Professional Documents
Culture Documents
19
Non-Neoplastic Diseases of
Salivary Glands
Nondevelopmental Cysts
Mucus extravasation phenomenon
Mucus retention cyst
Ranulas
816
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 817
Histologically, the tissue includes normal salivary Ontogenically, the parotid gland is the last of the
gland tissue either purely serous or mixed serous and salivary glands to be encapsulated, resulting in either
mucinous glands. incorporation/entrapment of lymphoid tissue within
the parotid or incorporation/entrapment of parotid
Intranodal Periparotid Salivary ducts and acini within the periparotid lymph nodes
epithelium.
Gland Tissue (Fig. 19-1) Histologically, the salivary gland tissue includes all
Not technically heterotopic but represents normal components of the salivary gland unit including
development ducts and acini but more often consists of serous
Generally accepted explanation for the occurrence of glands with scattered, well-formed ducts.
salivary gland tissue in periparotid lymph nodes is All pathologic lesions (non-neoplastic and neoplas-
entrapment during embryonic development rather tic) may originate from the intranodal salivary gland
than true ectopia, although this issue is still the tissues, including:
subject of debate. m Cysts, metaplasia, hyperplasia, and benign epi-
parenchyma during embryonic development rather than mastoid bone, and may be intimately associated
true ectopia. with the facial nerve
818 SECTION 6 Major and Minor Salivary Glands
Intraosseous salivary gland tissue is uncommon and of the masseter situated on the buccal fat pad.
tends to occur in the posterior mandible near the m Accessory tissue is normally connected to Stensen
angle beneath the mandibular canal and less fre- duct by a single accessory duct, although more
quently in the anterior mandible. than a single duct may be found.
Intraosseous salivary gland tissue is asymptomatic Clinically, lesions of accessory parotid tissue present
and is an incidental radiographic finding. with mass in the cheek.
No treatment is required. Histologically, accessory tissue is identical to the nor-
mally situated parotid tissue and reflects similar
Salivary Gland Heterotopia and pathologic processes that the main gland may exhibit
(e.g., inflammation, fatty infiltrate, other).
Salivary Gland Tumors Benign and malignant salivary gland tumors may
Salivary gland neoplasms occurring in sites that nor- arise in accessory parotid glands:
mally do not contain salivary gland tissue are usually m Benign tumors may include pleomorphic and
considered to originate from heterotopic salivary monomorphic adenomas, Warthin tumor, others.
gland tissue. m Malignant tumors reported include a wide variety
An exception to the above statement includes of types, including (but not limited to) mucoepi-
those salivary gland tumors arising in periparotid dermoid carcinoma, acinic cell adenocarcinoma,
lymph nodes without an identifiable parotid adenoid cystic carcinoma, carcinoma ex pleomor-
gland mass: phic adenoma, others.
m Clinical setting is one in which the intranodal Magnetic resonance imaging is helpful in the diag-
salivary gland tumor, specifically a malignant nosis and treatment of accessory parotid gland
tumor, is considered as being of unknown tumors.
primary origin. Best surgical approach to tumors in the accessory
m Clinical and radiologic search for the primary parotid region is via a standard parotid incision and
salivary gland tumor proves negative. concomitant superficial parotidectomy; this approach
m Entrapment of salivary gland parenchyma within to accessory parotid gland tumors is superior in that
lymph nodes during embryonic development it provides a better margin of resection and mini-
accounts for the intranodal salivary gland mizes functional and cosmetic deformities.
tissue.
m Salivary gland neoplasms, benign and malignant,
Pathology
Gross
Lesions are firm and sessile, varying in size from
0.5 to 3cm.
Histology
Submucosal proliferations of hypertrophied and/or
hyperplastic lobules of otherwise normal-appearing
mucinous acini
No significant inflammation or fibrosis are seen.
Overlying epithelium is unremarkable, although
pseudoepitheliomatous hyperplasia may be present.
A Differential Diagnosis
Salivary gland neoplasms:
m Submucosal lobular configuration composed of a
Squamous Metaplasia
and Mucous Cell
Metaplasia
Relatively common metaplastic changes that can be
B seen in a wide variety of lesions, including non-
neoplastic lesions and neoplasms (benign and
malignant)
Fig. 19-2. Adenomatoid hyperplasia. May occur spontaneously or occur as secondary to
A, B, Adenomatoid hyperplasia showing submucosal a traumatic event such as fine-needle aspiration
proliferation of hyperplastic lobules of normal-appearing biopsy or biopsy
mucinous acini without significant inflammation or fibrosis; For illustrations see Chapter 20 under Pleomorphic
the overlying squamous epithelium (A) is unremarkable. Adenoma and Warthin Tumor.
Cause is unknown and there is no association with glands of virtually every site in the upper aerodi-
sialadenosis or trauma. gestive tract, can be affected.
820 SECTION 6 Major and Minor Salivary Glands
A A
B B
and sublingual glands, the induction of that may slough, leaving a crater-like ulcer
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 821
Histology
At low magnification there is preservation of the
lobular architecture of the minor salivary glands.
Histologic hallmark is squamous metaplasia of resid-
ual acinar and ductal elements: B
m Squamous cells are typically bland in appearance
Associated findings include ulcerated mucosa and process in most cases occurs from 3 to 12 weeks.
pseudoepitheliomatous hyperplasia (PEH): m Debridement and saline rinses may aid in the
MEC, Mucoepidermoid carcinoma; NS, necrotizing sialometaplasia; PEH, pseudoepitheliomatous hyperplasia; SCC, squamous cell
carcinoma.
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 823
of NS.
m Scarcity of ulceration in SANS but typically
present in NS
m Absence of squamous metaplasia in SANS but
present in NS
Oncocytic Alterations
Oncocytic cells in the salivary glands occur in the
following settings:
m Oncocytic metaplasia B
m Oncocytosis (nodular or diffuse)
m Warthin tumor
Fig. 19-7. Oncocytic metaplasia.
m Variety of other lesions/tumors that may have A, Incidentally identified focus of oncocytic metaplasia
oncocytic cells including but not limited to: (arrows) in a parotid gland from an older aged individual.
Pleomorphic adenoma B, Oncocytic cells are characterized by the presence of
Basal cell adenoma granular eosinophilic cytoplasm.
Myoepithelioma
Canalicular adenoma
Mucoepidermoid carcinoma the percentage of the population with oncocytic
Acinic cell carcinoma metaplasia increases.
Others In contrast to oncocytoma (and oncocytosis), onco-
cytic metaplasia is nonmass-forming focal or limited
changes in one or more areas within the salivary
Oncocytic Metaplasia (Fig. 19-7) gland.
Non-neoplastic transformation of ductal and acinar Appear as isolated clusters of oncocytic cells within
epithelium to oncocytes: otherwise normal-appearing parenchyma
m Oncocytes are histologically characterized by Clear cell changes may be present.
cytoplasmic alteration (metaplasia) of epithelial Usually represents incidental histologic findings in
and/or myoepithelial cells with swelling of the salivary glands excised for other reasons
cytoplasm by mitochondrial hyperplasia giving Oncocytic cells may be seen in other non-neoplastic
the cell a characteristic granular eosinophilic processes (see oncocytosis immediately following),
appearance by light microscopy. as well as in numerous salivary gland tumors, in
Represents an aging phenomenon: cluding pleomorphic adenomas, Warthin tumor,
m Oncocytic metaplasia is generally not seen in oncocytoma, mucoepidermoid carcinoma, acinic cell
patients less than 50 years of age from which time carcinoma, oncocytic carcinoma, others.
824 SECTION 6 Major and Minor Salivary Glands
nodules
m Unencapsulated
A B
C D
Typically represent incidental finding found in asso- m In multifocal lesions, foci vary in size and shape.
ciation with another lesion Intercalated ducts are lined by single layer of cuboi-
Usually a small lesion measuring less than 5mm in dal to columnar cells with small round nuclei and
greatest dimension eosinophilic to amphophilic cytoplasm:
m There is an absence of nuclear pleomorphism or
Pathology increased mitotic activity.
Intercalated Duct Hyperplasia Acinic cells may be incorporated within the prolif-
Most common type of IDL eration and/or also identified at the periphery of
Characterized by unifocal or multifocal (and diffuse) most lesions.
unencapsulated proliferation of small ducts with Myoepithelial cells are consistently present around
minimal intervening stroma merging/blending imper- the ducts but are not discernible by light microscopy
ceptively with acinar and mucous cells of surround- requiring immunohistochemical staining with p63
ing salivary gland parenchyma or other markers (e.g., calponin, CK14, others) for
At low magnification appear as irregular pale foci identification.
contrasted with the surrounding darker-appearing Stromal hyalinization that may be periductal can be
salivary gland parenchyma: identified.
826 SECTION 6 Major and Minor Salivary Glands
appearance admixed with irregular hyperplasia- tions may not become apparent until adult life
like areas Presents as painless swelling of the parotid gland
m Give the impression of a transition from Majority are unilateral although bilateral lesions
hyperplastic intercalated ducts to adenomatous may occur.
areas May occasionally be tender or painful, which may
Alternatively may include a completely encapsulated be due to secondary infection
adenoma with separate discrete, hyperplastic foci Rarely, may be associated with facial paralysis
immediately adjacent to the capsule. Histogenesis remains controversial:
m Entrapped irregular ductal structures can be iden- m Suggested to originate from the branchial appa-
tified within capsule of the adenoma. ratus and/or develop from salivary gland inclu-
Clear intercalated duct cells may be present. sions in lymph nodes
Immunohistochemistry m Designation of lymphoepithelial cyst is histologi-
m CK7, S100 protein, estrogen receptor, lysozyme cally accurate and is more appropriate than bran-
positive; progesterone receptor negative chial cleft cyst.
m Myoepithelial cells positive for calponin and m Some authors believe that LECs, as well as sali-
A B
C D
the lesion; the latter correlate to the presence of (CD20, others) and T-cell (CD3, others) markers.
the lymphoid component in the cyst wall (see m Absence of Epstein-Barr virus (e.g., in situ hybrid-
Cyst wall composed of an abundant mature lym- through the epithelial component
phoid cell proliferation with readily identifiable ger- Cystic LESA lack features that can be seen in
minal centers LECs, including mucous (goblet) cells.
828 SECTION 6 Major and Minor Salivary Glands
m HIV-salivary gland disease (see later in this Approximately 85% occur in the parotid gland with
chapter): 10% in submandibular gland; remainder in various
Histology of LECs is similar to cystic lympho- other salivary gland sites.
epithelial lesions in HIV-associated salivary Obstructive changes that may result in the develop-
gland disease. ment of the salivary duct cyst include neoplasms,
Absence of features that might suggest postinflammatory strictures, calculi, and mucus
associated with HIV infection including plugs.
absence of:
Florid follicular hyperplasia Pathology
Multinuleated giant cells Gross
Lymphoepithelial cell islands Well-circumscribed and are usually uniloculated con-
Presence of p24 immunoreactivity in HIV- taining thin, watery, to viscous brown fluid
associated lesions Majority are 1 to 3cm, although may reach as large
Marked decrease in interfollicular CD4:CD8 as 10cm.
ratio observed in HIV+ compared with the HIV
negative cases Histology
Among the cystic neoplasms of the parotid that Sharply demarcated from the adjacent salivary gland
LECs may be confused with is Warthin tumor and parenchyma
cystic mucoepidermoid carcinoma (cystic MEC): Epithelium lining of the cysts may be single or mul-
m In contrast to Warthin tumor, LECs are unilocu- tilayered cuboidal, columnar, or squamous epithe-
lar, lack papillary architecture, and lack an epi- lium; mucus-containing goblet cells and oncocytic
thelial cell component with oncocytic cytoplasmic metaplasia may be seen.
changes. Cyst wall is composed of collagenized connective
m Cystic MECs are usually low-grade malignancies tissue of varying thickness.
characterized by the presence of an admixture of Sparse to minimal chronic inflammatory cell infil-
mucous cells, epidermoid cells, and intermediate trate can be present.
cells. Granulomatous inflammation may be present in the
These three cell types are absent in LEC. cyst wall and in the adjacent gland.
Further, MECs tend to be infiltrative neo- Adjacent salivary gland parenchyma may show duct
plasms, a feature that is not present in LECs. ectasia with inspissated secretions and chronic
Confusion with metastatic cystic squamous cell car- inflammation.
cinoma may occur, but LECs lack the cytologic
atypia and increased mitotic activity usually seen in Differential Diagnosis
metastatic cystic squamous cell carcinoma. Lymphoepithelial cyst:
m Marked inflammatory cell component typically
A B
C D
Polycystic (Dysgenetic) Women are almost always affected and the majority
of cases occur in childhood although patients range
Disease (Fig. 19-12) in age from the first to the seventh decade of life.
Definition: Rare developmental abnormality of the sali- Most patients have bilateral gland involvement, but
vary gland duct system histologically similar to polycys- occasionally only a single gland is involved.
tic diseases of other organs (e.g., kidney, liver, pancreas, The clinical presentation includes recurrent, painless
and lungs). swelling with abnormalities in the flow of saliva.
Based on a single case of familial occurrence, an
Clinical autosomal dominant mode of transmission has been
Polycystic disease represents approximately 0.2% of suggested.
benign salivary gland cysts with less than 20 cases
reported in the world literature. Pathology
The overwhelming majority of the reported cases Cytology
involve the parotid gland with rare involvement of Aspirate smears characterized by relatively clean
the submandibular gland. background, in which are distributed histiocytes, red
A B
C D
moid carcinoma, including mucous cells, epider- firm, raised vesicles with a blue or green appear-
moid cells, and intermediate assist in excluding a ance measuring in size from a few millimeters to
diagnosis of mucoepidermoid carcinoma. several centimeters.
832 SECTION 6 Major and Minor Salivary Glands
Differential Diagnosis
Diagnosis is usually straightforward and given the
absence of epithelial lining essentially excludes all
epithelial-lined cystic lesions (non-neoplastic and
neoplastic).
Clinical
Relatively uncommon
Tend to be slightly more common in men than in
women; occur over a wide age range but most often
B occur in the sixth to eighth decades of life
May occur in minor and major salivary glands but
most common site of occurrence is the floor of
Fig. 19-13. Mucus extravasation phenomenon. mouth, buccal mucosa, and the lips
A, B, Mucus extravasation phenomenon of the lip appearing Usually slow-growing and painless, appearing as a
as superficial raised vesicles with a bluish appearance. circumscribed and often fluctuant swelling; rarely,
associated pain or a burning sensation may be
present.
Deeper-seated lesions are movable, firm, nodular,
m Exact classification is subject of some debate:
and covered by normal-appearing mucosa. m Some classify this lesion with the more common
Characterized by extravasation of mucus into adja- ings, there is justification for separating these
cent tissue intermixed with granulation tissue and entities.
inflammatory cells:
m Lined by granulation tissue
Pathology
m Inflammatory cells may include numerous foamy Gross
histiocytes. Superficial lesions appear vesicular and bluish;
Associated minor salivary glands show variable deeper situated lesions are nodular and have the
degree of atrophy, ductal dilatation, fibrosis, and a same color as the associated soft tissue.
chronic inflammatory cell infiltrate.
Overlying epithelium of the involved site is intact Histology
and often thinned. Cysts usually unilocular but may be convoluted sim-
Histochemistry: ulating a multilocular or multicystic pattern
m Intraluminal and intramural mucus material True epithelial lined cysts:
is mucicarmine and diastase-resistant, PAS m Typically, epithelial lining consists of a uniform
A C
D E
A
Fig. 19-16. Simple ranula.
Simple ranula identified as a large, fluid-filled mass in the
lateral aspect of the floor of the mouth.
Clinical
B Rare as compared with the mucus escape phenom-
enon (extravasation mucocele)
No gender predilection; may affect any age group
Fig. 19-15. Mucus retention cyst. Most commonly a unilateral lesion but may be
A, Unilocular mucin-filled submucosal cyst. B, Cyst has an bilateral
epithelial lining composed of a uniform layer of cuboidal Cause considered similar to usual mucocele.
nonkeratinizing squamous epithelium. Ranulas are divided into two types:
m Simple ranula:
Histology
May be a unilocular or multilocular cystic lesion
Often associated with an epithelial lining; the
latter including squamous, cuboidal, or columnar
cells
Cysts contain amorphous eosinophilic material.
Differential Diagnosis
Epidermoid cyst A
Pleomorphic adenoma
Lipoma
NOTE: The histologic findings relative to all of the
above-listed lesions readily differentiate these entities
from a simple ranula.
Pathology
Histology
Appear as pools of mucus surrounded by fibrous
tissue, chronic inflammatory cells, including
histiocytes B
Associated epithelial lining is not seen.
Mucicarmine and PAS with diastase staining helpful Fig. 19-17. Plunging ranula.
in identifying extravasated material as mucus
Plunging ranula in which there is herniation from the floor
Differential Diagnosis of the mouth through the mylohyoid muscle with a
painless mass in (A) the submandibular area and (B) in the
Epidermoid cyst submental area.
Thyroglossal duct cyst
Cystic hygroma
Branchial cleft cysts
NOTE: The histologic findings and anatomic localiza-
tion relative to all of the above-listed lesions readily
differentiates these entities from a plunging ranula.
836 SECTION 6 Major and Minor Salivary Glands
Failure to include resection of the salivary gland rus, adenovirus, cryptococcus, and histoplasmo-
results in recurrence. sis may secondarily infect the salivary glands of
immunocompromised patients:
CMV sialadenitis may occur in the immune-
INFECTIOUS, INFLAMMATORY, competent patient, too.
AUTOIMMUNE LESIONS OF
SALIVARY GLANDS Mumps (Fig. 19-19)
Definition: Self-limiting illness caused by an RNA virus
Sialadenitis in the Paramyxoviridae family that affects salivary
Definition: Acute, subacute, or chronic inflammation of glands.
salivary glands due to a variety of causes including Synonym: Epidemic parotitis
infectious disease, inflammatory condition, part of a
systemic or localized autoimmune disease, secondary to Clinical
trauma or secondary to stone formation. Acute illness of school-aged children and teenagers;
Sialadenitis may be acute or chronic and result from uncommon in people 20 years of age and older
obstructive or nonobstructive causes. Due to immunization programs that include measles,
Nonobstructive sialadenitides are generally caused mumps, and rubella, mumps is uncommon in the
by an infectious agent and are divided into acute and United States.
chronic forms. Highly contagious; transmitted by droplet spread of
upper respiratory secretions
After an incubation period of around 16 to 18 days,
Acute Nonobstructive disease onset includes a prodrome of fever, headache,
(Infectious) Sialadenitis malaise, and nausea followed by painful, rapid swell-
ing of one or both parotid glands over a 1- to 3-day
Clinical period:
Infections of salivary glands may occur in a previ- m Pain is potentiated by foods that stimulate saliva-
ously healthy gland or may result from a decrease in tion, including citrus fruits or other sour liquids.
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 837
Pathology Clinical
Histologic findings include presence of a marked Include HIV-infected individuals with xerostomia,
lymphoplasmacytic cell infiltrate in periductal and enlargement of one or more major salivary glands,
periacinar tissues, as well as hemorrhage and or both of the above
necrosis. May represent the initial manifestations of HIV
Viral inclusions are not identified. infection
Exact incidence of salivary gland enlargement in
Treatment and Prognosis HIV-infected individuals is not known but has been
Self-limiting infection and treatment is symptomatic. considered to be about 5% of adult patients.
838 SECTION 6 Major and Minor Salivary Glands
Serology evaluation will confirm HIV positivity. infection characterized by persistent circulating
m Serologic markers that are present in Sjgren syn- CD8+ lymphocytosis accompanied by visceral
drome, including polyclonal hypergammaglobu- lymphocytic infiltration
linemia and production of organ-specific Primarily characterized by parotid gland
autoantibodies (anti-salivary duct antibodies, enlargement, sicca symptoms, and pulmonary
autoantibodies), nonorgan-specific (rheumatoid involvement occurs in HIV infection
factor, Anti-Nuclear Antibodies [ANA], anti-RO Appears to be an antigen (viral)-driven response
[SS-A], anti-LA [SS-B]) are commonly absent in Associated with CD8 lymphocytosis and the
HIV-SGD. presence of HLA-DR5 and appears to be a
CT scan and MRI show unilateral or bilateral mul- genetically determined host immune response
ticentric cysts of varying sizes. to HIV
Sjgren syndromelike illness has also been identi- In DILS, certain HIV-infected individuals
fied in AIDS patients, representing additional evi- develop oligoclonal expansion of CD8+ lym-
dence of the severely damaged immune system in phocytes characterized by a persistent circulat-
these patients. ing CD8+ lymphocytosis.
Diffuse infiltrative lymphocytosis syndrome These cells infiltrate multiple organs, but the
(DILS) and HIV-associated CD8+ lymphocytosis salivary glands and the lung constitute the
syndrome: major sites of involvement.
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 839
A A
B B
Cystic Changes
In addition to the lymphoid changes, multiple squa-
mous epithelial-lined cysts and lymphoepithelial
lesions are present.
Squamous epithelial-lined cysts and the lymphoepi-
thelial lesions typically permeated by mature
lymphocytes (typically monocytoid B-cells in epi-
myoepithelial islands)
Lymphoepithelial lesions formed by hyperplasia and
metaplasia of ductal epithelium
Origin of cysts appears to be from the salivary gland
Fig. 19-26. p24 immunoreactivity. (parotid) epithelial structures arising in intraparotid
Immunohistochemical staining against HIV p24 core or periparotid lymph nodes accounting for the lym-
antigen is confirmatory of HIV infection with reactivity (left) phoid component:
within the follicular dendritic cells of the germinal center m Similar cysts can be found in HIV-negative
and (right) multinucleated giant cells representing the patients.
reservoirs for the virus and/or antigen processing cells. Presence of HIV-1 suggests pathogenesis of salivary
gland lymphoepithelial lesions is primarily due to
In contrast to Sjgren syndrome, the greater this virus.
degree of salivary gland enlargement and Histochemistry:
extraglandular disease, including pulmonary, m For the lymphoid changes and the cystic lesions,
renal, gastrointestinal, breast, and muscle, as special stains for microorganisms are negative.
well as the low frequency of autoantibodies Immunohistochemistry:
and differing HLA associations seen in DILS, m Presence of B-cell lineage (e.g., CD20, others) and
serve to distinguish DILS from classic Sjgren T-cell lineage markers (CD3, others)
syndrome. m Epithelial markers (cytokeratins, others) delin-
m Primary treatment anti-HIV therapy eate squamous epithelial-lined cysts and epimyo-
epithelial islands.
Pathology m Immunoreactivity with HIV p24 core antigen can
[SS-A], anti-LA [SS-B]) are commonly absent in is less clear and is due to a category of lesions
HIV-SGD. referred to as chronic recurrent sialadenitis.
Cystic salivary gland neoplasms:
m In general, differentiation from salivary gland
Chronic Nonobstructive
neoplasms (benign and malignant) is straight-
forward because the cellular components that are
Sialadenitis
diagnostic for a given salivary gland neoplasm are Chronic nonobstructive sialadenitis may have spe-
absent in HIV-SGD. cific causes, including granulomatous sialadenitis
Malignant lymphomas: (infectious and noninfectious) or irradiation.
m Differentiation from malignant lymphoma is Sialadenitis secondary to radioactive iodine therapy
predicated on the presence of a heterogenous cell for thyroid carcinoma is common.
population and correlating IHC reactivity for B- Granulomatous inflammation of the salivary glands
and T-cells, as well as the absence of a monomor- most often is caused by duct obstruction (e.g.,
phic cell population, absence of cytologically calculi, carcinoma), resulting in extravasation of the
malignant cells, and absence of clonal cell popu- obstructed duct content into the salivary gland
lation by immunohistochemical and/or molecular parenchyma causing a foreign body granulomatous
diagnostic modes of evaluation. inflammatory reaction.
Granulomatous sialadenitis due to an infectious
cause is less common and is caused by a number of
Treatment and Prognosis diseases including (but not limited to) tuberculosis,
Treatment for HIV-SGD varies and includes actinomycosis, and cat-scratch disease.
surgical resection (parotidectomy, conservative Sarcoidosis is yet another cause of granulomatous
excision, curettage), radiation, and symptomatic sialadenitis associated with chronic nonobstructive
relief. sialadenitis (see later).
Highly active antiretroviral treatment (HAART) Granulomatous sialadenitis may occur as an isolated
has been shown to reduce the size of parotid phenomenon but is more commonly seen as part of
swellings and even result in regression of a systemic process; such a phenomenon may be seen
HIV-SGD: in association with sarcoidosis, cystic fibrosis, and
m Successful outcome reflected in diminution of Crohn disease.
viral load and to some degree of immune
restoration.
m Parotid gland involvement does not appear to
Sarcoidosis of Salivary
play any role in the course of the disease or pro-
gression to AIDS.
Glands (Fig. 19-27)
Prevalence of DILS had significantly decreased in the Definition: Sarcoidosis is a multisystem chronic (nonca-
post-HAART era, suggesting that DILS is an antigen seating) granulomatous disease of unknown cause that
(viral)-driven response and the primary treatment for affects a variety of sites, including (but not limited
it is anti-HIV therapy. to) lymph nodes, lungs, mucosal sites of the upper
HIV-SGD is benign but hematologic malignancies aerodigestive tract, salivary glands, skin, spleen, and
may occur in association with the HIV-SGD or liver.
develop subsequently: Synonym: Boeck disease
m Polymorphic B-cell lymphoproliferative disorders
ized by the parotitis, xerostomia, uveitis, and facial Gomori methenamine silver (GMS) and acid-fast
nerve palsy. bacilli (AFB), are negative.
m Parotid gland sarcoidosis:
Other granulomatous disease, primarily of infectious For a more complete discussion, including histopath-
cause, such as mycobacterial infection and fungal ologic features and illustrations, see Section 1, Sino-
infection: nasal Tract.
m Identification of microorganisms by special stains, Often a nodal-based proliferation occurring as part
microbiologic cultures, and/or molecular analysis of a generalized process involving lymph nodes;
allows for differentiation. SHML involve extranodal sites independent of the
Noncaseating granulomas unrelated to an infectious lymph node status
cause can be seen in association with rheumatoid Head and neck region represents one of the more
arthritis (rheumatoid nodule) and as a reactive common extranodal areas affected by SHML:
process in tissues (e.g., lymph nodes) adjacent to m Within the head and neck, there is predilection
malignancies; detailed clinical history should allow for the nasal cavity and paranasal sinuses.
for differentiating these lesions from sarcoidosis. m Virtually all head and neck sites may be affected
and xerostomia) suggesting a clinical diagnosis of may occur in association with other extranodal
Sjgren syndrome (SS): head and neck sites involved by SHML or occurs
In contrast to patients with sarcoidosis, patients independent of other sites of involvement.
with SS present more frequently with Raynaud Salivary gland involvement:
phenomenon, more often have autoantibodies, m No gender predilection
and minor salivary gland biopsy (MSGB) m Occurs over a wide age range
shows focal sialadenitis in the majority of the Parotid gland and submandibular glands are most
patients. often affected; lacrimal glands may also be involved.
Patients with sarcoidosis more frequently have Patients with salivary gland involvement present
parotid gland enlargement, mainly have pul- with a discrete, painless mass, which clinically may
monary and cutaneous involvement, lack auto- suggest a primary salivary gland tumor.
antibodies, and histopathologic findings of SHML may occur in association with HIV-infected
MSGB may show noncaseating granulomas. patients, Sjgren syndrome, and amyloidosis; SHML
In cases in which there are equivocal findings co-existing with Langerhans cell histiocytosis has
by MSGB, transbronchial lung biopsy may be also been reported.
required and the presence of noncaseating Salivary gland lesions are polypoid, nodular, or
granulomas is diagnostic of sarcoidosis. exophytic growths with a tan-white to yellow
appearance.
Treatment and Prognosis No ideal treatment:
Clinical course in the majority of patients is benign, m Treatment protocols should mirror the clinical
and spontaneous remission may occur within 2 years manifestations such that a range of therapeutic
of the diagnosis. modalities may be used.
Treatment for systemic sarcoidosis in which there is Transformation to a high-grade lymphoma may
extensive disease or disease that compromises normal rarely occur.
function can be by corticosteroid therapy.
Prognosis for systemic disease is generally good, with
up to 70% of patients improving or remaining stable
Chronic Obstructive Sialadenitis
after therapy. Most common cause of obstructive or occlusive sial-
Advanced multisystem disease leading to extensive adenitis is stone formation referred to as sialolithia-
pulmonary involvement and respiratory failure may sis (see later); less common causes of chronic
occur but is seen in only a small percentage of cases. obstructive sialadenitis include:
Less than 10% of patients die of pulmonary, cardiac, m Stenosis, stricture
m Ascending infections
Extranodal Sinus Histiocytosis with m Kussmaul disease (fibromucinous plugs in the col-
Idiopathic, histiocytic proliferative disorder that In children, mumps (see earlier) is a common cause
usually resolves spontaneously of sialadenitis; less common, children may also suffer
Synonyms: Rosai-Dorfman disease, Destombes- from recurrent parotitis, the cause of which remains
Rosai-Dorfman syndrome uncertain, characterized by:
844 SECTION 6 Major and Minor Salivary Glands
vary glands but are particularly common in the sub- Larger than those of the parotid gland, produc-
mandibular gland (Wharton duct), accounting for ing recurrent episodes of pain and swelling
80% to 90% of cases, and parotid gland (Stensen usually in association with meals
duct), accounting for 10% to 20% of cases: May be associated with sore throat or pharyn-
m Greater involvement of the submandibular gland gitis refractory to antibiotic therapy
is thought to be due to the higher mucin content m Parotid gland calculi are:
of its saliva with more adherent properties. Usually smaller than those of the submandibu-
m Sublingual or minor salivary glands are rarely lar gland
affected. May function as a ball-valve effect, producing
m Involvement of minor salivary glands usually intermittent obstruction and symptoms; the
includes the upper lip and buccal mucosa. latter include pain and swelling
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 845
A B
C D
If obstruction is not relieved, stasis of saliva ensues, material; stone development has no correlation to
potentially resulting in an associated bacterial infec- the serum calcium or phosphorus levels.
tion (most often due to Streptococcus viridans), Radiographic analysis represents the most reliable
manifested by expression from the ducts of mucopu- means to detect the presence of calculi:
rulent material (pus). m Majority of calculi are radiopaque and can be
location, calculi within Stenson duct are often not and may require special oblique views of the
palpable. cheek for visualization.
Calculi are formed by deposition of calcium phos- m Sialography may be of assistance but is often
phate and an organic matrix made up of various unnecessary, yielding limited additional informa-
amino acids and carbohydrates around a central tion and being a potential source of inducing an
nidus thought to be either bacteria or inorganic infection.
846 SECTION 6 Major and Minor Salivary Glands
Histology
Calculi may be seen within the parenchyma or in
the ducts as concentric laminations of calcification
peripherally surrounded by compressed epithelium.
Ductal epithelium may demonstrate mucous cell,
squamous, or oncocytic metaplasia.
A With chronicity of disease, parenchymal changes
may include fibrosis, parenchymal atrophy with loss
of acini, chronic inflammation, ductal dilatation, and
scarring.
Treatment directed toward treating the underlying Extra-pancreatic manifestations (e.g., scle-
which likely cause progressive fibrosis and organ Synonyms: Kttner tumor, punctate parotitis
damage m Mikulicz disease (MD):
Sclerosing mucoepidermoid carcinoma, see m Rarely multiple glands (major and minor) may be
include (but not necessarily limited to): m Antibodies associated with Sjgren syndrome
Ear, soft tissue, lymph nodes (e.g., anti-SSA, anti-SSB) are absent in IgG4-
Lacrimal gland associated sialadenitis.
m Serum ANCA and proteinase 3 levels are not
A B
C D
Histology
Histopathologic features of IgG4-related sialadenitis
include:
m Preservation of lobular architecture
A m Acinar atrophy
Immunohistochemical staining of the plasma cells includes cal diagnosis of IgG4-related disease:
(A) IgG4+ plasma cells and (B) IgG+ plasma cells. There Particularly applies to cases without elevated
is an IgG4+/IgG+ plasma cell ratio of >40% that in concentration of serum IgG4
conjunction with the light microscopic pathologic Strongly recommended even in straightforward
findings is confirmatory of the diagnosis of IgG4-related cases as it is a simple, highly reproducible test
sialadenitis. that provides strong confirmatory evidence for
the diagnosis.
Appropriate cutoff number of IgG4+ plasma
cells varies per organ and for salivary and
strongly suggest the diagnosis of CSS and obviate the lacrimal glands >100 per high-power field in
need of surgical intervention. conjunction with light microscopic features
FNAB findings include paucicellular to moderately considered highly suggestive for diagnosis
cellular aspirate characterized by the presence of Abundant IgG4-bearing plasma cells virtually
scattered tubular ductal structures often enveloped always present in inflamed lobules, interlobular
by collagen bundles or lymphoplasmacytic infiltrate, septae, and occasionally in germinal centers
isolated fragments of fibrous stroma, a background IgG4+ plasma cell count alone may not help to
rich in lymphoid cells, and paucity or absence of distinguish between IgG4-related disease and
acini. disorders that are not part of that disease
spectrum:
Gross Some inflammatory lesions not IgG4-related
Well-defined to circumscribed lesion involving a vari- disease associated with high numbers of
able proportion of affected gland or may involve IgG4+ plasma cells per high power field
entire affected gland (HPF) owing to abundance of plasma cells
852 SECTION 6 Major and Minor Salivary Glands
than IgG4+ plasma cell counts in establishing leads to rapid clinical and histologic improve-
diagnosis: ment accompanied by swift declines in serum
IgG4+/IgG+ plasma cell ratio on immunostain- IgG4 concentrations.
ing widely used to assess preferential shift to Rarely, extranodal marginal zone B-cell lymphoma
IgG4 production in affected sites (MALT) of salivary gland and salivary duct carci-
An IgG4+/IgG+ plasma cell ratio of >40% con- noma develop in background of IgG4 sialadenitis.
sidered cutoff value in any organ
In absence of other corroborative findings, a Lymphoepithelial Sialadentitis
IgG4+/IgG+ plasma cell ratio of >40% in and
of itself is not considered sufficient pathologic
(LESA) (Figs. 19-35 through 19-37)
evidence of IgG4-related disease: Definition: Non-neoplastic unilateral or bilateral
Applies particularly to cases with low overall enlargement of major or minor salivary glands, and/or
IgG4 count per HPF, in which there may be lacrimal glands associated with or occurring indepen-
a shift of >40% but pathologic diagnosis of dent of an autoimmune disease, and characterized by
IgG4-related disease is untenable in absence specific histopathologic findings.
of classic histopathologic features and a com- Synonyms: Benign lymphoepithelial lesions (BLEL);
patible clinical picture. myoepithelial sialadenitis (MESA); immune sialadenitis;
A variety of nonIgG4-related disease enti- Godwin tumor; Godwin lesion
ties can have IgG4+/IgG+ plasma cell ratios
of >40% including conditions sometimes Introduction
associated with elevated serum interleukin- Designation of benign lymphoepithelial lesion
6 (IL-6) concentrations (e.g., multicentric (BLEL) initially coined in 1933
Castleman disease, rheumatoid arthritis and Distinctive morphologic changes associated with
other immune-mediated conditions some- BLEL have been referred to by a variety of terms and
times occur with abundant IgG4+ plasma clinical settings
cells within tissue [IgG4+/IgG+ plasma cell Morphologic changes include the presence of lym-
ratio >40%] and elevated serum IgG4 phoepithelial islands or lesions:
concentrations) m Previously referred to as epimyoepithelial
m Plasma cells: islands
CD138 positive m Believed to be composed of ductal and myoepi-
Polytypic kappa and lambda light chain thelial cells resulting in replacement of the
by immunohistochemistry and/or in situ term BLEL with myoepithelial sialadenitis
hybridization (MESA)
m Additional findings: m Myoepithelial component has not been affirmed;
CD3+ interfollicular T-cells present especially hence the change in terminology to lymphoepi-
in association with ducts and acini thelial sialadenitis (LESA) and for the character-
CD20+ B-cells mostly restricted to lymphoid istic cell islands to be called lymphoepithelial
follicles islands or lesions.
Follicles express bcl6 and negative for bcl2 Morphologic changes of LESA are distinctive but
Cytogenetics and molecular genetics not pathognomonic and may be identified in a variety
m Immunoglobulin heavy chain includes polyclonal of salivary gland non-neoplastic and neoplastic
rearrangement in the majority of cases. lesions (Box 19-2), arguably most common in Sjgren
syndrome
Differential Diagnosis
Chronic sialadenitis, not otherwise specified
Sialolithiasis
Sjgren syndrome BOX 19-2 Occurrence of Lymphoepithelial Lesions
Lymphoepithelial sialadenitis (LESA) in Salivary Gland Diseases
Sarcoidosis
Sialolithiasis
Malignant lymphoma Sialadenitis (infectious and noninfectious)
Lymphoepithelial sialadenitis (LESA)
Treatment and Prognosis Sjgren syndrome and other connective tissue disorders
Excellent response to immunosuppression (e.g., HIV-associated disease (benign lymphoepithelial cysts)
Lymphoma
glucocorticoids, rituximab):
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 853
Clinical
More common in women than men (3:1); most
common in the fourth to seventh decades of life
Primarily affects parotid gland (80% to 85%) and
submandibular gland (10% to 15%)
Presentation includes unilateral diffuse and firm
swelling of involved glands:
m Approximately 20% may be bilateral
(MALT) type
Pathology
Histology
A Lymphoid infiltrate with follicular hyperplasia
surrounding and infiltrating salivary ducts with
parenchymal atrophy, disorganization and prolifera-
tion of the ductal epithelial cells to form the lympho-
epithelial lesions, the characteristic finding in LESA:
m General solid, cystic alterations of lymphoepithe-
A B
C D
Interfollicular regions show small lymphocytes, scat- Lymphoepithelial lesions contain lymphoid cells of
tered immunoblasts, and variable numbers of plasma B-cell lineage:
cells but not in broad sheets: m Evidence of clonality has been identified in these
m Polyclonal (interfollicular) lymphoid infiltrate is B-cell lymphocytes but in these examples there
predominantly of T-cells. typically is:
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 855
Cytokeratins positive
Molecular biology:
m Lymphoid infiltrates may reveal heavy- and light-
Differential Diagnosis
Most important differential diagnosis of LESA is
malignant lymphoma:
m Lymphomas of the major salivary glands may or
cytokeratin positive. B, CD45 reactivity is present in the Collars of monocytoid B-cells characterized by
lymphoid component surrounding and within the monomorphic, medium-sized cells with abun-
lymphoepithelial lesion. C, Lymphoid cell infiltrate shows dant, pale cytoplasm and bland, uniform
immunoreactivity for the B-cell marker CD20 and (D) T-cell nuclei, and distinct cell membranes around and
marker CD3.
infiltrating within salivary ducts forming lym-
phoepithelial lesions:
Represents the strongest clue to diagnosis of
In later stages of disease, plasma cells are more B-cells show aberrant coexpression of CD43
m Interstitial nephritis
m Atrophic gastritis
Sjgren Syndrome (SS) m Hepatobiliary diseases
thelia in multiple organs with associated dry eyes (kera- Symptoms may occur with or without autoimmune
toconjunctivitis sicca) due to lacrimal gland involvement or connective tissue disease:
and dry mouth (xerostomia) due to salivary gland m In relationship to connective tissue diseases, asso-
sicca) also had polyarthritis, dry mouth, and ele- egories, including those with a connective tissue
vated ESR. disease and those without connective tissue
Clinical syndrome is now referred to as Sjgren disease; the latter category referred to as sicca
syndrome (SS). syndrome.
Virtually all patients who fit the clinical defini- Primary or limited form of Sjgren syndrome
tion of SS have LESA; however, only 50% of occurs in the absence of another connective
patients with LESA have SS. tissue disease.
Secondary or complete form of Sjgren syn-
Clinical drome includes the presence of another connec-
Overwhelming majority of patients are women rep- tive tissue disease.
resenting from 80% to 90% of all cases. m Association with other diseases includes (but not
For women, median age is in the sixth decade; for limited to):
men median age is in the fifth decade: Autoimmune thyroiditis
m Rarely occurs in children Atrophic gastritis
Patients usually present with firm swelling of the Celiac disease
affected gland with or without pain. Inflammatory bowel disease
Lesions may be unilateral, bilateral, or there may be Primary biliary cirrhosis
successive enlargement of salivary and/or lacrimal Sinus histiocytosis with massive lymphade
glands. nopathy
Affected gland may be diffusely or focally (nodular) Despite the availability of many new imaging proce-
enlarged. dures, sialography has maintained its status as the
In order of occurrence, the parotid is primarily imaging procedure of choice for evaluating SS:
affected (83%), followed by the submandibular m Sialograms may show four different gradations of
gland (11%), and then other sites (6%): sialectasia, including punctate, globular, cavitary,
m Minor salivary gland involvement is considered and destructive.
uncommon. m Diagnostic accuracy of sialography is very high,
suring and papillary atrophy. applied between eyeball and lateral inferior eyelid
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 857
cornea and 0 to 3 score for lissamine green stain- grade of minor salivary gland biopsy.
ing of both the nasal and temporal bulbar con- m Patients with SS have altered immunoregulation:
BOX 19-4 Revised Rules for Classification of SS BOX 19-5 American College of Rheumatology (ACR)
Proposed Classification for SS (2012)
Primary SS
1. The presence of any four of the six items listed in Box Applies to individuals with signs/symptoms that may be
19-3 as long as either the histopathology (item IV) or suggestive of SS, will be met in patients who have at least
serology (item VI) is positive two of the following three objective features:
2. The presence of any three of the four objective criteria 1. Positive serum anti-SSA/Ro and/or anti-SSB/La or
items (i.e., III, IV, V, VI) (positive rheumatoid factor and ANA titer 1:320)
3. The classification tree procedure represents a valid 2. Labial salivary gland biopsy exhibiting focal lymphocytic
method for classification, although it should be more sialadenitis with a focus score 1 focus/4mm2
properly used in clinical-epidemiologic survey 3. Keratoconjunctivitis sicca with ocular staining score 3
(assuming that individual is not currently using daily eye
Secondary SS drops for glaucoma and has not had corneal surgery or
In patients with a potentially associated disease such as cosmetic eyelid surgery in the last 5 years)
another well-defined connective tissue disease, the presence Prior diagnosis of any of the following conditions would
of items I or II (listed in Box 19-3) plus any two from among exclude participation in SS studies or therapeutic trials
items III, IV, V (listed in Box 19-3) may be considered as because of overlapping clinical features or interference with
indicative of secondary SS criteria tests:
Exclusionary Criteria History of head and neck radiation treatment
Past head and neck radiation treatment Hepatitis C infection
Hepatitis C infection Acquired immunodeficiency syndrome
AIDS Sarcoidosis
Pre-existing lymphoma Amyloidosis
Sarcoidosis Graft versus host disease
Graft versus host disease IgG4-related disease
Use of anticholinergic drugs
SS, Sjgren syndrome.
Modified from Vitali C etal: European study group on From Shiboski SC etal: American College of Rheumatology
classification criteria for Sjgrens syndrome. Classification classification criteria for Sjgrens syndrome: a data-driven,
criteria for Sjgrens syndrome: a revised version of the expert consensus approach in the Sjgrens International
European criteria proposed by the American-European Collaborative Clinical Alliance cohort, Arthritis Care Res
Consensus Group, Ann Rheum Dis 61:554-558, 2002, Table 3. (Hoboken) 64(4):475-87, 2012, Table 7.
rules for classification, including exclusionary cri- potential therapeutic use of biologic agents in SS
teria (Box 19-4). showed:
In 2012 American College of Rheumatology Sensitivity and specificity of ACR criteria in
(ACR) criteria for Sjgren syndrome (SS) proposed diagnosing SS reported to be 90.37% and
(Box 19-5): 88.46%, respectively
m Need for new classification criteria based on Sensitivity of ACR criteria in diagnosing SS
apparent lack of standardization inherent to patients with and without labial biopsy
older criteria in the field and emergence of bio- reported to be 88.75% and 93.67 %, respec-
logic agents as potential treatments tively, with specificities of 88.89% and 88.37%,
m Also authors felt diagnosis must rely upon respectively
well-established objective tests clearly associated Most sensitive item adopted in ACR criteria
with systemic/autoimmune, oral, and ocular reported to be ocular staining score with sen-
characteristics of disease, and include alternate sitivity of 85.77%
tests only when they are diagnostically Most specific item was the labial salivary gland
equivalent. biopsy with a specificity of 88.89%.
Subsequent concordant studies of AECG and ACR Sensitivity and specificity of ACR criteria in
classification criteria yielded concordant results in diagnosing patients with SS relatively high and
majority of cases, and gene expression profiling sug- may serve as the diagnosis criteria in research
gests that patients meeting either set of criteria are and clinical practice.
more similar to other SS participants than to healthy ACR criteria must be validated.
controls: Cause
m No clear evidence for increased value of new m Remains unknown
ACR criteria over old AECG criteria from clinical m Likely causes are multifactorial
m More recent studies based exclusively on objec- mal response to one or more unidentified
tive tests, stringency of AECG criteria, and antigens:
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 859
studies suggesting a link between viral infection Labial Biopsy (Fig. 19-38)
and SS. Minor salivary glands may demonstrate histologic
m Genetic predisposition has been suggested on the alterations in patients with SS indicative of changes
basis of familial aggregation, animal models, and seen in major glands; as a result of these findings as
candidate gene association studies. well as ease of access a diagnostic tool in patients
A B
C D
suspected of having SS is the labial salivary gland m Controversy surrounds role of viruses such as
biopsy: EBV, HHV-8, T-lymphotropic virus-1, and hepa-
m Focus Score established in which foci contain- titis C virus in lymphomatous transformation in
ing 50 or more lymphocytes are counted setting of SS, but viruses have not definitively
2
m Focus scores greater than 1 focus/4mm support been found to play a role in lymphomatous
diagnosis of the salivary component of SS. transformation.
m An adequate biopsy specimen for histologic m Predictors for lymphoma development in SS
assessment and lymphocytic infiltrate grading remain to be definitively determined but may cor-
must include the following: relate to:
Specimen is taken from below clinically normal Recurrent or permanent swelling of major sali-
mucosa. vary glands
Sample includes at least five glands that are Lymphadenopathy, cryoglobulinemia, spleno-
separated from their surrounding connective megaly
tissue. Low complement levels of C4 and C3
Nonspecific chronic sialadenitis has been ruled Lymphopenia
out. Skin vasculitis or palpable purpura
Lacrimal gland biopsies may have more evident his- M-component in serum or urine
topathologic findings for SS than labial salivary Peripheral neuropathy, glomerulonephritis,
gland biopsies and recommendations include that and elevated beta2-microglobulin
labial salivary gland and lacrimal gland biopsies Additional factors may relate to
be performed in patients with suspected SS to Genetic factors, CD4 lymphocytopenia, and
reduce false-negative results and improve diagnostic ectopic germinal center-like structures in
accuracy. minor SG biopsies
Comparison of labial biopsies versus parotid gland Malignant transformation of a benign lymphoepi-
biopsies has shown that parotid gland biopsy adds thelial lesion to a malignant epithelial neoplasm
very little to the minor salivary gland biopsy in the (malignant lymphoepithelial lesion) occurs much less
diagnosis of primary SS, but that parotid inflamma- frequently than transformation to lymphoma:
tory changes may reflect disease duration and/or m Although lymphoepithelial carcinomas of sali-
long-term symptomatic treatment. thelial lesion except for the presence of a malig-
Patients with sicca symptoms involving the eyes and nant epithelial component instead of a benign
the mouth usually do not progress, but development epithelial component.
of (new) extraglandular manifestations occurs in m Increased incidence among Eskimos
most of SS patients over a 10- to 20-year follow-up m More common in men than in women; most fre-
manifestation, the therapeutic approach is similar to frequent site of occurrence; among Asians, the
systemic lupus erythematosus, although these thera- submandibular gland is most often involved.
pies have relatively little effect on tear or saliva flow. m Histologic picture of carcinomatous component
Risk of developing a malignant lymphoma in patients ranges from low to high grade.
with SS is markedly increased: m Some evidence linking Epstein-Barr virus (EBV)
m Estimated risk to be 44 fold with this neoplasm but there is equal evidence
m Majority (80%) are extranodal marginal zone showing an absence of EBV DNA in these
(MALT) type. neoplasms
More common in those patients with only sicca
components of syndrome FURTHER READING
m Predisposing factor to development of lymphoma
probably relates to prolonged immunologic and References may be accessed online at ExpertConsult
lymphoid hyperactivity .com.
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