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Salivary Glands

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Revised: 1 February 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

Normal Anatomy


Reviewer: Fatima Aly, M.D., National Institutes of Health (see Reviewers page)
Revised: 1 August 2010, last major update August 2010
Copyright: (c) 2004-2010, PathologyOutlines.com, Inc.

General
=========================================================================

Parotid gland
- Largest salivary gland (15-30g), 6 x 3 cm
- Has broad superficial lobe and smaller deeper lobe, with facial nerve usually between both lobes
- Difficult to surgically remove all parotid tissue
- Stensen’s duct (main duct) empties into oral cavity opposite crown of second maxillary molar
- 20% have accessory parotid gland and duct, usually overlying the masseter
- Parotid gland has own fascia (capsule), which is continuous with superficial layer of deep cervical fascia
- Contains 3-24 lymph nodes (not all with complete structural organization), usually lateral to facial nerve in superficial lobe

Submandibular gland
- Called submaxillary gland because British anatomists refer to mandible as “submaxilla”
- In submandibular triangle formed by anterior and posterior bellies of digastric muscle and inferior margin of mandible
- Weighs 50% of parotid gland (7-15g)
- Has own capsule, which is continuous with superficial layer of deep cervical fascia
- Wharton’s duct (submandibular duct) empties into floor of mouth on both sides of tongue frenulum at sublingual caruncula
- Lingual nerve wraps around Wharton’s duct, CN XII runs inferior and parallel to Wharton’s duct
- No lymph nodes within capsule, but 3-6 adjacent lymph nodes in submandibular triangle

Sublingual gland
- Smallest of major salivary glands (2-4g)
- Lies deep to floor of oral mucosa between mandible and genioglossus muscle
- Has no true fascial capsule
- Has no single dominant duct, but is drained by 10 small ducts (ducts of Rivinus)
- Occasionally, several of more anterior ducts may join to form a common duct (Bartholin’s duct), which typically empties into Wharton’s duct
- Bartholin’s duct unites with the submandibular duct just prior to its opening into the oral cavity at the sublingual caruncula on both sides of tongue frenulum

Minor salivary glands
- Except for the gingiva and anterior hard palate, minor salivary glands (500-1000, 1-5 mm each) are located throughout the submucosa of the oral cavity
- More numerous in posterior hard palate
- Each salivary unit has its own simple duct
- Most of these minor salivary glands are mucinous with the main exception of Ebner’s glands which are serous glands located in the circumvallate papillae of the tongue

Diagrams and Images
=========================================================================

Parotid gland

            

Major blood vessels         Local anatomy



AFIP Figure 1-6: The parotid gland has several periparotid (dark outline) and intraparotid (shaded) lymph nodes that drain portions of the ear, temporal region, lateral face, eyelids and conjunctiva. They in turn drain into the internal jugular lymph nodes. The submandibular lymph nodes are all extraglandular.



AFIP Figure 1-5: This illustration represents a horizontal section through the lateral portion of the pharynx and mandible at the level of the mastoid process. The parotid gland is traversed by the facial nerve, and the deep portion of the gland narrows and is bounded by the posterior of the ramus of the mandible, muscles of the styloid process and medial pterygoid muscle. Right: Tumors that arise within the deep portion of the gland may expand into the lateral pharyngeal space and produce swelling of the lateral pharyngeal wall.



AFIP Figure 1-4: This lateral view of the head shows the anatomic position and relationship of the parotid and submandibular glands to the ear, zygomatic arch, mandible and masseter muscle. The parotid gland duct (Stensen's duct) crosses the masseter muscle and penetrates the buccal tissues. Lobules of accessory parotid tissue are located along the course of the duct.



AFIP Figure 1-7: This illustration of the medial surface of the mandible and mylohyoid muscle shows the relationship of the submandibular, sublingual and parotid glands. The submandibular duct (Wharton's duct) runs anteriorly to the anterior floor of the mouth.


Submandibular gland

            

Surrounding structures


Sublingual gland


Surrounding structures



AFIP Figure 1-7: The right and left submandibular ducts (arrows) course anteriomedially in the floor of the mouth to openings at the lingual carunculae, which are only a few millimeters apart.

Additional references
=========================================================================

Otohns.net



Normal histology


Reviewer: Fatima Aly, M.D. (see Reviewers page)
Revised: 21 January 2013, last major update July 2010
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Definition
=========================================================================

● 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:
● Dense, basophilic, PAS+ intracytoplasmic secretory granules containing amylase
● Have central lumen that is rarely visible by H&E

Mucous acini:
● Larger than serous acini
● Irregular pattern
● Cells have abundant cytoplasm with clear mucin, well-rounded, basal nuclei, and are arranged around empty lumina
● Produce acid (positive for Alcian blue and mucicarmine) and neutral (PAS+) sialomucins

Myoepithelial cells:
● Surround acini and intercalated ducts and mediate contraction
● Have both epithelial and mesenchymal structures and functions, and are important in the morphology of most salivary gland tumors
● Myoepithelial cells surrounding intercalated ducts are more spindled and have fewer processes than those surrounding acini

Ducts:
● Either intercalated, striated or 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+ (Pathol Int 1999;49:500)
● Sebaceous glands are attached to parotid and submandibular ducts, and are considered part of normal holocrine differentiation [holocrine secretions are produced within the cell, then are released into the lumen after rupture of the plasma membrane], based on the occurrence of salivary tumors with sebaceous differentiation (Am J Surg Pathol 1989;13:879)

Parotid gland:
● Serous acini only; contains numerous basophilic zymogen granules; nuclei are uniform, round and in basal half of cell
● Intercalated ducts are long but small in comparison to acini and striated ducts
● Striated ducts are larger than intercalated ducts, 3-6x size of acinus; striations are due to folds in basal plasma membranes
● Contains small lymph nodes near or within the gland, which arise from interstitial lymphocytes
● Resembles pancreatic tissue, but parotid gland has adipocytes and pancreatic tissue has islets and centroacinar cells

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 (posterior dorsal and lateral): serous acini only
Palate, base and lateral border of tongue: predominantly mucous acini
Lip, cheek, apex of tongue: mixed serous and mucous acini

Physiology
=========================================================================

● The basement membrane protein perlecan/HSPG2 (heparan sulfate proteoglycan 2) triggers differentiation of salivary gland cells into self-assembling acini-like structures that express essential biomarkers and secrete alpha-amylase (Tissue Eng Part A 2009;15:3309)
● Serous glands produce thin watery fluid containing alpha amylase, which digests starches
● Mucinous glands produce viscous mucinous fluid higher in glycoproteins, which provides a lubricating film on oral mucosa

Diagrams
=========================================================================



Cytomorphologic features of various portions of the salivary system from the secretory end piece to the oral cavity are illustrated. From left to right are the acinus, intercalated duct, striated duct, excretory duct and oral cavity.

Micro images
=========================================================================


Parotid gland



Replacement of serous glands by sebaceous glands


Left: Clusters of large, pale-staining mucous cells (arrows) occasionally are present in the parotid gland, but the acini are overwhelmingly of serous type. Each serous acinus is composed of several pyramidal-shaped cells with basal nuclei and basophilic cytoplasmic granules.
Right: The serous cell granules are PAS+ and resistant to diastase digestion (PAS stain).



The cells of the intercalated duct (arrow) are small in comparison to the acinar cells and are cuboidal with pale-stained cytoplasm and central nuclei. A small lumen is evident.


The striated duct is larger than an acinus and much larger than the intercalated duct. The ductal cells are eosinophilic columnar cells with central nuclei and vertical cytoplasmic striations due to folds in the basal plasma membranes.


This small, interlobular excretory duct is lined by pseudostratified columnar epithelium and embedded in dense fibrous connective tissue.


Intraglandular adipose tissue in parotid gland
A: The parotid gland from a neonate contains no discernible adipose tissue.
B: There is a moderate amount of intralobular adipose tissue in parotid tissue from a middle-aged adult.
C: The intraparotid adipose tissue is quite prominent in the gland from an elderly person.



These intraparotid (left) and periparotid (right) lymph nodes are encapsulated and have subcapsular sinuses and germinal centers. Even the periparotid lymph node (right) is within the capsule and in contact with parenchymal tissue of the parotid gland.


Sebaceous cells in parotid gland.
The cells in two foci of sebaceous differentiation (arrows) are large with central nuclei and clear reticulated cytoplasm that is unreactive with mucicarmine stain. Small foci of sebaceous cells occur frequently in the parotid gland (Mucicarmine stain).



Facial nerve branches in parotid gland
A relatively large nerve lies adjacent to a lobule of parotid glandular tissue (left) while a smaller nerve branch is within a lobule and in contact with serous acini (right).


Submandibular gland



Left: In the submandibular gland, mucous acini comprise about 10% of acinar tissue. Serous cells are frequently located at the periphery of mucous acini as crescent-shaped cells (arrow). The striated ducts (arrowheads) are more prominent and the intercalated ducts are shorter than those in the parotid gland.
Right: The mucous cells are highlighted among the serous acini as rose pink cells (Mucicarmine stain).


Sublingual gland

The sublingual gland acini are typically elongated tubules of mucous cells with serous cell demilunes (a demilune is a cap in the shape of a half-moon)

Minor salivary glands of palate

Left: The palate contains the largest foci of intraoral salivary gland tissue, which is composed of mucous acini but no striated ducts.
Right: At high magnification, the mucous acini are round with central lumens. The mucous cells are pyramidal with very pale granular cytoplasm and nuclei located next to the basal plasma membranes.


Minor salivary glands of tongue

The minor salivary glands are small aggregates of unencapsulated mucous or serous glands. In the tongue they are in intimate contact with the striated muscle tissue.


Keratin cocktail stains intercalated, striated and interlobular ducts, but acinar and myoepithelial cells are mostly negative.


Left: Normal parotid tissue is S100 negative.
Right: In this parotid tissue adjacent to a mixed tumor, some of the myoepithelial and intercalated duct cells are S100+.



Left: The normally indistinct, elongated and flattened myoepithelial cells at the periphery of the acini, intercalated ducts and striated ducts are conspicuous due to their immunostaining for alpha-smooth muscle actin.
Right: The serous acinar cells immunostain for alpha-amylase.


Positive stains
=========================================================================

Luminal cells:
● AE1-AE3

Acinar cells:
● CK8/18, VEGF, GCDFP-15
● Estrogen receptor is variable (Eur J Oral Sci 2009;117:498)
● Parotid zymogen granules are PAS+, diastase resistant

Myoepithelial cells:
● Actin, myosin, CK5/6, CK14, p63, maspin
● Negative for vimentin (but neoplastic myoepithelial cells stain differently, Hum Pathol 1987;18:1218)

Electron microscopy description
=========================================================================

Acinar cells:
● Numerous cytoplasmic secretory (zymogen) granules in apical portion of cell
● Extensive rough ER and golgi
● Numerous mitochondria
● Numerous folds are present in basal lamina of acinar cells that are not distended with secretory product
● Mucous acinar cells have larger, more irregular secretory droplets that are more electron lucent than in serous acinar cells

Intercalated duct cells:
● Few special ultrastructural features
● May have some secretory granules
● Scant cytoplasm has basal rough ER, apical Golgi and mitochondria
● Lateral membranes interdigitate with neighboring cells

Myoepithelial cells:
● Between basal plasma membrane of acinar and intercalated duct cells and basal lamina
● Flattened and elongated with cytoplasmic processes extending around acinar and intercalated duct cells
● Long / irregular nuclei
● Desmosomes attach the myoepithelial cells to acinar and ductal cells

Striated duct cells:
● Striations are due to basal vertical folds
● Numerous mitochondria present

Electron microscopy images
=========================================================================



Variable-sized secretory granules occupy most of the apical portion of the cytoplasmic compartment. Parallel arrays of rough endoplasmic reticula lie adjacent to the basally located, round nucleus. The intercellular space contains interdigitations of adjacent cells and represents a canaliculus that is connected to the acinar lumen and is actually the beginning of the duct system (X11,300).


The myoepithelial cell lies between the basal lamina and the basal plasma membranes of the acinar cells. The cell body is flattened and the nucleus is elongated. In the cytoplasm are numerous microfilaments with focal dense bodies (arrow) (X13,300).


The relatively small cytoplasmic compartment contains a round nucleus, mitochondria, lipid vacuoles and an endoplasmic reticulum. There are a few short microvilli on the luminal surface, and intercellular connections are apical junctional complexes with several desmosomes (X6,000).


The basal plasma membranes have prominent vertical folds, and there are numerous mitochondria. The lateral surfaces have processes that interdigitate with adjacent cells. Apical junctional complexes and desmosomes connect adjoining cells (X6,000).

Videos
=========================================================================



Parotid gland


Submandibular gland


Sublingual gland



Embryology


Reviewer: Fatima Aly, M.D., NIH
Revised: 31 July 2010, last major update July 2010
Copyright: (c) 2004-2010, PathologyOutlines.com, Inc.

General
=========================================================================

● Derive from oral mucosa
● Arise in weeks 5-6 of embryonic life
● Parotid gland primordia (anlage) arises in weeks 5-6 from ectoderm, followed by submandibular gland primordia in week 6 from endoderm, then sublingual gland primordia in weeks 7-8 from endoderm
● Intraoral minor salivary glands develop during third month
● Primordia develop from primitive oral cavity (stomodeum) as buds, which proliferate as cords, form terminal bulbs, develop clefts and further proliferate as branches from original cord; then process is repeated
● Lumens form in epithelial cords and progress to terminal bulbs; cells differentiate into various ducts and acini

● Connective tissue diminishes with maturation, as do myoepithelial cells
● Parotid buds may penetrate intraparotid lymph nodes; rare with submandibular or sublingual structures

Diagrams
=========================================================================

   

AFIP Figure 1-2:
Left: the origin of the parotid gland, submandibular gland and sublingual gland from the epithelial lining of the primitive stomodeum is illustrated in the schematic drawing of the oral cavity of a 9-week-old embryo.
Right: photomicrograph in section through fetal tongue, linguogingivalgroove and buccal mucosa shows the proliferative epithelial cord of the developing parotid gland (arrow).



   

AFIP Figure 1-3:
Left: the primitive epithelial ducts and tubules are mostly undifferentiated and within a very loose, but moderately cellular, fibrous stroma in a 25-week-old fetus.
Right: at high magnification, the terminal tubules are a double layer of epithelial cells. The outer layer will differentiate into myoepithelial and basal cells, and the inner cells will become ductal and serous acinar cells.




Sebaceous differentiation


Reviewers: Nat Pernick, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Sebaceous type glands mixed with salivary gland acini
● Occurs in 10-40% of normal parotid glands, often in periductal locations in interlobular ducts

Micro description
=========================================================================

● Single, isolated sebaceous-type cells within serous or mucinous salivary acini or as fully developed sebaceous glands

Micro images
=========================================================================



Sebaceous glands replacing serous acini

References
=========================================================================

Arch Pathol Lab Med 2004;128:245



Saliva


Reviewer: Fatima Aly, M.D., National Institutes of Health (see Reviewers page)
Revised: 1 August 2010, last major update August 2010
Copyright: (c) 2004-2010, PathologyOutlines.com, Inc.

General
=========================================================================

● Formed by acinar cells
● High in amylase if secreted by serous glands
● High in sialomucin (neutral and acid) if secreted by mucous glands
● Saliva may be used for diagnostic testing, because it is composed of various molecules that are filtered, processed and secreted from the vasculature that nourish the salivary glands (Am J Dent 2009;22:241)

Diagrams and Images
=========================================================================

Mechanism of molecular transport from serum into salivary gland ducts

Additional references
=========================================================================

Wikipedia



Developmental disorders

Heterotopia


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 7 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called ectopia
● Normal salivary gland tissue at a site where normally not present
● Usually in head and neck
● Due to abnormal persistence and development of vestigial structures, misplacement of salivary gland rests along embryologic pathways of migration during development, or by salivary differentiation from 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 (Am J Surg Pathol 2004;28:139)

Additional references
=========================================================================

Am J Surg Pathol 2000;24:837



Developmental disorders

Polycystic disease


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 7 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Least common of the benign cystic lesions of the parotid gland.
● Also called dysgenetic disease
● Clinically characterized by recurrent, painless swelling of the involved gland(s) which are not associated with any other abnormality
● Not clear whether this is associated with cystic conditions of the kidney, liver, lung or pancreas
● Developmental disorder of mainly females with mainly bilateral gland enlargement

Micro description
=========================================================================

● Classically shows distended lobules composed of epithelial lined cysts imparting a honeycombed or lattice like appearance
● Cystic spaces contain eosinophilic material and eosinophilic bodies with concentric and radial patterns
● No associated inflammatory reaction
● The origin of the cyst epithelium is thought to be from the intercalated duct
● Residual islands of salivary glands may be interspersed between the cysts



Inflammation

Diffuse infiltrative lymphocytosis syndrome (DILS)


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 7 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● 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 section

Micro description
=========================================================================

● CD8+ lymphocytic infiltrate associated with HIV
● Resembles Sjogren’s syndrome, but the infiltrate is composed primarily of CD8+ cells, and salivary ductal epithelial atypia is common in the Cameroon in advanced HIV patients

Additional references
=========================================================================

Arch Pathol Lab Med 2000;124:1773



Inflammation

Kimura’s disease


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 7 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● 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 (Am J Surg Pathol 2004;28:505)
● May clinically simulate a neoplasm
● Chronic and indolent; rarely causes death

Treatment
=========================================================================

● Surgery; may recur

Micro description
=========================================================================

● Follicular hyperplasia, eosinophilic infiltrates, postcapillary venule proliferation

Differential diagnosis
=========================================================================

● Angiolymphoid hyperplasia with eosinophilia: all ethnic groups, superficial nodules, bleeding, pruritis, normal IgE and no eosinophilia



Inflammation

Mikulicz’s disease and syndrome


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 7 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Outdated terms
● Mikulicz disease referred to an idiopathic, painless, bilateral enlargement of lacrimal and salivary glands
● Mikulicz syndrome was similar, but due to identifiable disease processes such as tuberculosis, sarcoidosis, HIV infection
● Initially polyclonal, may evolve into lymphoma (MALT lymphoma, diffuse large B cell, SLL/CLL, rarely Hodgkin’s lymphoma, peripheral T cell lymphoma)

Gross description
=========================================================================

● Solid gray-white areas and occasional cysts

Micro description
=========================================================================

● 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



Inflammation

Necrotizing sialometaplasia


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 27 February 2012, last major update August 2011
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Reactive, self resolving condition of minor or occasionally major salivary glands, often hard or soft palate, probably due to ischemia or vasculitis

Clinical images
=========================================================================



42 year old woman with bilaterally ulcerated swellings of the palate

Gross description
=========================================================================

● Crater-like ulcerated lesion of hard palate

Micro description
=========================================================================

● Ulcerated surface mucosa
● Intraductal proliferation of metaplastic squamous epithelium containing trapped mucous cells in lobular but noninfiltrative pattern
● Pseudoepitheliomatous hyperplasia common with prominent inflammatory infiltrate and partial necrosis of salivary glands, associated with squamous metaplasia of adjacent ducts and acini

Micro images
=========================================================================



42 year old woman with bilaterally ulcerated swellings of the palate

Differential diagnosis
=========================================================================

● Squamous cell carcinoma, mucoepidermoid carcinoma, post-radiation changes



Inflammation

Sialadenitis


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 7 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Bacterial, viral or autoimmune

Bacterial sialadenitis
=========================================================================

● Rare, usually due to ascending infection of ductal system by Staph aureus, Staph viridans or gram negative bacteria
● Predisposing factors include obstructive lesions such as sialolithiasis, dehydration, malnutrition or immunosuppression
● Usually presents with 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 MALT lymphoma has ducts surrounded by broad coronas of monocytoid cells, infiltration of interfollicular region by monocytoid cells or atypical plasma cells containing Dutcher bodies, monoclonality by immunohistochemistry or flow cytometry, monocytoid infiltrates in regional lymph nodes (Mod Pathol 2002;15:255)
● Micro description: markedly hyperplastic lymphoid infiltrates with loss of salivary gland acini; ducts are surrounded by and infiltrated by lymphoid cells

Chronic sclerosing sialadenitis
=========================================================================

● Included in the spectrum of IgG4-related sclerosing diseases
● Either localized or systemic with bilateral involvement of submandibular glands
● May be associated with sclerosing cholangitis, retroperitoneal fibrosis or sclerosing pancreatitis
● Presents as stony hard Kuttner’s tumor if involves the submandibular gland
● Micro description: dilated ducts filled with inspissated secretions, lymphoplasmacytic infiltrate with variable germinal centers; late fibrosis and acinar atrophy; sialoliths in 50-80%

   
Lymphocytic infiltrate and fibrosis with ductal atrophy

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 sialadenitis
=========================================================================

● Often due to mumps (paramyxovirus), usually affects parotids, also pancreas, testes
● Also Epstein-Barr virus, coxsackievirus, influenza A, parainfluenza


Viral sialadenitis



Inflammation

Sialolithiasis


Reviewers: Fatima Aly, M.D., National Cancer Institute (see Reviewers page)
Revised: 8 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● 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

Gross images
=========================================================================



Removal of sialolith from Wharton’s duct

Micro description
=========================================================================

● Dilated ducts with squamous metaplasia, variable chronic inflammatory infiltrate, variable destruction of acini

Cytology images
=========================================================================



Benign duct obstructive lesion due to sialolithiasis



Inflammation

Sjogren’s syndrome


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Systemic autoimmune disease presenting typically with xerostomia (dry mouth), keratoconjunctivitis sicca (dry eyes), rheumatoid arthritis, hypergammaglobulinemia
● Occasionally involving 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
=========================================================================

● Requires presence of a number of clinical and pathologic features
● Adequate biopsy of minor salivary glands (5 or more glands) with a focus score of more than 1 focus/4mm square has been proposed as the diagnostic criteria

Micro description
=========================================================================

● Extensive lymphoid infiltrate with germinal centers, often interstitial fibrosis and acinar atrophy
● Usually no/rare epimyoepithelial islands in minor salivary glands, although may appear in major salivary glands

Differential diagnosis
=========================================================================

● Non-specific chronic sialadenitis: may show diffuse atrophy of glandular epithelium in lobes or entire glands, duct dilatation and interstitial fibrosis; inflammatory infiltrate may be focal but is commonly interstitial and scattered in pattern



Inflammation

Xerostomia


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 27 February 2012, last major update August 2011
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Clinical syndrome of dry mucosa, atrophy of tongue papillae with fissures, ulcerations, increased rates of dental caries especially at the gingival level of teeth
● Diverse etiology including autoimmune disease (Sjogren’s syndrome-dry eyes, inflammatory enlargement of salivary glands, xerostomia), drugs (anticholinergics), radiation therapy



Non-neoplastic tumors and tumor-like conditions

Adenomatoid hyperplasia of minor salivary glands


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Presents as submucosal nodule or mass; may be hyperplastic or hamartomatous in nature
● Usually hard palate, also retromolar but may occur anywhere in the oral cavity
● Called sialadenosis in major salivary glands
● Etiology unknown; in major salivary glands, sialadenosis is associated with metabolic conditions

Micro description
=========================================================================

● Coalescing lobules of normal mucinous acini



Non-neoplastic tumors and tumor-like conditions

Adenomatous ductal hyperplasia of major salivary glands


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● 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



Non-neoplastic tumors and tumor-like conditions

Amyloidosis


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● May involve salivary glands as tumor mass (amyloid tumor) or as a systemic disorder
● May cause sicca syndrome



Non-neoplastic tumors and tumor-like conditions

Benign lymphoepithelial cysts


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Often older women with Sjogren’s syndrome and autoantibodies
● Probably derives from salivary gland epithelium inclusion within a lymph node or from epithelium which induces a reactive lymphoid hyperplasia
● Parotid gland or upper cervical lymph nodes
● May be related to branchial cleft cyst, multilocular thymic cyst, Warthin’s tumor

Gross description
=========================================================================

● Usually unilocular but may be multilocular

Micro description
=========================================================================

● Cyst lined by glandular or squamous epithelium and surrounded by prominent lymphoid follicles with CD4+ cells, which may penetrate cyst lining

Differential diagnosis
=========================================================================

● Benign lymphoepithelial lesion, keratinous cyst (no associated lymphoid infiltrate), Warthin’s tumor (2 layers of oncocytic cells), low grade mucoepidermoid carcinoma (complex hyperplastic epithelium with mucinous cells), true branchial cleft cyst (presence of accompanying sinus tract or stalk)


HIV associated lymphoepithelial cyst
=========================================================================

● Resembles benign lymphoepithelial cyst
● Common in young individuals with HIV and usually involves the parotid gland
● Cyst epithelium derives from striated ducts
● Lymphocytes are polyclonal, CD8+
● Usually doesn’t progress to lymphoma
● In children, lesions may be monoclonal and resemble MALT but don’t progress to MALT lymphoma

Micro description
=========================================================================

● Lymphocytes may have clear cytoplasm and penetrate epithelium

Micro images
=========================================================================



Figure E



Non-neoplastic tumors and tumor-like conditions

Choristoma


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Gingival nodule of disorganized seromucinous salivary gland tissue mixed with sebaceous glands



Non-neoplastic tumors and tumor-like conditions

Epidermoid cyst


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Unilocular cystic formation with squamous lining containing a granular layer



Non-neoplastic tumors and tumor-like conditions

Lymphoid hyperplasia


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Prominent benign lymphoid proliferations, often within intraparotid lymph nodes



Non-neoplastic tumors and tumor-like conditions

Radiation effect


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually involves submandibular glands (most likely to be in field of radiation for oral cavity tumors)

Gross description
=========================================================================

● Firm, swollen glands

Micro description
=========================================================================

● Acinar atrophy, chronic inflammatory cells, squamous metaplasia of duct lining cells



Epithelial/myoepithelial tumors

General


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

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)

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

● 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

Sites
=========================================================================

● >90% arise in parotid gland, 5% in submandibular gland
● Deep parotid tumors may present as intraoral masses
● Sublingual tumors are rare and may be difficult to distinguish from minor salivary gland primary tumors of anterior floor of mouth
● Minor salivary gland tumors usually in hard palate (site with most glandular tissue); may arise in lymph nodes around salivary glands

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 gland site, facial nerve paralysis, high grade tumor



Epithelial/myoepithelial tumors

Classification


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● Classification 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 Pathol 2004;17:803)
WHO classification: stresses distinction between benign and malignant

Diagram
=========================================================================



Schematic of adenomas



Epithelial/myoepithelial tumors

Acinic cell carcinoma


Reviewers: Fatima Aly, M.D. (see Reviewers page)
Revised: 9 October 2011, last major update August 2011
Copyright: (c) 2003-2011, PathologyOutlines.com, Inc.

General
=========================================================================

● 1-3% of all salivary gland tumors; 3% of all parotid salivary gland tumors
● #2 childhood salivary gland malignancy after mucoepidermoid carcinoma
● 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, multinodularity

Case reports
=========================================================================

● Dedifferentiation with myoepithelial features after multiple resections (Arch Pathol Lab Med 2002;126:1104)
● Dedifferentiated parotid tumor with facial nerve involvement but no prior surgery (Arch Pathol Lab Med 2004;128:e52)
● Parotid tumors in 35 year old father and his 16 year old daughter (Arch Pathol Lab Med 1999;123:1118)
● Elderly patient with mass behind ear representing metastatic tumor (Case of Week #183)

Gross description
=========================================================================

● Encapsulated, tan-gray, firm to soft, solid/cystic; usually < 3 cm
● 3% bilateral or multicentric

Micro description
=========================================================================

● At scanning power, basophillia and prominent lymphoid infiltrate should raise suspicion of acinic cell carcinoma
● Tumor shows multidirectional differentiation towards acinar, ductal as well as myoepithelial elements
● Some tumor cells must demonstrate differentiation towards acinar cells
● 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

Micro images
=========================================================================



Papillary fronds with hobnail cells and vacuolated cells


Microcystic and solid patterns in tumors from father and daughter


Figure 3A-tumor (left) and normal salivary gland (right)

       
Various images


1-dedifferentiated parotid tumor with some classic areas; 2-mitotic figures and necrosis; 3-differentiated areas with basophilic cytoplasm and vesicular nuclei; 4-PAS+ diastase resistant granules


With clear cells


D: H&E; E: CK7; F: CK20


Dedifferentiated tumor

Cytology images
=========================================================================


           
Acinar-like cells but with larger nuclei, no ducts, no fibrofatty stroma and no “bunch of grades” architecture

Positive stains
=========================================================================

● Keratin, alpha-1-antichymotrypsin, alpha amylase; also vasoactive intestinal polypeptide, myoepithelial markers, granules are PAS+ diastase resistant
● May have focal neuroendocrine staining

EM description
=========================================================================

● Multiple round, electron flocculent material with variable granule density (dependent on fixation), cytoplasmic secretory granules

Differential diagnosis
=========================================================================

● Normal parotid gland: tumors lack striated and interlobular ducts, lack lobular architecture
● Thyroid carcinoma



Epithelial / myoepithelial tumors

Adenocarcinoma, not otherwise specified (NOS)


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 7 December 2012, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Invasive tumor, often aggressive, with glandular or ductal differentiation but no features characteristic of other specific types (Arch Pathol Lab Med 2004;128:1385)
● Common, 5-10% of salivary gland tumors
● 6-10% of salivary gland malignancies, 17% of parotid gland malignancies, 15% of minor salivary gland malignancies

Clinical features
=========================================================================

● Mean age 58 years (median 67 years), range 10-93 years
● Usually asymptomatic
● Often fixed to skin or deep tissues
● Palatal lesions often ulcerated and involve bone
● Gender predominance debated, recent reports show male predominance
● Cervical lymph node metastases in 23%, distant metastases in 37%
● Diagnosis of exclusion (not metastatic, not another salivary gland carcinoma)
● 5 year disease specific survivals is 57%

Sites
=========================================================================

● Parotid gland, submandibular gland, palate, buccal mucosa

Case reports
=========================================================================

● 49 year old man with parotid mass (Arch Pathol Lab Med 2004;128:487)

Treatment
=========================================================================

● Complete surgical excision

Gross description
=========================================================================

● Poorly circumscribed with infiltrative borders
● Solid tan cut surface with hemorrhage and necrosis

Micro description
=========================================================================

● Invasive with glandular or ductal differentiation but no features characteristic of other specific types
● Patterns include glandular spaces with cyst formation, papillary formation, solid sheets, comedonecrosis, hyalinized “shadow” nodules
● 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
● In situ component in 68% (Virchows Arch 2006;449:159)

Micro images
=========================================================================



Cellular tumor with glandular or ductlike structures, occasional pink cytoplasmic granules, occasional mucicarmine+ cells


Various images

Positive stains
=========================================================================

● CK7+/CK20- (Mod Pathol 2004;17:407), positive for EGFR, survivin, phosphoSTAT3, CK18, HER2
Uniform periductal staining of reactive myofibroblastic cells with calponin, smooth muscle actin, smooth muscle myosin heavy chain (Arch Pathol Lab Med 1999;123:801)

Negative stains
=========================================================================

● MYB (Mod Pathol 2011;24:1169)

Molecular / cytogenetics description
=========================================================================

● EGFR gene amplification, increased EGFR gene copy number
● HER2 amplification, high HER2 gene copy number
● KRAS mutation rarely (Arch Pathol Lab Med 2000;124:836)

Differential diagnosis
=========================================================================

Hybrid carcinoma
● Membranous adenoma
Metastatic adenocarcinoma
Polymorphous low grade adenocarcinoma
● Undifferentiated carcinoma



Epithelial / myoepithelial tumors

Adenoid cystic carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Deceptively benign histologic appearance and cribriform, solid or tubular pattern similar to cylindroma of skin (Arch Pathol Lab Med 2011;135:511)
● Formerly called cylindroma
● Most common in submandibular, sublingual or minor salivary glands; also seen in nose, sinus, upper airway
● 22% of salivary gland malignancies

Clinical features
=========================================================================

● Occurs in 5th to 6th decades
● Male predominance
● Slow growing, indolent but aggressive
● Recurrences are frequent; often late and difficult to predict
● Rarely lymph node metastases
● 5 year survival is 60%, 10 year is 30%, 15 year is 15%
● Recurrence rates by pattern: solid (100%), cribriform (89%), tubular (59%)
● 15 year survival rates by pattern: solid (5%), cribriform (26%), tubular (39%)
● Better prognosis for tumors of palate or parotid gland; poorer prognosis for dedifferentiated, p53+ tumors

Treatment
=========================================================================

● Radical surgery regardless of tumor differentiation, radiotherapy

Gross description
=========================================================================

● Small, poorly circumscribed or encapsulated and infiltrative, 1 to 8 cm

Micro description
=========================================================================

● Cribriform, solid or tubular pattern similar to cylindroma 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:
● Low grade (grade 1): tubular and cribriform patterns
● Intermediate grade (grade 2): 30% to 70% solid
● High grade (grade 3): >70% (varies) solid

Micro images
=========================================================================



Classic tumor with cribriform and tubular structures


Various images as part of case history


Low grade to high grade


H&E, CK7 and CK20


H&E and CD117


Comparison with polymorphous low grade adenocarcinoma

Cytology images
=========================================================================



Fine needle aspirate: small cells with bland nuclear features forming a pseudoglandular space containing a homogeneous, metachromatically staining hyaline globule

Positive stains
=========================================================================

● Cells in ducts: keratin, CEA, alpha-1-antichymotrypsin, S100, CD117/c-kit (Mod Pathol 2003;16:1224)
● Cells around pseudoglandular spaces: S100, actin, variable keratin
● Dedifferentiated tumor: S100
● Also CK7+/CK20- (Mod Pathol 2004;17:407), beta-catenin, calponin, smooth muscle myosin heavy chain, maspin, metallothionein
● Also MYB (65%, Am J Surg Pathol 2011;35:92)
● EGFR, HER2, survivin associated with aggressive behavior (Hum Pathol 2012;43:921)
● Markers and histologic features: phospho-JUN (perineural invasion), p63 (basal / myoepithelial compartmentalization, Mod Pathol 2005;18:645)
● Markers and prognostic features: Ki67 (shorter overall survival), phospho-P38 (better overall survival), phospho-STAT3 (low/distant metastases)

Negative stains
=========================================================================

● Estrogen and progesterone receptor, usually androgen receptor (Am J Clin Pathol 2003;119:801)

Electron microscopy description
=========================================================================

● Pseudoglandular spaces, intercellular spaces, abundant basal lamina, true glandular lumina
● Cells are intercalated ducts, myoepithelial, secretory and reserve cells

Molecular / cytogenetics description
=========================================================================

● MYB-NFIB fusion transcript (86%, Mod Pathol 2011;24:1169)
● c-kit mutations common (Mod Pathol 2009;22:1296)
● Also Wnt pathway (Mod Pathol 2004;17:1475), 1p-32-36 deletion (Clin Cancer Res 2008;14:5181), PTEN deletion (Br J Cancer 2012;106:719), HER2 amplification

Differential diagnosis
=========================================================================

Basal cell adenocarcinoma
Basal cell adenoma: capsule present, no perineural invasion
Pleomorphic adenoma: has squamous metaplasia and mesenchyme-like areas, no invasion, no perineurial invasion; GFAP+ and CD57+ (Arch Pathol Lab Med 2007;131:1373)
Polymorphous low grade adenocarcinoma: very rare in major salivary glands, bland uniform cells, CD117 weak/negative (Mod Pathol 2002;15:687), negative for smooth muscle markers, metallothionein (Arch Pathol Lab Med 1999;123:801, Mod Pathol 2008;21:105)


Dedifferentiated tumors

General
=========================================================================

● Rare aggressive variant with death usually within 5 years of diagnosis (Am J Surg Pathol 1999;23:465, Mod Pathol 2003;16:1265)
● Dedifferentiated component either poorly differentiated adenocarcinoma or undifferentiated adenocarcinoma

Micro description
=========================================================================

● Nuclear enlargement and irregularity, high mitotic count, loss of biphasic ductal-myoepithelial differentiation, comedonecrosis, fibrocellular desmoplasia (Am J Surg Pathol 2007;31:1683)

Micro images
=========================================================================



Left-classic, right-dedifferentiated tumor


Poorly differentiated and undifferentiated tumor


HER2, p53, Rb, Ki-67

Positive stains
=========================================================================

● p53, cyclin D1, HER2

Molecular / cytogenetics description
=========================================================================

● C-MYC amplification (Arch Pathol Lab Med 2011;135:123)



Epithelial / myoepithelial tumors

Adenosquamous carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, aggressive, high grade tumor with squamous and glandular components (Mod Pathol 2002;15:298)
● In minor (but not major) salivary glands and ducts
● >90% males, mean age 58 years (range 32-99 years)
● Symptoms: pain
● 5 year survival: 25%
● Metastases to lymph nodes; locoregional and distant recurrence in 70-80% even with primaries < 1 cm

Sites
=========================================================================

● Tongue, floor of mouth, nasal cavity, larynx, upper lip, palate, upper and lower alveoli

Treatment
=========================================================================

● Surgical resection with neck dissection, radiotherapy

Gross description
=========================================================================

● 2 mm to 1 cm erythroplakic ulcer or indurated submucosal nodule

Micro description
=========================================================================

● Variable histology
● Adenocarcinoma, squamous cell carcinoma and mixtures resembling mucoepidermoid carcinoma
● Adjacent tumors may cause multifocal carcinoma in situ involving salivary gland ducts, upward extension of intraductal carcinoma to involve mucosal epithelium, glassy squamous cells (Eur Arch Otorhinolaryngol 2003;260:509)
● Commonly perineurial invasion and widespread invasion of submucosa

Micro images
=========================================================================



Adenosquamous carcinoma (figure A) and other tumors with basal cell features

Positive stains
=========================================================================

● Mucicarmine, PAS with diastase, Alcian blue (pH 2.5 and 1.0), cytokeratin (Acta Pathol Jpn 1988;38:445), c-kit

Negative stains
=========================================================================

● Negative for vimentin, MYB (Am J Surg Pathol 2011;35:92)

Molecular / cytogenetics description
=========================================================================

● No KRAS or HRAS mutation (Arch Pathol Lab Med 2000;124:836)

Differential diagnosis
=========================================================================

Basal cell adenocarcinoma: CIS in the overlying mucosa; no glandular component
Mucoepidermoid carcinoma: has intermediate cells
Squamous cell carcinoma: including adenoid, basaloid and pseudoglandular variants



Epithelial / myoepithelial tumors

Basal cell adenocarcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 23 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Low grade malignant counterpart of basal cell adenoma; infiltrative with perineurial invasion and vascular invasion (Mod Pathol 2002;15:298)
● Also called basaloid carcinoma

Clinical features
=========================================================================

● 1-2% of salivary gland carcinomas
● Malignant counterpart of basal cell adenoma - 23% arise within preexisting basal cell adenomas
● Associated with dermal cylindromas
● Slow growing
● Usually parotid gland, adults, ages 50+, also in minor salivary glands
● No gender predilection
● Locally destructive
● 37% recur locally, 8% metastasize (solid pattern) to lymph nodes, 4% to lungs, but death from disease is unusual

Treatment
=========================================================================

● Excision with clear margins, radiotherapy for minor salivary gland lesions (Arch Pathol Lab Med 2007;131:1602)

Gross images
=========================================================================



Bisected specimen with focal hemorrhage

Micro description
=========================================================================

● Low grade malignancy similar to basal cell adenoma but infiltrative with perineurial invasion and vascular invasion
● Multicentric, variable cytologic atypia and mitotic activity
● Two cell types: small cells with scant cytoplasm and dark nuclei (may show palisading pattern) and polygonal cells with eosinophilic/amphophilic cytoplasm and clear nuclei
● Patterns: solid, trabecular, tubular, membranous
● No myxoid matrix, no cyst formation

Micro images
=========================================================================



Various images


Figure A is basal cell adenocarcinoma; others are mimics

Positive stains
=========================================================================

● CK7+/CK20- (Mod Pathol 2004;17:407), p53, HER2, CD117/c-kit (60%, heterogeneous, epithelial cells and not myoepithelial cells, Mod Pathol 2003;16:1224), BCL2, PS100, CEA, EMA, CK7

Negative stains
=========================================================================

● GFAP, smooth muscle actin

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: true cribriform structures, angular and hyperchromatic nuclei or prominent nucleoli, strong muscle marker staining
Adenosquamous carcinoma
● Basaloid ameloblastoma
● Basaloid squamous cell carcinoma: dysplasia in mucosal epithelium
● Low grade pleomorphic adenocarcinoma
Pleomorphic adenoma
Small cell carcinoma



Epithelial / myoepithelial tumors

Basal cell adenoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign tumor resembling pleomorphic adenoma but with basaloid cells and peripheral palisading
● First described by Kleinasser and Klein in 1967
● Also called monomorphic adenoma; excludes canalicular adenoma

Clinical features
=========================================================================

● 1-2% of epithelial tumors of salivary glands; 2% of benign salivary gland tumors
● Solitary, or part of Turban tumor Brooke-Spiegler syndrome
● Usually adults, 2/3 female, mean age 58 years
● Rarely is congenital and resembles embryoma
● Parotid gland or periparotid lymph nodes
● Low recurrence rate
● Rarely transforms; more likely if dermal analogue variant, (4% malignant transformation)
● Usually some myoepithelial differentiation using immunostains (Arch Pathol Lab Med 2000;124:401)

Treatment
=========================================================================

● Excision

Gross description
=========================================================================

● Encapsulated, often cystic, relatively small

Micro description
=========================================================================

● Solid, trabecular, trabecular-tubular, membranous or tubular growth of epithelial cells (morphological types) resembling pleomorphic adenoma but with peripheral palisading (Mod Pathol 2002;15:298)
● Basaloid cells, bland cytology, occasional peripheral palisading
● Fibrous stroma present
● Occasionally has acinar cells, squamous whorls or keratinization
● No invasion, no mesenchymal component, no perineurial invasion, no myxoid matrix, no cystic change

Micro images
=========================================================================



Various images


Morphologic variants


Calponin+ myoepithelial differentiation


Figure 5A: solid type basal cell adenoma; figure 5B: alpha smooth muscle actin+ myoepithelial cells

Cytology images
=========================================================================



Figure A: basal cell adenoma

Positive stains
=========================================================================

Ductal cells: keratin, alpha-1-antichymotrypsin, CEA, S100 (alpha subunit)
Basaloid cells: vimentin, actin, S100 (beta subunit)
● Also IL6 (Hum Pathol 1995;26:501)

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma
Basal cell adenocarcinoma
Pleomorphic adenoma
Polymorphous low-grade adenocarcinoma


Dermal analogue tumor

General
=========================================================================

● Uncommon subtype of basal cell monomorphic adenoma with clinical and histological resemblance to dermal cylindroma
● First described in 1974 by Drut and in 1977 by Headington and Reingold (Cancer 1977;39:2460, Cancer 1977;40:1702)
● Also called membranous tumor

Clinical features
=========================================================================

● Usually in parotid gland or intranodal parotid gland, ectopic salivary gland in lymph nodes (periparotid, cervical, Cancer 1987;59:1165)
● Sporadic or familial
● Histogenesis: germinal epithelium of ectodermal origin
● 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, Head Neck 2010;32:684), Warthin tumor
● Multicentricity and multiple recurrencies
● Long period of follow-up required
● Treat with resection, but 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 description
=========================================================================

● Usually unencapsulated, 50% multifocal, up to 3.5 cm

Micro description
=========================================================================

● Frequently nonencapsulated
● Jigsaw patterns of epithelial nests surrounded by deposition of basal lamina (thick eosinophilic hyaline basement membrane), resembling dermal eccrine cylindroma (Mod Pathol 2002;15:298) or rarely cutaneous spiradenoma (Hum Pathol 2009;40:1499)
● Two cell types: peripheral small cells with basophilic nuclei and palisading pattern; and large central cells with pale nuclei
● Larger nests may have cystic change and squamous metaplasia; may have oncocytic or sebaceous metaplasia
● May have coalescent membrane droplets within cell nests, malignant change (basal cell adenocarcinoma)
● No infiltration of adjacent parenchyma, nerves, blood vessels

Micro images
=========================================================================



Various images


Jigsaw patterns of basaloid nests

Cytology description
=========================================================================

● Geographic pattern, aggregates of uniform epithelial cells, ill defined cytoplasm, basement membrane-like material (Acta Cytol 2004;48:78, Acta Cytol 1997;41:1015)

Positive stains
=========================================================================

● PAS

Molecular / cytogenetics description
=========================================================================

● 16q12-13 abnormality (cylindromatosis gene, CYLD, Am J Surg Pathol 2002;26:778)

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: more cytologic atypia, hyperchromatic angular nuclei or distinct nucleoli; true cribriform pattern with basophilic matrix
Basal cell adenocarcinoma
● Basal cell adenoma, solid variant: see Acta Otolaryngol 1998;118:588
● Basaloid squamous cell carcinoma
Canalicular adenoma



Epithelial / myoepithelial tumors

Canalicular adenoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Distinct monomorphic adenoma with bilayered strands or ribbons of columnar cells with pure luminal ductal epithelial differentiation and loose, well vascularized stroma (Oral Surg Oral Med Oral Pathol 1983;56:608, Cancer 1973;31:1511)
● 1% of salivary gland tumors; 4-6% of minor salivary gland tumors (J Oral Pathol Med 2007;36:207)
● 20% of benign minor salivary gland tumors

Clinical features
=========================================================================

● Usually arises from minor salivary glands of upper lip or palate (Ann Diagn Pathol 1998;2:224); also parotid gland (Mod Pathol 2002;15:298)
● Female predominance for palate tumors
● Usually ages 50+ years
● Recurrence is uncommon
Symptoms: pain, multifocal swelling or synchronous bilateral tumors, ulceration

Case reports
=========================================================================

● 55 year old woman with tumor of upper lip (Med Oral Patol Oral Cir Bucal 2007;12:E1)
● 61 year old man with tumor of upper lip (Bull Tokyo Dent Coll 2004;45:229)
● 78 year old woman with multiple, bilateral tumors with synchronous occurrence (Clin Exp Dermatol 2009;34:e587)

Treatment
=========================================================================

● Excision, radiotherapy

Gross description
=========================================================================

● Often encapsulated, 22% multifocal
● Tumor may be received as fragmented specimen

Micro description
=========================================================================

● Bilayered strands or ribbons of columnar cells with loose, well vascularized stroma
● Often basaloid cells or trabecular features
● May infiltrate capsule and exhibit extracapsular tumor islands
● Often cystic change, apocrine, mucous or pigmented cells (Histopathology 1999;35:502)

Micro images
=========================================================================



Various images


GFAP staining


Figure 1: H&E and calponin-


Figure 1: H&E and calponin-

Positive stains
=========================================================================

● S100, AE1/3, CK19, CK7 (Oral Oncol 2001;37:365, Oral Surg Oral Med Oral Pathol 1994;78:761), EMA, vimentin
● Distinctive linear immunoreactive pattern of GFAP among cells in proximity to connective tissue interface (Head Neck Pathol 2007;1:27)
● Focal GFAP, focal CK8; PCNA

Negative stains
=========================================================================

● E-cadherin (Oral Oncol 2009;45:594)
● Myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin, Arch Pathol Lab Med 2000;124:401, Arch Pathol Lab Med 1999;123:801), CK14

Differential diagnosis
=========================================================================

Adenocarcinoma NOS
Adenoid cystic carcinoma: destructive infiltration, cribriform pattern, strong muscle markers+
Pleomorphic adenoma
Polymorphous low grade adenocarcinoma: vimentin- (Ann Diagn Pathol 2003;7:278), lack of linear GFAP at the tumor/connective tissue interface



Epithelial / myoepithelial tumors

Clear cell tumors


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 23 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon
● Mean age 72 years, range 30-88 years, no gender predominance
● Includes clear cell carcinoma, clear cell epithelial-myoepithelial carcinoma, clear cell myoepithelial carcinoma, sebaceous carcinoma
● Also clear cell variants of acinic cell carcinoma, oncocytoma and mucoepidermoid carcinoma
● Also metastatic renal cell carcinoma or balloon cell melanoma
● Treatment: excision with negative margins (Arch Pathol Lab Med 2002;126:676)

Positive stains
=========================================================================

● Keratin, vimentin (Acta Pathol Jpn 1988;38:445)



Epithelial / myoepithelial tumors

Clear cell carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● First described in 1975 by Mohamed (Cancer 1975;36:1057) and in 1983 by Chen (Hum Pathol 1983;14:91)
● <100 cases reported to date
● May be a type of squamous cell carcinoma (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:399)
● Varies from monomorphic tumor (with or without hyalinizing stroma) with squamous, glandular or no differentiation to monomorphic clear cell myoepithelial carcinoma to bimorphic epithelial-myoepithelial carcinoma (adenomyoepithelioma, glycogen rich adenoma and glycogen rich adenocarcinoma)

Clinical features
=========================================================================

● Usually adult women with painless mass; 91% in minor salivary gland tumors (palate, base of the tongue)
● 1% of intraoral minor salivary gland tumors; also occur in major salivary glands
● Usually age 30+ years
● May occur in pleomorphic adenoma (Acta Cytol 2006;50:687), be associated with HIV (Int J Oral Maxillofac Surg 2011;40:760)
● Low grade but also aggressive
● 19% lymph node positive, 8% distant metastases, 3% have death due to disease

Case reports
=========================================================================

● 50 year old woman with intra-oral minor salivary gland tumor (Ann Acad Med Singapore 2007;36:857)

Treatment
=========================================================================

● Surgical excision with adequate margins, radiotherapy (possibly)
● Treat recurrences aggressively (Arch Pathol Lab Med 2002;126:676)

Gross description
=========================================================================

● Infiltrating, scar-like

Micro description
=========================================================================

● 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

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● PAS diastase sensitive (glycogen), cytokeratin (high molecular weight), CEA, EMA
● Also S100 (varied), NSE, alpha-1-antichymotrypsin, MAM3, MAM6 (Anticancer Res 1994;14:825), CK7, CK17, CK19 (Virchows Arch A Pathol Anat Histopathol 1988;412:515)

Negative stains
=========================================================================

● Mucin, smooth muscle actin, calponin, vimentin, CK10/13, CK20

Electron microscopy description
=========================================================================

● Abundant glycogen (Ultrastruct Pathol 1996;20:519), desmosomes, peripheral tonofilaments, squamoid differentiation, prominent interdigitating microvilli without actin myofilaments or dense bodies
● No lipid, no zymogen granules, no true ductal lumina, no myoepithelial differentation

Electron microscopy images
=========================================================================



Various images

Differential diagnosis
=========================================================================

Acinic cell carcinoma: negative for glycogen, fat and mucin
● Clear cell change in oncocytic tumors
Epithelial-myoepithelial carcinoma
● Metastatic renal cell carcinoma: positive for RCC, glycogen, vimentin and CD10, negative for high molecular weight cytokeratin, CEA, S100, muscle markers; abundant lipid but no squamoid differentiation by EM (Am J Surg Pathol 1999;23:1532)
Mucoepidermoid carcinoma: positive for mucin
Myoepithelioma: also positive for glycogen
● Sebaceous carcinoma
● Sebaceous neoplasms: positive for fat


Hyalinizing subtype

General
=========================================================================

● Nests of clear cells surrounded by hyalinized bands with foci of myxohyaline stroma; first described in 1994 by Milchgrub
● 1% of intraoral salivary gland tumors
● Usually women
● Often intraoral salivary glands at base of tongue or palate; also parotid, minor salivary glands of nasopharynx and jaw
● Low grade malignancies with 15% nodal metastases and possible late recurrence
● Must exclude other clear cell tumors (ORL J Otorhinolaryngol Relat Spec 1999;61:48)

Case reports
=========================================================================

● 36 year old woman (J Oral Maxillofac Pathol 2011;15:335)
● Adult woman with aggressive tumor of tongue (Oral Oncol 2004;40:348)

Treatment
=========================================================================

● Surgery, radiotherapy

Clinical images
=========================================================================



36 year old woman

Micro description
=========================================================================

● Solid masses, nests, infiltrating cords or single file clear cells composed of glycogen with mild atypia or eosinophilic cytoplasm
● Hyalinized or rarely myxoid stroma (Head Neck Pathol 2009;3:179), cystic degeneration, necrosis, mitotic foci, anaplasia

Micro images
=========================================================================



Clear to eosinophilic cytoplasm, EMA+, negative for muscle markers




Various images


36 year old woman

Cytology description
=========================================================================

● Cohesive small and large epithelial cells with sharp outlines, focal nuclear overlapping, small nucleoli (Diagn Cytopathol 2000;23:333)

Positive stains
=========================================================================

● PAS, EMA, CK5, 6, 7, 8, 14, 17, 18 (Am J Surg Pathol 1994;18:74, Eur J Histochem 2008;52:251)
● Also collagen 1, 3, 4, tenascin, fibronectin (Oral Oncol 2002;38:364)

Negative stains
=========================================================================

● CK20, vimentin, S100, muscle specific actin, smooth muscle actin, calponin, mucin, desmin

Molecular / cytogenetics description
=========================================================================

● EWSR1-ATF1 rearrangement (Genes Chromosomes Cancer 2011;50:559)



Epithelial / myoepithelial tumors

Cystadenocarcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 23 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● First described in 1968 by Bookbinder (J Am Osteopath Assoc 1968;67:672)
● Invasive tumor with cystic growth pattern, usually conspicuous papillary component

Clinical features
=========================================================================

● Mean age 59 years, range 20-86 years
● Male gender predominance
● Often major salivary glands, but also lips, buccal mucosa, palate, tongue, retromolar area, floor of mouth, ectopic salivary glands
● Usually indolent behavior, but occasionally recurs locally or metastasizes to lymph nodes (Ear Nose Throat J 2011;90:E6)

Treatment
=========================================================================

● Surgery, radiotherapy for high grade tumors

Gross description
=========================================================================

● Cystic masses, 0.4 to 6 cm

Micro description
=========================================================================

● Invasive, cystic growth pattern, 75% with conspicuous papillary component
● Well or poorly differentiated, composed of small cuboidal cells, large cuboidal cells, tall columnar cells or mixture (Am J Surg Pathol 1996;20:1440)
● Cyst rupture with hemorrhage and granulation tissue is common
● Does not involve the native duct system
● Variants include mucinous (aggressive, Auris Nasus Larynx 2005;32:301, Acta Cytol 2001;45:605), oncocytic (children), papillary (low grade, often in minor salivary glands, Int J Surg Pathol 2008;16:341, Auris Nasus Larynx 2007;34:259)

Micro images
=========================================================================



Various images


Papillary cystadenocarcinoma

Cytology description
=========================================================================

● Ball-like, cohesive, overlapping cells, vacuolated cytoplasm (Diagn Cytopathol 2010;38:377)

Cytology images
=========================================================================



Papillary cystadenocarcinoma

Positive stains
=========================================================================

● NSE, S100, MAM6, MAM3, lyzozyme, lactoferrin, alpha-antichemotripsin

Molecular description
=========================================================================

● Usually no HER2 amplification (Pathology 2011;43:459)



Epithelial / myoepithelial tumors

Epithelial myoepithelial carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Rare low grade tumor with epithelial and myoepithelial components and frequent local recurrence
● Also called glycogen rich adenoma (clear cell pattern), myoepithelioma (spindle cell and plasmacytoid patterns), myoepithelial carcinoma (if only myoepithelial differentiation and marked cytologic atypia)

Clinical features
=========================================================================

● < 0.5% of salivary gland tumors
● 80% arise in parotid gland
● Mean age 60 years; 60% in women
● Previously considered benign, but with sufficient follow-up, there are rare regional nodal metastases and distant metastases to lung and kidney (Arch Pathol Lab Med 2002;126:676)
● Recurrence related to margin status, angiolymphatic invasion, necrosis, myoepithelial anaplasia
● In overtly malignant cases (cytologic atypia and infiltrative), metastases in 47%, and 29% die of disease after mean 32 months

Case reports
=========================================================================

● 59 year old woman with slow growing parotid tumor (Case of the Week #54)

Gross description
=========================================================================

● Well delineated, firm, infiltration into adjacent tissue
● Usually 2-3 cm

Micro description
=========================================================================

● 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
● Often mild nuclear pleomorphism
● May have high grade transformation / dedifferentiation: overt cytologic malignancy, infiltrative growth and perineurial invasion (Am J Surg Pathol 2010;34:1258)
● Variable mitotic activity; may have ancient change, sebaceous features, Verocay-like change
● Variants include apocrine, dedifferentiated, double clear, ex-pleomorphic adenoma, oncocytic (senescence phenotype), with myoepithelial anaplasia (myoepithelial overgrowth, Arch Pathol Lab Med 2009;133:950)
● Dedifferentiated variant: undifferentiated carcinoma of clear cell, spindle cell, squamous cell type; atypia in >20% cells, no myoepithelial differentiation, older patients, more aggressive behavior, extraglandular and metastastic extension,

Micro images
=========================================================================



Case of week #54


Left to right: AE1-AE3, S100


Well circumscribed, double cell layers, hyalinizing and clear cell patterns


Oncocytic-Sebaceous and Apocrine

Cytology description
=========================================================================

● Cellular, with single cells and naked nuclei
● Biphasic pattern may not be evident since 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; S100, p63 (Cancer 2005;105:240), smooth muscle actin, smooth muscule myosin heavy chain, vimentin (Am J Surg Pathol 2007;31:44)
● Epithelial component: keratin and EMA (strong), occasional S100; also c-kit, BCL2
● Apocrine variant: AR, GCDFP-15, HER2

Negative stains
=========================================================================

● CEA

Electron microscopy images
=========================================================================



Oncocytic-Sebaceous and Apocrine variants

Differential diagnosis
=========================================================================

Clear cell carcinoma: usually affects minor salivary glands, unencapsulated, negative for myoepithelial markers
Malignant mixed tumor
● Metastatic renal cell carcinoma
● Myoepithelial carcinoma: lacks epithelial component (Am J Surg Pathol 2000;24:761)
Oncocytoma
● Other biphasic tumors include adenoid cystic carcinoma: prominent cribriform pattern and polymorphous low grade adenocarcinoma: affects intraoral salivary glands, clear cells do not predominate, not associated with ductal cells
● Plasmacytoma
Pleomorphic adenoma: biphasic but with prominent myxochondroid stroma, myoepithelial cells usually lack cytoplasmic clearing
● Skeletal muscle tumors



Epithelial / myoepithelial tumors

Giant cell tumor of salivary glands


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Very rare salivary gland tumor of evenly distributed osteoclastic giant cells in background of mononuclear cells
● First reported in 1984 by Eusebi (Am J Clin Pathol 1984;81:666); <20 cases reported to date

Clinical features
=========================================================================

● Mean age 62 years, range 28-92 years; 80% male
● 87% of salivary gland tumors occur in parotid gland; 13% in submandibular gland
● Giant cell component may be neoplastic
● Uncertain histogenesis, may be a carcinoma
● 50% associated with carcinoma (usually salivary duct carcinoma or carcinoma ex pleomorphic adenoma / malignant mixed tumor/ carcinosarcoma, Ann Diagn Pathol 2009;13:114)
● 13% die of disease; 48% 5 year survival - more aggressive than giant cell tumor of bone, less aggressive than undifferentiated carcinoma
● Presents as rapidly enlarging mass, often with lymph node metastases

Treatment
=========================================================================

● Resection of tumor and lymph nodes, radiotherapy

Gross description
=========================================================================

● No peripheral mineralized bone shell

Micro images
=========================================================================



57 year old man with parotid tumor

Micro description
=========================================================================

● 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 (Am J Surg Pathol 2004;28:953)
● Osteoid or mature bone present; either pure or associated with at least focal carcinoma

Micro images
=========================================================================



57 year old man with parotid tumor

Cytology description
=========================================================================

● Numerous osteoclast-like multinucleated giant cells and many malignant mononuclear cells (Acta Cytol 2006;50:80)

Cytology images
=========================================================================



57 year old man with parotid tumor

Positive stains
=========================================================================

● Mononuclear cells: EMA, CEA, androgen receptor, p53, histiocytic markers
● Osteoclast giant cells: CD68, vimentin
● Carcinoma cells: CK7, CK8, EMA, androgen receptor, HER2, GCDFP15, histiocyte markers

Electron microscopy description
=========================================================================

● Giant cells are similar to bone osteoclasts
● Mononuclear cells have numerous microvilli and some cell junctions but few lysosomes

Molecular / cytogenetics description
=========================================================================

● 17p13LOH (carcinoma and GCT components), 10q23 LOH (carcinoma)



Epithelial / myoepithelial tumors

Hybrid carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Rare; 2+ distinct tumors in same topographic area, each at least 10% of total volume, producing a single clinical and macroscopic tumor mass (Eur J Cancer B Oral Oncol 1996;32B:251)
● Includes masses with a benign tumor component
● Often epithelial-myoepithelial carcinoma as one of the tumors
● 0.4% of salivary gland tumors in one series (Mod Pathol 2002;15:724)

Clinical features
=========================================================================

● Mean age 53-62 years, range 28-81 years
● Usually parotid gland, 0.4% parotid tumors (less than 20 cases reported), submandibular gland, palate
● May have cervical lymph node metastases, distant metastases
● Must sample thoroughly since only one component may be aggressive, prognosis based on most aggressive component (Arch Pathol Lab Med 1999;123:698, Eur Arch Otorhinolaryngol 2003;260:312)

Case reports
=========================================================================

● Congenital hybrid basal cell adenoma-adenoid cystic carcinoma (Pediatr Pathol 1986;6:199)
● Two young children with hybrid basal cell adenoma-adenoid cystic carcinoma (Pathology 1990;22:187)

Treatment
=========================================================================

● Surgery, radiotherapy

Micro description
=========================================================================

● Two or more distinct tumors in same topographic area, minor component should be at least 10% of the tumor

Micro images
=========================================================================



Figures A/B: epithelial-myoepithelioma carcinoma and basal cell adenocarcinoma


Various tumors

Cytology description
=========================================================================

● Features suggestive of both tumor types

Electron microscopy images
=========================================================================



Salivary duct carcinoma and squamous cell carcinoma components

Differential diagnosis
=========================================================================

● Biphasic tumors
● Collision tumors: distinct masses that meet
● Dedifferentiated tumors / tumors with high grade transformation
● Recurrent tumor



Epithelial / myoepithelial tumors

Inflammatory myofibroblastic tumor


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Uncommon salivary gland tumor of myofibroblasts and chronic inflammatory cells; benign behavior at this site
● Some cases are neoplastic
● Also called inflammatory pseudotumor; formerly called plasma cell granuloma
● Usually >50 years, males
● Parotid gland most common salivary gland site

Clinical description
=========================================================================

● Recurrent painful swelling

Case reports
=========================================================================

● 66 year old man with parotid tumor with clonal cytogenetic abnormalities (Acta Otolaryngol 2005;125:433)
● 70 year old man with submandibular gland tumor and autoimmune-like symptoms (Arch Pathol Lab Med 2001;125:1095)

Treatment
=========================================================================

● Surgical resection

Gross description
=========================================================================

● Firm nodules, homogeneous yellow gray

Micro description
=========================================================================

● Myofibroblasts, histiocytes, plasma cells, lymphocytes (Am J Surg Pathol 1992;16:896)

Micro images
=========================================================================



Multinodular tumor with thick fibrous bands, plasma cells and lymphocytes, spindle cells in poorly formed fascicles, smooth muscle actin+


Various images

Cytology description
=========================================================================

● Groups of spindle cells without cytologic atypia, inflammatory cells, foamy histiocytes (Acta Cytol 2004;48:574)

Positive stains
=========================================================================

● Spindle cells: CD68/KP1, smooth muscle actin, muscle specific actin, vimentin

Differential diagnosis
=========================================================================

MALT lymphoma
Myoepithelioma
Sialadenitis



Epithelial / myoepithelial tumors

Intraductal carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Rare (< 20 cases reported), in situ form of salivary duct carcinoma, entity is controversial
● First described in 1983 by Chen (J Laryngol Otol 1983;97:189)
● Also called low grade cribriform cystadenocarcinoma, low grade salivary dyct carcinoma; ambiguity exists regarding non-invasive ex-pleomorphic adenoma
● May represent preinvasive phase of some salivary duct carcinomas

Clinical features
=========================================================================

● Mean age 62 years, range 32-91 years, usually female
● Usually affects major salivary glands (parotid), intraparotid lymph nodes (Head Neck Pathol 2011;5:321), palate
● Excellent prognosis - no metastases or mortality reported
● May recur with incomplete excision as intraductal or invasive tumor
● Recommended to sample extensively and stain for myoepithelial cells with p63 and actin to rule out invasion

Treatment
=========================================================================

● Total parotidectomy (if parotid location) or wide excision to prevent recurrence / progression

Case reports
=========================================================================

● 44 year old woman with mass in buccal mucosa arising from minor salivary glands (Am J Surg Pathol 2004;28:266)
● 59 year old woman with tumor arising in intraparotid lymph node (Head Neck Pathol 2011;5:321)

Gross description
=========================================================================

● May be multifocal, cystic

Micro description
=========================================================================

● Unencapsulated but circumscribed intraductal neoplasm in micropapillary, cribriform, solid, comedo or clinging patterns, with preservation of myoepithelial cells surrounding intraductal tumor
● Resembles breast DCIS with pure intraductal proliferation of tumor cells
● May have apocrine-like vacuoles (Am J Surg Pathol 2006;30:1014), focal necrosis, sclerotic stroma, lipofuschin
● Variable atypia, variable mitotic figures, no invasion

Micro images
=========================================================================



Intraductal tumors resembling breast DCIS


Arising in intraparotid lymph node

Cytology description
=========================================================================

● Overlapping, cytoplasmic vacuoles, inconspicuous atypia (Diagn Cytopathol 2011;39:218)

Positive stains
=========================================================================

Epithelial cells: high molecular weight cytokeratin, EMA, AE1-AE3, CK7, CK19, BRST2, AR; S100 (50%)
Myoepithelial cells: p63 (nuclear stain), muscle specific actin, CK14, calponin, AR, BRST2

Negative stains
=========================================================================

● ER, PR, p53, HER2, CK20

Differential diagnosis
=========================================================================

Acinic cell carcinoma-papillary cystic variant
● Cribriform adenocarcinoma: arises in tongue
Cystadenocarcinoma
Metastases when intranodal
Salivary duct carcinoma: males, invasive, CK19+
Warthin tumor



Epithelial / myoepithelial tumors

Inverted ductal papilloma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Benign tumor of minor salivary glands, parotid which resembles inverted papilloma of nasal cavity
● Derives from proximal salivary gland excretory duct (Cancer 1982;49:519)
● Usually adults (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:68), no gender preference

Case reports
=========================================================================

● 49 year old man with mass in buccal mucosa of mandible (Pathol Int 2006;56:457)

Treatment
=========================================================================

● Resection, does not recur

Gross description
=========================================================================

● Small submucosal mass

Micro description
=========================================================================

● Complex invaginations of well differentiated squamous or basaloid epithelium with microcysts, mucous cells including goblet cells, columnar lining cells

Micro images
=========================================================================



Inverted papilloma of head & neck, not salivary glands

Positive stains
=========================================================================

● CK13, CK14; less strong for CK8, CK18



Epithelial / myoepithelial tumors

Keratocystoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare benign tumor with multicystic spaces lined by squamous cells with focal solid epithelial nests
● First reported by Seifert (as choristoma, Virchows Arch 1999;434:355) and Nagao (Mod Pathol 2002;15:1005)

Clinical features
=========================================================================

● Very rare neoplasm of children/adults, < 20 cases reported
● Usually parotid gland; may derive from salivary ducts undergoing squamous metaplasia
● Excision appears to be adequate treatment

Case reports
=========================================================================

● 37 year old man with parotid nodule (J Clin Pathol 2010;63:758)

Gross images
=========================================================================



Multicystic tumor filled with keratin

Micro description
=========================================================================

● Benign tumor with multicystic spaces, without lobular architecture, 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 abundant eosinophilic cytoplasm and bland, uniform nuclei
● May have collageneous stroma, expansive growth
● Focal foreign-body reaction against keratin
● Occasional normal mitotic figures
● No necrosis, no invasion, no angiolymphatic invasion, no perineurial invasion, no atypia, no mucous cells

Micro images
=========================================================================



Squamous lined cysts filled with keratin


Immunostains


37 year old man with parotid tumor

Positive stains
=========================================================================

● Cytokeratin (AE1-AE3, CK14, CK17; focal CK13, focal CK19), Ki-67 (outer basal layer only), collagen type IV positive material around cysts/cell nests

Negative stains
=========================================================================

● Alpha smooth muscle actin, S100, CK8, CK18

Differential diagnosis
=========================================================================

Epidermal/dermoid cysts
Mucoepidermoid carcinoma
Necrotizing sialmetaplasia
Squamous cell carcinoma
● Squamous metaplasia in other conditions



Epithelial / myoepithelial tumors

Large cell neuroendocrine carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Extremely rare high grade tumor with neuroendocrine features (organoid, solid, trabecular and rosette-like patterns) and large polygonal cells with coarse chromatin and prominent nucleoli, high mitotic rate, frequent necrosis
● Less than 20 reported cases - must rule out metastatic disease

Clinical features
=========================================================================

● Usually age 60+ years, affects parotid gland
● Aggressive behavior

Case reports
=========================================================================

● 72 and 73 year old men with parotid tumors (Mod Pathol 2000;13:554)
● 74 year old man with parotid mass (Auris Nasus Larynx 2005;32:89)

Treatment
=========================================================================

● Surgery, radiotherapy

Micro description
=========================================================================

● Organoid, solid, trabecular and rosette-like patterns of large polygonal cells with coarse chromatin and prominent nucleoli, high mitotic rate, frequent necrosis

Micro images
=========================================================================



Solid growth of large tumor cells with prominent nucleoli


Organoid growth, peripheral palisading and rosette-like pattern


Neuroendocrine stains and p53

Cytology description
=========================================================================

● Resembles undifferentiatiated carcinoma

Cytology images
=========================================================================



Large, loosely cohesive, pleomorphic tumor cells with prominent nucleoli

Positive stains
=========================================================================

● Neuroendocrine markers (chromogranin, synaptophysin), cytokeratin, p53, BCL2, epidermal growth factor receptor, cyclin D1, Ki-67, CK20

Negative stains
=========================================================================

● Polyoma virus (Am J Surg Pathol 2011;35:1806)

Molecular / cytogenetics description
=========================================================================

● 9p21 LOH and p16 mutation, TP53 LOH and mutation

Electron microscopy images
=========================================================================



Desmosome-like junctions and neurosecretory granules

Differential diagnosis
=========================================================================

Merkel cell carcinoma: CK20+
● Undifferentiated carcinoma



Epithelial / myoepithelial tumors

Lipoadenoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Slow growing tumor with glandular structures with sertoliform features and adipose tissue; oncocytic and sebaceous differentiation
● Initially described by Yau in 1997 (Mod Pathol 1997;10:242)

Clinical features
=========================================================================

● Usually men; affects parotid, submandibular glands
● May derive from striated duct

Case reports
=========================================================================

● 55 year old woman with oncocytic lipoadenoma (Int J Clin Exp Pathol 2012;5:1000)
● 64 year old man with oncocytic lipoadenoma (Pathol Res Pract 2010;206:66)
● 66 year old woman with 11 cm oncocytic tumor (Hum Pathol 1998;29:410)

Treatment
=========================================================================

● Complete excision

Micro description
=========================================================================

● Mature adipose cells (>90% mass) and proliferated glandular tissue (sharply demarcated, duct-acinar units or proliferated glands, may resemble sertoliform tubules), oncocytic change, sebaceous differentiation, squamous metaplasia

Micro images
=========================================================================



Various images

Cytology description
=========================================================================

● Adipocytic background, oncocytic cells; resembles oncocytoma, acinic cell carcinoma with oncocytic change (Acta Cytol 2009;53:437)

Stains
=========================================================================

● Positive for EMA, cytokeratin, CK19, CK7, CK14, CK5/6, alpha-1-antichymotrypsin (Virchows Arch 2006;449:722)
● Negative for calponin, actin
● Dual epithelial population with ductal (CK19, CK7) and basal cell (p63, CK14, CK5/6) differentiation in oncocytic areas

Molecular / cytogenetics description
=========================================================================

● t(12,14)/HMGA rearrangements



Epithelial / myoepithelial tumors

Lymphoepithelioma-like carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Undifferentiated carcinoma common / familial in Eskimos and Chinese; presents as unilateral mass of parotid gland, submandibular gland or minor salivary glands in adults

Clinical features
=========================================================================

● May be associated with uterine lymphoepithelioma-like carcinoma
● Metastases common to regional lymph nodes; distant metastases to liver, lung, bone
● Treatment with surgery and radiotherapy; relatively good outcome (Br J Radiol 2006;79:52)

Case reports
=========================================================================

● 29 year old woman with submandibular gland tumor (Chin Med J (Engl) 2006;119:1315)
● 50 year old woman with EBV+, c-kit+ tumor (Head Neck 2006;28:182)

Micro description
=========================================================================

● 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, granuloma, amyloid; no benign lymphoepithelial lesion

Micro images
=========================================================================



Diffuse lymphoid infiltration around atrophic acini of salivary gland


H&E, keratin (low/high power each)

Positive stains
=========================================================================

● Keratin, EBV (Histopathology 1997;31:75, J Clin Pathol 1995;48:1022), c-kit, EMA, AE1

Negative stains
=========================================================================

● AE3



Epithelial / myoepithelial tumors

Malignant mixed tumor


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually defined as carcinoma that develops in association with benign primary or recurrent pleomorphic adenoma
● Rare spectrum of carcinomas demonstrating abrupt transition from benign tumor (usually pleomorphic adenoma); often adenocarcinoma NOS, myoepithelial, salivary duct, terminal duct or undifferentiated carcinomas, usually with benign stroma
● Also called carcinoma ex pleomorphic adenoma

Clinical features
=========================================================================

● 4% of salivary neoplasms, 12% of salivary malignancies, but only 1% of intraoral salivary gland or minor salivary gland neoplasms
● 5% of parotid tumors but 18% of malignant parotid tumors
● Median age 55 years, average age 60 years, but also children (9% of salivary gland neoplasms in children), teenagers
● Associated with pleomorphic adenomas: 2% risk of malignant transformation if present < 5 years, 10% risk if 15 years
● Note: prior history of pleomorphic adenoma may be 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)
● Clinically, have sudden increase in growth, pain or facial paralysis, facial tingling, trismus
● 23% have recurrence, 56% regional or nodal metastases, 44% distant metastases (lung, bone/vertebral column, abdominal organs, CNS, kidney), 30-50% survival at 5 years

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
● Extent of invasion, vascular invasion, atypical mitoses
● Pathological stage, tumor size, proliferation index (Arch Pathol Lab Med 2009;133:1763)

Case reports
=========================================================================

● 47 year old man with parotid tumor containing pleomorphic adenoma and rhabdomyosarcoma (Arch Pathol Lab Med 2001;125:812)
● 71 year old man with submandibular tumor with giant cell component (Arch Pathol Lab Med 2000;124:1559)

Treatment
=========================================================================

● Surgery, radiotherapy, chemotherapy
● Possibly WT1 peptide based immunotherapy, trasuzamab/capecitabine

Gross description
=========================================================================

● Widely infiltrative with hemorrhage and necrosis
● Average size 4 cm, mean size 6 cm
● May be encapsulated

Micro description
=========================================================================

● Abrupt transition from benign tumor (usually pleomorphic adenoma); often adenocarcinoma NOS, myoepithelial, salivary duct, terminal duct, undifferentiated, usually with benign stroma (rarely stroma is chondrosarcoma)
● Extensively infiltrative with marked atypia, necrosis, frequent mitotic figures, perineural and vascular invasion
● Occasionally benign pleomorphic adenoma is present with hyalinization and hypocellularity
● Malignant component: adenoid cystic carcinoma, carcinosarcoma (with chondro-, lipo-, rhabdomyo- and spindle cell sarcoma component), clear cell carcinoma, epithelial-myoepithelial carcinoma, giant cell tumor, mucoepidermoid carcinoma, salivary duct carcinoma, sarcomatoid carcinoma, sebaceous carcinoma, small cell carcinoma, squamous cell carcinoma
● May have ossification, increased lymphatic vessels
● Current classification/prognostic subtypes: in situ carcinoma (earliest stage, intracapsular), non-invasive (intracapsular, including in situ carcinoma), minimally invasive (<1.5 mm) and invasive (Hum Pathol 2010;41:927)
● Note: clinical malignant behavior is associated only with cytologically malignant foci beyond the capsule of original tumor

Micro images
=========================================================================



Squamous cell carcinoma, rhabdomyosarcoma and myoglobin+ sarcomatous component


Resembling oncocytic papillary adenocarcinoma with osteoclast-like giant cells


Salivary duct carcinoma arising from pleomorphic adenoma

Cytology description
=========================================================================

● Poorly differentiated carcinoma, macronucleoli, irregular nuclear membranes

Positive stains
=========================================================================

● AE1/AE3 (97%), CK7 (94%), EMA (86%), CEA (75%), vimentin (52%), S100, S100P, p53 (41%), HER2 (30%) (Hum Pathol 2001;32:596, Am J Surg Pathol 2011;35:346)
● Also B72.3, PLAG1 (Mod Pathol 2005;18:1048), CEA, IL6, galectin 1 and 3, peroxiredoxin, PDGFA, PDGFRalpha (Hum Pathol 2009;40:390), E-cadherin, AR, XIAP, p21, topo2alpha, nuclear and cytoplasmic beta catenin, maspin, tenascin and fibronectin, cyclin D1, PCNA/Ki67, cytoplasmic and nuclear p16 (Arch Pathol Lab Med 2011;135:882), EGFR, Mcm2 and TGFbeta
● Also STAT3, p63 (variable), pRb, COX2, GCDFP15 and MUC1, 2, 5AC, 6 (mucin rich salivary duct carcinoma type), FGF2 (in situ carcinoma)

Negative stains
=========================================================================

● Estrogen and progesterone receptors, CK20, desmin, actin, GFAP, EBV ISH, PLUNC, NCAM

Molecular / cytogenetics description
=========================================================================

● Associated with 8q12-13 and 12q13-15 rearrangements
● Diploid or aneuploid
● Abnormal karyotype
● LOH at 3p, 6q, 8p, 8q, 12q, 8q, 9p, 17p
● Amplification of MYC, MDM2, HMGA2, MGC2177, PLAG1, PMSC6P, LYN, WIF1 rearrangement and loss of other allele
● qMSP abnormal methylation, RASSF1 methylation and the epigenotype panel p16/hTERT/RASSF1/WT1 related to malignancy

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: Mcm2 higher
● Carcinosarcoma: LOH at 17q21 and 9p21 (Mod Pathol 2006;19:350)
● De novo carcinoma: PLAG1+
Pleomorphic adenoma: no malignant component
Polymorphous low grade adenocarcinoma
Schwannoma



Epithelial / myoepithelial tumors

Metastases to salivary glands


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Metastases usually to intraparotid or submandibular lymph nodes (Pathol Res Pract 1986;181:684)
● Most common submandibular metastatic tumors are metastatic squamous cell carcinoma from upper aerodigestive tract or skin, or melanoma to submandibular lymph nodes
● Distant metastases to salivary glands also arise from breast, colon, kidney, lung, prostate



Epithelial / myoepithelial tumors

Mucoepidermoid carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Cords, sheets and clusters of mucous, squamous, intermediate and clear cells
● Most common malignant tumor in salivary glands
● Also most common radiation induced neoplasm

Clinical features
=========================================================================

● 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 (Am J Surg Pathol 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

Prognostic factors
=========================================================================

● Poor prognostic factors: older age, male, submandibular gland, extraglandular extension, vascular invasion, necrosis, high mitotic rate, high histologic grade

Case reports
=========================================================================

● 55 year old man with low grade parotid tumor and dedifferentiation (Hum Pathol 2003;34:1068)

Treatment
=========================================================================

● Complete excision, possibly radiation therapy

Gross description
=========================================================================

● Low grade: well circumscribed with gray-white, mucin filled cysts

Micro description
=========================================================================

● Cords, sheets and 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, goblet-type cells, oncocytic change, inflammatory reaction to extravasated mucin or keratin
● 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

Micro images
=========================================================================



Various images


Cases in children


Spindled morphology


H&E, CK7+ and CK20-

Cytology images
=========================================================================



Low grade with background mucin, two types of cells with bland nuclear features (squamoid with dense cytoplasm and glandular with vacuolated cytoplasm)


High grade with malignant squamous cells


Low grade and oncocytic tumors

Positive stains
=========================================================================

● Low grade: CK7, CK14, antimitochondrial antibodies

Electron microscopy description
=========================================================================

● Mixed luminal epithelial cells and myoepithelial cells

Electron microscopy images
=========================================================================



Spindled morphology

Molecular / cytogenetics description
=========================================================================

● Associated with t(11;19)(q14-21;p12-13)

Differential diagnosis
=========================================================================

Adenosquamous carcinoma: has anaplastic nuclear features
Metastatic carcinoma
Necrotizing sialometaplasia
● Poorly differentiated adenocarcinoma


Oncocytic variant

General
=========================================================================

● Rare variant; oncocytic tumor cells are 60%+ of neoplasm
● First identified by Chomette (Ann Pathol 1982;2:29)
● <10% of all mucoepidermoid carcinomas
● Parotid, submandibular gland
● Female gender prevalence

Micro description
=========================================================================

● Frequently low grade, oncocytic cells of intermediate cell type, cystic pattern

Positive stains
=========================================================================

● PTAH (granular cytoplasmic staining, Am J Surg Pathol 1999;23:523), antimitochondrial antibodies, p63 (Am J Surg Pathol 2009;33:409)

Negative stains
=========================================================================

● Androgen receptor

Molecular / cytogenetics description
=========================================================================

● 71% MAML2 rearrangement (Hum Pathol 2011;42:2001, Hum Pathol 2011;42:2052)

Differential diagnosis
=========================================================================

Acinic cell carcinoma
Metastases may be similar to lung, kidney, breast metastases
● Oncocytic carcinoma
Oncocytoma
Pleomorphic adenoma



Epithelial / myoepithelial tumors

Myoepithelioma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare benign tumor composed only of myoepithelial cells
● Formerly considered a variant of pleomorphic adenoma
● See also epithelial-myoepithelial carcinoma

Clinical features
=========================================================================

● 1% of salivary gland tumors, more common in parotid and minor salivary gland tumors
● Mean age 54 years, also children
● May be associated with myasthenia gravis
● Recur locally if incomplete removal
● Imaging: well circumscribed, lobulated, inhomogeneous enhancement, apparent diffusion coeficient on MRI different from Warthin tumor and similar to pleomorphic adenoma (AJNR Am J Neuroradiol 2009;30:591)

Case reports
=========================================================================

● 29 year old woman with plasmacytoid myoepithelioma of palate (Head Neck Pathol 2011;5:154)
● 80 year old man with cystic clear cell myoepithelioma of parotid gland (Oral Maxillofac Surg 2009;13:45)

Clinical images
=========================================================================



Plasmacytoid myoepithelioma of minor salivary glands

Gross description
=========================================================================

● Up to 5 cm; encapsulated, may have cystic change

Micro description
=========================================================================

● Solid (nonmyxoid), myxoid (pleomorphic adenoma-like), reticular (canalicular-like) or mixed patterns of myoepithelial cells with no ductal differentiation
● Plasmacytoid cells, spindle cells, clear cells, epithelioid cells, oncocytic cells, hyaline cells
● Mucoid or hyaline stroma, rarely lipomatous
● Rarely synchronous with adenoid cystic carcinoma
● Rarely with intracapsular invasion

Micro images
=========================================================================



Plasmacytoid myoepithelioma of palate


Plasmacytoid myoepithelioma of minor salivary glands


Myoepithelioma of minor salivary gland of cheek

Cytology description
=========================================================================

● Nuclear grooves, intranuclear cytoplasmic inclusions, nuclear striations (zebra lines), myxoid matrix; no marked pleiomorphism, no mitoses

Positive stains
=========================================================================

● Vimentin, GFAP, S100, calponin (Braz Dent J 2007;18:192), HHF35, CD10, cytokeratin 5/6, CK7, CK14, CEA
● Also muscle specific actin

Negative stains
=========================================================================

● CEA, p53, HER2

Molecular / cytogenetics description
=========================================================================

● Aneuploid or diploid, 12q alterations, chromosome 8q involved in malignant phenotype

Differential diagnosis
=========================================================================

● Epidermal cyst: similar clinically
Squamous cell carcinoma
● Undifferentiated carcinoma
Warthin tumor: similar on ultrasound



Epithelial / myoepithelial tumors

Oncocytoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign tumor composed of oncocytes
● Also called oxyphilic adenoma
● 1-2% of salivary gland neoplasms; more frequent than oncocytosis and oncocytic carcinoma

Clinical features
=========================================================================

● Usually parotid gland mass, also submandibular gland or minor salivary glands
● Mean age 60 years
● 20% associated with radiation therapy or radiation exposure
● Rarely bilateral, multiple
● Rarely synchronous with Warthin tumor or carcinoma ex-pleomorphic adenoma
● May occur in trisomy 7 or in BHD syndrome
● Specific MRI features: T1 hypointense, isointense to normal gland on fat-saturated T2 and postcontrast T1; CT features: enhancing tumor and nonenhancing cystic component (AJNR Am J Neuroradiol 2011;32:1703, AJNR Am J Neuroradiol 2010;31:1413)

Case reports
=========================================================================

● 68 year old man with parotid mass (J Cytol 2012;29:80)
● 79 year old woman with parotid tumor with multinodular oncocytic hyperplasia (Arch Pathol Lab Med 2003;127:e53)

Treatment
=========================================================================

● Local excision
● Excellent prognosis, but may have late recurrence

Gross description
=========================================================================

● Well circumscribed with fibrous capsule, solid, tan-red-brown, lobulated, often small, may have cystic spaces

Gross images
=========================================================================



Red-brown tumor

Micro description
=========================================================================

● Eosinophilic or clear cell (glycogen) with sheets, trabeculae, acini or follicular patterns of monotonous large polygonal cells with well defined cell borders, deeply eosinophilic, granular cytoplasm, small round nuclei
● Vascular stroma, may have clear cell change, background of oncocytic nodular hyperplasia, psammoma bodies, tyrosine-rich crystals
● No mitotic figures, no elastosis

Micro images
=========================================================================



Various images


Red brown tumor with central scar, oncocytes packed with mitochondria, oncocytic metaplasia of ducts

Cytology images
=========================================================================



Various images


Figure A: oncocytoma, B: acinic cell carcinoma

Positive stains
=========================================================================

● PTAH, CK5/6, CK8/18, CK10/13, EMA, Ki-67, p63 (Head Neck Pathol 2007;1:123)
● Also antimithocondrial antibody, CK7+/CK20-
● High viral load of high risk HPV (Int J Biol Markers 2007;22:239), CEA, GFAP, variable S100

Negative stains
=========================================================================

● Myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin, Arch Pathol Lab Med 1999;123:801), CEA, GFAP

Electron microscopy description
=========================================================================

● Packed with mitochondria with partitions

Differential diagnosis
=========================================================================

Metastases: prostate carcinoma is PSA+, renal cell carcinoma is p63+, CD10+, CK20+
● Oncocytic carcinoma: malignant features, invasive, high Ki-67, regional nodal or distant metastases
● Oncocytic metaplasia: no mass
● Oncocytoid artifact: electrocautery
Oncocytosis
Warthin tumor: FNA has lymphoid component, mucus, necrosis



Epithelial / myoepithelial tumors

Oncocytosis


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Either parotid cysts lined by oncocytes or well defined clusters of oncocytes (mm to cm)
● First reported by Schwartz (Cancer 1969;23:636)
● Also called multinodular oncocytoma, multifocal adenomatous oncocytic hyperplasia

Clinical features
=========================================================================

● Benign, multifocal / nodular or diffuse proliferation of oncocytic cells, usually in parotid gland
● May be bilateral

Case reports
=========================================================================

● 68 year old man with 6 cm parotid swelling (J Cytol 2012;29:80)
● 78 year old man (Laryngorhinootologie 2004;83:185)

Micro description
=========================================================================

● Either parotid cysts lined by oncocytes or well defined clusters of oncocytes (mm to cm)
● Oncocytes (oxyphilic cells) are large ductal epithelial cells with eosinophilic granular cytoplasm

Micro images
=========================================================================



Parotid gland specimen

Cytology description
=========================================================================

● Oncocytic cells

Cytology images
=========================================================================



Various images

Electron microscopy description
=========================================================================

● Numerous mitochondria

Differential diagnosis
=========================================================================

● Normal aging: increased oncocytes
Oncocytoma: distinct mass
● Rhabdomyoma: may resemble at intraoperative frozen section; positive for skeletal muscle markers; different morphology on permanent section (Arch Pathol Lab Med 1983;107:638)
● Sialadenosis: may resemble diffuse oncocytosis (Laryngol Rhinol Otol (Stuttg) 1982;61:691)
Warthin’s tumor: double layer of epithelial cells resting on dense lymphoid stroma with variable germinal centers



Epithelial / myoepithelial tumors

Oxyphilic carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Malignant counterpart of oncocytoma
● Also called malignant oncocytoma, oncocytic carcinoma

Clinical features
=========================================================================

● Very rare; usually males, tumor of parotid or submandibular gland
● High grade tumor that arises de novo or in oncocytoma (J Oral Pathol Med 1998;27:225)
● May occur after radiotherapy (J Exp Clin Cancer Res 1998;17:65)
● Disease specific 5-year survival of 54% (Oral Oncol 2010;46:773)
● May recur, have regional / distant metastases (including bone)

Case reports
=========================================================================

● 53 year old man with oncocytic carcinoma ex pleomorphic adenoma (Head Neck Pathol 2010;4:49)
● 67 year old man with metastatic tumor to bone (South Med J 2009;102:659)

Micro description
=========================================================================

● Adenocarcinoma type architecture, malignant appearing oncocytic cells with infiltrative growth, mucus production, perineural invasion
● Atypia, mitotic figures
● May occur in pleomorphic adenoma

Micro images
=========================================================================



Oncocytic carcinoma ex pleomorphic carcinoma


Various images

Positive stains
=========================================================================

● PTAH, p63 (Head Neck Pathol 2007;1:123), MA903; increased MIB1 / Ki-67 rate

Differential diagnosis
=========================================================================

● Renal cell carcinoma: p63 negative



Epithelial / myoepithelial tumors

Papillary adenocarcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 28 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare tumor of well defined papillary structures, usually mucin, no squamous or intermediate cell components; call papillary cystadenocarcinoma if prominent cystic component

Clinical features
=========================================================================

● 27% of salivary gland adenocarcinomas; also seen in oral cavity
● Mean age 64 years, median 48 years (different series), also occurs in children
● May arise in intraductal papilloma (Arch Pathol Lab Med 2000;124:291, ORL J Otorhinolaryngol Relat Spec 1994;56:112)
● Slow growth pattern with nodal metastases and recurrence
● Low grade tumors may be rare variant of polymorphous low-grade adenocarcinoma (PLGA)
● Even low grade tumors may have aggressive behavior (Oral Surg Oral Med Oral Pathol 1992;73:591)

Clinical features
=========================================================================

● 5 year old child with tumor in minor salivary gland (Arch Otolaryngol 1983;109:827)
● 12 year old boy with submandibular gland tumor (AJNR Am J Neuroradiol 1996;17:1038)
● 51 year old boy with palate mass and low grade tumor (Head Neck Pathol 2008;2:316)
● Arising in minor salivary glands (Head Neck 1989;11:237)

Gross description
=========================================================================

● Often large, with hemorrhage and necrosis

Micro description
=========================================================================

● Well defined papillary structures, usually mucin, no squamous or intermediate cell components (Am J Surg Pathol 1984;8:367)
● May appear as focal malignant component in otherwise benign mucinous cystadenoma; may occur in malignant mixed tumor associated with myoepithelial carcinoma (Ann Plast Surg 1997;39:656)

Micro images
=========================================================================



Papillary adenocarcinoma




51 year old man with low grade tumor with metastases


PLUNC protein expression

Positive stains
=========================================================================

● CK7+/CL20- (Histopathology 2007;51:26), TAG72 (Oral Dis 2000;6:112), CEA, p53, Ki67, PCNA higher in papillary zones (Anticancer Res 1996;16:2693)
● Also PLUNC proteins (Oral Dis 2008;14:613)

Molecular description
=========================================================================

● Aneuploid or diploid (J Oral Pathol Med 2007;36:371)

Differential diagnosis
=========================================================================

Acinic cell carcinoma
Metastases: may resemble thyroid primary
Mucoepidermoid carcinoma: has intermediate and squamoid cells
Polymorphous low-grade adenocarcinoma: FNA shows stromal fragments and hyaline globules



Epithelial / myoepithelial tumors

Pleomorphic adenoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 30 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common tumor of salivary glands
● Painless, slow growing tumor, composed of biphasic population of epithelial and mesenchymal cells
● Also called benign mixed tumor

Clinical features
=========================================================================

● Often women in 30’s, but any age
● 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 Pathol 2000;31:498), which may be a myoepithelial or ductal reserve cell
● 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), radiation exposure

Case reports
=========================================================================

● 28 year old man with submandibular mass (Case of the Week #243)

Treatment
=========================================================================

● Wide local excision (25% recur with enucleation, 4% with adequate parotidectomy)
● Recurrences are usually within 18 months, but can be up to 50 years later (Arch Pathol Lab Med 2008;132:1445)
● After surgery for recurrent tumor, 25% recur again

Gross description
=========================================================================

● 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

Gross images
=========================================================================



White tumor with myxoid cut surface


Various images

Micro description
=========================================================================

● 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
● Myoepithelial basal layer or overlying pseudoepitheliomatous hyperplasia; tumor may be very cellular
● Stroma is myxoid, hyaline, chondroid, rarely adipose tissue or osseous; mucin often present
● Occasional angiolymphatic invasion
● May have adenoid cystic pattern
● No mitotic figures, no necrosis

Micro images
=========================================================================





Various images

Cytology description
=========================================================================

● Clusters of benign epithelial cells with blue myxoid matrix and tyrosine-rich crystals

Cytology images
=========================================================================



Bland epithelial cells and fibrillar, metachromatically staining stroma


Various images

Positive stains
=========================================================================

● Ductal component: 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

Molecular / cytogenetics description
=========================================================================

● Normal or rearrangements of 8q12 or 12q14-15

Electron microscopy description
=========================================================================

● Features of epithelial and mesenchymal cells


Benign metastasizing mixed tumors

General
=========================================================================

● Controversial but distinctive clinical entity with late metastasis (6-52 years) after tumor excision to bone, CNS, kidney, liver, lung, lymph nodes, maxilla, pharynx, skin, sphenoid sinus; benign morphology in original and metastatic tumor
● Some limit diagnosis to cases in which metastasis is identical to salivary gland pleomorphic adenoma
● Rare, <50 cases reported
● 24% are incidental findings
● Mean age 33 years
● Associated with incomplete pleomorphic adenoma surgery / local recurrence, post cardiac transplant patient / immunosuppression (Mod Pathol 1998;11:1142)
● 5 year disease specific and disease free survivals of 58 and 50%
● Metastasis thought to occur via vascular channels due to tumor fragmentation or seeding at surgery
● Possible predictive features of metastatic behavior: mitoses, infiltrative growth pattern, myoepithelial cell proliferation

Case reports
=========================================================================

● 37 year old man with spinal cord compression after submandibular tumor (Arch Pathol Lab Med 2003;127:887)
● 48 year old man with palate tumor metastasizing to sphenoid sinus (Clin Exp Otorhinolaryngol 2010;3:172)
● 53 year old woman with solitary kidney mass and subsequent parotid mixed malignant tumor (Am J Surg Pathol 2000;24:1159)

Treatment
=========================================================================

● Surgery; radio- or chemotherapy of limited value (Arch Otolaryngol Head Neck Surg 2006;132:788)

Micro images
=========================================================================



Sphenoid sinus metastasis from palate


Spinal cord metastasis from submandibular tumor (MRI and H&E)

Stains
=========================================================================

● PR+, ER- in both tumor components (J Med Assoc Thai 2009;92:1250); also p53, bcl2, Ki-67
● Also CD105, p21

Molecular / cytogenetics description (?)
=========================================================================

● May be diploid, hyopodiploid or aneuploid (Cancer Genet Cytogenet 1998;102:59, Rev Stomatol Chir Maxillofac 1996;97:26)
● 3p deletions



Epithelial / myoepithelial tumors

Polymorphous low grade adenocarcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 30 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Common tumor of palate with infiltrative growth, multiple architectural growth patterns and cellular uniformity, first described in 1983 (Oral Surg Oral Med Oral Pathol 1983;56:157)
● Also called terminal duct carcinoma, lobular carcinoma, low grade papillary adenocarcinoma
● 10% of minor salivary gland tumors but only 1% of all malignant salivary gland tumors

Clinical features
=========================================================================

● #2 most common palate tumor (after adenoid cystic carcinoma); less common in Japanese
● In major salivary glands, usually associated with pleomorphic adenoma
● Median age 54 years, range 22-71 years, 2/3 women
● Rare in teenagers, but aggressive
● Slow growing, not painful
● More than focal papillary growth is associated with cervical nodal metastases
● Difficult diagnosis on biopsy, frozen section or fine needle aspiration (Arch Pathol Lab Med 2009;133:1763)

Treatment
=========================================================================

● Conservative wide excision
● 9-30% recur, nodal metastases in 9-15%, 10% have distant metastases (lung) or tumor related death
● Long term follow-up required (Am J Surg Pathol 2000;24:1319)
● Positive or unknown surgical margins are associated with local recurrence

Gross description
=========================================================================

● Exophytic, may be ulcerated
● Average size 2 cm

Micro description
=========================================================================

● Triad of infiltrative growth, multiple architectural growth patterns, cellular uniformity
● Nonencapsulated but often well circumscribed tumor with diverse (polymorphous) growth patterns (cribriform, fascicular, microcystic, mixed, papillary [focal], pseudoadenoid cystic [without true lumens], single file, solid, strand-like, tubular) (Am J Surg Pathol 1984;8:367)
● Infiltrative borders as small islands and tubules
● Mucoid and hyaline stroma (may contain calcifications)
● Cells have only mild atypia with uniform, bland nuclei (occasional mucus, clear or oncocytic cells), but with perineurial invasion (prominent, frequent, targetoid pattern) common around small nerves
● No/rare mitotic figures, rare tumor necrosis
● High grade transformation shows atyipia, necrosis, mitoses, MIB index, p53 overexpression

Micro images
=========================================================================



Various images


Low grade features


Polymorphous patterns


H&E, CK7 and CK20


H&E, CD117, galectin 3

Positive stains
=========================================================================

● CK7, CK8, CK14, p63, EMA (luminal and nonluminal cells), S100 (Am J Surg Pathol 1988;12:461), galectin3 (cytoplasmic, Mod Pathol 2002;15:687), vimentin
● Focal CEA
● Also membrane E-cadherin, kallikrein8, kallikrein13, osteopontin, beta-6, tenascin C, MMP1, intense catepsin, maspin, MCM2, COX2, beta-catenin (nuclear and cytoplasmic), DNMT1 (DNA methytransferase)
● Also laminin, collagen IV, fibronectin positive stroma

Negative stains
=========================================================================

● Myoepithelial markers (alpha smooth muscle actin, smooth muscle myosin heavy chain, calponin), CD117 (may be weak, Mod Pathol 2003;16:1224), GFAP negative/low, CK13, CK19, CK20, kallikrein3, E2F1, PLUNCs, cyclin D1
● No HER2 overexpression

Molecular / cytogenetics description
=========================================================================

● Diploid, but chromosome 12 abnormalities
● No t(11,19)
● 6q, 11q deletions in metastatic cases, few copy number alterations

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: bilayered tubules, nuclear atypia, CD117+, CK5/7+, cyclin D1+, galectin3+, luminal EMA, weak vimentin S100 and CEA, higher Ki67 and MCM2; also positive for myoeptihelial markers, methallothionin; cytokeratin/integrin pattern of apical luminal positivity vs bipolar pattern in PLGA (Mod Pathol 2008;21:105)
Basal cell adenoma
Carcinoma ex-pleomorphic adenoma / malignant mixed tumor
Cystadenocarcinoma has papillary areas but prominent cystic areas
Epithelial-myoepithelial carcinoma
● Metastatic lobular breast carcinoma: see Arch Pathol Lab Med 2000;124:157
● Monomorphous adenoma
Papillary adenocarcinoma (low grade)
Pleomorphic adenoma: circumscribed, no perineurial invasion, although both may extend focally into adjacent minor salivary glands



Epithelial / myoepithelial tumors

Salivary duct carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

See colloid / mucin rich, low grade below

General
=========================================================================

● Uncommon tumor resembling invasive and in situ ductal carcinoma of breast, either high grade (papillary/micropapillary [Am J Surg Pathol 2004;28:319], sarcomatoid, colloid) or low grade (cribriform) (Arch Pathol Lab Med 2009;133:1763)
● First described in 1968 by Kleinsasser (Arch Klin Exp Ohren Nasen Kehlkopfheilkd 1968;192:100)

Clinical features
=========================================================================

● 0.2-2% of salivary gland tumors, 10% of salivary gland malignancies
● Usually elderly (most 50+ years, range 22-91 years), 75% males, may cause facial palsy
● Usually parotid gland (may be bilateral), also submandibular gland, minor salivary glands
● May arise in pleomorphic adenoma, polymorphous low grade adenocarcinoma, Warthin tumor, or de novo
● May be associated with osteoclast type giant cell tumor, IgG4 related chronic sclerosing sialadenitis (Hum Pathol 2009;40:881)
● May be hybrid tumor / synchronous with adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, pleomorphic adenoma, squamous cell carcinoma (head and neck), Warthin tumor (Arch Pathol Lab Med 2011;135:1088)
● High grade tumors are aggressive with tumor infiltration into soft tissue, and frequent recurrence (60%)
● Metastases to regional lymph nodes and distant sites (bone, bowel, CNS, gingiva, inguinal lymph node, liver, lung, skin, uterus, vagina)
● Disease specific survival at 2 years is 75%, at 5 years is 55%

Poor prognostic factors
=========================================================================

● > 3 cm, metastases, small intraductal component, ER beta-, p53+,. HER2+, MMP9+, chromosome 7 polysomy

Treatment
=========================================================================

● Excision with regional lymph node sampling, radiation and chemotherapy
● Possibly prostate cancer-like hormonal therapy, docetaxel, paclitaxel, trasuzumab

Gross description
=========================================================================

● White-tan mass with solid or cystic cut surface or necrosis; firm, ill defined, infiltration of adjacent parenchyma
● Up to 7 cm (mean 3.5 cm)

Micro description
=========================================================================

● Resembles invasive ductal carcinoma of breast, either high grade (papillary/micropapillary, sarcomatoid [Hum Pathol 2000;31:208], colloid) or low grade (cribriform)
● Cells have eosinophilic cytoplasm, marked nuclear pleomorphism, vesicular nuclei, prominent nucleoli, squamoid
● May have anaplastic keratin+ cells, spindle, multinucleated, oseosarcomatous, rhabdoid or squamoid cells; no goblet cells, no apocrine cells
● Frequent perineurial and vascular invasion, fibrous and hyalinized stroma; numerous mitotic figures
● May have dystrophic calcification or necrosis (comedo-necrosis sometimes), neutrophil tumor cell cannibalism, cystic change, neuroendocrine features
● May be in situ only (Am J Surg Pathol 2004;28:266)
● May be associated with squamous cell carcinoma, bilateral chronic sialadenitis

Micro images
=========================================================================



Various images


Figure 1: cribriform pattern, 2: oncocyte-like cells, 3: infiltrating in cords, 4: perineurial invasion


Various patterns


H&E, CK7 and CK20


H&E and PPAR gamma expression

Cytology description
=========================================================================

● Necrosis, large polygonal cells, cribriform groups, oncocytic appearance

Positive stains
=========================================================================

● CK 5/6, CK7, CK8/18, CK19, CK20, EMA, CEA, B72.3; high Ki67, PCNA
● Also androgen receptor (>90%), PPAR gamma (80%, Mod Pathol 2003;16:1218), GCDFP-15 (especially intraductal component), PSA (60%, Am J Surg Pathol 2000;24:579), HER2 (50%), PAP (20%)
● Also BER-EP4, proline, glutamic acid, leucin-rich protein-1, ER beta, EGFR, COX2, E-cadherin (Am J Surg Pathol 2007;31:1645)
● Also Topo II alpha, alpha lactalbumin, p16, PELP, CD147, MMP9, MMP13, MCM2 (Hum Pathol 2005;36:670)
● Also MUC1, MUC2, MUC4, MUC6, MNAR, BUB1B, MAD2l1, Casp10, TGFalpha, laminin, collagen IV, TAG72/B72.3
● Also Lewis Y, cathepsin D, p16, pRb, CD44v6, CD44s(focal), high geminin index
● Overexpression of MMPII, cyclinD1, CDK4, mdm2, E2F1, p53

Negative stains
=========================================================================

● Calponin, smooth muscle actin, muscle specific actin, CK14 (in situ growth pattern), amylase, DOG1 (Mod Pathol 2012;25:919), MMP1 (nuclear), bcl2

Electron microscopy description
=========================================================================

● Interlobular or excretory duct origin (2 cell types: electron-lucent cytoplasm with scant organelles and second type with numerous mitochondria)

Molecular / cytogenetics description
=========================================================================

● Diploid or aneuploid, 6q alterations more frequently and 17p/17q less frequently than breast invasive ductal carcinoma
● Also chromosome 7 polysomy, 12q amplification, 9p LOH, methylation of MGMT, DAPK, RASSF1

Differential diagnosis
=========================================================================

Adenocarcinoma NOS: androgen receptor+
Metastatic carcinoma breast carcinoma is ER+, CEA-
● Eccrine sweat gland carcinoma: GCDFP15-
Mucoepidermoid carcinoma: particularly high grade mucoepidermoid carcinoma, which is androgen receptor+, has epidermoid and mucous cells
● Oncocytic adenocarcinoma: no prominent comedonecrosis or papillary growth, phosphotungstic acid+
Polymorphous low grade adenocarcinoma
Squamous cell carcinoma: similar appearance on cytology
● Terminal duct adenocarcinoma: more indolent


Colloid carcinoma (mucin rich) variant of salivary duct carcinoma

General
=========================================================================

● Very rare variant with large extracellular mucin lake (50% or less of tumor), containing clusters and single tumor cells
● May represent extreme variation of extracellular mucin expression
● Prognosis similar to classic type
● Usually major salivary glands, men

Treatment
=========================================================================

● Resection, radiotherapy

Micro images
=========================================================================



Figure C

Positive stains
=========================================================================

● CK7, EMA, androgen receptors, GCDFP-15, CEA, MUC2, MUC5B, MUC6 (Am J Surg Pathol 2003;27:1070), variable HER2 overexpression

Negative stains
=========================================================================

● CK20, S100, myoepithelial markers, ER, PR, MUC5AC, MUC7

Differential diagnosis
=========================================================================

Metastases
● Mucinous/colloid carcinoma of breast: better prognosis
Mucoepidermoid carcinoma: AR negative, intermediate and clear cells


Low grade salivary duct carcinoma

General
=========================================================================

● Rare tumor composed of cysts lined by small, multilayered, bland ductal cells with fine chromatin and small nucleoli
● Also called low grade intraductal carcinoma, low-grade cribriform cystadenocarcinoma, intraductal carcinoma, intraductal carcinoma with microinvasion
● First reported in 1996 (Cancer 1996;78:958)

Clinical features
=========================================================================

● Usually parotid gland
● Median age 64 years
● Excellent prognosis; no recurrence if complete resection

Treatment
=========================================================================

● Surgery, rarely radiotherapy

Gross description
=========================================================================

● Unencapsulated

Micro description
=========================================================================

● Must sample entire tumor to determine extent of invasion, rule out high grade foci
● 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 (Am J Surg Pathol 2004;28:1040)
● Attenuated myoepithelial cell layer, sclerotic stroma with secondary changes (inflammation, hemorrage, calcification)
● May have indistinct cytoplasm membranes, apocrine-type cytoplasmic microvacuoles, lipofuscin-like pigment
● May be entirely intraductal, have definite stromal invasion, transition between low grade and high grade areas
● May have adenosquamous carcinoma-like features
● Rarely goblet cells or oncocytoid cells
● No/rare mitotic figures or necrosis

Micro images
=========================================================================



Arising in intraparotid lymph node


Resembling ADH of breast

Positive stains
=========================================================================

● S100, calponin (myoepithelial cells lining cystic spaces), CK14, p63, GCDFP-15 (Am J Surg Pathol 2006;30:1014)
● Also MUC1, MUC2, MUC4, MUC6, CK19, AR, ER, PR

Negative stains
=========================================================================

● CK20, p53

Differential diagnosis
=========================================================================

Cystadenocarcinoma: no resemblance to breast ADH or DCIS, usually widely invasive
Acinic cell carcinoma-papillocystic variant: smaller vacuoles, S100-, zymogen granules by EM



Epithelial / myoepithelial tumors

Salivary duct papilloma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, benign papillary proliferations of bland cuboidal/columnar epithelial cells with fibrovascular cores, inflammation
● Also called intraductal papilloma, intraductal papillary tumor
● Usually in minor salivary glands, rare in parotid or sublingual glands

Clinical features
=========================================================================

● Usually adults, present with mass, discomfort with chewing (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:68)
● Probably of luminal ductal origin

Case reports
=========================================================================

● 41 year old man with parotid mass (Acta Otolaryngol 2002;122:314)
● 47 year old man with minor salivary gland tumor (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:e34)
● Two cases, benign sublingual tumor and parotid papilloma with microinvasion and intraparotid lymph node metastases (Arch Pathol Lab Med 2000;124:291)

Treatment
=========================================================================

● Surgery

Micro description
=========================================================================

● Papillary proliferations of bland cuboidal/columnar epithelial cells with fibrovascular cores, inflammation, few mitoses
● May have acinar cell differentiation, ductal cyst by obliteration, malignant transformation to adenocarcinoma

Micro images
=========================================================================



Intraductal papillary proliferation


Papillary, tubular and solid patterns


Microinvasion


Smooth muscle actin demonstrates no invasion


Upper lip tumor has papillary proliferation of epithelial cells with numerous intricately branching fronds in cystically dilated duct lumen

Positive stains
=========================================================================

● Alcian blue and PAS+ mucous cells, CK7, CK18, EMA, vimentin; variable CEA, S100, GCDFP-15
● Malignant cases may be positive for p53, Ki67

Negative stains
=========================================================================

● HER2, smooth muscle actin, GFAP, CK14

Cytology description
=========================================================================

● Compact clusters of papillary monomorphic columnar cells with abundant finely vacuolar cytoplasm; oval nuclei basally located, indistinct nucleol; no squamous cells (Acta Cytol 1999;43:457)

Electron microscopy images
=========================================================================



A: secretary granules, rough endoplasmic reticulum, golgi apparatus and mitochondria; B: microvilli on luminal surface of epithelial cells appear to be secretory; C: annulate lamellae composed of parallel arrays of cisternae have small annuli or fenestrae

Differential diagnosis
=========================================================================

● Metastatic papillary thyroid carcinoma
● Papillary cystadenocarcinoma
● Papillary cystadenoma
Acinic cell carcinoma-papillary cystic variant
Polymorphous low grade adenocarcinoma
Salivary duct carcinoma
Sialadenoma papilliferum



Epithelial / myoepithelial tumors

Sebaceous adenoma / lymphadenoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare benign tumor with nests and islands of bland epithelium composed in part of sebaceous elements, with lymphoid stroma
● Called sebaceous lymphadenoma if lymphoid stroma is prominent
● Also called benign lymphoepithelial cyst with sebaceous differentiation

Clinical features
=========================================================================

● 0.1% of salivary gland neoplasms, <0.5% of salivary adenomas
● Over 90% occur in or near the parotid gland or in minor salivary glands
● May arise from salivary duct inclusions within parotid lymph node, similar to Warthin’s tumor (Am J Clin Pathol 1980;74:683)
● Fine needle aspiration cytology identifies a benign process, but usually not diagnosed prior to excision (Acta Otorhinolaryngol Ital 2007;27:144)

Case reports
=========================================================================

● 53 year old woman with progressively enlarging, painless parotid mass (University of Pittsburgh Case of Month 281)
● 57 year old man with neck mass (Arch Pathol Lab Med 2005;129:e171)
● 67 year old woman with parotid mass (Acta Otorhinolaryngol Ital 2007;27:147)
● 68 year old woman with synchromous squamous cell carcinoma (World J Surg Oncol 2003;1:30)
● 86 year old man with stable parotid mass (Case of the Week #103)
● Benign tumor with transition to sebaceous adenocarcinoma (Eur Arch Otorhinolaryngol 2006;263:940)

Treatment
=========================================================================

● Excision is curative, no/rare recurrences, rare malignant transformation (Eur Arch Otorhinolaryngol 2006;263:940)

Gross description
=========================================================================

● Solid or cystic, well circumscribed, tan-yellow mass, up to 3 cm, with variable encapsulation

Gross images
=========================================================================



Case of week #103: large nodule is sebaceous adenoma, small nodule on left is oncocytoma


Parotid gland masses


Various images


With synchronous squamous cell carcinoma

Micro description
=========================================================================

● Benign, encapsulated, solid and cystic (Mod Pathol 2012;25:26)
● Nests and islands of benign squamous cells, often lining a cyst; epithelial nests have focal sebaceous differentiation
● Background is prominent lymphoid infiltrate, often with germinal centers
● May be associated foreign body reaction, histiocytes, oncocytic change
● Rarely malignant change to sebaceous carcinoma
● May be combined / hybrid / synchronous tumors with Warthin tumor, acinic cell carcinoma, adenoid cystic carcinoma, squamous cell carcinoma (Eur J Cancer B Oral Oncol 1996;32B:251, Pathol Res Pract 1993;189:577, J Oral Surg 1979;37:826)

Micro images
=========================================================================



Case of week #103: large nodule


Benign parotid mass with sebaceous features and lymphoid stroma


Parotid gland mass


Various images


Malignant transformation

Cytology description
=========================================================================

● Mixed population of large and small lymphocytes, plasma cells and occasional tingible body macrophages
● 3 dimensional, cohesive aggregates of epithelial cells, often with cytoplasmic vacuoles characteristic of sebaceous differentiation, surrounded by layers of basaloid cells (Acta Cytol 2004;48:551, Acta Cytol 2004;48:551)

Cytology images
=========================================================================



Diff Quik touch prep

Positive stains
=========================================================================

● p63, 34betaE12, CK5/6, CK18, CK7

Negative stains
=========================================================================

● EBV, HPV, HHV8

Molecular / cytogenetics description
=========================================================================

● May have trisomy 9 (Oncol Rep 1994;1:561)

Differential diagnosis
=========================================================================

Low grade mucoepidermoid carcinoma: epithelial islands, ducts and cysts tend to be haphazardly distributed with variable shapes and sizes; usually infiltration of connective tissue or parenchyma; cells have some atypia, cells are mucin+
● Normal sebaceous glands: present in 10% of parotid glands but no mass
Warthin’s tumor: prominent cysts and lymphoid stroma, cysts have bilayered oncocytic epithelium



Epithelial/myoepithelial tumors

Sialadenoma papilliferum


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare benign biphasic tumor with exophytic squamous component and endophytic glandular component
● Well differentiated papillary hyperplastic squamous epithelium covering ductal component of cleftlike cystic spaces lined by cuboidal or columnar epithelium with occasional goblet cells
● First described by Abrams in 1969 (Cancer 1969;24:1057)

Clinical features
=========================================================================

● Usually hard palate (Arch Pathol Lab Med 2001;125:1595) or parotid gland of men over 40 years; also children (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e51)
● Painless
● Tends to recur after excision

Case reports
=========================================================================

● 65 year old man with parotid tumor (Head Neck 2011 Nov 11 [Epub ahead of print])
● 79 year old woman with malignant transformation of sialadenoma papilliferum of the palate (Virchows Arch 2004;445:641)
● 82 year old woman with mucoepidermoid carcinoma arising in a background of sialadenoma papilliferum (Head Neck Pathol 2009;3:59)
● Recurrence in buccal mucosa 3 years after excision (J Laryngol Otol 1995;109:787)

Gross description
=========================================================================

● Well circumscribed, round/oval, papillary tumor of mucosal surface

Micro description
=========================================================================

● 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, dysplasia and in situ carcinoma in exophytic component (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:e27)
● Has malignant counterpart, or evolves to mucoepidermoid carcinoma or epithelial-myoepithelial carcinoma with high grade carcinoma

Micro images
=========================================================================



Floor of mouth tumor


Hard palate cases


Mucoepidermoid carcinoma arising in a background of sialadenoma papilliferum

Positive stains
=========================================================================

Squamous epithelium and ductal structures: CK7, AE1-AE3, CEA, EMA
Ductal structures: also CAM 5.2, S100
● Also CK8, CK19 (Int J Oral Maxillofac Surg 2004;33:621)
● One study identified 2 subsets of basally-located cells: (a) positive for CK14, S100, GFAP, vimentin and smooth muscle actin - similar to myoepithelial cells; (b) CK13+ and CK14+ only (J Oral Pathol Med 1996;25:336)

Negative stains
=========================================================================

● CK20, desmin, muscle specific actin, HPV (J Cutan Pathol 1999;26:259)

Electron microscopy description
=========================================================================

● Oncocyte is predominant cell; contains numerous mitochondria, parallel filaments within cell cytoplasm attached by desmosomes (Arch Pathol Lab Med 1986;110:523)

Differential diagnosis
=========================================================================

● Papillary syringocystadenoma
Warthin’s tumor



Epithelial / myoepithelial tumors

Signet ring cell adenocarcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare adenocarcinoma subtype first described by Ghannoum and Freedman (Am J Surg Pathol 2004;28:29)
● Represents 2% of primary minor salivary gland malignancies; less common in major salivary glands
● Adults, mean age 56 years, female predilection
● Slow growing with favorable outcome; low grade behavior with no recurrence / metastases, based on limited data

Case reports
=========================================================================

● 18 year old man (youngest reported, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:e33)
● 38 year old woman with parotid mass (Head Neck 2011;33:1656)
● 52 year old man with 40 pack-year smoking history (Diagn Cytopathol 1997;17:374)
● Involvement of lower lip with low grade behavior (Hum Pathol 2012;43:303)

Micro description
=========================================================================

● Non-circumscribed tumor composed of bland, extracellular mucin containing signet ring cells (scattered cells or nests) that invade in narrow parallel strands, with scattered small nests or individually infiltrating cells, eccentric indented nuclei, mild atypia; mixed with eosinophilic and clear cells
● Often perineurial invasion, but no angiolymphatic invasion
● Minimal ductal differentiation
● No necrosis, no/rare mitoses,
● No solid, cribriform or papillary components

Micro images
=========================================================================



Encapsulated and centrally cystic


Cells have large intracytoplasmic vacuole with Alcian blue-positive mucin


CK14+ basal cells of residual ducts, which contain some signet ring cells simiar to the tumor cells

Positive stains
=========================================================================

● CAM 5.2, smooth muscle actin, GFAP, p63, cytokeratin, MUC1, MUC2, MUC5AC, MUC6, GCDFP15

Negative stains
=========================================================================

● Calponin, HER2, myoepithelial markers

Differential diagnosis
=========================================================================

● Colloid (mucinous) carcinoma
● Mammary analogue secretory carcinoma: see Histopathology 2012;61:387
● Metastatic signet ring cell adenocarcinoma (lung)
Mucoepidermoid carcinoma
Polymorphous low grade adenocarcinoma
Salivary duct carcinoma: see Med Mol Morphol 2012;45:45 for mucin-rich variant



Epithelial / myoepithelial tumors

Small cell carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare aggressive tumor resembling small cell carcinoma of lung (Am J Surg Pathol 2004;28:762)
● Pure or with squamous cell carcinoma or adenocarcinoma

Clinical features
=========================================================================

● 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 (arising from ductal neuroendocrine stem cells, Pathol Int 1999;49:887)
● 2 and 5 year survival of 70% and 46%

Case reports
=========================================================================

● 48 year old woman with 3 year history of right cheek mass (Head Neck Pathol 2012;6:502)
● 61 year old man with parotid tumor (Arch Pathol Lab Med 1995;119:183)
● 63 year old man with oral cavity tumor (Mod Pathol 1990;3:631)
● 79 year old man with submandibular mass (Ear Nose Throat J 2012;91:E10)
● 91 year old man with good outcome after irradiation (Clin Transl Oncol 2008;10:303)

Treatment
=========================================================================

● Chemotherapy, radiotherapy

Micro description
=========================================================================

● Resembles 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
● May occur in carcinoma ex pleomorphic adenoma

Micro images
=========================================================================



Various images


87 year old woman with long term survival

Positive stains
=========================================================================

● Keratin (punctuate perinuclear staining), CK20 (75%, paranuclear dotlike pattern, Am J Surg Pathol 1997;21:226), EMA, at least one neuroendocrine marker (chromogranin, synaptophysin, CD57/Leu7, CD56, neuron specific enolase)

Negative stains
=========================================================================

● TTF1, Merkel cell polyoma virus (Am J Surg Pathol 2011;35:1806)

Electron microscopy description
=========================================================================

● Variable dense core secretory granules

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: solid variant resembles small cell carcinoma, but has focal cribriform architecture, myoepithelial differentiation, no neuroendocrine differentiation
Large cell neuroendocrine carcinoma: cells > 30 microns, moderate N/C ratio, coarse chromatin, prominent nucleoli
Lymphoma: CD45+, keratin-
Melanoma: S100+, HMB45+, vimentin+, CK-
● Merkel cell carcinoma
Metastases: small cell carcinoma from lung or other site; squamous cell carcinoma
● Small cell anaplastic carcinoma with neuroendocrine features
● Small cell epidermoid carcinoma: different findings on electron microscopy
● Small cell undifferentiated carcinoma: negative neuroendocrine markers



Epithelial / myoepithelial tumors

Squamous cell carcinoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 29 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● True salivary gland primaries of squamous cell carcinoma are very rare; most squamous cell carcinomas are metastases to intraparotid lymph nodes from primaries in oral cavity, upper aerodigestive tract or skin
● Squamous cell carcinomas represent 16-54% of malignant salivary gland tumors, about 11% of malignant tumors of major salivary glands

Clinical features
=========================================================================

● Squamous cell carcinomas (primary or secondary) are most frequent parotid malignant tumor (30-37%), represent 4% of submandibular gland tumors
● Usually men (when considering major salivary gland tumors); also associated with AIDS
● May occur in Stensen duct
● Rapid painless growth with infiltration of surrounding structures, regardless of origin; may cause acute facial paralysis
● Aggressive behavior, with 50% 5 year survival (Arch Pathol Lab Med 2001;125:740)

Treatment
=========================================================================

● Radical surgery, radiation therapy

Gross description
=========================================================================

● Large, poorly encapsulated mass

Micro description
=========================================================================

● Classic features of squamous cell carcinoma
● May have perineural invasion, clear cell change
● Often component or coexisting with other tumors: carcinosarcoma, epidermoid cyst, epithelial-myoepithelial carcinoma, malignant mixed tumor, mucoepidermoid carcinoma, sarcomatoid carcinoma, salivary duct carcinoma, sebaceous lymphadenoma, Warthin tumor (Mod Pathol 2002;15:724)

Micro images
=========================================================================



Various images


Metastasis to parotid gland

Positive stains
=========================================================================

● CK7 (variable, Mod Pathol 2004;17:407), CK13, CK14, CK19; also vimentin, p53, cyclin D1, MDM2, p63 diffuse (basaloid type)

Negative stains
=========================================================================

● CK20, COX2, CK8, factor XIIIa, p16, CDK4, Rb, E2F1
● Loss of E-cadherin

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma: p63+, resembles basaloid squamous cell carcinoma (Mod Pathol 2005;18:645)
High grade mucoepidermoid carcinoma: intermediate cells, mucus cells, COX2+



Epithelial / myoepithelial tumors

Warthin’s tumor


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Common tumor of parotid gland with double layer of epithelial cells resting on dense lymphoid stroma
● Also called papillary cystadenoma lymphomatosum papilliferum, adenolymphoma
● #2 most common benign salivary gland tumor (after pleomorphic adenoma)

Clinical features
=========================================================================

● Almost always in parotid gland; 10% of parotid gland tumors
● 70% of bilateral salivary gland tumors are Warthin’s tumors
● Occasionally in oral cavity, larynx, cervical lymph nodes (Auris Nasus Larynx 2004;31:293)
● Usually male smokers age 40+ years
● Arises from incorporation of lymphoid tissue in parotid gland or induction of cystic and oncocytic changes by inflammatory infiltrate
● Associated with tuberculosis, Brucella mellitensi
● May occur synchronous with pleomorphic adenoma and salivary duct carcinoma
● Malignant change (1%) to lymphoma, Merkel cell carcinoma, adenocarcinoma NOS, basal cell carcinoma, mucoepidermoid carcinoma, oncocytic carcinoma, salivary duct carcinoma, squamous cell carcinoma, Warthin adenocarcinoma

Case reports
=========================================================================

● 76 year old man with tumor of nasopharynx (Case of the Week #112)

Treatment
=========================================================================

● Surgical excision
● 2% recur after resection

Gross description
=========================================================================

● 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

Gross images
=========================================================================



Well-demarcated gray-yellow tumor

Micro description
=========================================================================

● 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

Micro images
=========================================================================



Nasopharyngeal tumor


Various images

Cytology description
=========================================================================

● Squamous appearance of degenerated oncocytes

Cytology images
=========================================================================



Various images

Positive stains
=========================================================================

● Keratin (CK7, CK 8/18, CK19), mitochondrial markers
● Focal CEA, CK5/6, CK10, CK14, p63, 34betaE12

Negative stains
=========================================================================

● Amylase, vimentin, desmin, smooth muscle actin, EBV, HHV8

Electron microscopy description
=========================================================================

● Oncocytes are stuffed with mitochondria with cup shapes or concentric-ring forms but no partitions

Molecular / cytogenetics description
=========================================================================

● Not clonal (Hum Pathol 2000;31:1377, Mod Pathol 2005;18:964), although cases with coexisting mucoepidermoid carcinoma are associated with t(11;19) and the CRTC1/MAML2 fusion transcript (Genes Chromosomes Cancer 2008;47:309)
● Diploid, t(11,19), HHV8 DNA may be positive

Differential diagnosis
=========================================================================

Acinic cell carcinoma
Squamous cell carcinoma: may resemble at fine needle aspiration



Lymphoma–general


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Represent 5% extranodal lymphoma, 3% of salivary gland neoplasms, 10% of malignant salivary gland tumors

Clinical features
=========================================================================

● 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 (may arise from MALT, Leuk Lymphoma 2007;48:1793), follicular lymphoma, MALT or SLL/CLL
● Increased risk with autoimmune disease or HIV
● Usually good prognosis (Acta Haematol 2004;112:203)

Case reports
=========================================================================

● 69 year old man with isolated swelling of neck (J Clin Pathol 2002;55:61)

Micro images
=========================================================================



Mantle cell lymphoma


Primary T cell lymphoma



Lymphomas

MALT lymphoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Similar to MALT lymphoma elsewhere; low grade monocytoid B cells surround ducts and produce lymphoepithelial lesions
● Often associated with Sjogren’s syndrome (Mod Pathol 2000;13:4) or benign lymphoepithelial lesion, perhaps due to chronic antigenic stimulation

Clinical features
=========================================================================

● Most common lymphoma of salivary glands - 3% of tumors of major salivary glands; also occur in minor salivary glands
● Often bilateral, 30% multiglandular
● Cystic, 1-6 cm (median 2 cm), with ill demarcated margins (on imaging)
● May occur in children, post-transplantation (Am J Surg Pathol 2000;24:100), associated with Sjogren's syndrome, HIV, scleroderma, sialolithiasis, Waldenstrom macroglobulinemia (Am J Clin Pathol 2001;116:683), Warthin tumor
● Indolent, excellent prognosis, although 35% recur at 5 years
● Treat with radiotherapy

Diagnosis
=========================================================================

● Monoclonal by immunohistochemistry or flow cytometry; monocytoid infiltrates in regional lymph nodes
● Monoclonality in lymphoid infiltrates by PCR is insufficient for diagnosis

Case reports
=========================================================================

● Chronic sclerosing sialadenitis / Kuttner’s tumor (Am J Surg Pathol 2001;25:1546)

Micro description
=========================================================================

● Monocytoid cells surround ducts; low grade B cells
● May be Helicobacter pylori positive (tumor may regress after treatment)
● May have amyloid deposits, transformation to diffuse large B cell lymphoma

Micro images
=========================================================================



52 year old man


Parotid gland

Positive stains
=========================================================================

● CD19, CD20, CD22
● CXCL12, nuclear FOXP1, nuclear BCL10
● Rarely CD5+ (Hum Pathol 2012;43:1436)

Negative stains
=========================================================================

● CD5 (usually), CD10, BCL1/cyclin D1, CD45RD, EBV, HHV8

Molecular / cytogenetics description
=========================================================================

4 types of translocations (some organ specificity):
  ● t(14;18)(q32;q21): IGH / MALT1 (10-20% of salivary gland MALT)
  ● t(11;18)(q21;q21): API2 / MALT1
  ● t(1;14)(p22;q32): BCL10 / IGH
  ● t(3;14)(p14.1;q32): FOXP1 / IGH.t

● t(11;18)(q21;q21) is specific
● Also DAP-K methylation, A20 deletion, aneuploid

Differential diagnosis
=========================================================================

Kuttner tumor: may coexist



Lymphomas

T cell lymphoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Includes adult T cell leukemia, angiocentric T cell lymphoma (associted with necrotizing sialometaplasia, Ann Diagn Pathol 2009;13:60), HTLV1 lymphoma, peripheral T cell lymphoma, T/NK cell lymphoma (with hemophagocytic syndrome)
● Very rare

Clinical features
=========================================================================

● Parotid, submandibular gland, palate
● May occur post-transplant
● May be EBV+ (in CD56+ cases)
● Associated with Sjogren disease

Case reports
=========================================================================

● 34 year old woman with NK cell lymphoma of parotid gland (ORL J Otorhinolaryngol Relat Spec 2003;65:219)
● 42 year old man with AIDS and parotid gland tumor with NK/T cell phenotype (Arch Pathol Lab Med 2002;126:738)
● 48 yr old woman with HTLV1 related tumor secondary to blood transfusions for menorrhagia (Diagn Cytopathol 2004;31:333)
● 58 year old man with parotid tumor mass (Pathol Int 2012;62:60)
● 66 year old man with neck and pharyngeal masses (Pathol Int 2010;60:326)
● 69 year old man with primary T cell lymphoma resembling MALT (J Clin Pathol 2002;55:61)
● Adult T cell leukemia involving bilateral parotid and submandibular glands (Eur J Haematol 2004;73:332)
● Parotid T cell lymphoma post cardiac transplant (J Oral Maxillofac Surg 2001;59:673)

Micro descriptions
=========================================================================

● Prominent lymphoepithelial lesions similar to those in B cell lymphomas (Hum Pathol 1997;28:238); other features associated with specific diagnosis

Micro images
=========================================================================



NK cell tumor cells with large vesicular nuclei and prominent nucleoli, CD3+, UCHL1+, TIA1+, EBER+ by ISH


Primary T cell lympoma resembling MALT



Sarcomas

Angiosarcoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2014, last major update September 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare in salivary glands (only 4% of all angiosarcomas), usually parotid (primary or secondary) or submandibular gland (primary)
● Mean age 55 years
● No gender prevalence
● Often relatively good outcome at this site, even with high grade features (Mod Pathol 2003;16:263, Cancer 1986;58:1305)

Case reports
=========================================================================

● 17 year old boy with one year history of slow growing, tender submandibular mass (Acta Otolaryngol 2003;123:440)
● 77 year old woman with poorly differentiated tumor (Cesk Patol 2009;45:69)
● Arising from congenital hemangioma of parotid gland (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96:66)

Micro description
=========================================================================

● Usually spindled cells with solid or vasoformative growth pattern, often epithelioid (28%)
● May have low, intermediate or high grade features
● May occur in congenital hemangioma

Micro images
=========================================================================



Various images (primary and secondary tumors)

Positive stains
=========================================================================

● CD31, CD34, EMA, factor VIII, Ulex



Sarcomas

Desmoplastic small round cell tumor


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Aggressive neoplasm associated with EWS-WT1 translocation; not strictly a sarcoma
● Usually abdomen or pelvis; rare in salivary glands (Eur Arch Otorhinolaryngol 2008;265:S47)

Case reports
=========================================================================

● 22 year old man with parotid gland tumor (Hum Pathol 1999;30:430)
● 24 year old man with submandibular gland tumor (Hum Pathol 2010;41:438)
● 41 year old man with history of diabetes mellitus (Appl Immunohistochem Mol Morphol 2011;19:70)

Micro description
=========================================================================

● Solid nests of round/oval cells surrounded by cellular desmoplastic stroma; also necrosis, cystic degeneration, glandular arrangements, signet ring-like cells, pseudorosette formations
● May have areas without desmoplastic stroma

Micro images
=========================================================================



Small bowel tumor

Cytology description
=========================================================================

● Cohesive clusters of small cells with hyperchromatic nuclei and fine granular chromatin, fibromyxoid desmoplastic stroma

Cytology images
=========================================================================



Various images-site unspecified

Positive stains
=========================================================================

● Cytokeratin, desmin, neuron-specific enolase, WT1 (nuclear staining), EMA, CD56

Molecular / cytogenetics description
=========================================================================

● EWS-WT1 fusion transcript



Sarcomas

Hemangioendothelioma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Vascular tumor of anastomosing thin walled capillaries growing between salivary ducts and acini
● Also called juvenile hemangioma
● Most common salivary gland tumor of infants/children

Clinical features
=========================================================================

● Often congenital, involves parotid gland, submandibular gland; more common in females
● Not malignant; intermediate behavior between angioma and angiosarcoma
● May be associated with Kasabach-Merritt syndrome
● 70-95% regress spontaneously by age 7 years
● Fine needle aspiration may be useful for diagnosis (Arch Pathol Lab Med 2001;125:1340)

Case reports
=========================================================================

● 4 month old boy with growing lobulated mass (Pathol Int 1999;49:668)
● 3 year old boy with submandibular swelling due to lymphadenopathy (Virchows Arch 2006;448:843)
● 28 year old man with parotid tumor (Chir Ital 2004;56:457)
● 44 year old woman with submandibular mass (Auris Nasus Larynx 2008;35:157)
● 48 year old woman treated with superficial parotidectomy (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:730)

Treatment
=========================================================================

● Delay excision in hope of spontaneous regression; postoperative radiotherapy

Gross description
=========================================================================

● Diffuse soft mass uninvolved with overlying skin
● Periglandular muscular extension

Micro description
=========================================================================

● Anastomosing thin walled capillaries growing between salivary ducts and acini
● Variable mitotic figures, epithelioid or Kaposiform patterns, microcalcifications

Micro images
=========================================================================



Case of Week #77: thigh mass

Cytology description
=========================================================================

● Spindle shaped cells in sheets and clusters in bloody background
● Cell block shows ductal structures trapped in sheets of spindle cells

Cytology images
=========================================================================



Hypercellular clusters of bland spindle cells surrounding ductal structures in cell block, factor VIII+, CD34+

Positive stains
=========================================================================

● CD34 and factor VIII, CD31, vimentin, smooth muscle actin
● Ki-67: 6%
● May have CMV+ ducts

Differential diagnosis
=========================================================================

● Hemangioma



Sarcomas

Liposarcoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare in oral cavity or salivary glands; metastases must be excluded
● Median age 51 years, range 30-70 years; no childhood cases, no gender preference
● Better prognosis than at other sites - may recur, but no metastases or deaths due to disease (Mod Pathol 2002;15:1020)

Case reports
=========================================================================

● 53 year old man who metastatic myxoid liposarcoma to parotid (Diagn Cytopathol 2011;39:780)
● 77 year old man with primary atypical lipomatous tumor of parotid (Ear Nose Throat J 2009;88:E10)
● 80 year old woman with pleomorphic liposarcoma of parotid (Am J Otolaryngol 2004;25:432)

Treatment
=========================================================================

● Complete excision and careful follow-up

Gross description
=========================================================================

● Mean 4.2 cm (1.5-6.0 cm)

Micro description
=========================================================================

● Well differentiated, myxoid, dedifferentiated or pleomorphic
● Increased lipoblasts

Micro images
=========================================================================



Parotid liposarcomas


Head and neck liposarcomas, not necessarily salivary glands


Metastatic myxoid liposarcoma to parotid



Sarcomas

Undifferentiated sarcoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● <75 cases reported at this site
● Most frequent salivary gland sarcomas are rhabdomyosarcoma, malignant fibrous histiosarcoma, malignant schwannoma, fibrosarcoma
● Diagnosis of exclusion (no primary lesion elsewhere)

Case reports
=========================================================================

● 6 year old boy with parotid gland undifferentiated pleomorphic sarcoma (Head Neck 2008;30:970)
● 53 year old man with parotid tumor (Arch Pathol Lab Med 2002;126:849)
● 59 year old man with acinic cell carcinoma with undifferentiated spindle cell transformation.(J Laryngol Otol 1994;108:902)

Treatment
=========================================================================

● Chemotherapy, radiotherapy

Gross images
=========================================================================



Pink tan soft tumor

Micro description
=========================================================================

● Low grade/fibromyxoid sarcoma

Micro images
=========================================================================



Tumor with osseous metaplasia


Primitive undifferentiated sarcoma

Differential diagnosis
=========================================================================

Malignant mixed tumor
● Spindle cell carcinoma

Additional references
=========================================================================

Int J Pediatr Otorhinolaryngol 2011;75:558, Cancer 1986;58:1305



Other tumors

Embryoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Rare malignant tumor, diagnosed at or near birth, resembling epithelial anlage of salivary glands but in arrested state of differentiation (Ann Otol Rhinol Laryngol 1992;101:958, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:109)
● Also called sialoblastoma

Clinical features
=========================================================================

● Childhood epithelial salivary gland tumor; common among the perinatal tumors
● Occurs in submandibular, parotid or minor salivary glands; also ectopic salivary gland tissue
● Uni- or multinodular, 2-7 cm, rapid growth
● May recur locally or involve regional lymph nodes; also lung metastases

Case reports
=========================================================================

● Female infant with tumor arising in ectopic salivary gland tissue in cheek (J Plast Reconstr Aesthet Surg 2009;62:e241)
● Male infant with congenital tumor arising in minor salivary gland of buccal mucosa (Fetal Pediatr Pathol 2011;30:32)
● 3 month old boy with submandibular swelling of insidious onset (J Pediatr Surg 2008;43:e11)
● 3 month old girl with recurrent and metastatic tumor (Rare Tumors 2011;3:e13)
● 18 month old girl with parotid gland tumor (Pediatr Blood Cancer 2010;55:1427)
● 2 year old old with 2 cm mass in parotid gland with increasing anaplasia (Am J Surg Pathol 1999;23:342)
● 6 year old girl with recurrent tumor (Acta Cytol 2003;47:1123)

Treatment
=========================================================================

● Excision; chemotherapy if cannot completely excise (Pediatr Blood Cancer 2010;55:374); possibly brachytherapy

Micro description
=========================================================================

● Ductules and solid organoid nests of basaloid cells with fine chromatin and cuboidal epithelial cells
● 2 histological patterns: favorable pattern with semiencapsulation of benign basaloid cells with intervening stroma; unfavorable pattern with anaplastic basaloid cells, broad pushing to infiltrative periphery and minimal stroma (Ann Diagn Pathol 2006;10:320)
● Variable necrosis, variable mitotic activity, variable nuclear atypia, no perineurial invasion

Micro images
=========================================================================



One year old boy with parotid tumor


Recurrent and metastatic tumor


Nests of basaloid cells with poorly demarcated eosinophilic cytoplasm and round, vesicular nuclei

Cytology description
=========================================================================

● Tight, solid clusters of atypical basaloid cells plus dispersed epithelial and myoepithelial cells with metachromatic magenta hyaline globular material

Positive stains
=========================================================================

● Cytokeratin (ductal structures), S100, smooth muscle actin, calponin, p63
● Also AFP, cytoplasmic HER2, p53; Ki67 index increases with recurrence and may predict behavior (Pediatr Dev Pathol 2010;13:32)

Differential diagnosis
=========================================================================

Adenoid cystic carcinoma
Basal cell adenoma
Pleomorphic adenoma: may have embryonal structures
● Teratoma



Other tumors

Granular cell tumor


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, Pathol2gyOutlines.com, Inc.

General
=========================================================================

● Granular cells (large eosinophilic cells with granular cytoplasm and small central nuclei) similar to tumors elsewhere

Clinical features
=========================================================================

● Usually parotid gland
● Multinodular, associated with paresis or may be painless
● Cases associated with surgical trauma may have features of traumatic neuroma

Case reports
=========================================================================

● 30 year old woman with parotid gland tumor (Int J Oral Maxillofac Surg 1999;28:383)
● 54 year old woman with a painless submandibular tumor (Laryngorhinootologie 2005;84:755)
● 74 year old man with submandibular tumor but no prior trauma (Arch Pathol Lab Med 2001;125:1000)
● Parotid gland tumor (Int J Surg Pathol 2008;16:213)
● Tumor arising from facial nerve trunks (Ann Diagn Pathol 1999;3:35)

Treatment
=========================================================================

● Complete resection

Micro description
=========================================================================

● Large eosinophilic cells with granular cytoplasm and small central nuclei

Micro images
=========================================================================



Parotid gland tumor: H&E and S100


Granular cells near nerve fascicles (arrows), S100+

Positive stains
=========================================================================

● PAS, S100, CD68, alpha-1-antitrypsin

Differential diagnosis
=========================================================================

Acinic cell carcinoma: similar appearance at frozen section



Other tumors

Lipoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign tumor; rare in salivary glands, but usually involves parotid gland (Laryngol Rhinol Otol 1986;65:485)
● More common than lipomatosis
● Clinical findings are nonspecific (J Oral Maxillofac Surg 2006;64:1583)

Clinical features
=========================================================================

● 3% of parotid tumors - #2 most common benign mesenchymal neoplasms of major salivary glands (#1 is schwannoma)
● Often incidental (Rev Stomatol Chir Maxillofac 1988;89:117)
● Ages 40+, usually men, occasionally children

Case reports
=========================================================================

● Infant girl with parotid angiolipoma (Laryngoscope 1988;98:818)
● 36 year old woman with 3.5 cm parotid lipomatous pleomorphic adenoma (Pathol Res Pract 1999;195:247)
● 44 year old man with slow growing, asymptomatic parotid mass (Diagn Cytopathol 2013;41:171)
● 47 year old man with spindle cell lipoma of parotid gland diagnosed by fine needle aspiration (Arch Pathol Lab Med 2001;125:820)
● 56 year old man (Br J Oral Maxillofac Surg 2010;48:203)

Treatment
=========================================================================

● Simple excision, usually do not recur (J Korean Med Sci 1996;11:522, Arch Otolaryngol 1976;102:230)

Micro description
=========================================================================

● Bland appearing adipose tissue; osteolipoma or angiolipoma variants exist

Micro images
=========================================================================



Spindle cell lipoma of parotid gland


Pleomorphic lipoma with classic floret-like cells


Chondroid lipoma of lip has chondroid and lipomatous features

Cytology description
=========================================================================

● Nonspecific findings (Eur Arch Otorhinolaryngol 2008;265:S47); spindle cell lipomas have bland appearing spindle cells in myxoid background, CD34+ mature fat cells; S100 may be negative

Cytology images
=========================================================================



Spindle cell lipoma: bland spindle cells with myxoid change and fat, CD34+

Differential diagnosis
=========================================================================

Pleomorphic adenoma: may have extensive lipometaplasia / lipomatosis (Am J Surg Pathol 2005;29:1389)



Other tumors

Lipomatosis


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 27 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Diffuse deposition of adipose tissue (usually throughout parotid gland) with overall enlargement of gland but no distinct mass
● Associated with alcoholism, cirrhosis, diabetes, hormonal abnormalities, malnutrition
● May be preceded by sialadenosis (acinar cell hypertrophy, interstitial edema, ductal atrophy)
● Slow growing, usually in parotid gland, may affect children
● May recur

Case reports
=========================================================================

● 5 month old girl with rapidly progressive parotid lipomatosis (Saudi Med J 2003;24:898)
● 9 year old boy (Int J Clin Pract 2009;63:335)
● 38 year old man with myoepithelioma of minor palatinal salivary glands with extensive lipomatosis (Laryngorhinootologie 2005;84:432)
● 47 year old man with well circumscribed 3 cm parotid nodule (Ann Pathol 2002;22:219)
● Slow growing parotid mass (J Pediatr Surg 1996;31:1422)

Micro images
=========================================================================



In parotid gland of HIV+ man

Differential diagnosis
=========================================================================

Myoepithelioma: some cases have coexisting lipomatosis
Pleomorphic adenoma: some cases have lipometaplasia or lipomatous foci (Am J Surg Pathol 2005;29:1389)



Other tumors

Melanoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 28 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Unusual site; typically sheets of cells with abundant eosinophilic cytoplasm and prominent nucleoli
● Median age 66 years, range 30-84 years
● Usually represents metastatic disease from head and neck, and is common metastasis to parotid (Arch Pathol Lab Med 2000;124:1780)

Clinical features
=========================================================================

● Often represents metastatic disease
● Primary parotid tumors may be amelanotic
● Intraparotid sentinel lymph node often assessed for head and neck melanoma staging (Laryngoscope 2006;116:1461)
● Clinically presents with rapid increase in size
● Poor prognosis due to distant spread (Laryngoscope 2003;113:1070); rare patients have prolonged survival after surgery

Case reports
=========================================================================

● 40 year old woman with rapidly growing submandibular mass (Turk Patoloji Derg 2011;27:77)
● 71 year old man with jejunal melanoma metastatic to parotid (J Am Acad Dermatol 2003;49:319)
● Parotid mass (Diagn Cytopathol 2011;39:373)
● Primary melanoma of parotid (Acta Cytol 2009;53:435)
● Amelanotic melanoma primary in parotid (J Int Med Res 2008;36:1435)

Treatment
=========================================================================

● Surgery, radiotherapy for primary melanoma

Gross description
=========================================================================

● Often multiple nodules

Micro description
=========================================================================

● Sheets of cells with abundant eosinophilic cytoplasm and prominent nucleoli
● Often spindle cell regions, angiolymphatic invasion, desmoplasia; may metastatise in salivary gland pleomorphic adenoma

Micro images
=========================================================================



Various melanomas

Micro images
=========================================================================



Desmoplastic melanoma metastatic to submandibular gland


Left: parotid lymph node, right: parotid gland


Left: S100, right: HMB45

Positive stains
=========================================================================

● S100, HMB45, MART1

Differential diagnosis
=========================================================================

Schwannoma
● Undifferentiated carcinoma



Other tumors

Rosai-Dorfman disease


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 28 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Histiocytic proliferation with emperipolesis in background of plasma cells and lymphocytes
● First described by Destombes (1965), Rosai and Dorfman (Arch Pathol 1969;87:63)
● Also called sinus histiocytosis with massive lymphadenopathy
● Unknown origin, but associated with immunologic abnormalities

Clinical features
=========================================================================

● Rarely presents as salivary gland involvement without significant lymphadenopathy
● Usually long clinical course with exacerbations and remissions and eventual complete remission
● Primarily submandibular and parotid glands

Case reports
=========================================================================

● 9 and 10 year old brothers (Dentomaxillofac Radiol 2007;36:428)
● 44 year old man with involvement of salivary glands, cervical lymph nodes, nasal and maxillary sinus mucosa (J Cytol 2009;26:111)
● 45 yr old woman with enlarged submandibular gland (Diagn Cytopathol 2005;33:187)
● 48 year old with systemic lupus erythematosus and parotid gland involvement (Arch Pathol Lab Med 2001;125:1348)
● 71 year old man with parotid mass (J Laryngol Otol 1997;111:1091)
● Child with involvement of submandibular glands (Laryngoscope 2010;120:S228)
● Involving parotid, cervical lymph nodes, breast (J La State Med Soc 2008;160:35)

Micro description
=========================================================================

● Histiocytic proliferation with emperipolesis in background of plasma cells and lymphocytes, with eventually effacement of organ and formation of fibrous bands

Micro images
=========================================================================



Emperipolesis, histiocytic proliferation, S100+


Nasal mucosa / cervical lymph nodes

Cytology description
=========================================================================

● Moderate cellularity, large histiocytes, lymphoplasmocytic infiltrate, histiocytic lymphagocytosis

Cytology images
=========================================================================



Cervical lymph nodes

Positive stains
=========================================================================

● S100

Differential diagnosis
=========================================================================

Melanoma: may phagocytose hematopoietic cells, HMB45+, neoplastic melanocytes with marked atypia
Metastatic carcinoma
● Sinus histiocytosis



Other tumors

Schwannoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Neural tumor that may arise from facial nerve and present as salivary gland tumor
● Adults or children; often occurs in intranodal parotid gland
● Rarely diagnosed pre-operatively
● Slow growing, usually asymptomatic, neurological signs when associated with nerve compression

Case reports
=========================================================================

● 7 year old boy with slow growing, painless preauricular mass present for 3 years (Kulak Burun Bogaz Ihtis Derg 2008;18:175)
● 67 year old woman with parotid mass (J Laryngol Otol 2009;123:912)
● 70 year old woman with painless swelling of floor of mouth (Ann Diagn Pathol 2012;16:141)
● 75 year old woman with 3 cm tumor of parotid gland (Acta Cytol 2006;50:529)
● Asymptomatic parotid mass diagnosed as facial nerve schwannoma intraoperatively (Am J Otolaryngol 2008;29:126)
● CXPA which occurred in the parotid gland, showing retrograde perineural invasion (Auris Nasus Larynx 2008;35:291)

Treatment
=========================================================================

● Surgery for multiple schwannoma; may recur if incomplete resection

Gross description
=========================================================================

● Encapsulated tumor

Micro images
=========================================================================



Tumor of sublingual gland

Micro description
=========================================================================

● Resembles schwannoma elsewhere; pseudoglandular (J Oral Pathol Med 2006;35:379) and ancient schwannoma variants may be present

Micro images
=========================================================================



Various images


Tumor of sublingual gland shows (left to right): thin fibrous capsule, spindle cells with palisading pattern, residual gland in center of tumor (Alcian blue pH2.5 / PAS), S100+

Cytology description
=========================================================================

● Uniform spindle cells with scant, ill defined cytoplasm and cigar-shaped nuclei; also lymphocytes, foamy histiocytes, Verocay body clusters

Stains
=========================================================================

● S100+, neurofilament-

Differential diagnosis
=========================================================================

● Carcinoma ex-pleomorphic adenoma
Pleomorphic adenoma: may have schwannoma-like features or spindle cells (Rare Tumors 2011;3:e40)



Other tumors

Sialolipoma


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 28 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon lipoma variant composed of mature adipose tissue mixed with acinar, ductal, basal and myoepithelial cells of normal salivary gland
● First described in 2001 by Nagao (Histopathology 2001;38:30)

Clinical features
=========================================================================

● Mean age 61 years, but wide age range at presentation
● Female gender predominance for minor salivary gland location
● Parotid and submandibular glands, hard and soft palate
● May be due to entrapment of salivary gland elements by lipoma
● Benign behavior, no recurrences reported

Case reports
=========================================================================

● Congenital sialolipoma in female infant (Int J Pediatr Otorhinolaryngol 2005;69:429)
● Female newborn with slight facial asymmetry (Head Neck Pathol 2008;2:36)
● 3 year old girl with sialolipoma with diffuse sebaceous differentiation (Pediatr Dev Pathol 2007;10:138)
● 3 year old boy with submandibular gland tumor (J Pediatr Surg 2011;46:408)
● 18 year old man with submandibular sialoangiolipoma (Natl J Maxillofac Surg 2012;3:98)
● 68 year old woman with sensation of "large foreign body" in throat (Case of the Week #49)
● 72 year old woman with painless swelling of hard palate (Head Neck Pathol 2010;4:249)
● 73 year old man with submandibular mass (Indian J Pathol Microbiol 2009;52:379)
● 77 year old woman with submandibular mass (Br J Oral Maxillofac Surg 2008;46:599)

Treatment
=========================================================================

● Surgical excision; no malignant transformation or recurrences (Ann Diagn Pathol 2011;15:6 )

Gross description
=========================================================================

● Well circumscribed, resembles lipoma
● Median 2 cm (range, 1-4 cm)

Gross images
=========================================================================



Well circumscribed tumor


Parotid sialoangiolipoma

Micro description
=========================================================================

● 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 stroma, oncocytic changes, sebaceous differentiation
● Vascular variant is sialoangiolipoma

Micro images
=========================================================================


Case of the week #49:


Peripheral lipomatous tissue with central salivary gland elements


Lipoma like areas


Acini and dilated ducts


Ducts with fibrosis of wall infiltrated by lymphocytes



Lower lip tumor


Submandibular sialoangiolipoma


Parotid sialoangiolipoma



Miscellaneous

Features to report


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Tumor histologic type and pattern
● Anatomic site of origin/location, side
● Tumor size
● Tumor histologic grade (for mucoepidermoid carcinoma, adenocarcinoma NOS, malignant mixed tumor, adenoid cystic carcinoma)
● Tumor extension (intra- or extraglandular), to adjacent structures
● Status of resection margins
● Vascular invasion
● Perineural invasion
● Lymph nodes: for each level, number obtained, number involved by tumor, size of largest nodal metastases, presence of extracapsular spread, side, if appropriate: major nerve (e.g. facial) or vessel (e.g. jugular vein), bone, skin involvement



Miscellaneous

Fine needle aspiration


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● 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 (Arch Pathol Lab Med 2000;124:87)
● Occasionally induces 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)

Diagnostic difficulties
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● Extensive squamous metaplasia may resemble squamous cell carcinoma or mucoepidermoid carcinoma (Mod Pathol 2002;15:342)
● Basal cell adenoma may resemble adenoid cystic carcinoma (solid type)
● Oncocytic proliferations may resemble acinic cell carcinoma

Tables
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Classification table

Micro images
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Squamous metaplasia


Various images



Miscellaneous

Frozen section


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● Useful to determine extent of surgery needed, particularly for parotid tumors
● Most common error is to diagnose mucoepidermoid carcinoma as benign



Miscellaneous

Grossing


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 24 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● 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

Note also presence or absence of:
● Capsule
● Cartilage, calcific deposits
● Cystic change
● Extraglandular extension
● Localized / diffuse nature of tumor
● Margin involvement
● Necrosis
● Solitary / multifocal tumor



Miscellaneous

TNM staging


Reviewer: Adriana Handra-Luca, M.D. (see Reviewers page)
Revised: 26 January 2013, last major update September 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

General
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● Use for staging 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)
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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: Moderately advanced disease; tumor invades skin, mandible, ear canal or facial nerve
T4b: Very advanced disease; tumor invades skull base or pterygoid plates or encases carotid artery

Note: extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues or nerve (except T4a and T4b)
● Microscopic evidence alone does not constitute extraparenchymal extension

Regional lymph nodes (N)
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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)
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M0: No distant metastasis
M1: Distant metastasis
Mx: Cannot be assessed

Stage grouping
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I: T1 N0 M0
II: T2 N0 M0
III: T3 N0 M0 or T1-3 N1 M0
IVA: T4a N0-1 M0 or T1-T4a N2 M0
IVB: Any T N3 M0 or T4b any N M0
IVC: Any T any N M1

End of Salivary Glands > Superpage


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