplasia, mitoses & necrosis)
• Rarely arises from
• Salivary nests within mandible: central salivary carcinoma
• Ectopic salivary tissue in parapharyngeal space

• Histologically composed of epidermoid (squamoid), mucous &

intermediate cells
• MECT1/MAML2
Prof S. Subbiah et al
fusion genes t(11:19), disrupts NOTCH pathway- 940-
80% of MEC, favorable prognosis
 ADENOID CYSTIC CARCINOMA

• M/C in submandibular & minor SG

• Slow growing, insidious, high degree of neurotropism, PNI+, local
invasion & recurrence
• Salivary glands, oral cavity, nasopharynx, nasal cavity, PNS,
lacrimal glands, lower respiratory tracts, breast, lungs
• Hard , fixed & may tether overlying skin
• Histology: ductal & myoepithelial cells- 3 growth patterns:
cribriform, tubular & solid
• Pulmonary mets are frequent
• MYB protooncogene – translocation (6,9) – fusion of MYB & NFIB10 –
Prof S. Subbiah et al

65% of ACC, worst prognosis

ADENOCARCINOMAS SQUAMOUS CELL LYMPHOMA
CARCINOMA Of
Parotid gland
1. Acinic cell DD: metastasized 85% Non Hodgkin type
carcinomas 10%, intraparotid nodes Arises from
m/c in parotid, from synchronous or • intra glandular
indolent+ high previously treated skin nodes
grade cancer • Nondiscrete
2. Mammary analog lymphoid tissue
secretory carcinoma within the gland
3. Salivary duct 40% SCC, 40% parenchyma
carcinoma melanoma (extra nodal) –
4. Myoepithelial 5%
carcinoma 1. Primary lymphoma
5. Carcinoma ex – associated with
pleomorphic Sjogren syndrome-
adenoma worst prognosis
2. Part of
disseminated
Prof S. Subbiah et al lymphoma 11
 CLINICAL EVALUATION
PAROTID GLAND TUMORS

• Asymptomatic mass
1. Superficial lobe: M/C, rubbery nodular mass, anterior to lobule of ear
in the tail of parotid
• Presence of cervical nodes, facial nerve dysfunction, invasion of skin-
malignancy

2. Deep lobe: fullness in retromandibular region, medial displacement of

soft palate, tonsil, lateral pharyngeal wall
3. Accessory parotid tissue (21%) along stenson’s duct: mass in
midportion of cheek.
Prof S. Subbiah et al 12
4. Diffuse enlargement: Lymphoma, Sjogren’s, Kim-Kimura’s disease
 CLINICAL EVALUATION

SUBMANDIBULAR SALIVARY GLAND TUMORS

• Mass in submandibular region

• Pain- obstruction ± inflammation
• Bimanual palpation differentiates it from enlarged node

MINOR SALIVARY GLAND TUMORS

• Submucous mass ± ulcerated
• Paranasal sinus: facial pain, swelling
• Nasal cavity: obstruction, epistaxis
Prof S. Subbiah et al 13
• Larynx: hoarseness, sore throat
• Pain
 RADIOLOGICAL EVALUATION
• Location & extent

• Xray, sialography, nuclear scans- seldom indicated

• USG:
• Precise location of tumor in gland
• Differentiates solid & cystic components
• Guided FNAC

• CT & MRI – better visualization

• Differentiating solid , cystic
• Relation with soft tissue & bone,
• Nodal involvement

• CT:
• Minor SG: tumor extension, resectability
• Parotid: differentiating deep lobe tumors of parotid from tumors
Prof S. Subbiah et al 14
originating from parapharyngeal origin
• Bone erosion
 RADIOLOGICAL EVALUATION

• MRI:
• Differentiating ectopic or minor SG tumors, assessing
deep lobe, extra glandular extension
• Cranial nerve involvement, soft tissue extension, skull
base invasion, intracranial extension.
• T2 MRI: hypo intensity- malignant, hyperintensity-
benign

• Warthin, pleomorphic adenoma- PET avid

Prof S. Subbiah et al 15
 PATHOLOGY

• FNA – preferred method, USG guidance improves diagnostic yield

• FNAB 21G
• 81-98% sensitivity, 60-75% specificity.
• Can say benign vs malignant
• Disadvantages:
• Does not provide cellular architecture
• In differentiating subtypes

• Core needle biopsy:

• 14-21G
• Histologic architecture is preserved
• IHC
Prof S. Subbiah et al 16
 IHC

• HER 2:
• Cancers of salivary gland of excretory duct origin
• Salivary ductal carcinoma
• Mucoepidermoid carcinoma
• Regional nodal spread+, worse survival

• EFGR:
• >50% OF MEC, SDC

• C-KIT:
• Adenoid cystic carcinoma
• Absence of c-kit expression: poor prognosis
Prof S. Subbiah et al 17
T
Stage
Tis Carcinoma insitu
T1 ≤2cm, no extra parenchymal extension Stage
T2 2.1-4cm, , no extra parenchymal extension
T3 >4cm, extra parenchymal extension 0 Tis
T4a Moderately advanced. Invading skin,
mandible, ear canal, facial nerve I T1
T4b Very advanced. Invades skull base, pterygoid
plates, encases carotid artery II T2

III T3
N T0-3 N1
Stage IVA T4a N0,1
N1 I/L, Single, ≤3cm, no ENE T0-4a N2
N2a I/L, Single, 3.1-6cm, no ENE B T4b
N3
2b I/L, Multiple, ≤6cm, no ENE
C M1
2c C/L, Multiple, ≤6cm, no ENE
N3a >6cm node, no ENE
Prof S. Subbiah et al 18

3b ENE+
 RISK CLASSIFICATION

Prof S. Subbiah et al 19
 TREATMENT OF PAROTID
TUMORS
• Superficial parotidectomy: in T1, T2 well lateralized tumor.
Margin: 1cm, <1mm near facial nerve.
• Total Conservative parotidectomy: in extensive tumors, both
lobes removed with preservation of facial nerve
• Radical parotidectomy: parotid, facial nerve & involved
structures- skin, muscle, bone.
• Extended radical parotidectomy: excision of auditory canal,
ascending ramus of mandible, temporal bone resection± facial
nerve resection ± neck dissection- for High grade, high stage
tumors
• If frozen section of facial nerve at stylomastoid foramen is
Prof S. Subbiah et al 20

positive: do mastoidectomy
 TREATMENT OF PAROTID
TUMORS
• If R1 resection on facial nerve can be attained: preserve facial
nerve & give adjuvant RT
• Close margins/ R1 resection is acceptable in the vicinity of
facial nerve, as adjuvant RT – respectable local control

• EXTRACAPSULAR DISSECTION: Benign parotid gland tumors.

• LRR (1.3-1.5% vs 2-2.4% in superficial parotidectomy)
• Complication rates (temporary facial nerve palsy 7% vs 25%,
frey’s syndrome 0% vs 60%)

Prof S. Subbiah et al 21
• GREATER AURICULAR NERVE: Lies on tail of parotid-
lateral border, anterior & posterior branches
• AURICULOTEMPORAL NERVE: Posterior to parotid,
branch of V3. Parasympathetic from otic ganglion

• DEEP LOBE TUMORS:

• Most common tumors in prestyloid compartment of
parapharyngeal space (masticator space)
• DD: ectopic salivary tumors, minor SG tumors in lateral
Prof S. Subbiah et al 22
pharyngeal wall.
 PAROTID NODES

• 20 nodes within & adjacent to the capsule of parotid

• 1st echelon nodes: temporal scalp, cheek, ear & external
auditory canal

• Efferent lymphatics drain into superior & middle

jugular chain.

Prof S. Subbiah et al 23
TREATMENT OF SUBMANDIBULAR
GLAND TUMOR

• Benign & early stage: gland excision

• Extensive: en bloc resection of submandibular triangle
with adjacent muscles, nerves, bone, skin

• NO LYMPHOID TISSUE WITHIN THE PARENCHYMA OF

GLAND
Prof S. Subbiah et al 24
 MANDIBULAR BRANCH OF
FACIAL NERVE
• Surface marking:
• 2 fingerbreadths below & anterior to the angle of
mandible

• Posterior facial vein – runs parallel to cervical branch,

runs deep to mandibular branch

• Both posterior facial vein & cervical branch – are divided,

retracting the stump of posterior facial vein cephalad will
Prof S. Subbiah et al
protect mandibular branch- HAY’S MARTIN MANEUVER.25
 SUBMANDIBULAR GLAND

Prof S. Subbiah et al 26
 NECK DISSECTON
• Incidence of NODAL METASTASIS:
• Parotid 13-25%
• Submandibular: 14-33%
• Sublingual: 14%, minor- 10-33%
• High grade tumors (32-62% in major, 40% in minor SG)

• N1: therapeutic nodal dissection

• ELECTIVE NECK DISSECTION:

• High risk/grade tumors, locally advanced:
• Zbaren et al.: Lower recurrence rates(12% vs 26%), 5YR DFS (86%
vs 69%)
• Herman et al. : Elective neck dissection vs RT- similar recurrence
rate & cause specific survival
• T4, high grade, all minor salivary gland tumors, recurrent tumors: need
neck dissection or RT
Prof S. Subbiah et al 27

• Adenoid Cystic Carcinoma: don’t need neck dissection if N0

 COMPLICATIONS OF SURGERY

• Facial nerve palsy

• Hemorrhage
• Sialocoele – treated with botox / completion parotidectomy
• Frey syndrome
• Hypoesthesia of greater auricular nerve- numbness of ear
lobe & skin
• Injury to Marginal mandibular nerve, lingual &
hypoglossal nerve

Prof S. Subbiah et al 28
 FACIAL NERVE

• Facial nerve divides parotid to superficial 80%, deep lobe

• Exits from stylomastoid foramen lateral to styloid process
& located cephalad to posterior belly of digastric & antero-
inferior to EAC, where it enters parotid
• Main trunk lies : around 5-15mm, are at a point where
the tip of mastoid process, cartilaginous auditory
canal, superior border of posterior belly of digastric
meet.
• Branch of posterior auricular artery lies just above
facial nerve
• PES ANSERINUS: point at which main facial nerve divides 1 st 29
Prof S. Subbiah et al

time.
 FACIAL NERVE

• LOWER DIVISION:
• CERVICAL BRANCH: Platysma
• MARGINAL MANDIBULAR: Lower lip
depressors (deep to platysma, lateral to
facial vein)

• MID FACE DIVISION:

• ZYGOMATICO BUCCAL BRANCH:
• Buccal (near stenson's duct)
• Zygomatic branch -runs parallel to
transverse facial artery - lower eyelid groups

• UPPER FACE DIVISION:

• FRONTAL BRANCH:
Prof S. Subbiah et al Frontalis & superior 30

orbicularis oculi
 FACIAL NERVE INJURY

• 13-100%
• Causes: stretching, entrapment, compression, thermal & ischemic
injuries
• Permanent paralysis: 5% (>12 months)
• Management:
• Primary tension free repair- fine, permanent, interrupted sutures
• Facial nerve reconstruction with primary suturing/ interposition
grafts /cable graft: will recover facial symmetry in 6 months
• Greater auricular & sural nerve is used for reconstruction

• Prevention:
Prof S. •Subbiah
Meticulous
et al dissection 31

• Intraop nerve monitoring

REHABILITATION OF PARALYSED
FACE
• GOAL: Dynamic pan facial reanimation
• Static procedures
• Gold or platinum weight in upper eyelid

• Nerve transfers/nerve grafting

• Nerve to masseter transfer for lower eyelid motion or eye
sphincter closure- A/E: blinking during mastication
• Mini hypoglossal nerve transfer- reanimate lower face by end to
side coaptation of marginal mandibular nerve

• Preferred: facial nerve grafting

• Preference for distal facial branches
Prof S. Subbiah•et alZygomatic
branch (runs parallel to transverse facial artery)- smile & 32

lower eyelid motion

 REHABILITATION OF PARALYSED
FACE
• If proximal nerve trunk is not available for reconstruction
• Dual nerve transfers: nerve to masseter to zygomaticus branches for
smile, blink & mini hypoglossal nerve for lower facial motion
• Labbe’s procedure:
• Alternative approach to dynamic smile: temporalis transfer to the
oral commissure
• Brow ptosis:
• Direct browlift, endoscopic procedures
• Anterolateral thigh flap, rectus abdominis flap : for parotid defect

• Lateral tarsorrhaphy, canthoplasty, gold weight implant of upper eyelid,

static or dynamic reconstruction of oral commissure
Prof S. Subbiah et al 33
 FREY SYNDROME
• Gustatory sweating, flushing
• Common complication
• Aberrant healing of the transected parasympathetic nerve fibers that
innervate parotid gland & sympathetic fibers that innervate cutaneous
sweat glands & blood vessels.
• Diagnosis:
• Clinical symptoms: 14-43% (within 4 months postop)
• Starch iodine test: 43-96%

• <10%- intractable symptoms

• Treatment:
• Topical perspirants
• Superficial botulinum toxin A application

•ProfPrevention:
S. Subbiah et al 34

• SMAS, superficial temporal artery fascia STAF, SCM flaps, alloderm

interpositional grafts
 RADIOTHERAPY

• T3, T4 tumors
• N+
• High & intermediate grade tumors
• Positive margins (including low grade MEC, benign tumors)
• PNI, LVI
• Adenoid cystic carcinoma- any grade or type
• In Low risk tumor: if recurrent, positive margins
• Pleomorphic adenoma- multiple recurrences, capsule
Profrupture,
S. Subbiah et al positive margins 35
 RADIOTHERAPY

• Undissected nodal regions: 50Gy

• Negative margins, nodes positive: 60Gy
• Positive margins, ENE: 66Gy
• Gross disease : 70Gy
• PNI: RT to skull base along the course of all nerves involved &
ganglion

• Definitive radiotherapy: 70Gy

• Locoregionally advanced, unresectable, unfit patient
• ± Concurrent
Prof S. Subbiah et al chemotherapy with platinum agents- for SCC of upper 36
aerodigestive tracts
 PARTICLE THERAPY

• Neutron, proton, carbon ions are used

• Need particle accelerators
• Biological benefit: high linear energy transfer of neutron
& carbon ion therapy. Protons- high linear energy
transfer at the end of the bragg peak.
• High conformality- allows possible dose escalation

Prof S. Subbiah et al 37
 COMPLICATIONS OF
RADIOTHERAPY
• Xerostomia
• Toxicity to auditory system, external auditory canal
stenosis, SNHL, chronic otitis media (due to eustachian
tube dysfunction)
• Fibrosis
• Lymphedema
• ORN of mandible
• Toxicity to Optic structures, brainstem, brain
Prof S. Subbiah et al 38
 SYSTEMIC THERAPY

• Ongoing trial RTOG 1008 – compared adjuvant RT to CRT

(weekly cisplatin) in high risk patients

• ADT (bicalutamide & LHRH) & HER2 directed therapies: high

risk malignant tumors with positive expression.

• Ongoing trial NCT04620187: TDM-1 along with platinum

based chemotherapy for high risk, resected salivary ductal
carcinoma with her2+
Prof S. Subbiah et al 39
 RECURRENT, METASTATIC
DISEASE
• ADENOID CYSTIC CARCINOMA: CLINICAL TRIAL
• ACCURACY TRIAL: NOTCH1- NOTCH CLEAVAGE INHIBITOR AL-101
• MONTHLY CYCLOPHOSPHAMIDE, DOXORUBICIN, CISPLATIN (CAP)
• VINORELBINE ± CISPLATIN
• VEGF TK INHIBITORS- LENVATINIB, AXITINIB
• VEGFR-2 SPECIFIC INHIBITOR: RIVOCERANIB (APATINIB)
• PD 1 INHIBITOR: PEMBROLIZUMAB

• NON- ADENOID CYSTIC CARCINOMA: CLINICAL TRIAL

• NTRK INHIBITORS: LAROTRECTINIB, ENTRECTINIB
• HER 2 + , ERBB2 GENE AMPLIFICATION: TZ ± PZ ± TAXANES, T-DM 1, TZ-
DERUXTECAN
• ADT: LEUPROLIDE (LHRH ANALOGUE) + BICALUTAMIDE
Prof S. Subbiah et al 40
• IN HRAS MUTATION: ORAL FARNESYLTRANSFERASE INHIBITOR: TIPIFARNIB
 FACTORS PREDICTIVE OF
OUTCOME
• Reliable prognostic factors: clinical stage & histologic grade, type
• Good prognosis: acinic cell carcinoma & low grade MEC
• Worst prognosis: anaplastic & squamous cell carcinoma
• Adjuvant RT: improves survival only in advanced cases

• Clinical Factors prediction cancer specific survival: (5Yr CSS)

• Clinical stage (I- 97%, IV- 26%)
• Facial nerve involvement (25%, 78%)
• Skin involvement (30%, 71%)
• Advanced T stage (T1 97%, T4 22%)
• Positive parotid or lateral neck nodes (N+ 32%, N0 87%)
• Pathologic Factors prediction cancer specific survival:
• PNI (48%, 90%)
•Prof
LVI (41%,89%)
S. Subbiah et al 41
• Close/positive margins 64%, NEGATIVE margins 88%
• Histologic grade (LG 100%, HG 44%)
 INCIDENCE OF DISTANT
METASTASES
• SALIVARY DUCT CARCINOMA (53%)
• ADENOCARCINOMA (42%)
• ADENOID CYSTIC CARCINOMA (14%)
• ACINIC CELL CARCINOMA (16%)
• CARCINOMA EX PLEOMORPHIC
ADENOMA (20%)
• MUCOEPIDERMOID CARCINOMA (7%)
• MYOEPITHELIAL CARCINOMA (6%)
• HIGH GRADE CARCINOMA (23%)
Prof S. Subbiah et al 42
 NOMOGRAMS PREDICTIVE OF
OUTCOME
• TNM STAGING:
• To assess prognosis
• Plan treatment
• Evaluate treatment results
• Compare outcomes between institutions

• DISADVANTAGES:
• Other tumor & patient related variables are not taken into
account

Prof S. Subbiah et al 43
 NOMOGRAMS PREDICTIVE OF
OUTCOME
• Developed for overall survival, disease specific survival,
risk of recurrence
• OVERALL SURVIVAL: Based on age, cT4, grade, PNI,
tumor size. Concordance index (CI): 0.81
• CANCER SPECIFIC SURVIVAL: Based on cT4, grade,
PNI, positive nodal metastasis & margins. Concordance
index (CI): 0.86
• RECURRENCE: Based on age, grade, PNI, vascular
invasion, & nodal metastasis. Concordance index (CI):
Prof S. Subbiah et al 44
0.85
 TAKE HOME POINTS
Low grade histology SURGERY
T1 or T2
Nodes positive SURGERY ± NECK
High grade DISSECTION/Adjuvant
T3, T4 RADIATION
Close (<2mm) or positive margins SURGERY + Adjuvant RADIATION
High grade
T3, T4
Pathologic cervical nodes
Perineural invasion
Distant metastasis or Unresectable CHEMOTHERAPY

• SURGERY- MAINSTAY TREATMENT

• CLOSE MARGINS/ R1 RESECTION IS ACCEPTABLE IN THE VICINITY OF FACIAL NERVE, AS
ADJUVANT RT – RESPECTABLE LOCAL CONTROL
• ADVANCED UNRESECTABLE TUMORS- PALLIATIVE RT
• PROTON: LIMITS RT TO ADJACENT VITAL STRUCTURES, DELIVERS EFFECTIVE TARGET DOSE.
Prof S. Subbiah et al 45
• SYSTEMIC THERAPY: PALLIATIVE
• EGFR, HER2, ER, AR TARGETED AGENTS- INVESTIGATIONAL