Malignant Salivary gland neoplasm - Dr. Mudit Gupta

2
Introduction Epidemiology
Clinical pictures
of different
glands
Risk factors
Histogenetic
theories of
tumorigenesis
TNM Staging
Histopathological
classification
Treatment
7/18/2021
SALIVARY GLAND MALIGNANCY/ DR. MG

Salivary carcinoma is uncommon
pathology .
Unique from other head and neck
cancer :-
1. Multiplicity of tumour types
2. Pleomorphic adenoma has pre malignant
potential.
3. Indolent growth pattern but still reoccur
and metastasize
Broad pathological classification:-
1. Epithelial tumours->80%
2. Mesenchymal tumours-<20%
3. Hemolymphoid tumours
Watkinson and Gilbert, Stell & Maran’s
Textbook of Head and Neck Surgery and
Oncology.
Watkinson, Clarke, and Clarke, Scott-
Brown’s Otorhinolaryngology and Head
and Neck Surgery.
7/18/2021
SALIVARY GLAND MALIGNANCY/ DR. MG 4

7/18/2021

Malignant tumors
◦ Acinic cell carcinoma
◦ Secretory carcinoma
◦ Mucoepidermoid carcinoma
◦ Adenoid cystic carcinoma
◦ Polymorphous low-grade
adenocarcinoma
◦ Epithelial-myoepithelial carcinoma
◦ Clear cell carcinoma
◦ Basal cell adenocarcinoma
◦ Sebaceous adenocarcinoma
◦ Intraductal carcinoma
◦ Cystadenocarcinoma
◦ Adenocarcinoma , NOS
◦ Salivary duct carcinoma
◦ Myoepithelial carcinoma
◦ Carcinoma ex pleomorphic adenoma
◦ Carcinosarcoma
◦ Poorly differentiated carcinoma
◦ Squamous cell carcinoma
◦ Oncocytic carcinoma
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6

Epithelial tumours account
for 95%
USA – 10 per million per
year
Europe - slightly less
(Belgium, Netherlands, the
UK and Finland having
about 6–7 new cases per
million per year)
Indian subcontinent- 0.6
per million per year in
males and females each. Mishra, et al. “Head and Neck Cancer : Global Burden
and Regional Trends in.” (2014).
7/18/2021

Flint et al.,
Cummings
Otolaryngology -
Head and Neck
Surgery ,2014
7/18/2021 9

 Parotid Gland : 64–80% of all tumours ,of which 15–32% are malignant.
 Submandibular glands : 7 to 11% of all tumours ,of which 41–45% being
malignant.
 Sublingual gland : <1% of all tumours ,of which 70–90% are malignant.
 Minor salivary gland tumours :9 to 23% of all tumours ,of which 80% being
malignant.
7/18/2021 10
Watkinson, Clarke, and Clarke, Scott-Brown’s
Otorhinolarnygology and Head and Neck Surgery.

Radiation exposure
Smoking, Alcohol
Aflatoxin B1 (Canadian livestock)
Nitrosamines, Silica dust
Cytomegalovirus
Diet – lack of PUFA
C-erbB-2 over expression - high grade tumour
Ki-67 : adverse prognostic effect in adenoid cystic
carcinoma
 EBV -undifferentiated carcinoma.
7/18/2021

BICELLULAR THEORY
Proximal secretory duct cell -
intercalated duct and
myoepithelial cells.
Intercalated duct stem cell:
Acinic cell carcinoma, Adenoid
cystic carcinoma, Pleomorphic
adenoma, Oncocytoma.
Excretory duct stem cell:
Squamous cell carcinoma &
Mucoepidermoid carcinoma.
RESERVE CELL THEORY
Tumor arise from the adult
differentiated counter part of
salivary gland unit.
Acinar cell: Acinic tumor
Striated duct cell: Warthin’s
tumor & Oncocytoma
Intercalated duct &
Myoepithelial cells: Mixed
tumor
Excretory duct cells:
Mucoepidermoid carcinoma &
Squamous cell carcinoma
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TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 2 cm or less, without extra parenchymal extension*
T2 Tumour more than 2 but less than 4 cm, without extra parenchymal extension
T3 Tumour more than 4 cm, and/or has extra parenchymal extension
T4a Tumour invades skin, mandible, ear canal and/or Facial nerve involvement (moderately
advanced disease)
T4b Tumour invades base of skull, and/or pterygoid plates and/ or encases carotid artery (very
advanced disease)
7/18/2021 SALIVARY GLAND MALIGNANCY/ DR. MG 17

N1 Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension, without extra nodal
extension
N2a Single ipsilateral node > 3–6 cm, without extra nodal extension
N2b Multiple ipsilateral nodes < 6 cm
N2c Bilateral or contralateral nodes < 6 cm
N3a Node(s) > 6 cm, without extra nodal extension
N3b Single or multiple nodes, with extra nodal extension

MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

Stage 0 TIS N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1 T2 T3 N1 M0
Stage IVA T4a N0 M0
T4a N1 M0
T1 T2 T3 N2 M0
T4a N2 M0
Stage IVB T4b Any N M0
Any T N3 M0
Stage IVC Any T Any N M1

1. Short duration history
2. Rapid growth
3. Fixation to skin
4. Induration
5. Ulceration of the skin
6. Pain
7. Facial nerve palsy
7/18/2021
Pre-auricular lump

 Asymptomatic ,discrete pre-auricular or infra-auricular lumps.
 A small percentage present only as a swelling of the soft palate or
lateral oropharynx and 1% arise in the accessory parotid gland
(along the Stensen duct).
 Post styloid region: CN IX,X,XI,XII involvement.
 Cervical lymphadenopathy.
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Skin involvement
Intra oral lump arising
from deep lobe
Klotz DA, et al.
Laryngoscope
2000
Flint et al., Cummings Otolaryngology -
Head and Neck Surgery E-Book.

 Painless mass or swelling under the jaw
 Distortion of the floor of the mouth
 Skin invasion or ulceration
 Nerve paresis or paralysis
1. Hypoglossal N- weakness of tongue
2. Lingual nerve of Trigeminal nerve(V3)-Numbness of
tongue
3. Mandibular branch of the VII nerve- weakness of lower
lip
 28% regional lymph node metastasis.
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Skin involvement
lump in the
submandibular triangle
Flint et al., Cummings Otolaryngology
- Head and Neck Surgery E-Book.

 Fixation of gland
 Nerve paresis or paralysis
1. Lingual nerve of Trigeminal nerve(V3)-
2. Mandibular branch of the VII nerve.
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Mass in the floor of the mouth. A case of
adenoid cystic carcinoma of the sublingual
gland.
Flint et al., Cummings
Otolaryngology - Head and Neck
Surgery E-Book.

 Found throughout the entire upper aero digestive
tract
 Signs & symptoms depend upon the anatomical
site involved.
1. Hard palate – ulceration
2. Nose & nasopharynx- obstructive symptoms
 Local invasion of tumours into surrounding tissue
common
1. ET dysfunction
2. Hoarseness
Mucoepidermoid carcinoma (low grade) of
palate.
Watkinson, Clarke, and Clarke, Scott-Brown’s
Otorhinolaryngology and Head and Neck Surgery.
Flint et al., Cummings Otolaryngology -
Head and Neck Surgery E-Book.
Patient with salivary duct carcinoma extending
into maxillary sinus and nasal cavity.
26

7/18/2021 29

MUCOEPIDERMOID
CARCINOMA
 Most common (45%) salivary
malignancy
 Parotid : 50-70%
 Minor salivary glands : 15-35%
 Submandibular glands: 6-11%
 All ages, children.
 F>M
 Low, intermediate and high grade
Watkinson and Gilbert, Stell
& Maran’s Textbook of Head
and Neck Surgery and
Oncology.
Mucoepidermoid carcinoma (low grade) of
palate.
7/18/2021

 Presentation
o Low-grade: Slow growing, painless
mass
o High-grade: Rapidly enlarging, +/-
pain, +/- metastasis to lymph nodes,
+/- facial palsy
 Gross pathology
o Well-circumscribed to partially
encapsulated to unencapsulated
o Solid tumor with cystic spaces
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 Patients with tumors of equal
HPE grade - better prognosis in
the parotid gland than
submandibular gland
HISTOPATHOLOGY
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Low-grade
Mucus cell > epidermoid
cells
Prominent cysts
Mature cellular elements
Intermediate-grade
Mucus = epidermoid
Fewer and smaller cysts
Increasing
pleomorphism and
mitotic figures
High-grade
Epidermoid > mucus
Solid tumor cell
proliferation
Mistaken for SCCA,
Mucin staining

Treatment
Influenced by site, stage, grade.
Stage I & II - Wide local excision
Stage III & IV- Radical excision +/- neck dissection +/- postoperative
radiation therapy
5 yr.
survival
15 yr.
survival
Low Grade 70% 50%
High Grade 47% 25%
Survival rates:
Mucoepidermoid carcinoma treated by partial
maxillectomy.
7/18/2021

ADENOID CYSTIC
CARCINOMA
 Overall 2nd most common malignancy
(30%)
 More common in submandibular,
sublingual and minor salivary glands
 60% minor salivary glands
 25-33% parotid
 Most common malignancy of the
submandibular gland
 M = F
 5th decade
7/18/2021

Presentation
Asymptomatic enlarging mass
Insidious growth over many years
Pain due to peripheral nerve
invasion
Facial nerve palsy may be evident
Gross pathology
Well-circumscribed
Solid, rarely with cystic spaces
Infiltrative
Adenoid Cystic Carcinoma of right hard palate
7/18/2021

PERI-NEURAL SPREAD
Spread into, and along, peripheral nerves occurs
in 80 percent of cases (well established
prognostic factor)
Two mechanisms:
- Direct spread
- Embolic mechanism
50% cases
More likely if tumour is large
Skip lesions of facial nerve
Bad prognosis – nerve palsy
Recurrence : 30-50%
7/18/2021 36

DISTANCE
METASTASIS
 Lung metastasis – Characteristic
 Metastasis : Lungs, bone, liver
 Lymph node metastases are rare
 Local recurrences are common (30–50% of cases)
 Calculated cumulative Mets
 70% at 5 years
 100% at 10 years
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HISTOLOGY
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Cribriform pattern
• Most common, best prognosis
• “swiss cheese” appearance
Tubular pattern
Layered cells forming duct-like structures
Basophilic mucinous substance
Solid pattern
Solid nests of cells without cystic or tubular spaces
Worst prognosis

 Treatment
 Complete local excision
 Tendency for perineural invasion: facial nerve sacrifice
 Postoperative RT
 Prognosis
 Local recurrence: 30-50%
 Distant metastasis: Lungs
 Indolent course: 5-year survival 72%, 15-year survival
34%
(Ross et al., 2001)
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ACINIC CELL CARCINOMA
Third most common parotid
malignancy
5th decade
F>M
Bilateral parotid disease in 3%
Presentation
Solitary, slow-growing, often
painless mass
7/18/2021

Gross pathology
Well-demarcated
Most often homogeneous
Histology
Solid and microcystic patterns
Most common
Solid sheets
Numerous small cysts
Polyhedral cells
Small, dark, eccentric nuclei
Basophilic granular cytoplasm
7/18/2021

 Treatment
 Total parotidectomy with neck
dissection
 +/- postoperative RT
 Late recurrence
 Prognosis
 5-year survival: 76-96%
 15-year survival: 50-55%
(Luukkaa et al., 2005)
7/18/2021

ADENOCARCINOMA
 Rare
 6th to 7th decades
 F > M
 Parotid and minor salivary glands
 Presentation:
 Enlarging mass
 25% with pain or facial weakness
7/18/2021

 Histology
 Heterogeneity
 Presence of glandular structures and absence of
epidermoid component
 Low grade : Papillary, Mucinous
 High grade : Trabecular, Clear cell, Sebaceous
 Treatment ( All regarded high grade )
 Neck dissection
 Prognosis
 Local recurrence: 51%
 Regional metastasis: 27%
 Distant metastasis: 26%
 15-year cure rate:
 Stage I = 67%
 Stage II = 35%
 Stage III = 8% 7/18/2021 44

POLYMORPHOUS LOW-GRADE
ADENOCARCINOMA
• 2nd most common malignancy in minor salivary glands
• 60% palate, 20% cheek, 12% lips
• 7th decade , F > M
• Painless, submucosal mass
• Morphologic diversity
• Solid, glandular, cribriform, ductular, tubular, trabecular, cystic
 Propensity for perineural spread
 15% cervical metastasis
 Local recurrence – 15 years after treatment
 Treatment
 Complete yet conservative excision
7/18/2021

MALIGNANT MIXED TUMORS
7/18/2021
1.Carcinoma ex-
pleomorphic
adenoma
•Carcinoma
developing in the
epithelial
component of
preexisting
pleomorphic
adenoma
1.Carcinosarcoma
•True malignant
mixed tumor—
carcinomatous
and sarcomatous
components
1.Metastasizing
pleomorphic
adenoma
•Metastatic
deposits of
otherwise typical
pleomorphic
adenoma

CARCINOMA EX-PLEOMORPHIC
ADENOMA
 2-4% of all salivary gland neoplasms
 6th-8th decades
 Parotid > submandibular > palate
 2nd most common parotid malignancy
 Presentation - Longstanding painless mass with
sudden enlargement, facial palsy (parotid gland
involvement)
 Risk Factors :
Men > 40 years
Tumour in deep lobe
Solitary nodules > 2 cm
H/o surgery (recurrence)
H/o Radiotherapy
Risk: 5 - 6% in 20 years
Clinical photograph of the patient with
left submandibular mass
7/18/2021 47

Gross pathology
Poorly circumscribed
Infiltrative
Hemorrhage and necrosis
Histology
Malignant cellular change
adjacent to typical pleomorphic
adenoma
Carcinomatous component
Adenocarcinoma
Undifferentiated
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Treatment
Radical excision
Neck dissection (25% with lymph node involvement
at presentation)
Postoperative RT
Prognosis: poor
Dependent upon tumor size, invasion, cervical
metastasis, high grade, carcinoma making > half of
tumor mass, origin – major gland.
Cause-specific survivals
 40 percent at 5 years,
 24 percent at 10 years,
 19 percent at 15 years
Computed tomography scan
neck axial view showing
cervical lymph nodes
7/18/2021

CARCINOSARCOMA
 Rare: <.05% mostly seen in parotid
 6th decade ,M = F
 H/O previously excised pleomorphic adenoma
(recurrence), recurring pleomorphic treated with RT
• Histology :
 Biphasic appearance
 Sarcomatous component
 Carcinomatous component
 Treatment :
 Radical excision
 Neck dissection
 Chemotherapy (distant metastasis)
7/18/2021 50

SQUAMOUS CELL
CARCINOMA
1.6% of salivary gland neoplasms
7th-8th decades
M:F = 2:1
Criteria :
1. Tumour must arise from the
gland itself and not from
lymph nodes within the gland
2. There must be no regional or
adjacent tumour
3. High-grade mucoepidermoid
carcinoma must be excluded 7/18/2021 51

Treatment
Radical excision
Neck dissection (Even N0 neck)
Postoperative RT
Prognosis
5-year survival: 24%
10-year survival: 18%
7/18/2021

EPITHELIAL-MYO-EPITHELIAL
CARCINOMA
• < 1% of salivary neoplasms
• 6th-7th decades, F > M
• Parotid (77%)
• Histology
• Tumor cell nests
• Two cell types
• Thickened basement membrane
• Treatment
• Surgical excision
7/18/2021

UNDIFFERENTIATED
CARCINOMA
 Lymphoepithelial carcinoma
 Eskimos: parotid, F > M, EBV
 Asian: submandibular, M > F
7/18/2021

Batsakis and Rugezi criteria
 Extra-glandular lymphoma must
not be present
 There is histological proof that the
lymphoma involves the gland
parenchyma and not the
intraglandular lymph nodes
 Immunohistochemical screening
must confirm the presence of
lymphoma markers
7/18/2021
• Primary lymphoma : 5% of extra-
nodal lymphomas
• 2% of all salivary gland tumors
• Almost all primary lymphomas of
the salivary glands affect the
parotid
• Sjogren's syndrome: Risk of
developing a Lymphoma in this
syndrome is said to be 40 times
that of the normal

Hodgkin’s lymphoma
Most cases occur in the parotid gland
Represent disease involvement of intra-parotid
lymph nodes
Primary non-Hodgkin’s lymphoma
De novo
Secondary (lymphoepithelial sialadenitis)
50-70 years
Solitary, painless mass in de novo cases
History of waxing and waning enlargement of
several glands in the secondary forms
7/18/2021

True extra nodal involvement only happens with NHL
 Low-grade non-Hodgkin's lymphoma (NHL) is either not treated at
all or, if it is, conservative monomodal management (eg.
Chlorambucil)
 High-grade lesions treated aggressively eg.VAPEC-B.
 Both groups have a median survival of approximately eight years
 Low grade lymphoma solely involving a salivary gland: Local
excision or radiotherapy
7/18/2021

 Metastases to the salivary glands arise from the skin of the head
and neck ( Pinna and eyelid), lung, breast and kidney
 Happen in little over 1 percent of head and neck skin squamous
carcinomas
 Malignant cutaneous melanoma can involve the parotid lymph
nodes than 2 percent.
 Skin tumours posterior to the facial artery and vein 50 % of parotid
nodal metastasis
 Skin cancer anterior to these involve the parotid in only 3 percent of
cases
7/18/2021

 Cure rates are dismal
 Parotidectomy en bloc with a neck dissection in continuity with the
primary lesion is indicated
 Five-year survival rates are little more than 10 percent
7/18/2021

7/18/2021
X-RAY USG CT scan MRI
CT
sialography
FNAC

63
Clinical
•Primary site
•Age
•Local tissue invasion
Histological
•Low grade
•High grade
Molecular
•ERBB2
•Ki67
•PCNA

Surgery Neck
dissection
Radiotherapy Chemotherapy
7/18/2021

66
Total conservative parotidectomy
• Tumour extension into deep parotid lobe
• Tumour primarily arises in deep lobe
• Recurrent pleomorphic adenoma
• Malignant tumours
• Performed with preservation of facial nerve (
No gross nerve invasion / Function +)
Total radical parotidectomy
• Total parotidectomy + Facial nerve sacrifice
• Macroscopic nerve invasion
• Frozen section
• Nerve grafting
Extended radical parotidectomy
• Resection of:-
• Masseter
• Temporalis muscle
• Ascending ramus of mandible,
• TM joint, EAC, Zygomatic arch or mastoid
process.

POST-OPERATIVE
COMPLICATIONS
1. Skin flap necrosis
2. Hematoma
3. Wound infection / gape
4. Salivary fistula – Pressure bandage
5. Facial nerve paralysis – which could be:
a. Temporarily: 10 – 50%
b. Permanent: 5% (O’Brien et al.,
2003)
6. Numbness of the ear due to injury of great
auricular nerve
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7. Frey’s syndrome (Gustatory sweating syndrome)
Incidence : 50% of the patients.
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N0
•Controversial
•High grade histology
•High stage malignancy
N+
•Ipsilateral lymph node dissection
•Modified radical neck dissection
7/18/2021

•Level I-IV
Parotid gland
•Level I-III
Submandibular and Sublingual gland
7/18/2021

RADIOTHERAP
Y
7/18/2021
72

Radiotherapy without surgery – limited role
Results of Surgery + RT better than Surgery alone.
Recommended postop RT for:
1. High-grade histology
2. Tumours > 4cm size
3. Recurrent disease
4. Inadequate surgical margins / Positive margin
5. Perineural invasion
6. Extension of disease beyond the gland (Capsule)
7. Nodal disease
Neutron RT : Superior locoregional control than Conventional RT but
same survival
High complication with Neutron RT
7/18/2021

No studies to date have shown these agents to be
effective
Palliative treatment
1. Locally advanced unresectable disease
2. Recurrent
3. Metastatic disease
c-KIT and ERBB2 gene expression has been over expressed in
ADCC  Trastuzumab and imatinib
7/18/2021

CONCLUSION
7/18/2021
76

Malignancies of the major salivary glands represent a rare and
diverse group of cancers
Knowledge about tumor staging and histologic grading is necessary
for prognostic predictions, patient counseling, and treatment
planning
10 year disease specific survival for Stage I, II, II/IV tumours was
96,61 & 17% respectively
7/18/2021

1. Flint, Paul W., Bruce H. Haughey, K. Thomas Robbins, J. Regan Thomas, John K.
Niparko, Valerie J. Lund, and Marci M. Lesperance. Cummings Otolaryngology -
Head and Neck Surgery E-Book. Elsevier Health Sciences, 2014.
2. Watkinson, John C., Raymond W. Clarke, and Ray C. Clarke. Scott-Brown’s
Otorhinolarnygology and Head and Neck Surgery. Taylor & Francis Group, 2018.
3. Watkinson, John, and Ralph Gilbert. Stell & Maran’s Textbook of Head and Neck
Surgery and Oncology. CRC Press, 2011.
4. mishra, anupam, and rohit mehrotra.
DOI:Http://Dx.Doi.Org/10.7314/APJCP.2014.15.2.537 Head and Neck Cancer in
India: Global and Regional Trends, n.d.
5. Shield, Kevin D., Jacques Ferlay, Ahmedin Jemal, Rengaswamy
Sankaranarayanan, Anil K. Chaturvedi, Freddie Bray, and Isabelle Soerjomataram.
“The Global Incidence of Lip, Oral Cavity, and Pharyngeal Cancers by Subsite in
2012.” CA: A Cancer Journal for Clinicians 67, no. 1 (January 1, 2017): 51–64.
https://doi.org/10.3322/caac.21384.
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6. “Asian Pacific Journal of Cancer Prevention.” Accessed October 10, 2019.
http://journal.waocp.org/?sid=Entrez:PubMed&id=pmid:24568456&key=2014.15.2.5
37.
7. Bhat, VadishaSrinivas, Kolathingal Biniyam, AjazAbdul Aziz, and SunilKumar
Yeshwanth. “Carcinoma Ex-Pleomorphic Adenoma of Submandibular Salivary
Gland: A Case Report and Review of Literature.” Journal of Dr. NTR University of
Health Sciences 6, no. 3 (2017): 185. https://doi.org/10.4103/2277-8632.215518.
8. Mishra, Sonal, and Y.C. Mishra. “Minor Salivary Gland Tumors in the Indian
Population: A Series of Cases over a Ten Year Period.” Journal of Oral Biology and
Craniofacial Research 4, no. 3 (2014): 174–80.
https://doi.org/10.1016/j.jobcr.2014.11.002.
9. Zdanowski, Rafael, Fernando Luiz Dias, Mauro Marques Barbosa, Roberto Araújo
Lima, Paulo Antônio Faria, Adriano Mota Loyola, and Kellen Christine Nascimento
Souza. “Sublingual Gland Tumors: Clinical, Pathologic, and Therapeutic Analysis of
13 Patients Treated in a Single Institution.” Head & Neck 33, no. 4 (April 2011):
476–81. https://doi.org/10.1002/hed.21469.
7/18/2021

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Malignant Salivary gland neoplasm - Dr. Mudit Gupta

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