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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Salivary Glands Intro • Salivary glands are exocrine SALIVARY glands • 3 pairs of large glands GLAND located extra-orally • Major salivary glands – Parotid (serous) TUMOURS – Submandibular (mixed) – Sublingual (mucous) Prof R V SUBRAMANYAM • Minor salivary glands – Labial, lingual, palatal, Oral & Maxillofacial Pathology buccal, glossopalatine & retro molar glands • Function: Production of saliva

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Salivary Glands Intro Normal Salivary Gland Structure

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Cells in Salivary Glands and Ducts CLASSIFICATION (Foote & Frazell, 1954) BENIGN MALIGNANT • Pleomorphic adenoma • Malignant mixed tumor (mixed tumor) • Mucoepidermoid tumor • Papillary cystadenoma • Squamous cell carcinoma lymphomatosa • Adenocarcinoma • Oxyphil adenoma – Adenoid cystic • Sebaceous cell – Trabecular or solid adenoma – Anaplastic – Mucous cell • Benign lymphoepithelial – Pseudoadamantine lesion – Acinic cell • Unclassified – Unlassified

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours CLASSIFICATION (Thackray & Lucas, 1974) CLASSIFICATION (AFIP, Ellis & Auclair, 1990) BENIGN MALIGNANT BENIGN MALIGNANT • Pleomorphic adenoma • Pleomorphic adenoma • Adenocarcinomas • Mucoepidermoid tumor • Warthin’s tumor • Acinic cell adenocarcinoma (mixed tumor) • Acinic cell tumor • Basal cell adenoma • Basal cell adenocarcinoma • Monomorphic adenoma • Myoepithelioma • Clear cell adenocarcinoma – Adenolymphoma • Carcinomas • Canalicular adenoma • Cystadenocarcinoma – Oxyphil adenoma – Adenoid cystic • Oncocytoma • Sebaceous adenocarcinoma • Cystadenoma • Lymphadenocarcinoma – Tubular adenoma – Adenoid cystic carcinoma – Clear cell adenoma • Sebaceous adenoma • Adenoid cystic carcinoma – Epidermoid carcinoma • Sialadenoma • Mucinous adenocarcinoma – Basal cell adenoma – Undifferentiated • Ductal papillomas • Malignant mixed tumor – Trabecular adenoma – Sialadenoma papilliferum – Carcinoma ex mixed tumor – Sebaceous adenoma • Connective tissue and – Inverted ductal papilloma – Metastasizing mixed tumor – Sebaceous lymphadenoma metastatic tumors – Lymphadenoma – Carcinosarcoma – Intraductal papilloma

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours CLASSIFICATION (AFIP) Salivary gland tumours: Introduction • Carcinomas • Uncommon: 2 - 4% of head & neck tumours – Squamous cell carcinoma • Distribution – Mucoepidermoid carcinoma – Adenosquamous carcinoma – Parotid: 70% overall; 75% benign – Epithelial-myoepithelial carcinoma – Submandibular: 10% overall; 50% benign – Oncocytic carcinoma – Sublingual / Minor: 20% overall; 25% benign; – Salivary duct carcinoma – Most common site for minor: Palate – Myoepithelial carcinoma – Others • Age predilection: – Mesenchymal tumors – Benign: > 40 yrs – Lymphomas – Malignant: > 60 yrs – Metastatic tumors • Gender predilection: – Benign: Females – Malignant: Men=Women • Most common benign tumour: Pleomorphic adenoma 4/20/2008 R V SUBRAMANYAM 4/20/2008 R V SUBRAMANYAM 10 9

Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Salivary gland tumours: Introduction Aetiology of salivary gland tumours in general • Most common malignant tumour: Mucoepidermoid • Viruses: EBV, CMV carcinoma • Ionizing Radiation – >>Frequency in submandibular gland than parotid – Most common malignancy in Submandibular gland: – A dose of ≥ 140 rad increases risk of tumour Adenoid cystic carcinoma development – Minor sg tumours of retromolar area, floor of the mouth • Occupation & tongue are more likely to be malignant – Asbestos mining, shoe manufacturing, plumbing • In Children – 65% of tumours are benign – most common • Hormones Haemangioma, followed by pleomorphic adenoma – Role of hormones like oestrogen still controversial – 35% of tumours are malignant – most common Mucoepidermoid carcinoma 4/20/2008 R V SUBRAMANYAM 11 4/20/2008 R V SUBRAMANYAM 12

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pathogenesis of SGT Origin of Salivary Gland Tumors • Bicellular stem cell theory: tumours arise from 1 of 2 undifferentiated stem cells: – the excretory duct reserve cell: squamous cell and MEC – the intercalated duct reserve cell: pleomorphic adenomas, oncocytomas, adenoid cystic carcinomas, adenocarcinomas, and acinic cell carcinomas. • Multicellular theory: Each tumour type is associated with a specific differentiated cell of origin within the salivary gland – Squamous cell carcinomas arise from excretory duct cells – pleomorphic adenomas arise from the intercalated duct cells – oncocytomas arise from the striated duct cells – acinic cell carcinomas arise from acinar cell

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Origin of Salivary Gland Tumors Origin of Salivary Gland Tumors Normal Structure Cell of Origin Tumour

Excretory Duct Excretory Duct Reserve Squamous Cell Carcinoma Cells Mucoepidermoid Carcinoma

Striated Duct Intercalated Duct Oncocytoma Reserve Cell Intercalated duct Intercalated Duct Adenoid Cystic Carcinoma Reserve Cell Acinus Intercalated Duct Pleomorphic adenoma Reserve Cell Monomorphic adenoma Myoepithelioma Acinic cell carcinoma Adenocarcinoma Myoepithelial cell Intercalated Duct Adenocarcinoma Reserve Cell

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours SALIVARY GLAND TUMOURS Pleomorphic Adenoma: Definition • Pleomorphic adenoma • Also called mixed tumour (Minssen, 1874) • Warthin’s tumour • Both are misnomers • Mucoepidermoid carcinoma – Not mixed – not derived from 2 germ layers – Not pleomorphic – no pleomorphism of cells • Adenoid cystic carcinoma • The term pleomorphic adenoma was suggested • Polymorphous low grade adenocarcinoma by Willis, 1948 • Acinic cell carcinoma • A benign tumor of the salivary gland composed of variable admixture of epithelial (ductal, and non-ductal) elements and mesenchymal (chondroid, myxoid and osseous) components.

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Pathogenesis Pleomorphic Adenoma: Demographics • Myoepithelial cell (Hubner et al, 1971) • Most common neoplasm of salivary glands – 70% of parotid tumors • Intercalated duct reserve cell (Regezi & – 50% of submandibular tumors Batsakis, 1977) – 45% of minor salivary gland tumors • Both (Batsakis, 1980) – 6% of sublingual tumors • Age predilection • Neoplastically altered epithelial cell (Dardick et – 4th- 6th decade; Average 43 years al, 1982) • Gender predilection – Females • Site predilection – Parotid – lower pole of superficial lobe – Palate 4/20/2008 R V SUBRAMANYAM 19 4/20/2008 R V SUBRAMANYAM 20

Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Clinical features Pleomorphic Adenoma: Clinical features • Painless & slow growing • Single nodular, firm, slightly compressible mass • Not fixed • Palatal tumors – posterolateral aspect • Recurrent lesions appear to be multinodular and are less mobile than the original tumor

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Gross features Histologic classification (Foote & Frazell, 1954) • Irregular, round to ovoid mass • Principally myxoid → • Well defined borders Most common • Major salivary glands: • Myxoid & cellular Incomplete fibrous capsule or components equal unencapsulated • Predominantly cellular • Minor salivary glands: Unencapsulated • Extremely cellular → • Homogeneous tan to white Least common; More cut surface aggressive • Occasionally Haemorrhage and infarction

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Histopathology Pleomorphic Adenoma: Histopathology • Morphologic diversity is the hallmark of • Myoepithelial cells forming pleomorphic adenoma – Spindle cells, plasmacytoid cells • Glandular epithelial cells forming • Connective tissue stroma exhibits – anastomosing trabeculae – Fibrous interlacing bundles – Sheets & islands – sometimes with keratin pearls – Myxoid, Chondroid, Chondromyxoid, & Osseous – ducts – tubular pattern areas – Cystic spaces lined by squamous epithelium – Eosinophilic hyaline areas – basement lamina – Proliferating papillae material – Presence of tyrosine crystals – unique to this tumour

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Histopathology Pleomorphic Adenoma: Histopathology

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Histopathology Pleomorphic Adenoma: Histopathology

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Histopathology Pleomorphic Adenoma • Features Suggestive of Malignancy: • Clinically – Pain & Rapid growth – Enlargement of regional lymph nodes – Fixation to overlying skin/mucosa & underlying tissues – Surface ulceration – Facial nerve paralysis • Histologically – Atypia (pleomorphic or hyperchromatic nuclei) – Increased mitotic figures – Abnormal / bizarre mitotic figures –Necrosis

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Pleomorphic Adenoma: Management Tyrosine Crystals • Massive eosinophilic crystals that form floral arrangements- • Surgical excision rosettes (H&E stain) – If superficial lobe is involved, superficial •1st reported by Bullock in 1953 partoidectomy with preservation of facial nerve • Finely granular & electron dense • Non-birefringent; No solid internal structure – Tumours of deep lobe – total parotoidectomy • Not true crystals, but tyrosine-rich crystalloids • Submandibular gland – total removal of gland • More in Blacks • Also seen in • Palate – excised down to periosteum + overlying – carcinoma ex pleomorphic adenoma mucosa – Cylindroma – terminal duct adenocarcinoma – connective tissues of larynx • Formed from substances secreted by myoepithelial cells and are subsequently assembled extracellularly 4/20/2008 R V SUBRAMANYAM 33 4/20/2008 R V SUBRAMANYAM 34

Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Warthin Tumour: Definition Warthin Tumour: Pathogenesis • Described 1st by Hildebrand in 1895 • Heterotopic salivary gland tissue in the parotid • Warthin, Albrecht & Artz in 1929 coined the term lymph node papillary cystadenoma lymphomatosum • Proliferation of salivary gland ductal epithelium • Also called adenolymphoma, but it is a which is associated with secondary formation of misnomer as it suggests malignancy lymphoid tissue • A benign tumor that almost exclusively occurs in • Smokers are at more risk than non-smokers parotid gland comprising lymphoid and epithelial • EBV has also been implicated components.

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Warthin Tumour: Demographics Warthin Tumour: Clinical features •2nd most common benign neoplasm of salivary • Bilateral in 5-14% of cases; Most are glands; 4-11% of all sgt metachronous • Age predilection: elderly; 40 – 70 years; Avg 60 • Painless & slow growing years • Nodular mass, firm to fluctuant mass. Not fixed. • Gender predilection: Males; Recent studies = • Ear symptoms (tinnitus, deafness, earache) • Race predilection: More in whites than blacks • Facial nerve paralysis • Site predilection: Tail of the parotid near the • The ability to concentrate sodium pertechnetate angle of the mandible (99mTc) is suggestive of Warthin’s tumor

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Warthin Tumour: Clinical features Warthin Tumour: Gross features • Oval or spherical mass • Well encapsulated • Firm or rubbery in consistency • Single or multiple cystic spaces • Cystic fluid clear, serous, mucoid, brown-tinged or semi- solid caseous • Solid portions greyish white (lymphoid areas)

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Warthin Tumour: Histopathology Warthin Tumour: Histopathology Lining epithelium in papillary • Focal areas of squamous or projections protruding into cystic mucous metaplasia and spaces comprising sebaceous gland inclusions • Oncocytes with finely granular • Cystic spaces contain eosinophilic cytoplasm, forming 2 rows of: eosinophilic cellular debris – Inner luminal layer – tall • Connective tissue exhibits columnar cells with – Lymphoid stroma with germinal hyperchromatic nuclei; Fuzzy centres; mainly T cells due to microvilli – Scattered mast cells and plasma – Outer cuboidal layer with cells vesicular nuclei

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Warthin Tumour: Histopathology Warthin Tumour: Histopathology

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Warthin Tumour: Management Mucoepidermoid Carcinoma: Definition • Surgical excision •1st described by Masson and Berger in 1924 • 6-12% recurrent rate • Originally called mucoepidermoid tumour (Stewart, Foote & Becker, 1945) • Malignant tumor of salivary glands composed of mucous, squamous, intermediate, columnar and clear cells often with prominent cystic growth.

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours MEC: Pathogenesis MEC: Demographics • Aetiology • Most common malignant salivary gland tumor – Therapeutic radiation •2nd most common tumour • Pathogenesis • Most common malignant tumour in children – Ductoacinar cells • Occurs in both major and minor salivary glands • Cuboidal, goblet, clear & squamoid cells • There may be a history of ionizing radiation – Myoepithelial cell • Age predilection: 30-70 yrs; peak 5th decade • Myoepithelial, intermediate, clear & squamoid cells • Gender predilection: >> Women 1.5:1 • Site predilection: Parotid (50-70% of cases) & palate (20%). Can occur in bone also.

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours MEC: Clinical features MEC: Gross features • Slow growing solitary nodule, • Lacks capsule. May be partially usually painless encapsulated • High grade: Rapid growth, • Firm painful / tender • Pink to tan to gray cut surface • Sometimes fluctuant with blue or red colour • Cysts with mucoid content • Trismus, facial paralysis, • 1-12 cm drainage from ear, dysphagia • Numbness of related teeth • Ulceration or haemorrhage in minor sgt

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours MEC: Histopathology MEC: Histopathology • Epidermoid (squamous) cells • Patterns of epithelial cell component – polygonal with intercellular bridges but keratin pearls and single cell keratinization very rare – Solid islands • Intermediate cells – basaloid cells with scanty basophilic cytoplasm to larger and more – Cords oval cells with more abundant pale eosinophilic cytoplasm –Cystic – considered to be progenitor of mucous & epidermoid cells • Mucous cells – Cystic with papillary structures – occur singly or in clusters and have pale and sometimes foamy cytoplasm, a distinct cell boundary, and small, peripherally placed, •Stroma compressed nuclei. Can be identified by using stains such as mucicarmine or alcian blue. – Fibrous • Clear cells (glycogen, mucin) – Lymphoid infiltrate • Occasionally oncocytic metaplasia – Lymphoid follicles

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours MEC: Low grade MEC: Intermediate grade • Well formed glandular • Fewer and smaller cysts structures or microcysts lined • Solid areas of epidermoid by a single layer of mucus- cells or squamous cells with secreting columnar cells intermediate basaloid cells • Mucus cells >> epidermoid • Mucus cells < epidermoid cells cells • May have papillary infoldings • Papillary cystic infoldings of • No cytologic pleomorphism; epidermoid or basaloid cells Mitoses extremely rare

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours

MEC: High grade Histologic grading (Auclair, Goode, Ellis, 1992) • Solid nests and cords of PARAMETER POINT VALUE intermediate basaloid cells and Intracystic component <20% +2 epidermoid cells Neural invasion +2 • Mild to moderate nuclear pleomorphism Necrosis +3 • Cystic areas (<20%) & mucous Mitosis >4/ 10 HPF +3 cells less Anaplasia +4 • Epidermoid cells >> mucous GRADE TOTAL SCORE cells • More mitotic figures (usually > 4 Low grade 0-4 to 10/ HPF), necrosis, and Intermediate grade 5-6 perineural invasion High grade >7 4/20/2008 R V SUBRAMANYAM 55 4/20/2008 R V SUBRAMANYAM 56

Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours MEC: Histopathology MEC: Histopathology

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Mucoepidermoid carcinoma Mucoepidermoid carcinoma

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours MEC: Management Adenoid cystic carcinoma: Definition • Surgical excision • First described by Billroth and called it – Early stage: subtotal partoidectomy cylindroma – Advanced tumours: Total removal of parotid • Foote & Frazell suggested adenoid cystic • Submandibular gland: total removal carcinoma in 1853 • Minor glands • A malignant epithelial neoplasm of ductal and – Low grade: modest margin myoepithelial cells growing in cribriform, tubular, – High grade: Wide margin solid and cystic patterns • Recurrences uncommon • Prognosis becomes worse with increasing grade

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Pathogenesis Adenoid cystic carcinoma: Demographics • Ductal cells • Most common malignant tumor of • Myoepithelial cells submandibular gland • Age predilection: Middle aged • Gender predilection: Females • Site predilection: Submandibular gland, palate, parotid

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Clinical features Adenoid cystic carcinoma: Clinical features • Slow growing tumor • Small tumors movable by palpation, larger tumors adherent to skin and soft tissues • Tenderness and pain – common & important • Facial nerve paralysis • Mucosal ulceration • Underlying bone destruction (palatal tumours)

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Gross features Adenoid cystic carcinoma: Histopathology • Well circumscribed, rarely encapsulated Firm • Epithelial cells •Gray white – Tumour cells: Uniform, small, cuboidal, little cytoplasm and uniform round nuclei – Myoepithelial cells: Indistinct cell borders, amphophilic to clear cytoplasm and uniform round- oval to angular-irregular nuclei – Arranged in different patterns

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Histopathology Adenoid cystic carcinoma: Histopathology • Cribriform (Swiss cheese-like)- islands of basaloid cells with multiple cystic spaces having basophilic mucoid material (GAGs) &/or eosinophilic hyaline (basal lamina) • Tubular – cells form small ducts or tubules within hyalinized stroma • Solid – sheets or islands of cells; cellular pleomorphism, mitotic activity & necrosis may be seen

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Histopathology Adenoid cystic carcinoma: Histopathology •Stroma – Hyalinized eosinophilic stroma – Peripheral nerve invasion

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Histopathology Adenoid cystic carcinoma: Histopathology

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Adenoid cystic carcinoma: Cytopathology Adenoid cystic carcinoma: Management • Surgical excision ± radiation • Prone to local recurrence and eventual distant metastasis

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Oral Pathology Lecture Series :: Salivary Gland Tumours Oral Pathology Lecture Series :: Salivary Gland Tumours Read on your own the basic features of THANK YOU & HAPPY SUMMER HOLS! • Polymorphous low grade adenocarcinoma • Adenocarcinoma NOS • Acinic cell carcinoma

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