Salivary Gland Pathology

major salivary glands

-parotid glands: parotid duct = Stensen’s duct, exits at parotid papilla (2nd maxillary molars), serous saliva

-sublingual glands: 8-20 ducts, smaller - ducts of Rivinus (exit on floor of mouth), larger - duct of Bartholin (merges with Wharton’s duct), mucous saliva

-submandibular glands: submandibular duct = Wharton’s duct, exits at sublingual caruncles on either side of lingual frenum, mixed serous and mucous saliva

minor salivary glands

-600+

-locations: anterior and posterior tongue, buccal and labial mucosa, mid- to posterior palate, also nasal cavity/paranasal sinuses, pharynx, larynx, lungs

-NO MINOR SALIVARY GLANDS on anterior hard palate and gingiva (except retromolar pad)

-primarily mucous saliva- exception = von Ebner’s glands, around circumvallate papillae of the tongue, serous saliva

parotid papilla

-flap of tissue overlying communication of Stensen (parotid) duct with oral cavity

sublingual caruncles, plicae (folds)

-caruncles: opening of submandibular (Wharton) ducts

-plicae/folds: opening of sublingual ducts (ducts of Rivini)

functions of saliva

-hydration

-cleansing

-lubrication

-digestion: starch, carbohydrates

-antimicrobial: salivary proteins, lysozymes, lactoferrin, lactoperoxidase, cystatins, histatins, secretory IgA

-remineralization

-taste: enhances taste perception

salivary gland histology

palatal cysts of the newborn

-50-75% of neonates

-1-3mm yellow/white papules

-self-healing- resolve within several weeks

-scattered over hard/soft palatal mucosa

-probably derived from epithelium associated with developing minor salivary glands

-epstein pearls- same or different? → midline of palate, may be derived from fusion of palatal processes during embryonic development

-no consistent eponyms^

-compare with gingival cysts of newborn- scattered over alveolar ridge and derived from dental lamina

major salivary gland disease

-hyposalivation and xerostomia

-Sjogren syndrome

-IgG4-related disease

-sialadenosis (sialosis)

-mumps (epidemic parotitis)*

-acute transient parotitis (anesthesia mumps)

-HIV salivary gland disease

hyposalivation and xerostomia

-hyposalivation: objective decrease in salivary flow, may or may not be associated with xerostomia

-xerostomia: subjective complaint of dryness, may or may not be associated with hyposalivation

hyposalivation- most common causes

-dehydration- not enough water, too much coffee/tea/alcohol

-polypharmacy

-anxiety/depression- chronic stimulation of sympathetic nervous system → inhibition of serous saliva

-mouth breathing

-smoking

-radiation therapy

-Sjogren syndrome

-any disease that can affect the salivary glands

hyposalivation clinical features

-difficulty eating, swallowing, speaking

-dental instruments stick to mucosa

-coated (hairy) tongue

-taste changes

-oral burning

-candidiasis

-cervical/interproximal caries

hyposalivation scoring

hyposalivation management

-symptoms difficult to manage

-constant hydration

-avoid caffeinated beverages (mildly diuretic)- coffee, tea, soda

-saliva substitutes (biotene)- spray, gel seem to be superior to rinse

-xylitol chewing gum

-sialogogues- pilocarpine 5mg TID, cevimeline 30mg TID

-caries prevention: brushing, flossing, diet, fluoride trays/varnish, SDF? (not FDA approved yet), routine dental visits and radiographs, glass ionomer better for cervical decay, avoid acidic beverages- coffee, tea, soda, energy drinks, wine

Sjogren syndrome

-systemic autoimmune disease primarily targeting exocrine glands, particularly of eyes and mouth

-lacrimal gland dysfunction: keratoconjunctivitis sicca (dry eyes), salivary gland dysfunction: dry mouth

-other organs may be affected in 25% of cases: skin, joints, lungs, heart, GI tract

-striking (9:1) female ratio

-may present secondary to another autoimmune disease (rheumatoid arthritis most commonly)

-signs/symptoms of ocular and oral discomfort

-30-50% of patients: firm enlargement of salivary glands, usually bilateral

Sjogren syndrome diagnostic criteria

-2 out of the following 3 criteria must be met:

1) positive serum: Anti-SSA or Anti-SSB or RF + ANA (ANA >/= 1:320)

2) ocular staining score >/=3 (fluorescein, lissamine, rose bengal eye stain)

3) focal lymphocytic sialadenitis (FLS) with focus score >/= 1 focus/4mm² in labial salivary gland biopsy

-^1 = single most important criterion

-dry eyes/mouth may be seen in absence of evidence of autoimmune disease, known as sicca complex

focal lymphocytic sialadenitis

-cluster of 50+ lymphocytes

-often periductal

Sjogren syndrome management

-dry mouth: basic self-care measures, regular preventive dental care, artificial saliva, sialogogues

-dry eyes: artificial tears, topical cyclosporine, steroids, others

-severe/persistent sicca manifestations or extraglandular manifestations: systemic therapy such as hydroxychloroquine, rituximab

-5-10% of pts: MALT lymphoma, usually in parotid

IgG4-related disease

-fibro-inflammatory condition characterized by: tendency to form tumefactive lesions at multiple sites/organs, common microscopic features regardless of organ involved, elevated serum IgG4 concentrations

-unifies many conditions previously considered organ-specific or idiopathic: autoimmune pancreatitis (type 1), mikulicz syndrome (salivary/lacrimal swelling), Kuttner tumor (submandibular gland), riedel thyroiditis, eosinophilic angiocentric fibrosis, patients may be treated with systemic steroids, rituximab

Mikulicz syndrome

-historical term referring to swelling of lacrimal and parotid/submandibular glands

-non-specific clinical presentation that may be seen in IgG4-related disease, Sjogren syndrome, sarcoidosis, others

Kuttner tumor

-chronic sclerosing sialadenitis

-firm enlargement of submandibular gland

-typically bilateral

-Kuttner tumor

sialadenosis (sialosis)

-chronic, bilateral, diffuse, non-inflammatory, non-neoplastic swelling of major salivary glands

-acinar hypertrophy and ductal atrophy

-primarily affects parotid glands, but occasionally involves the submandibular glands

-usually painless, may be tender

-may be idiopathic or may be associated with: chronic malnutrition, obesity, diabetes mellitus, alcoholism, liver disease, eating disorders, meds

-management ranges from surgery to pilocarpine to observation

mumps (epidemic parotitis)

-caused by paramyxovirus gene

-highly infectious, spread by respiratory droplets, most common viral cause of sialadenitis^^

-acute, self-limited viral syndrome, approximately 2 week duration, sporadic outbreaks still occasionally occur despite routine MMR vaccination

-treatment symptomatic/palliative

mumps clinical features

-last approximately 2 weeks

-low-grade fever, malaise, headache, myalgia

-parotitis: 95% of cases, bilateral in 90%, lasts approximately 10 days, increased serum amylase

-epididymoorchitis with testicular pain and swelling, 40% of males, may result in impaired fertility, complete sterility rare

-oophoritis, pancreatitis

-aseptic meningitis

acute transient parotitis (surgical mumps)

-transient inflammation and enlargement of salivary glands after general anesthesia

-usually subsides within few hours

-very rarely causing serious symptoms warranting urgent intervention, patient kept NPO and administered atropine, combination of factors (trauma, infection, hypersensitivity reactions, dehydration, excretory duct obstruction by position, calculi, thickened secretions)

-dry oral cavity/parotid susceptible to ascending infection (frequently S. aureus)

-increasingly uncommon surgical complication- pre- and peri-operative antibiotics/IV fluid routinely administered

-currently most commonly seen in elderly patients taking many medications

HIV salivary gland disease

-approximately 5% of HIV-infected individuals affected

-enlargement of one or more salivary glands- typically parotid, frequently accompanied by cystic degeneration (lymphoepithelial cyst, cystic lymphoid hyperplasia)

-manifestation of diffuse infiltrative lymphocytosis syndrome

HIV salivary gland disease- diffuse infiltrative lymphocytosis syndrome (DILS)

-rare oligoclonal expansion of CD8+ T cells in peripheral blood of HIV-infected patients

-diffuse lymphocytic infiltration of various organs (lungs, peripheral nerves, salivary glands, lacrimal glands

-Sjogren-like clinical picture

-pts with DILS have very high levels of HIV proviral DNA in peripheral nerves- lymphocytic infiltration is driven by HIV antigens

HIV salivary gland disease management

-reduction of size with antiretroviral therapy

-surgical excision

traumatic and obstructive salivary gland diseases

-mucocele and ranula

-salivary duct cyst

-sialolithiasis

mucocele

-common condition exclusively affecting intraoral minor salivary glands: lower lip = 80%

-most common in 1st-3rd decades

-traumatic etiology, usually biting on lip = laceration of excretory salivary duct, mucin spillage into connective tissue

-not a cyst: no epithelial lining

mucocele clinical presentation and tx

-dome-shaped, translucent/bluish nodule

-fluctuant

-often increasing and decreasing in size, especially around mealtimes

-treated with surgical excision of swelling and damaged salivary gland (to prevent recurrence)

mucoceles of ventral tongue affect

-glands of Blandin-Nuhn

mucoceles of the retromolar pad

-very rare

-mucocele-like presentation should raise suspicion for a neoplasm, especially mucoepidermoid carcinoma

superficial mucocele

-less common than conventional mucocele

-may be seen in pts with hyposalivation, lichen planus, chronic GvHD

-appear as small blisters

-often burst/heal within few days

-occasionally painful

ranula

-mucocele of sublingual gland

-may elevate tongue, resulting in dyspnea

-treated by excision of mass and associated sublingual gland

-occasionally treated by marsupialization

ranula and “plunging” ranula

-sublingual gland sits above mylohyoid, in sublingual space

-many ranulas present as intraoral swellings involving sublingual space

-occasionally, ranula may involve submylohoid space → known as plunging ranula, presents as extraoral swelling, ± intraoral swelling

-mylohyoid separates sublingual (intraoral) from submylohyoid (extraoral) space

-spaces communicate at posterior margin of mylohyoid

-35-50% of people have defect in midportion of mylohyoid

____ may be seen in plunging ranula imaging

-tail sign

-represents escape of lesion from sublingual space

salivary duct cyst (mucus retention cyst)

-reactive, balloon-like dilation of excretory salivary duct

-secondary to mucus plugging

-usually <1cm, translucent to yellow

-common sites of occurrence: parotid, mandibular vestibule/lower lip/buccal mucosa, floor of mouth, paranasal sinuses (mucous retention cyst)

-asymptomatic and conservatively excised

sialolithiasis

-sialolith: calcification within salivary gland or duct

-begins around nidus of debris: mucus, bacteria, etc.

-localized process: no relation to hypercalcemia, nephrolithiasis, cholelithiasis

-clinically symptomatic sialoliths affect 0.5% of population at some point in lifetime

-location; submandibular gland 70-90%, parotid, upper lip

submandibular gland

-longest excretory duct of all glands, upward flow against gravity

-viscous saliva due to high mucous content

-saliva has higher pH and contains twice as much calcium (compared to parotid), favoring mineralization

major salivary sialoliths present with pain/swelling at ____

-mealtime

-due to obstruction of salivary flow

minor salivary sialoliths

-usually asymptomatic and firm

-may cause local tenderness/swelling

diagnosis of submandibular stones

-plain films (occlusal)

-not all stones sufficiently calcified to be visible

-other imaging techniques (sialogram, MRI, CT) may be necessary

sialolith on panoramic radiograph

-may appear superimposed over angle/body of mandible on panoramic radiographs

bacterial sialadenitis

-often a consequence of obstruction

-pain, swelling, erythema, ± fever

-purulent drainage from duct

bacterial sialadenitis management

-non-invasive removal: gland massage, sialogogue prescription, antibiotic prescription when infection/purulent discharge present (associated with longstanding cases)

-surgical excision: intraoral approach under local anesthesia (sialendoscopy, followed by salivary gland massage, sour diet, sialogogues to stimulate salivary glow/prevent scarring over duct orifice)

necrotizing sialometaplasia

-unusual condition resulting from salivary gland infarction/necrosis- necrosis ischemic in origin but cause usually unknown (HIF-1alpha, VEGF, EGFR upregulated)

-alarming clinical presentation mimics malignancy- rapidly developing ulceration, may be painful

-typically occurs on palatal mucosa unilaterally- most common location for benign and malignant salivary gland neoplasms as well, 30% of cases bilateral or involve midline area

-3:1 male predilection

necrotizing sialometaplasia healing and diagnosis

-self-healing over 1-6 months

-biopsy (most often) necessary for diagnosis- clinical presentation non-specific and suggestive of malignancy

neoplasms of the salivary glands

-uncommon and very heterogeneous group of neoplasms- 2-5% of head and neck malignancies

-parotid gland: 60-75% of salivary gland tumors

-parotid >> minor salivary glands > submandibular gland > sublingual gland

-pleomorphic adenoma comprises approximately half of all (benign and malignant) salivary gland tumors

-most salivary gland malignancies have low-grade biologic behavior

-peak incidence 5th-7th decades, slight female predilection- generally few known risk factors

salivary gland tumors- benign and malignant

-parotid gland: 75% benign (site of predilection for pleomorphic adenoma), 25% malignant

-minor salivary glands/submandibular gland: 40-60% benign, 40-60% malignant

-sublingual gland: 10-30% benign, 70-90% malignant

salivary gland tumors by age

-most common salivary gland tumor in infants: hemangioma

-most common salivary gland tumor in children, adolescents, and adults: pleomorphic adenoma

-most common salivary gland malignancy in children, adolescents, and adults: mucoepidermoid carcinoma

primary salivary gland tumors by location- minor salivary glands (exclusively or predominantly)

-canalicular adenoma

-polymorphous (low-grade) adenocarcinoma

-cribriform adenocarcinoma of minor salivary glands

-hyalinizing clear cell carcinoma

-sialadenoma papilliferum

-inverted ductal papilloma

-intraductal papilloma

primary salivary gland tumors by location- major and minor salivary glands

-pleomorphic adenoma

-basal cell adenoma

-myoepithelioma

-cystadenoma

-cystadenocarcinoma

-mucoepidermoid carcinoma

-secretory carcinoma

-adenoid cystic carcinoma

-adenocarcinoma, not otherwise specified

primary salivary gland tumors by location- major salivary glands (exclusively or predominantly)

-warthin tumor

-oncocytoma

-sclerosing polycystic adenosis

-lymphadenoma

-sebaceous lymphadenoma

-acinic cell carcinoma

-carcinoma ex pleomorphic adenoma

-metastasizing pleomorphic adenoma

-basal cell adenocarcinoma

-epithelial-myoepithelial carcinoma

-myoepithelial carcinoma

-salivary duct carcinoma

-intraductal carcinoma

-squamous cell carcionma

-lymphoepithelial carcinoma

-neuroendocrine carcinoma

-neuroendocrine carcinoma

-oncocytic carcinoma

-mucinous adenocarcinoma

-sebaceous carcinoma

-sialoblastoma

clinical presentation of salivary gland neoplasms

-generally similar presentation regardless of specific disease

-benign/malignant tumors usually present as painless mass/swelling- frequently mobile, unless on hard palatal mucosa, may be covered by normal or ulcerated mucosa/skin

-pain/paresthesia/paralysis suggestive or perineural invasion- parotid malignancies may invade facial nerve

-most common intraoral lesions: palate, upper lip, buccal mucosa

differential diagnosis of palatal masses

1) salivary gland neoplasm (1. pleomorphic adenoma, 2. mucoepidermoid carcinoma, 3. adenoid cystic carcinoma, 4. polymorphous (low-grade) adenocarcinoma)

2) lymphoma

3) soft tissue neoplasm

4) if ulcerated, may consider SCC, necrotizing sialometaplasia, infectious

5) common things are common- dental abscess

diagnosis of salivary gland neoplasms

-imaging to localize disease (particularly for major salivary gland swellings)- CT, MRI, ultrasound

-biopsy necessary for diagnosis

-ultrasound-guided FNA or core needle biopsy (particularly for major salivary gland swellings) or incisional biopsy (often for minor salivary gland swellings)

pleomorphic adenoma (benign mixed tumor)

-pleomorphic- marked microscopic heterogeneity between PAs and within the same PA

-mixed- contains mixture of epithelial/myoepithelial cells, and mesenchymal elements (bone, cartilage, fat)

-most common salivary gland tumor of major and minor salivary glands

-80% occur in parotid

-characterized by PLAG1 and HMGA2 gene rearrangements

pleomorphic adenoma management

-parotid tumors: superficial parotidectomy (increased risk of recurrence if treated by enucleation alone)

-submandibular/sublingual tumors: removal of gland

-minor salivary gland tumors: conservative excision

carcinoma ex pleomorphic adenoma

-malignancy occurs within 5-10% of PAs

-1.6% of PAs present less than 5 years

-9.5% of PAs present more than 15 years

-time period for malignant transformation approximately 20 years

-parotid > submandibular >> minor salivary glands

-oral cavity PAs come to clinical attention early

-presents as sudden or rapid enlargement of long-standing/painless/slowly-enlarging mass

-pain, facial nerve paresis, soft tissue fixation may occur

mucoepidermoid carcinoma

-most common: salivary gland malignancy, intraoral salivary gland malignancy, pediatric salivary gland malignancy, intraosseous salivary gland malignancy

-2nd most common salivary gland neoplasm: 10-15% of all salivary gland neoplasms, 30% of all salivary gland malignancies

-just over 50% occur in major salivary glands (90% in parotid)

-minor salivary glands: palatal mucosa most common site, retromolar pad MEC may look like mucocele

mucoepidermoid carcinoma- histology and biologic behavior

-consists of mucous, epidermoid, and intermediate cells

-characterized by CRTC1-MAML2 t(11;19)(q21;p13) translocation

-classified as low, intermediate, or high grade: low, intermediate MEC → 5 year DSS >95%; high grade → 5 year DSS 67%

-major salivary gland MEC: roughly equal incidence of low, intermediate, high grade

-minor salivary gland MEC: 90-95% low or intermediate grade

warthin tumor

-unusual salivary tumor arising from salivary epithelium arising within periparotid lymph nodes- likely a reactive process and not a true neoplasm

-well-established association with smoking

-strong male predilection due to historical smoking habits- male predilection less strong today

-second most common benign salivary gland “tumor”

-indolent course: if diagnosed by FNA, excision may not be necessary

-10% of Warthin tumors bilateral

-may present synchronously or metachronously

warthin tumor histology

acinic cell carcinoma

-low-grade carcinoma with a tendency to recapitulate normal serous acini

-91% 5 year survival

-most common in parotid

-second most common pediatric salivary malignancy

adenoid cystic carcinoma

-salivary malignancy characterized by striking tendency for perineural invasion

-pain, facial nerve paralysis in many parotid carcinomas

-equally distributed between major and minor salivary glands

-characterized by MYB-NFIB t(6;9) translocation

adenoid cystic carcinoma biologic behavior

-perineural invasion accounts for relentless clinical course with distant metastases late in disease course

-5 year OS: 60-90%

-10 year OS: 29-80%

-15 year OS: 29-55%

-several microscopic growth patterns: cribriform (“swiss cheese”), tubular, solid (negative prognostic factor), trabecular

canalicular adenoma

-striking predilection for: upper lip (rare cases may occur on buccal mucosa), females (4:1), elderly (7th decade)

-pattern of tumor cell growth resembles tubules/canaliculi

polymorphous (low-grade) adenocarcinoma

-salivary gland malignancy occurring near exclusively in minor salivary glands

-variable (polymorphous) microscopic appearance

-generally indolent clinical behavior, metastasis exceptional (>95% DSS at 10 years)

-PRKD1 mutations in over 70% of cases

-for unknown reasons, may induce changes to overlying epithelium- may appear rough, orange peel-like

-treated with wide local excision; neck dissection only if clinically evident nodes

secretory carcinoma of salivary gland

-secretory carcinoma exhibits ETV6-NTRK3 t(12;15) translocation and characteristic microscopic findings regardless of site involved

-secretory carcinoma of breast, salivary glands, thyroid, skin

-slight male predilection

-may occur in major or minor salivary glands

salivary duct carcinoma

-high-grade salivary malignancy with distinct male predilection

-rapid enlargement with or without pain

-radical neck dissection and postoperative radiotherapy preferred treatment

-distant metastases in 50-70% of pts

-60-80% of patients die from disease within 5 years

-microscopically resembles ductal carcinoma of breast

-parotid most common site