Salivary glands - Printer Friendly Version
6 August 2006
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See also Oral cavity and oropharynx
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Primary references, normal anatomy, normal histology, embryology, sebaceous differentiation, saliva
Developmental disorders: heterotopia, polycystic disease
Inflammation: diffuse infiltrative lymphocytosis syndrome, Kimura’s disease, Mikulicz’s disease, necrotizing sialometaplasia, sialadenitis, sialolithiasis, Sjogren’s syndrome, xerostomia
Non-neoplastic tumors/tumor-like conditions: adenomatoid hyperplasia, adenomatous ductal hyperplasia of major salivary glands, amyloidosis, benign lymphoepithelial cyst, choristoma, epidermoid cyst, lymphoid hyperplasia, radiation effect
Epithelial/myoepithelial tumors: general, classification, acinic cell carcinoma, adenocarcinoma NOS, adenoid cystic carcinoma, adenosquamous carcinoma, basal cell adenocarcinoma, basal cell adenoma, canalicular adenoma, clear cell tumors, clear cell carcinoma, cystadenocarcinoma, epithelial myoepithelial carcinoma, giant cell tumor, hybrid carcinomas, inflammatory myofibroblastic tumor, intraductal carcinoma, inverted ductal papilloma, keratocytoma, large cell neuroendocrine carcinoma, lipoadenoma, lymphoepithelioma-like carcinoma, malignant mixed tumor, membranous adenoma, metastases, mucoepidermoid carcinoma, myoepithelioma, oncocytoma, oncocytosis, oxyphilic carcinoma, papillary adenocarcinoma, pleomorphic adenoma, polymorphous low grade adenocarcinoma, salivary duct carcinoma, salivary duct papilloma, sebaceous adenoma/lymphadenoma, sialadenoma papilliferum, signet ring adenocarcinoma, small cell carcinoma, squamous cell carcinoma, Warthin’s tumor
Lymphomas: lymphoma-general, MALT lymphoma, T cell lymphoma
Sarcomas: angiosarcoma, desmoplastic small round cell tumor, hemangioendothelioma, liposarcoma, undifferentiated sarcoma
Other tumors: embryoma, granular cell, lipoma, lipomatosis, melanoma, Rosai-Dorfman disease, schwannoma, sialolipoma
Miscellaneous: TNM staging, grossing, frozen section, fine needle aspiration, features to report
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), January 1999 to Sept 2004
Archives of Pathology and Laboratory Medicine (Archives) January 1999 to Aug 2004
Human Pathology, January 1999 to Aug 2004
Modern Pathology, January 1999 to Sept 2004
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby-Year Book, Inc., 2004
The 2001 USCAP Long Course, Mod Path 2002;15:298
Johns Hopkins textbook of images
Journal search terms: salivary, parotid, sublingual, submandibular
Please refer to these primary references for more detailed discussions and photographs
Major salivary glands are parotid gland (14-28g), submandibular / submaxillary gland (7-8g), sublingual gland (3g)
Parotid gland
Stensen’s duct (main duct) empties into oral cavity opposite crown of second maxillary molar
Has broad superficial lobe and smaller deeper lobe, with facial nerve usually between both lobes
Submandibular/submaxillary gland
Wharton’s duct empties into floor of mouth on both sides of tongue frenulum
Sublingual gland
Bartholin’s duct empties into floor of mouth on both sides of tongue frenulum
Minor salivary glands
Found in lip, gingival, floor of mouth, check, hard palate, soft palate, tongue, tonsils, oropharynx
Compound exocrine glands with ductal and acinar portions; acinar portion is serous, mucinous or mixed
Acini are lined by luminal cells, which are enclosed by myoepithelial cells
Serous acini: PAS+ intracytoplasmic secretory granules; have basally located intercellular capillaries
Mucous acini: well-rounded, basal nuclei; arranged around empty lumen; produce acid and neutral sialomucins
Myoepithelial cells: surround acini, mediate acinar contraction
Ducts are intercalated, striated and interlobular, all with outer basal cells and inner luminal cells
Intercalated ducts have reserve cells that regenerate acinar tissue and terminal duct system
All epithelium is PSA+
Sebaceous glands are attached to parotid and submandibular ducts (see below)
Parotid gland: serous acini only; contains small lymph nodes near or within the gland
Submandibular/submaxillary gland: predominantly serous but also mucinous acini
Sublingual gland: predominantly mucinous but also serous acini
Minor salivary glands:
von Ebner’s glands of tongue: serous acini only
Palate, base and lateral border of tongue: predominantly mucous acini
Lip, cheek, apex of tongue: mixed serous and mucous acini
Ectodermal structures, arise from solid epithelial buds of oral mucosa
Connective tissue diminishes with maturation, as do myoepithelial cells
Parotid buds may penetrate intraparotid lymph nodes; rare with submandibular or sublingual structures
Sebaceous type glands mixed with salivary gland acini
Occurs in 10-40% of normal parotid glands, often in periductal locations in interlobular ducts
Micro: single, isolated sebaceous-type cells within serous or mucinous salivary acini or as fully developed sebaceous glands
References: Archives 2004;128:245
Formed by acinar cells
High in amylase if secreted by serous glands; high in sialomucin if secreted by mucous glands
Developmental disorders
Also called ectopia
Normal salivary gland tissue at a site where normally not present
Usually in head and neck
Due to misplacement of salivary gland rests along embryologic pathways of migration during development, or by salivary differentiation of remnants of primitive embryologic structures
Intranodal (periparotid most common) or extranodal
May undergo same pathologic processes as usual salivary gland tissue
Most common neoplasm is Warthin’s tumor
Intranodal
More common than extranodal
In infants, most nodes within/near parotid gland contain salivary gland tissue, usually in medullary portion of node
Frequent but less common in adults
Usually composed of intercalated and intralobular ducts, but also serous type acini and immature ducts
Extranodal
May be high or low in head and neck
High: mandible, mastoid bone, external and middle ear, tonsil, mylohyoid muscle, palatine tonsil, gingiva, pituitary gland, cerebellopontine angle; due to abnormalities in migration of embryonic tissue
Low: related to bronchial pouches in lower neck, thyroid gland or parathyroid gland; most commonly at medial border of right sternocleidomastoid muscle near sternoclavicular joint
Case reports: 53 year old woman with cerebellopontine angle solitary fibrous tumor with ectopic salivary gland tissue (AJSP 2004;28:139)
References: AJSP 2000;24:837
Also called dysgenetic disease
Developmental disorder of females with bilateral gland enlargement
Inflammation
Diffuse infiltrative lymphocytosis syndrome
CD8+ lymphocytic infiltrate associated with HIV
Often involves salivary glands (present in 1-6% of US HIV+ patients vs. up to 50% in Africa)
Also affects lacrimal glands, kidney, muscle, nerve, liver, lung, GI, breast
Graded on 0-4 scale, 0: no infiltrate, 4: 2+ foci of 50 or more mononuclear cells in a 4-mm2 area of a section
Micro: resembles Sjogren’s syndrome; salivary ductal epithelial atypia common in Cameroon in advanced HIV patients
References: Archives 2000;124:1773
Rare chronic inflammatory disorder involving deep subcutaneous tissue of head and neck, often with lymphadenopathy and salivary gland involvement
Usually Asian males with elevated serum IgE and eosinophilia
US study showed 85% males, mean 32 years old, range 8-64 years, affects blacks, whites and Asians; rarely salivary gland involvement (AJSP 2004;28:505)
May clinically simulate a neoplasm
Chronic and indolent; rarely causes death
Treatment: surgery; may recur
Micro: follicular hyperplasia, eosinophilic infiltrates, postcapillary venule proliferation
DD: angiolymphoid hyperplasia with eosinophilia (all ethnic groups, superficial nodules, bleeding, pruritis, normal IgE and no eosinophilia)
Also called benign lymphoepithelial lesion
Presents as slow, bilateral, symmetric enlargement of salivary and lacrimal glands
May subside during acute infections
May be confined to salivary gland, usually part of Sjogren’s syndrome
Increased incidence with HIV
Initially polyclonal, may evolve into lymphoma (diffuse large B cell or SLL/CLL, rarely Hodgkin’s lymphoma, peripheral T cell lymphoma)
Gross: solid gray-white areas and occasional cysts
Micro: marked lymphocytic infiltration with lymphoid follicles surrounding solid epithelial nests (epimyoepithelial islands); also scattered histiocytes and dendritic cells; excess hyaline basement membrane material deposited between cells; also acinar atrophy and destruction, lymphoepithelial lesions, monocytoid B cells; usually no fibrosis, no involvement of large ducts
Reactive condition of minor or occasionally major salivary glands, often hard or soft palate, probably due to ischemia or vasculitis
Gross: ulcerated lesion of hard palate
Micro: ulcerated surface mucosa; intraductal proliferation of metaplastic squamous epithelium containing trapped mucous cells in lobular but noninfiltrative pattern; pseudoepitheliomatous hyperplasia common; vascular proliferation with prominent inflammatory infiltrate and partial necrosis of salivary glands, associated with squamous metaplasia of adjacent ducts and acini
DD: squamous cell carcinoma, mucoepidermoid carcinoma, post-radiation changes
Bacterial, viral or autoimmune
Bacterial
Rare, usually due to obstruction (sialolithiasis); caused by Staphylococcus aureus, Streptococcus viridans, gram negative bacteria
Stones may be due to obstruction of duct orifice by food or trauma-related edema
Also associated with dehydration, malnutrition, immunosuppression
Usually unilateral, painful enlargement of salivary gland; may cause abscess requiring surgical drainage
Chronic sialadenitis
Also called lymphoepithelial sialadenitis (LESA)
Relatively common
Chronic lymphocytic inflammation, often without symptoms
Associated with obstruction (with atrophy and fibrosis), rheumatoid arthritis (older women), Sjogren’s syndrome, sialolithiasis, mumps
50% are monoclonal by PCR, but this is insufficient to diagnose MALT lymphoma without other evidence of malignancy (such as monoclonality by immunohistochemistry or flow cytometry or monocytoid infiltrates in regional lymph nodes)
Micro: markedly hyperplastic lymphoid tissue infiltrates salivary gland with loss of acini; ducts are surrounded by and infiltrated by lymphoid cells
DD: MALT lymphoma (ducts surrounded by broad coronas of monocytoid cells, infiltration of interfollicular region by monocytoid cells or atypical plasma cells containing Dutcher bodies)
References: Mod Path 2002;15:255
Chronic sclerosing sialadenitis
Unilateral; lymphoplasmacytic periductal infiltrate leading to encasement of ducts in thick fibrous tissue
May require surgical excision
Usually due to sialolithiasis and NOT associated with systemic autoimmune disease, although may be due to an immune process (Mod Path 2002;15:845)
Kuttner’s tumor: involvement of submandibular gland
Micro: dilated ducts filled with inspissated secretions, associated lymphoplasmacytic infiltrate with variable germinal centers; late fibrosis and acinar atrophy; sialoliths in 50-80%
Granulomatous sialadenitis
Due to tuberculosis, sarcoidosis, fungal infections, duct obstruction (may contain mucin pools)
Sclerosing polycystic adenosis
Discrete mass, usually in parotid gland, formed by fibrous stroma overlying dilated and hyperplastic ductal and acinar structures
May have apocrine metaplasia and transluminal bridges with cribriform growth
May have prominent atypia
Viral
Often due to mumps (paramyxovirus), usually affects parotids, also pancreas, testes
Also Epstein-Barr virus, coxsackievirus, influenza A, parainfluenza
Stones (calculi) within salivary ducts
Most common within submandibular gland (saliva may be more saturated with calcium salts)
Stones may have foreign body or bacterial nidus; also composed of carbonate apatite
Produces swelling of distal salivary gland tissue, then glandular inflammation and induration with destruction of acini
Treatment: surgical removal, disintegration of calculi with shock-wave lithotripsy
Micro: dilated ducts with squamous metaplasia, variable chronic inflammatory infiltrate, variable destruction of acini
Xerostomia (dry mouth), keratoconjunctivitis sicca (dry eyes), rheumatoid arthritis, hypergammaglobulinemia
Autoimmune disorder that affects not only salivary glands and lacrimal glands of Mikulicz’s disease, but also minor salivary glands and occasionally lymph nodes, lung, kidney, bone marrow, skeletal muscle, skin, liver
Associated with autoimmune thyroiditis, systemic vasculitis, MALT lymphomas
Variable amyloid deposition outside the salivary glands
Diagnosis: labial gland biopsy
Micro: extensive lymphoid infiltrate with germinal centers, often interstitial fibrosis and acinar atrophy; usually no/rare epimyoepithelial islands in salivary glands, although may appear in skin sweat glands
Dry mouth
Associated with Sjogren’s syndrome
Gross: dry mucosa, atrophy of tongue papillae with fissures, ulcerations
DD: radiation therapy, anticholinergic drugs
Non-neoplastic tumors and tumor-like conditions
Nodular hyperplasia of minor salivary glands
Usually hard palate, also retromolar
Adenomatous ductal hyperplasia of major salivary glands
May coexist with epithelial-myoepithelial carcinoma, chronic parotiditis, other salivary gland tumors
May be precursor lesion to salivary gland tumors
Composed of intercalated duct epithelium
May involve salivary gland as tumor mass (amyloid tumor) or as a systemic disorder
May cause sicca syndrome
Parotid gland or upper cervical lymph nodes
Epithelium may be induced by lymphoid hyperplasia
May be related to branchial cleft cyst, multilocular thymic cyst, Warthin’s tumor
Gross: unilocular or multilocular
Micro: cyst lined by glandular or squamous epithelium and surrounded by prominent lymphoid follicles, which may penetrate cyst lining
HIV associated lymphoepithelial cyst
Resembles benign lymphoepithelial cyst or Mikulicz’s disease or both
Common in HIV+ patients, usually parotid gland, almost always cystic
Cyst epithelium derives from striated ducts
Lymphocytes are polyclonal; usually don’t progress to lymphoma
In children, lesions may be monoclonal and resemble MALT but don’t progress to MALT lymphoma
Micro: lymphocytes may have clear cytoplasm and penetrate epithelium
Gingival nodule of disorganized seromucinous salivary gland tissue mixed with sebaceous glands
Unilocular cystic formation with squamous lining containing a granular layer
Prominent benign lymphoid proliferations, often within intraparotid lymph nodes
Usually involves submandibular glands (most likely to be in field of radiation for oral cavity tumors)
Gross: firm, swollen glands
Micro: acinar atrophy, chronic inflammatory cells, squamous metaplasia of duct lining cells
Epithelial/myoepithelial tumors
Risk factors: radiation exposure (atomic bomb survivors, radiation therapy, chemoradiation therapy) with mean latency after low dose radiation exposure of 11 years for malignant tumors and 21 years for benign tumors; alcohol and tobacco are NOT risk factors except for Warthin’s tumor (associated with smoking)
Site: most are in parotid gland; sublingual tumors are rare and may be difficult to distinguish from minor salivary gland primary tumors of anterior floor of mouth
Benign: pleomorphic adenoma (50%), Warthin’s tumor (5%), oncocytoma, basal cell adenoma, ductal papilloma
Malignant: mucoepidermoid carcinoma (15%), polymorphous low grade adenocarcinoma (10%), acinic cell carcinoma, adenoid cystic carcinoma, malignant mixed tumor, squamous cell carcinoma (1%)
Bilateral tumors: Warthin’s tumor is most common, also pleomorphic adenoma and acinic cell carcinoma
>90% arise in parotid gland, 5% in submandibular gland, remainder in sublingual or minor salivary glands
Minor salivary gland tumors: usually in hard palate (site with most glandular tissue)
May arise in lymph nodes around salivary glands; deep parotid tumors may present as intraoral masses
15% of parotid tumors are malignant, 40% elsewhere
Children: pleomorphic adenoma most common, but more often malignant; most common malignant tumors are mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma
Regional lymph nodes: nodal metastases usually evident on initial clinical evaluation; low grade tumors rarely metastasize to regional nodes, high grade tumors often do; nodal involvement tends to be orderly from intraglandular to adjacent nodes to upper and midjugular nodes, and occasionally to retropharyngeal nodes; bilateral nodal involvement is rare
Metastases: usually to lungs
Treatment:
Parotid gland tumors - superficial lobe tumors are treated with superficial / partial parotidectomy with preservation of facial nerve
Total parotidectomy with sacrifice of facial nerve may be necessary if high grade or advanced tumor
Neck dissection necessary if nodal involvement
Submandibular tumors - total excision; often recur because of difficulty of getting good margins due to closeness of mandible
Radiation therapy -for inoperable tumors
Poor prognostic factors: postoperative recurrence, submandibular site, facial nerve paralysis, high grade tumor
Difficult because most tumors arise from or differentiate to epithelial or myoepithelial cells, which can undergo various metaplastic changes (oncocytic, chondroid, squamous, sebaceous)
Subtypes are clustered based on expression of myoepithelial, luminal and basal cell phenotypes (Mod Path 2004;17:803)
WHO classification: stresses distinction between benign and malignant
Mod Path subscribers: schematic of adenomas
1-3% of salivary gland tumors; #2 childhood salivary gland malignancy after mucoepidermoid carcinoma
Conflicting reports on gender predominance, peaks in 20’s and 40’s
Usually parotid and minor salivary glands, also parotid lymph nodes
10-15% metastasize (usually to local lymph nodes), 10-30% recur (may be due to inadequate excision)
80-90% recur if incompletely excised
5 year survival 90%, 20 year survival 60%
Less aggressive in minor salivary glands
Poor prognostic factors: high stage, pain or fixation, gross invasion, desmoplasia, anaplasia or dedifferentiated component, increased mitotic figures, necrosis, neural invasion, incomplete resection, large size, involvement of deep lobe of parotid
Case reports: dedifferentiation with myoepithelial features after multiple resections (Archives 2002;126:1104), dedifferentiated parotid tumor with facial nerve involvement but no prior surgery (Archives 2004;128:e52), parotid tumors in 35 year old father and his 16 year old daughter (Archives 1999;123:1118)
Gross: encapsulated, tan-gray, firm to soft, solid/cystic; usually < 3 cm; 3% bilateral or multicentric
Micro: variable patterns - solid, microcystic, papillary cystic (associated with hemorrhage), follicular; variable cell types - uniform acinar (serous) type cells with basophilic granular cytoplasm, clear cells (hypernephroid pattern, contains glycogen or mucin), vacuolated, intercalated duct, nonspecific glandular cells (smaller, syncytial); few mitotic figures; may have prominent lymphoid follicles at periphery (lymphoid stroma), psammoma bodies
Positive stains: keratin, alpha-1-antichymotrypsin, alpha amylase, vasoactive intestinal polypeptide, myoepithelial markers, granules are PAS+ diastase resistant; may have focal neuroendocrine staining
EM: multiple round, electron dense, cytoplasmic secretory granules
DD: normal parotid (tumors lack striated and interlobular ducts, lack lobular architecture), thyroid carcinoma
Adenocarcinoma, not otherwise specified (NOS)
Common, 5-10% of salivary gland tumors
Mean 58 years old, range 10-93 years
Often fixed to skin or deep tissues; palatal lesions often ulcerated and involve bone
Sites: parotid gland, submandibular gland, palate, buccal mucosa
Diagnosis of exclusion (not metastatic, not another salivary gland carcinoma)
Treatment: complete surgical excision
Case reports: 49 year old man with parotid mass (Archives 2004;128:487)
Gross: poorly circumscribed with infiltrative borders; solid tan cut surface with hemorrhage and necrosis
Micro: glandular or ductal differentiation but no features characteristic of other specific types; small clusters of cuboidal, round or ovoid cells with distinct borders and abundant cytoplasm; may have clear cell or oncocytic features; low, intermediate or high grade based on cytomorphic features
DD: polymorphous low grade adenocarcinoma, metastatic adenocarcinoma, membranous adenoma
Adenoid cystic carcinoma
Formerly called cylindroma
Most common in submandibular, sublingual or minor salivary glands
Also seen in nose, sinus, upper airway
Slow growing but aggressive; 50% metastasize, often silently to lung or bone; recurrences are frequent and often late
5 year survival is 60%, 10 year is 30%, 15 year is 15%
Higher recurrence rates for solid (100%) vs. cribriform (89%) vs. tubular (59%) patterns
15 year survival rates by pattern are solid (5%), cribriform (26%), tubular (39%)
Poorer prognosis for dedifferentiated, p53+ tumors
Better prognosis for tumors of palate or parotid gland
Perineurial invasion may be due to expression of brain derived neutrotrophic factor (Hum Path 2002;33:933)
Treatment: radical surgery regardless of tumor differentiation
Gross: small, solid, poorly encapsulated and infiltrative
Micro: cribriform, solid or tubular pattern similar to cylindromas of skin; small bland myoepithelial cells with scant cytoplasm and dark compact angular nuclei surround pseudoglandular spaces with PAS+ excess basement membrane material and mucin; peripheral perineurial invasion and small true glandular lumina; no squamous differentiation; no extensive necrosis
Note: presence of pseudoglandular lumina, true glandular lumina and perineurial invasion is usually required for diagnosis
Dedifferentiated tumors have irregular tumor islands composed of anaplastic cells with abundant cytoplasm and desmoplastic stroma
Grading: tubular and cribriform patterns are considered low grade/grade 1; 30% to ~70% solid is intermediate grade/grade 2, predominantly solid is high grade/grade 3.
Positive stains: cells in ducts - keratin, CEA, alpha-1-antichymotrypsin, S100, CD117/c-kit; cells around pseudoglandular spaces - S100, actin, variable keratin; dedifferentiated tumor - S100
Cytogenetics: loss of heterozygosity at 6q23-25 ( t[6;9][q21-24;p13-23] )
EM: pseudoglandular spaces, intercellular spaces, abundant basal lamina, true glandular lumina; cells are intercalated ducts, myoepithelial, secretory and reserve cells
DD: pleomorphic adenoma (not invasive, no perineurial invasion, has squamous metaplasia and mesenchyme-like areas), polymorphous low grade adenocarcinoma (very rare in major salivary glands, bland uniform cells, CD117 weak/negative)
References: AJSP 1999;23:465, Mod Path 2003;16:1224 (CD117 expression). Mod Path 2002;15:687 (CD117/c-kit)
Dedifferentiated tumors
Rare aggressive variant with death usually within 5 years of diagnosis
Dedifferentiated component either poorly differentiated adenocarcinoma or undifferentiated adenocarcinoma
References: Mod Path 2003;16:1265
Rare, aggressive
In minor (but not major) salivary glands and ducts
>90% males, mean age 58 years (range 32-99 years)
Sites: tongue, floor of mouth, nasal cavity, larynx
Metastases: in 70-80% even with primaries < 1 cm; variable histology
Treatment: surgical resection with neck dissection
5 year survival: 25%
Gross: 2 mm to 1 cm erythroplakic ulcer or indurated submucosal nodule
Micro: adenocarcinoma, squamous cell carcinoma and mixtures resembling mucoepidermoid carcinoma; may have multifocal carcinoma in situ involving salivary gland ducts, upward extension of intraductal carcinoma to involve mucosal epithelium, glassy squamous cells; commonly perineurial invasion and widespread invasion of submucosa
Positive stains: mucicarmine, PAS with diastase, Alcian blue (pH 2.5 and 1.0)
DD: mucoepidermoid carcinoma, squamous cell carcinoma, pseudoglandular squamous cell carcinoma
Also called basaloid carcinoma
1-2% of salivary gland carcinomas
Malignant counterpart of basal cell adenoma; 23% arise within basal cell adenomas
10-14% are associated with skin adnexal tumor syndrome
Usually parotid gland, ages 50+
37% recur locally, 8% metastasize (solid pattern) to lymph nodes, 4% to lungs; death from disease in unusual
Associated with dermal cylindromas
Treatment: excision with clear margins
Micro: low grade malignancy similar to basal cell adenoma but infiltrative with perineurial invasion and vascular invasion; variable cytologic atypia and mitotic activity; solid, trabecular, tubular or membranous patterns; no myxoid matrix
Positive stains: p53, HER2, CD117/c-kit
DD: adenoid cystic carcinoma (true cribriform structures, angular and hyperchromatic nuclei or prominent nucleoli, strong muscle marker staining)
Also called monomorphic adenoma
2% of benign salivary gland tumors
Usually adults, 2/3 female, mean age 58 years; rarely is congenital and resembles embryoma
Parotid gland or periparotid lymph nodes
Benign; rarely transforms, more likely if dermal analogue variant
Usually some myoepithelial differentiation using immunostains (Archives 2000;124:401)
Treatment: excision
Gross: encapsulated, often cystic, relatively small
Micro: solid, trabecular or tubular growth of epithelial cells resembling pleomorphic adenoma but with peripheral palisading; no histologic evidence of myoepithelial differentiation; fibrous stroma present; occasionally has acinar cells, squamous whorls or keratinization; no invasion, no mesenchymal component, no perineurial invasion, no myxoid matrix
Positive stains: ductal cells -keratin, alpha-1-antichymotrypsin, CEA, S100 (alpha subunit); basaloid cells - vimentin, actin, S100 (beta subunit)
DD: basal cell adenocarcinoma, adenoid cystic carcinoma, pleomorphic adenoma
Dermal analogue tumor
Also called membranous tumor
Uncommon subtype, usually in parotid gland or intranodal parotid gland
Usually men, mean age 60 years old
25-38% have cutaneous tumors
Occasionally coexists with multiple dermal cylindromas (Brooke-Spiegler syndrome, autosomal dominant salivary gland-skin adnexal tumor syndrome)
25-37% recur, 28% undergo malignant transformation to basaloid adenocarcinoma with destructive infiltrative growth beyond gland margins and perineurial or vascular invasion, but not necessarily pleomorphism, necrosis or mitotic activity
Gross: usually unencapsulated, 50% multifocal
Micro: jigsaw patterns of epithelial nests surrounded by deposition of basal lamina, resembling dermal eccrine cylindroma; larger nests may have cystic change and squamous metaplasia; may have coalescent membrane droplets within cell nests
Cytogenetics: 16q12-13 abnormality (cylindromatosis gene, CYLD)
DD: adenoid cystic carcinoma (more cytologic atypia, hyperchromatic angular nuclei or distinct nucleoli; true cribriform pattern with basophilic matrix)
References: AJSP 2002;26:778
4% of minor salivary gland tumors
Usually arises from minor salivary glands of upper lip or palate
Usually ages 50+ years
Recurrence is uncommon
Gross: often encapsulated, 22% multifocal; tumor may be received as fragmented specimen
Micro: bilayered strands or ribbons of columnar cells with loose, well vascularized stroma; often basaloid cells or trabecular features; often cystic change
Positive stains: S100, focal GFAP
Negative stains: myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin)
DD: adenoid cystic carcinoma (destructive infiltration, cribriform pattern, strong muscle markers+)
Uncommon
Mean age 72 years, range 30-88 years, no gender predominance
Clear cell carcinoma, clear cell epithelial-myoepithelial carcinoma, clear cell myoepithelial carcinoma, sebaceous carcinoma
Also clear cell variants of acinic cell carcinoma, oncocytoma, mucoepidermoid carcinoma
Also metastatic renal cell carcinoma or balloon cell melanoma
References: Archives 2002;126:676
Usually adult women with painless mass in minor salivary glands
Treatment: surgical excision with adequate margins; treat recurrences aggressively
Gross: infiltrating, scar-like
Micro: trabeculae, cords, islands or nests of monomorphic clear cells; also cells with eosinophilic and granular cytoplasm; infiltrative borders; variable atypia; no/rare mitotic figures; no myoepithelial differentiation
Positive stains: PAS diastase sensitive (glycogen), cytokeratin (high molecular weight), CEA, EMA
Negative stains: mucin, S100, smooth muscle actin, calponin, vimentin
EM: abundant glycogen, desmosomes, peripheral tonofilaments, squamoid differentiation, prominent interdigitating microvilli without actin myofilaments or dense bodies; no lipid, no zymogen granules, no true ductal lumina
DD: myoepithelioma (also positive for glycogen), sebaceous neoplasms (positive for fat), mucoepidermoid carcinoma (positive for mucin), acinic cell carcinoma (negative for glycogen, fat and mucin), clear cell change in oncocytic tumors, metastatic renal cell carcinoma (positive for RCC, glycogen, vimentin and CD10, negative for high molecular weight cytokeratin and CEA, abundant lipid but no squamoid differentiation by EM)
References: AJSP 1999;23:1532
Hyalinizing subtype
Nests of clear cells surrounded by hyalinized bands with foci of myxohyaline stroma
Often affects intraoral salivary glands at base of tongue or palate; also within nasopharynx and jaw
Low grade malignancies with 15% nodal metastases and possible late recurrence
Micro: solid masses, nests, infiltrating cords or single file clear cells composed of glycogen with mild atypia or eosinophilic cytoplasm; hyalinized stroma, rare mitotic figures
Positive stains: EMA
References: AJSP 1994;18:74
Mean 59 years old, range 20-86 years
Often in major salivary glands, but also in lips, buccal mucosa, palate, tongue, retromolar area, floor of mouth
Usually indolent, but occasionally recurs locally or metastasizes
Gross: cystic masses, 0.4 to 6 cm
Micro: invasive, cystic growth pattern, 75% with conspicuous papillary component; composed of small cuboidal cells, large cuboidal cells, tall columnar cells or mixture; cyst rupture with hemorrhage and granulation tissue is common; does not involve the native duct system
References: AJSP 1996;20:1440
Epithelial myoepithelial carcinoma
Rare (less than 0.5% of salivary gland tumors); 80% arise in parotid gland
Mean age 60 years; 60% in women
Terminology may be confusing; also called glycogen rich adenoma (clear cell pattern), myoepithelioma (spindle cell and plasmacytoid patterns), myoepithelial carcinoma (if only myoepithelial differentiation and marked cytologic atypia)
Low grade malignancies with frequent local recurrences; previously often considered to be benign, but with sufficient follow-up, there are rare regional nodal metastases and distant metastases to lung and kidney
In overtly malignant cases (cytologic atypia and infiltrative), metastases are found in 47% and 29% die of disease after mean 32 months
Case reports: Case of Week #54
Gross: well delineated, firm, infiltration into adjacent tissue; usually 2-3 cm
Micro: low grade with epithelial and myoepithelial components; often multinodular with partial thick fibrous capsule; most tumor cells have myoepithelial features with clear cytoplasm or naked nuclei; focally, there are ducts or tubules with an outer rim of myoepithelial cells and inner, dark ductal cells with scant eosinophilic cytoplasm and round, bland nuclei; also islands, nests or sheets of spindle cells, plasmacytoid (hyaline) cells; may have overt cytologic malignancy, infiltrative growth and perineurial invasion; often mild nuclear pleomorphism; variable mitotic activity
Cytology: cellular, with single cells and naked nuclei; biphasic pattern may not be evident since the clear cells have fragile cytoplasm and often appear as naked nuclei (Diagn Cytopathol 2003;28:163)
Positive stains: myoepithelial component - PAS+, diastase sensitive due to cytoplasmic glycogen; also S100+, p63+ (Cancer 2005;105:240), smooth muscle actin+, variable keratin; epithelial component - keratin and EMA (strong), occasional S100+
Negative stains: CEA
DD: plasmacytoma, skeletal muscle tumors, oncocytoma, malignant mixed tumor, myoepithelial carcinoma (defined as lacking any epithelial component, AJSP 2000;24:761), pleomorphic adenoma (biphasic but with prominent myxochondroid stroma, myoepithelial cells usually lack cytoplasmic clearing); other biphasic tumors include adenoid cystic carcinoma (prominent cribriform pattern) and polymorphous low grade adenocarcinoma (affects intraoral salivary glands, clear cells do not predominate and are not associated with ductal cells); clear cell carcinoma (usually affects the minor salivary glands, unencapsulated, lack epithelial cells and are negative for myoepithelial markers), metastatic renal cell carcinoma
References: AJSP 2000;24:761, Archives 2002;126:676
Giant cell tumor of salivary glands
Very rare; first reported in 1984
Mean age 62 years, range 28-92 years; 80% male
87% in parotid gland; 13% in submandibular gland
Uncertain histogenesis, may be a carcinoma; giant cell component may be neoplastic
50% associated with carcinoma (usually salivary duct carcinoma or carcinoma ex pleomorphic adenoma / malignant mixed tumor)
13% die of disease; more aggressive than giant cell tumor of bone, less aggressive than undifferentiated carcinoma (48% 5 year survival)
Presents as rapidly enlarging mass
Gross: no peripheral mineralized bone shell
Micro: evenly distributed osteoclastic giant cells in background of mononuclear cells; nuclei differ between mononuclear cells and osteoclastic giant cells (unlike giant cell tumor of bone)
Positive stains: mononuclear cells - EMA, CEA, androgen receptor, histiocytic markers
EM: giant cells are similar to bone osteoclasts; mononuclear cells have numerous microvilli and some cell junctions but few lysosomes
References: AJSP 2004;28:953
Very rare (< 0.1% of salivary gland tumors)
2 distinct tumors in same topographic area producing a single clinical and macroscopic tumor mass
Epithelial-myoepithelial carcinomas are overrepresented in this category
Must sample thoroughly since only one component may be aggressive
Mean age 53-62 years, range 28-81 years
Usually parotid gland
DD: collision tumors (distinct masses that meet), biphasic tumors, recurrent tumor
References: Archives 1999;123:698, Mod Path 2002;15:724
Inflammatory myofibroblastic tumor
Also called inflammatory pseudotumor; formerly called plasma cell granuloma
Uncommon, usually benign behavior, non-neoplastic
Case reports: 70 year old Japanese man with submandibular gland tumor and autoimmune-like symptoms (Archives 2001;125:1095)
Micro: myofibroblasts and chronic inflammatory cells
DD: MALT lymphoma
Rare controversial entity (< 20 cases reported), in situ form of salivary duct carcinoma
Mean age 62 years, range 32-91 years
Usually affects major salivary glands
Excellent prognosis; no metastases or mortality reported; may recur with incomplete excision as intraductal or invasive tumor
May represent preinvasive phase of some salivary duct carcinomas
Recommended to sample extensively and stain for myoepithelial cells with p63 and actin to rule out invasion
Treatment: total parotidectomy or wide excision to prevent recurrence / progression
Case reports: 44 year old woman with mass in buccal mucosa arising from minor salivary glands (AJSP 2004;28:266)
Gross: may be multifocal, cystic
Micro: unencapsulated but circumscribed intraductal neoplasm in micropapillary, cribriform, solid, comedo or clinging patterns, with preservation of myoepithelial cells surrounding intraductal tumor; resembles breast DCIS; variable atypia, variable mitotic figures, no invasion
Positive stains: epithelial cells - high molecular weight cytokeratin, EMA, S100 (50%), myoepithelial cells - p63 (nuclear stain), muscle specific actin
Negative stains: ER, PR, p53
Resembles inverted papilloma of nasal cavity
Benign
Gross: small submucosal mass
Micro: complex invaginations of well differentiated squamous epithelium with microcysts, mucous cells and columnar cell lining
Very rare, < 10 cases reported
Appear to be derived from salivary ducts undergoing squamous metaplasia
Benign; excision appears to be adequate treatment
Micro: benign tumor with multicystic spaces lined by squamous cells with focal solid epithelial nests; parakeratotic and orthokeratotic keratinization without a granular layer; outer layer has bud-like protrusions; cells have bland, uniform nuclei and abundant eosinophilic cytoplasm; occasional normal mitotic figures; focal foreign-body reaction against keratin; no necrosis, no invasion, no angiolymphatic invasion, no perineurial invasion, no atypia, no mucous cells
Positive stains: cytokeratin, Ki-67 (outer basal layer only)
Negative stains: alpha smooth muscle actin, S100
DD: squamous cell carcinoma, mucoepidermoid carcinoma, squamous metaplasia in other conditions
References: Mod Path 2002;15:1005
Large cell neuroendocrine carcinoma
Extremely rare
2 cases reported in parotid glands in men ages 72 and 73 years (Mod Path 2000;13:554)
Aggressive behavior
Micro: organoid, solid, trabecular and rosette-like patterns of large polygonal cells with coarse chromatin and prominent nucleoli, high mitotic rate, frequent necrosis
Positive stains: neuroendocrine markers, cytokeratin, p53, bcl2, epidermal growth factor receptor, cyclin D1, Ki-67
Negative stains: CK20
Molecular: 9p21 abnormalities
DD: undifferentiated carcinoma, Merkel cell carcinoma (CK20+)
Glandular structures with sertoliform features and adipose tissue
May derive from striated ducts
Lymphoepithelioma-like carcinoma
Type of undifferentiated carcinoma common in Eskimos and Chinese, often familial in these groups
Unilateral mass of parotid gland or submandibular gland of adults
Metastases common to regional lymph nodes; distant metastases to liver, lung, bone
Relatively good outcome
Micro: malignant epithelial islands resembling nonkeratinizing large cell carcinoma and lymphoid tissue with germinal centers; occasional spindled areas; often perineurial invasion; may have starry sky pattern
Positive stains: keratin, EBV (often)
Also called carcinoma ex pleomorphic adenoma, carcinosarcoma if malignant epithelial/myoepithelial and mesenchymal components
Rare
Usually malignant transformation of benign pleomorphic adenomas; 2% risk if present < 5 years, 10% risk if 15 years duration for pleomorphic adenoma
Clinically, have sudden increase in growth, pain or facial paralysis
Associated with surgery or radiation therapy
Often prior history of pleomorphic adenoma is difficult to obtain but necessary for diagnosis unless benign tumor coexists with malignant tumor
Note: must rule out malignant mixed tumor if a high grade carcinoma of salivary glands is difficult to classify, by vigorous searching for a benign mixed tumor (may be 5 mm or less)
50% survival at 5 years
Metastases to regional lymph nodes, lungs, bone (vertebral column), abdominal organs
Prognostic factors (must thoroughly sample tumor): stage, extent of invasion beyond the capsule (<8 mm is associated with benign behavior); histologic type and grade of carcinoma, proliferation index, proportion of carcinoma
Case reports: 47 year old man with parotid tumor containing pleomorphic adenoma and rhabdomyosarcoma (Archives 2001;125:812), 71 year old man with submandibular tumor with giant cell component (Archives 2000;124:1559)
Gross: widely infiltrative with hemorrhage and necrosis
Micro: malignant epithelium, often salivary duct carcinoma, undifferentiated carcinoma or adenocarcinoma NOS, terminal duct carcinoma or myoepithelial carcinoma, usually with benign stroma; malignant tumor is extensively infiltrative with necrosis, perineurial invasion, frequent mitotic figures, marked nuclear atypia; occasionally benign pleomorphic adenoma is present with hyalinization and hypocellularity
Note: clinical malignant behavior is associated only with cytologically malignant foci beyond the capsule of original tumor
Less commonly the stromal component is chondrosarcoma or other malignancy, with no preexisting benign component and aggressive behavior
Positive stains: AE1/AE3 (97%), CK7 (94%), EMA (86%), CEA (75%), vimentin (52%), S100 (29%), p53 (41%), HER2 (30%), B72.3
Cytogenetics: associated with 8q12-13 and 12q13-15 rearrangements
References: Hum Path 2001;32:596
Micro: multinodular foci of epithelial islands surrounded by thick, eosinophilic, hyaline layer; no infiltration of adjacent parenchyma, nerves, blood vessels
Usually to intraparotid or submandibular lymph nodes
Most common submandibular metastatic tumors are metastatic squamous cell carcinoma from upper aerodigestive tract or skin, or melanoma to submandibular lymph nodes
Distant metastases arise from lung, kidney, breast, prostate gland, colon
Most common malignant tumor in salivary glands; most common radiation induced neoplasm
2/3 occur in parotid gland; also in palate
Wide age range, mean 49 years, range 15-86 years, no gender predominance
Low grade: 15% recur, 5 year survival 90-98%; usually stage I
High grade: 25% recur, 5 year survival 50-56%; deaths usually within first 5 years
Note: significant grading disparity exists between pathologists (AJSP 2001;25:835)
AFIP point system: 2 points if <20% intracystic component; 2 points if necrosis; 2 points if neural invasion; 3 points if 4+ mitotic figures/10 HPF; 4 points if anaplasia; low grade if total score is 0-4 points, intermediate grade if 5-6 points, high grade if 7+ points
Poor prognostic factors : older age, male, submandibular gland, extraglandular extension, vascular invasion, necrosis, high mitotic rate, high histologic grade
Treatment: complete excision, possible radiation therapy
Case reports: 55 year old man with low grade parotid tumor and dedifferentiation (Hum Path 2003;34:1068)
Gross: low grade - well circumscribed mass with gray-white, mucin filled cysts
Micro: cords, sheets, clusters of mucous, squamous, intermediate and clear cells; low to high grade, although even high grade tumors lack marked nuclear atypia, frequent mitotic figures or extensive necrosis; occasional focal sebaceous cells, oncocytic change, inflammatory reaction to extravasated mucin or keratin and goblet-type cells; no squamous cell carcinoma in situ
Low grade: mucinous and intermediate cells with bland nuclei form glandular spaces
High grade: solid and infiltrative growth pattern of atypical epidermoid and intermediate cells with cytoplasmic clearing and small number of mucinous cells; <20% intracystic component
Positive stains: low grade - CK7, CK14, antimitochondrial antibodies
Cytogenetics: associated with t(11;19)(q14-21;p12-13)
EM: mixed luminal epithelial cells and myoepithelial cells
DD: poorly differentiated adenocarcinoma, adenosquamous carcinoma (has anaplastic nuclear features), necrotizing sialometaplasia, metastatic carcinoma
Oncocytic variant
Oncocytic tumor cells are 60% or more of neoplasm
<10% of all mucoepidermoid carcinomas
Positive stains: PTAH (granular cytoplasmic staining), antimitochondrial antibodies
References: AJSP 1999;23:523
Defined as benign tumor composed only of myoepithelial cells
May have hyalinization and myxoid matrix production
See also epithelial myoepithelial carcinoma above
Also called oxyphilic adenoma
1-2% of salivary gland neoplasms
Benign tumor composed of oncocytes
Usually in parotid gland, also submandibular gland
Mean age 60 years; tumors with clear cells are more common in women
20% associated with radiation therapy or radiation exposure
Malignant if regional nodal or distant metastases, cellular pleomorphism, frequent mitotic figures or invasion
Treatment: local excision; excellent prognosis
Case reports: 79 year old woman with tumor of deep lobe of parotid gland with oncocytic hyperplasia (Archives 2003;127:e53)
Gross: well circumscribed with fibrous capsule, solid, tan-red-brown, lobulated, often small, may have cystic spaces
Micro: sheets, trabeculae, acini or follicular patterns of monotonous large polygonal cells with well defined cell borders, deeply eosinophilic, granular cytoplasm, small round nuclei; may have clear cell change, psammoma bodies, tyrosine-rich crystals; no mitotic figures
Negative stains: myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin)
EM: packed with mitochondria with partitions
DD: oncocytic metaplasia, oncocytosis
Also called multinodular oncocytoma, multifocal adenomatous oncocytic hyperplasia
Benign
Micro: either parotid cysts lined by oncocytes or well defined clusters of oncocytes; oncocytes (oxyphilic cells) are large ductal epithelial cells with eosinophilic granular cytoplasm
EM: numerous mitochondria
DD: normal aging (increased oncocytes), Warthin’s tumor, oncocytoma
Also called malignant oncocytoma
Malignant counterpart of oncocytoma
Very rare
Micro: atypia, mitotic figures, infiltrative growth
<3% of parotid tumors; also in oral cavity
Called cystadenocarcinoma if prominent cystic component
Poor prognosis if stromal invasion; similar prognosis to low grade mucoepidermoid carcinoma if no stromal invasion
Gross: often large, with hemorrhage and necrosis
Micro: well defined papillary structures, usually mucin, no squamous or intermediate cell components; may have only focal malignant component in otherwise benign mucinous cystadenoma
DD: mucoepidermoid carcinoma, acinic cell carcinoma, metastatic carcinoma (thyroid, other)
Also called benign mixed tumor
Most common tumor of salivary glands
Often women in 30’s, but any age
Painless, slow growing tumor
90% occur in parotid gland (represent 60% of parotid tumors; 50% occur in tail, 25% in superficial lobe, 25% in deep lobe), 10% in submandibular gland, rare in sublingual gland; represents 50% of salivary gland tumors of palate
Epithelial and mesenchymal (myxoid, hyaline, chondroid, osseous) cells often arise from same cell clone (Hum Path 2000;31:498), which may be a myoepithelial or ductal reserve cell
Radiation exposure increases risk
No difference in behavior based on proportion of various elements
Risk factors for malignant transformation: submandibular location, older age, larger size, prominent hyalinization, increased mitotic rate (if present, sample tumor more thoroughly)
Treatment: wide local excision (25% recur with enucleation, 4% with adequate parotidectomy)
Recurrences are usually within 18 months, but also up to 50 years later; after surgery for recurrent tumor, 25% recur again
Gross: well-demarcated, partially encapsulated, gray-white myxoid, rubbery mass with solid cut surface, often 6 cm or less, tumor extensions into adjacent tissue may be subtle
Micro: not as well circumscribed as may grossly appear, with tongue like protrusions into surrounding salivary gland; thick capsule if present in deep parotid lobe; biphasic population of epithelial and mesenchymal cells; epithelial cells are glandular or occasionally squamous; may be spindled or oval, have large hyperchromatic nuclei; have myoepithelial basal layer or overlying pseudoepitheliomatous hyperplasia or be very cellular; stroma is myxoid, hyaline, chondroid, rarely adipose tissue or osseous; occasional angiolymphatic invasion; mucin often present; may have adenoid cystic pattern; no mitotic figures, no necrosis
Positive stains: ductal component - keratin (CK19, CK14), EMA, CEA, alpha-1-antitrypsin, alpha-1-antichymotrypsin, GCDFP-15, PSA (50%), PAP (50%), myoepithelial component - keratin, actin, myosin, other smooth muscle proteins, S100 (particularly in cartilaginous areas), GFAP
Negative stains: amylase, p53
Cytology: clusters of benign epithelial cells with blue myxoid matrix and tyrosine-rich crystals
Cytogenetics: normal or rearrangements of 8q12 or 12q14-15
EM: features of epithelial and mesenchymal cells
Benign metastasizing mixed tumors
Rare, <50 cases reported
Late metastasis (6-52 years) after tumor excision to lymph nodes, lung, bone, skin, spinal cord or kidney with benign morphology in original and metastatic tumor
Associated with prior local recurrence and occasionally with immunosuppression
Metastasis thought to occur via vascular channels due to tumor fragmentation or seeding at surgery
22% mortality
Case reports: 53 year old woman with solitary kidney mass and subsequent parotid mixed malignant tumor (AJSP 2000;24:1159), 37 year old man with spinal cord compression after submandibular tumor (Archives 2003;127:887)
Polymorphous low grade adenocarcinoma
Also called terminal duct carcinoma, lobular carcinoma, low grade papillary adenocarcinoma
Usually palate; second most common tumor at this location after adenoid cystic carcinoma
In major salivary glands is usually associated with pleomorphic adenoma
Median age 54 years, range 22-71 years, 2/3 women
12-30% recur, nodal metastases in 10-15%, 10% have distant metastases or tumor related death (AJSP 2000;24:1319)
Protracted clinical course; 9-17% recur locally, 9% metastasize to regional lymph nodes, rarely metastasizes to lung, transforms to high grade tumor or causes death
More than focal papillary growth is associated with cervical lymph node metastases
Positive or unknown surgical margins are associated with local recurrence
Treatment: conservative wide excision
Micro: nonencapsulated but often well circumscribed tumor with diverse (polymorphous) growth patterns (tubular, cribriform, focally papillary, solid, fascicular, microcystic, single file, pseudoadenoid cystic [without true lumens], strand-like, mixed); infiltrative borders as small islands and tubules; mucoid and hyaline stroma; cells have only mild atypia with uniform, bland nuclei, but with perineurial invasion common around small nerves; no/rare mitotic figures, rare tumor necrosis
Positive stains: S100, EMA, keratin, focal GFAP, focal muscle specific actin, focal CEA
Negative stains: myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin), CD117 (may be weak)
DD: pleomorphic adenoma (circumscribed, no perineurial invasion, although both may extend focally into adjacent minor salivary glands), basal cell adenoma, adenoid cystic carcinoma (bilayered tubules, nuclear atypia, muscle markers+), cystadenocarcinoma (also has papillary areas), metastatic lobular breast carcinoma (Archives 2000;124:157)
References: AJSP 1988;12:461 (stains), AJSP 1984;8:367, Mod Path 2002;15:687 (CD117/c-kit)
Uncommon; usually elderly, 75% males
Usually parotid gland, also submandibular gland
High grade tumors are aggressive with frequent metastases to regional lymph nodes and distant sites, 70% mortality
May arise from pleomorphic adenoma or polymorphous low grade adenocarcinoma or de novo
Aggressive, 60% have nodal or distant metastases; commonly tumor infiltration into soft tissue at diagnosis
>60% die from tumor, usually within 5 years
Poor prognostic factors: > 3 cm, metastases, small intraductal component
Treatment: excision with regional lymph node sampling and radiation therapy; possibly prostate cancer-like hormonal therapy
Gross: white-tan masses with solid or cystic cut surface or necrosis
Micro: resembles breast carcinoma subtypes, both high grade (papillary, sarcomatoid, colloid) or low grade (cribriform with Roman-bridge structures, see also below), with in situ and invasive components; cells have eosinophilic cytoplasm, marked nuclear pleomorphism with vesicular nuclei, prominent nucleoli; frequent perineurial and vascular invasion, fibrous and hyalinized stroma, mitotic figures; may have dystrophic calcification
Positive stains: keratin, EMA, CEA, B72.3, androgen receptors (>90%), PPAR gamma (80%), GCDFP-15 (especially intraductal component), PSA (60%), PAP (20%), 50% HER2
Negative stains: ER, PR (80% negative), S100, myoepithelial markers
DD: metastatic carcinoma, polymorphous low grade carcinoma, mucoepidermoid carcinoma
References: AJSP 2000;24:579, Hum Path 2000;31:208 (sarcomatoid), Mod Path 2003;16:1218 (PPAR gamma expression)
Colloid carcinoma (mucin rich) variant of salivary duct carcinoma
Very rare; poor outcome
May represent extreme variation of a common occurrence of extracellular mucin
Micro: large extracellular mucin lakes containing clusters and single tumor cells
Positive stains: keratin (CK7), EMA, androgen receptors, GCDFP-15, CEA, MUC2, MUC5B, MUC6, variable HER2 overexpression
Negative stains: CK20, S100, myoepithelial markers, ER, PR, MUC5AC, MUC7
References: AJSP 2003;27:1070
Low grade salivary duct carcinoma
Rare (<1% of salivary gland carcinomas), first reported in 1996
Median 64 years
Usually parotid gland
May be entirely intraductal or locally invasive
Excellent prognosis
Treatment: surgery
Gross: unencapsulated
Micro: single to multiple dominant cysts accompanied by adjacent intraductal proliferation; cysts lined by small, multilayered, bland ductal cells with fine chromatin and small nucleoli; smaller ductal structures have variable proliferating ductal epithelium with cribriform, micropapillary or solid patterns resembling ADH or low grade DCIS of breast; may have indistinct cytoplasm membranes, apocrine-type cytoplasmic microvacuoles; lipofuscin-like pigment; may have definite stromal invasion, transition between low grade and high grade areas; rarely goblet cells or oncocytoid cells; no/rare mitotic figures or necrosis
Positive stains: S100, calponin (myoepithelial cells lining cystic spaces)
Negative stains: HER2
DD: papillocystic variant of acinic cell carcinoma (smaller vacuoles, S100 negative, zymogen granules by EM), cystadenocarcinoma (no resemblance to breast ADH or DCIS, usually widely invasive)
References: AJSP 2004;28:1040
Also called intraductal papilloma, intraductal papillary tumor
Very rare
Benign; usually in minor salivary glands
Case reports: benign sublingual tumor and microinvasive intraductal parotid tumor (Archives 2000;124:291)
Micro: papillary proliferations of bland cuboidal/columnar epithelial cells with fibrovascular cores
DD: papillary cystadenoma, papillary cystadenocarcinoma, papillary-cystic variant of acinic cell carcinoma, salivary duct carcinoma, polymorphous low grade adenocarcinoma, metastatic papillary thyroid carcinoma
Sebaceous adenoma / lymphadenoma
Benign tumors with predominantly sebaceous component
Sebaceous lymphadenoma if prominent lymphoid stroma
Lymphadenoma if epithelial glandular cells and lymphoid stroma but no sebaceous glands
Rare benign tumor of salivary gland origin
Usually hard palate or parotid gland of men over 40 years
Gross: well circumscribed, round/oval, papillary tumor of mucosal surface
Micro: biphasic, with well differentiated papillary hyperplastic squamous epithelium covering ductal component of cleftlike cystic spaces lined by cuboidal or columnar epithelium with occasional goblet cells; variable oncocytes and squamous metaplasia
Positive stains: squamous epithelium - CK7, AE1-AE3, CEA, EMA; ductal structures - CK7, AE1-AE3, CAM 5.2, CEA, EMA, S100
Negative stains: CK20, GFAP, desmin, muscle specific actin
EM: oncocyte is predominant cell; contains numerous mitochondria, parallel filaments within cell cytoplasm attached by desmosomes (Archives 1986;110:523)
DD: Warthin’s tumor, papillary syringocystadenoma
References: Archives 2001;125:1595
Signet ring cell adenocarcinoma
Rare subtype of adenocarcinoma (2% of primary minor salivary gland malignancies)
Slow growing with favorable outcome, based on limited data
Micro: non-circumscribed tumor composed of bland, mucin containing signet ring cells that invade in narrow parallel strands, with scattered small nests or individually infiltrating cells; often perineurial invasion; minimal ductal differentiation; no solid, cribriform or papillary components; no angiolymphatic invasion
Positive stains: CAM 5.2, smooth muscle actin, GFAP, p63
Negative stains: calponin
DD: mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma, colloid (mucinous) carcinoma
References: AJSP 2004;28:89
Rare; aggressive; pure or with squamous cell carcinoma or adenocarcinoma
2% of parotid gland carcinomas, 4% of minor salivary gland malignancies
Usually age 50+ but also < 30 years
Either neuroendocrine (Merkel cell or pulmonary varieties) or ductal types
Micro: resemble lung tumors with solid areas of small spindled to ovoid cells with minimal cytoplasm, hyperchromatic nuclei with fine chromatin, indistinct nuclei; high mitotic activity, geographic necrosis; often a better differentiated carcinoma is present; rarely squamous or ductal differentiation; does not arise from surface epithelium but may involve it secondarily
Positive stains: keratin (punctuate perinuclear), CK20 (75%, paranuclear dotlike pattern), EMA, at least one neuroendocrine marker (chromogranin, synaptophysin, CD57/Leu7, neuron specific enolase)
EM: variable dense core secretory granules
DD: adenoid cystic carcinoma-solid variant (focal cribriform architecture, myoepithelial differentiation, no neuroendocrine differentiation); lymphoma (CD45+, keratin-), melanoma (S100+, HMB45+, vimentin+, CK-), large cell undifferentiated carcinoma (cells > 30 microns, moderate N/C ratio, coarse chromatin, prominent nucleoli), metastatic squamous cell carcinoma
References: Mod Path 1990;3:631, Mod Path 2002;15:264, AJSP 2004;28:762
True salivary gland primaries of squamous cell carcinoma are very rare
Most tumors of parotid gland are metastases to intraparotid lymph nodes from primaries in oral cavity, upper aerodigestive tract or skin
May represent malignant component of malignant mixed tumor or high grade mucoepidermoid carcinoma
Rapid growth with infiltration of surrounding structures, regardless of origin
50% 5 year survival
Treatment: radical surgery, radiation therapy
Gross: large, poorly encapsulated mass
References: Archives 2001;125:740
Warthin’s tumor
Also called papillary cystadenoma lymphomatosum papilliferum, adenolymphoma
Almost always in parotid gland
Usually male smokers age 40+ years
Arise from incorporation of lymphoid tissue in parotids or induction of cystic and oncocytic changes by inflammatory infiltrate; non-neoplastic (Hum Path 2000;31:1377)
70% of bilateral salivary gland tumors are Warthin’s tumors
Rarely transforms to lymphoma, adenocarcinoma, mucoepidermoid carcinoma, squamous cell carcinoma, oxyphilic carcinoma or Merkel cell carcinoma
Treatment: surgical excision; 2% recur after resection
Gross: encapsulated, lobulated, pale gray surface, multicystic with mucinous/serous secretion, 10-15% multifocal/bilateral; 2-5 cm; may be fixed to overlying skin; may undergo hemorrhagic infarction, particularly after fine needle aspiration
Micro: double layer of epithelial cells resting on dense lymphoid stroma with variable germinal centers; cystic spaces narrowed by polypoid projections of lymphoepithelial elements; surface palisading of oncocytic columnar cells with underlying discontinuous basal cells; occasional features are cilia, squamous metaplasia associated with infarct-like necrosis, mast cells, dendritic cells, mucin secreting cells, sebaceous cells; very rarely signet ring cells; no myoepithelial component
Positive stains: keratin (CK7, CK 8/18, CK19), mitochondrial markers; focal CEA
Negative stains: amylase, vimentin, desmin
Cytogenetics: associated with t(11;19)(q14-21;p12-13) as is mucoepidermoid carcinoma
EM: oncocytes are stuffed with mitochondria with cup shapes or concentric-ring forms but no partitions
Lymphomas
3% of salivary gland neoplasms
Mean age 63 years
Primary lymphomas may arise from intraparotid lymph node or within parotid or submandibular gland
Unilateral masses, often diffuse large B cell lymphoma, follicular lymphoma, MALT or SLL/CLL
Increased risk with autoimmune disease
3% of tumors of major salivary glands
Indolent, excellent prognosis
Most common lymphoma of salivary glands
Often associated with Sjogren’s syndrome or benign lymphoepithelial lesion, perhaps due to chronic antigenic stimulation
May arise post-transplantation (AJSP 2000;24:100)
Case report arising in chronic sclerosing sialadenitis / Kuttner’s tumor (AJSP 2001;25:1546)
Diagnosis: monoclonality by immunohistochemistry or flow cytometry or monocytoid infiltrates in regional lymph nodes; monoclonality in lymphoid infiltrates by PCR is insufficient for diagnosis
Micro: monocytoid cells surround ducts
Positive stains: CD19, CD20, CD22
Negative stains: CD5 (usually), CD10, bcl-1/cyclin D1
Molecular: t(11;18)(q21;q21) is specific; encodes c-IAP2-MLT fusion protein
Very rare
Often EBV+
Case reports: 42 year old man with AIDS and parotid gland tumor with NK/T cell phenotype (Archives 2002;126:738)
Sarcomas
Extremely rare in salivary glands, usually parotid (primary or secondary) or submandibular gland (primary)
Often have relatively good outcome
Micro: usually spindled cells with solid or vasoformative growth pattern, often epithelioid
References: Mod Path 2003;16:263
Desmoplastic small round cell tumor
Case reports: parotid gland of 22 year old man (Hum Path 1999;30:430)
Positive stains: cytokeratin, desmin, neuron-specific enolase
Molecular: EWS-WT1 fusion transcript
Also called juvenile hemangioma
Most common salivary gland tumor of infants/children; often girls
Often congenital, involves parotid gland
Not malignant; 70-95% regress spontaneously by age 7 years
May be associated with Kasabach-Merritt syndrome
Fine needle aspiration may be useful for diagnosis (Archives 2001;125:1340)
Treatment: delay excision in hope of spontaneous regression
Gross: diffuse soft mass uninvolved with overlying skin
Micro: anastomosing thin walled capillaries growing between salivary ducts and acini; variable mitotic figures
Cytology: spindle shaped cells in sheets and clusters in bloody background; cell block shows ductal structures trapped in sheets of spindle cells
Positive stains: CD34 and factor VIII
Rare in oral cavity or salivary gland region
Median age (oral/salivary gland) is 51 years, range 30-70 years; no childhood cases
No gender predominance
Better prognosis than at other sites; no metastases or deaths due to disease
Treatment: complete excision and careful follow-up
Gross: mean 4.2 cm (1.5-6.0 cm)
Micro: usually well differentiated, myxoid or dedifferentiated; increased numbers of lipoblasts are present
References: Mod Path 2002;15:1020
<75 cases reported
Most frequent salivary gland sarcomas are rhabdomyosarcoma and malignant fibrous histiosarcoma
Diagnosis of exclusion (no primary lesion elsewhere)
Case reports: 53 year old with parotid tumor (Archives 2002;126:849)
DD: spindle cell carcinoma, malignant mixed tumor
Other tumors
Also called sialoblastoma
Very rare; diagnosed at or shortly after birth
Cellular epithelial parotid tumor in infants with embryonal or blastomatous appearance
May recur locally or involve regional lymph nodes
Case reports: 21 month old with 1-2 cm mass in parotid gland with increasing anaplasia over time (AJSP 1999;23:342)
Micro: ductules and solid organoid nests of basaloid cells with fine chromatin and cuboidal epithelial cells; variable necrosis, variable mitotic activity, variable nuclear atypia, no perineurial invasion
Positive stains: cytokeratin (ductal structures), S100
DD: teratoma
Cases associated with surgical trauma may have features of traumatic neuroma
Case reports: 74 year old man with right submandibular lesion but no prior trauma (Archives 2001;125:1000)
Micro: large eosinophilic cells with granular cytoplasm and small central nuclei
Positive stains: PAS, S100, CD68, alpha-1-antitrypsin
Rarely involves parotid gland
Case reports: 47 year old man with spindle cell lipoma of parotid gland diagnosed by fine needle aspiration (Archives 2001;125:820)
Diffuse deposition of adipose tissue throughout parotid gland with overall enlargement of parotid but no distinct mass
Associated with diabetes, cirrhosis, alcoholism, malnutrition, hormonal abnormalities
May be preceded by sialadenosis (acinar cell hypertrophy, interstitial edema, ductal atrophy)
Unusual
Median age 66 years, range 30-84 years
Usually represents metastatic disease from head and neck
Poor prognosis; rare patients have prolonged survival after surgery
Gross: often multiple nodules
Micro: sheets of cells with abundant eosinophilic cytoplasm and prominent nucleoli; often spindle cell regions, angiolymphatic invasion
References: Archives 2000;124:1780
Also called sinus histiocytosis with massive lymphadenopathy
Rarely presents as salivary gland involvement without significant lymphadenopathy
Unknown origin, but associated with immunologic abnormalities
Usually long clinical course with exacerbations and remissions and eventual complete remission
Case reports: 48 year old with systemic lupus erythematosus and parotid gland involvement (Archives 2001;125:1348)
Micro: histiocytic proliferation with emperipolesis in background of plasma cells and lymphocytes with eventually effacement of organ and formation of fibrous bands
Positive stains: S100
DD: sinus histiocytosis, metastatic carcinoma, melanoma (also phagocytose hematopoietic cells)
May arise from facial nerve and present as salivary gland tumor
Gross: encapsulated
Micro: resembles schwannoma elsewhere
Uncommon
First described in 2001 (Histopathology 2001;38:30)
Wide age range
Parotid gland, hard and soft palate cases
Benign behavior, no recurrences reported
Case reports: floor of mouth (Kaohsiung J Med Sci 2004;20:410), parotid gland (J Craniomaxillofac Surg 2006;34:43), Case of the Week #49
Gross: well circumscribed, resemble lipoma
Micro: mature adipose tissue mixed with acinar, ductal, basal and myoepithelial cells of normal salivary gland; also duct ectasia with fibrosis, prominent lymphoid infiltrates with nodular aggregates in the stroma
Miscellaneous
Major salivary gland tumors only (parotid, submandibular, sublingual glands)
Tumors arising in minor salivary glands are staged according to anatomic site of origin
Primary tumor (T)
TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
T1: tumor 2 cm or less in greatest dimension without extraparenchymal extension*
T2: tumor more than 2 cm but not more than 4 cm in greatest dimension without extraparenchymal extension*
T3: tumor more than 4 cm in greatest dimension or tumor having extraparenchymal extension*
T4a: tumor invades skin, mandible, ear canal or facial nerve
T4b: tumor invades skull base or pterygoid plates or encases carotid artery
* Note: extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes
Regional lymph nodes (N)
NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2: metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N2a: metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b: metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c: metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3: metastasis in a lymph node more than 6 cm in greatest dimension
Distant metastasis (M)
MX: distant metastasis cannot be assessed
M0: no distant metastasis
M1: distant metastasis
Stage grouping
I : T1 N0 M0
II : T2 N0 M0
III : T3 N0 M0 or T1-T3 N1 M0
IVA : T4a N0-N1 M0 or T1-T4a N2 M0
IVB : Any T N3 M0 or T4b any N M0
IVC : Any T any N M1
At least one section per 1 cm of tumor for large tumors, including tumor center and periphery
Submit entire tumor if can do so in 5 sections or less
Submit resection margins
Save intervening levels on biopsies for special stains
For neck dissections, should have 6 or more lymph nodes if selective dissection and 10 or more if modified radical neck dissection
Useful to determine extent of surgery needed, particularly for parotid tumors
Most common error is to diagnose mucoepidermoid carcinomas as benign
Rapid, reliable, safe
FNA > 90% sensitive, but may induce necrotic and reparative changes in tumor, particularly oncocytic tumors
Induces numerous histologic changes, including hemorrhage, multinucleated giant cells and inflammation, granulation tissue and fibrosis, squamous cell metaplasia, infarction and necrosis, subepithelial stromal hyalinization; occasionally cholesterol clefts, pseudoxanthomatous reaction, pseudocapsular invasion, microcystic degeneration
Core biopsy not recommended as tumor may implant along needle tract
Recommended to initially classify as normal tissue/inflammation, pleomorphic adenoma, Warthin’s tumor, cyst, small cell epithelial lesion, large cell epithelial lesion (low grade or high grade), spindle cell lesion (low grade or high grade)
Classification diagram (Mod Path subscribers)
Diagnostic difficulties: extensive squamous metaplasia may resemble squamous cell carcinoma or mucoepidermoid carcinoma; basal cell adenoma may resemble adenoid cystic carcinoma (solid type); oncocytic proliferations may resemble acinic cell carcinoma
References: Archives 2000;124:87, Mod Path 2002;15:342
Tumor histologic type and pattern
Anatomic site of origin
Tumor size
Tumor histologic grade (for mucoepidermoid carcinoma, adenocarcinoma NOS, malignant mixed tumor, adenoid cystic carcinoma)
Tumor extension to adjacent structures
Status of resection margins
Vascular invasion
Perineural invasion
Lymph nodes: for each level, number obtained, number involved by tumor, size of nodal metastases, presence of extracapsular spread
End of Salivary gland chapter / outline