CH 19 Non-Neoplastic Diseases of Salivary Glands

Chapter
19
Non-Neoplastic Diseases of
Salivary Glands
CLASSIFICATION OF NON-NEOPLASTIC SALIVARY

GLAND LESIONS
BOX 19-1 Classification of Non-Neoplastic Salivary Gland Lesions
Developmental Lesions Infectious, Inflammatory, and Autoimmune Disease

Heterotopias Bacterial sialadenitis
Mumps
Hyperplasia and Metaplasia HIV salivary gland disease
Adenomatoid hyperplasia Chronic sialadenitis
Squamous metaplasia Nonobstructive
Necrotizing sialometaplasia Infectious
Oncocytic changes (oncocytic metaplasia, oncocytosis) Noninfectious
Intercalated duct lesions (intercalated duct hyperplasia; Obstructive
[intercalated duct adenoma]) Sialolithiasis
True Cysts Sialadenosis
Lymphoepithelial cyst IgG4-related sialadenitis
Salivary duct cyst Lymphoepithelial sialadenitis
Polycystic (dysgenetic) disease Sjgren syndrome
Nondevelopmental Cysts
Mucus extravasation phenomenon
Mucus retention cyst
Ranulas
Salivary gland tissue has been reported in thyroglos-

DEVELOPMENTAL LESIONS sal duct, capsules of the thyroid gland and parathy-
roid glands, mediastinum, tonsils, and gingiva, as
Heterotopic Salivary Glands well as more distant sites, including the prostate
See Section 7, The Ear and Temporal Bone. gland, vulva, and rectum.
Definition: Salivary gland tissue located in sites other
than those appropriate for the normal anatomic distri-
bution of salivary glands. Heterotopic Salivary Gland Tissue
Synonyms: Ectopic salivary glands; salivary gland
choristoma
in the Lower Neck
Most of these examples occur in the lower antero-
Clinical lateral neck along the medial border of the sterno-
Majority of heterotopic salivary gland tissue occurs cleidomastoid muscle.
in head and neck sites. Most common presenting symptom is a draining
Most common locations include the periparotid sinus on the anterior aspect of the neck along the
lymph nodes, the middle ear, and the lower neck; less medial border of the sternocleidomastoid muscle
frequent sites of occurrence include: near the sternoclavicular joint.
m Upper neck Sinuses drain saliva-like material, usually a very
m External ear (auditory canal), middle ear limited quantity but the amount may increase during
m Intraosseous sites (e.g., mandible) meals.
m Cerebellopontine angle Localized nontender swelling associated with the
m Pituitary gland sinus may be the only complaint.
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-
thelial ductal proliferations

m Benign and malignant salivary gland neoplasms:
Represent primary intranodal neoplasms with

the gland proper being devoid of tumor
A malignancy arising from intranodal salivary
gland tissue:
May present as mass lesion within the
node separate from adjacent major salivary
glands
In the absence of an identifiable primary
neoplasm from an adjacent salivary gland,

these intranodal foci can be considered as
the primary site for the development of the
malignancy.
Heterotopic Salivary Gland Tissue

A in the Middle Ear
See Section 7, The Ear and Temporal Bone.
Heterotopic salivary gland tissue in the middle ear is
discovered in the evaluation of patients for conduc-
tive hearing loss.
Most cases are associated with ossicular abnormali-
ties of the incus and stapes.
Patients range in age from the first to sixth decades
but most are under 21 years of age.
Because the ossicles originate from the first (malleus
and incus) and second (stapes) branchial arch, the
presence of salivary gland tissue is considered a
developmental abnormality involving the branchial
arches.
Heterotopic salivary gland tissue has been seen in
B
association with anomalies that suggest the branchio-
otorenal (BOR) syndrome; in addition, a syndrome
Fig. 19-1. Intranodal parotid parenchyma. including salivary gland choristoma in association
with branchial arch abnormalities, most commonly
A, B, Periparotid lymph node with intranodal salivary gland
the second, as well as abnormalities of the facial
parenchyma composed of all components of salivary gland
parenchyma including serous acini and ducts. This is a nerve, has been identified.
normal and fairly frequent finding in periparotid lymph Salivary gland tissue in the middle ear:
nodes believed to represent entrapment of salivary gland m May extend into the eustachian tube, involve the
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
m Represents an admixture of seromucinous glands m Pleomorphic adenoma, monomorphic adenomas

and adipose tissue; the latter contributes to the (e.g., Warthin tumor), acinic cell adenocarci-
yellow appearance of the tissue noma, mucoepidermoid carcinoma, adenoid
m Recapitulates the acinar arrangement of normal cystic carcinoma, adenocarcinoma not otherwise
salivary glands; ducts may be identified specified, carcinoma ex pleomorphic adenoma,
m Is situated within the submucosa sialoblastoma, others
In general conservative surgical resection is curative;
however, this tissue is slow growing and in conjunc-
tion with potential complications from surgery, par-
Accessory Parotid Gland
ticular to the facial nerve surgical intervention may Represent isolated lobules of parotid gland paren-
not be advised. chyma separated from the main body of the gland
A biopsy may be required to establish a diagnosis. situated along a major salivary duct
Incidence reported up to 56% in an autopsy series
Intraosseous Heterotopic Accessory parotid tissue is spheric or oblong, mea-
suring from 0.5 to 3cm in greatest dimension.
Salivary Gland Tissue m Accessory tissue can be seen anterior to the border
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,
may originate within periparotid nodal salivary

gland parenchyma presenting as a mass separate HYPERPLASIA AND
from adjacent major salivary glands (i.e., parotid METAPLASIA IN THE
gland). SALIVARY GLANDS
m In the absence of an identifiable primary neo-
plasm from an adjacent salivary gland, these Adenomatoid Hyperplasia of

intranodal foci can be considered as the primary
site.
Mucous Salivary Glands (Fig. 19-2)
A wide variety of tumor types occur in salivary gland Definition: Hyperplastic or hamartomatous prolifera-
heterotopia, including (but not limited to): tion of the mucous acini of salivary gland tissue.
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
single cell type (i.e., mucinous acini) should allow

for differentiation from benign and malignant
salivary gland neoplasms.
Treatment and Prognosis

Surgical excision is curative.
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.
Necrotizing Sialometaplasia (NS)

Clinical (Figs. 19-3 through 19-6)
Relatively uncommon lesion that tends to occur Definition: Benign, self-healing (reactive) inflammatory
slightly more often in men than in women process of salivary gland tissue, which clinically and
Occurs in all age groups, although it is more common histologically may be mistaken for a malignant
in adults than in children neoplasm.
Majority of cases involve the hard or soft palates; Synonym: Adenometaplasia
less common sites of occurrence include the retromo-
lar mucosa; involvement of major salivary glands has Clinical
not been reported. Tends to affect men more than women; occurs over
Clinical presentation includes a localized painless a wide age range with the average age of occurrence
mass often discovered during routine dental exami- in the fifth and sixth decades of life
nation; ulceration of the overlying mucosa is not Most commonly involves the intraoral minor sali-
present: vary glands, particularly involving the palate:
m Often mistaken for a salivary gland neoplasm m Major salivary glands, as well as minor salivary
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.
A A
B B
Fig. 19-3. Necrotizing sialometaplasia. Fig. 19-4. Necrotizing sialometaplasia.

A, Necrotizing sialometaplasia (NS) of the palate appearing A, Low magnification shows submucosal lobular necrosis
as a deep, crater-like ulcerative lesion. B, Less commonly of the salivary glands consisting of acinus-sized pools of
NS may appear as a submucosal nodular swelling. mucin with preservation of the lobular architecture; the
surface squamous epithelium is intact. B, At higher
magnification, the metaplastic minor salivary glands show
Larynx may be affected but is a rare site of
m
rounded, smooth borders with bland squamous epithelial
occurrence. cells, uniform nuclei, and abundant eosinophilic cytoplasm
with occasional preservation of ductal lumina; mucous
Most common presenting problem is that of a pain-
cells are not seen.
less ulcerated lesion or a nodular swelling, which is
usually unilateral but may be bilateral:
m May be associated with pain, numbness, or a
burning sensation and dysphagia

m Uncommonly, may present with anesthesia of the sialometaplasia occurred 6 to 8 days after arte-
greater palatine nerves rial ligation.
Pathogenesis: Inciting event is primarily but not exclusively
m Believed to be secondary to trauma and/or an thought to be due to ischemia.
ischemic event with compromise of the vascular May occur de novo unassociated with a traumatic
supply to salivary glands leading to ischemic event or it may occur in association with other non-
necrosis: neoplastic lesions or in association with a neoplasm
Ischemia may be iatrogenically induced after (benign or malignant)
an operative procedures (surgery, postintuba-
tion, postbronchoscopy), anesthesia, or Pathology
radiotherapy. Gross
Mean duration of 18 days from the time of the Typically appears as a deep, crater-like ulcerative
insult to the development of the lesion lesion, measuring from 1 to 3cm:
In experimental studies on rat submandibular m May appear as a submucosal nodular swelling
and sublingual glands, the induction of that may slough, leaving a crater-like ulcer
Fig. 19-5. Necrotizing sialometaplasia.

Left, The features on routine sections are usually
diagnostic but (right) mucin stains may be helpful in
delineating the presence of residual mucous cells.
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
with uniform nuclei and abundant eosinophilic

cytoplasm. Fig. 19-6. Necrotizing sialometaplasia of the
m Preservation of ductal lumina and/or scattered
sinonasal tract.
mucocytes may or may not be identified. A, Presence of lobular necrosis (bottom left and center)
m Lobular architecture is maintained and metaplas- with adjacent metaplastic seromucous glands. B, At higher
tic lobules vary slightly to moderately in size and magnification the metaplastic epithelial cells are atypical
shape, have smooth edges. characterized by the presence of nuclear pleomorphism,
m Metaplastic foci may be surrounded by granula-
hyperchromasia, increased nuclear-to-cytoplasmic ratio and
tion tissue and mixed acute and chronic inflam- individual cell necrosis raising the concern for a possible
diagnosis of squamous cell carcinoma. However, based on
matory reaction.
the overall architectural findings including preservation of
m In some examples, the squamous metaplastic foci
lobular architecture of the minor salivary glands and
may be atypical, including irregular contours of absence of definitive evidence of invasive growth, the
metaplastic lobules with nuclear hyperchromasia, findings support a diagnosis of necrotizing sialometaplasia.
increased nuclear-to-cytoplasmic ratio, dyskera- Long-term follow-up of the patient proved the lesion to be
tosis, and mitoses, suggesting a possible diagnosis benign with no recurrence or progression of disease.
of squamous cell carcinoma:
Preservation of lobular architecture of the
involved minor salivary glands should allow cell-related markers (e.g., p63, calponin,
for differentiation from carcinoma but in any smooth muscle actin) and keratin subtypes in
given example it may be challenging differenti- NS suggested as possible differentiating find-
ating NS from squamous cell carcinoma. ings from squamous cell carcinoma but do not
Low proliferation rate (<10%) by Ki67 unequivocally differentiate NS from squamous
staining and absence of p53 reactivity may cell carcinoma
support a diagnosis of NS but do not unequivo- Necrotic lobules consist of acinus-sized pools of
cally differentiate NS from squamous cell mucin, which may extend into adjacent tissue, elicit-
carcinoma. ing a granulation tissue reaction with associated
Presence of myoepithelial cells along the acute and chronic inflammation:
periphery of the metaplastic lobules as m Necrotic lobules may not be present in all cases
determined by reactivity for myoepithelial so that the designation of sialometaplasia without

necrotizing would be more appropriate in such

a situation. Treatment and Prognosis
With regeneration, mitoses, individual cell necrosis, NS are self-limiting lesions that heal by secondary
enlarged nuclei, and prominent nucleoli can intention:
be seen. m Depending on the size of the lesion, the healing
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
m PEH results when the metaplastic lobules present healing process.

in excretory ducts and merge with surface Recurrences do not usually occur.
epithelium.
This reaction may be so striking, presenting a Subacute Necrotizing
diagnostic nightmare in separation from an
infiltrating squamous cell carcinoma.
Sialadenitis (SANS)
Histochemistry: Nonspecific inflammatory condition of unknown
m Intraluminal and/or intracytoplasmic mucicar- cause affecting oral minor salivary glands:
mine and diastase-resistant, PAS-positive material m Some authorities believe that SANS should not be
may be identified. included within the spectrum of necrotizing sialo-

metaplasia and most likely represents an infec-
Differential Diagnosis (Table 19-1) tious process or perhaps an immune response to
Mucoepidermoid carcinoma an unknown allergen.
Adenosquamous carcinoma m Other authorities believe SANS may represent the
Squamous cell carcinoma early or minimal form of NS.

NOTE: The retention of the overall lobular architec- In either case, SANS most often is characterized by
ture, bland appearance of the squamous nests with a localized palatal swelling, accompanied by an
rounded or smooth edges, and retention of residual abrupt onset of pain.
ductal lumina and mucocytes help in differentiating NS Patients range in age from 15 to 45 years, with a
from the malignant neoplasms listed above. mean age of 21.9 years.
TABLE 19-1 Necrotizing Sialometaplasia: Differential Diagnosis
NS MEC, Low-Grade SCC

Architecture/growth Retention of lobular Cystic and solid; may be Haphazard, infiltrative growth
architecture circumscribed to encapsulated
without invasion or show
infiltrative growth
Cellular components Smooth round to oval nests Admixture of mucous, Nests and cords of squamous
of metaplastic squamous intermediate (basaloid) and cells with irregular outlines and
epithelium with bland epidermoid (squamous) cells; variable amount of cytologic
cytology; may show bland cytology; irregular cell atypia; may entrap residual
residual ductal lumina with nests glands but the tumor itself
mucous cells contains no mucin
Cyst formation Absent Present (prominent Absent
component)
Surface epithelium May show PEH; usually not Uninvolved; not connected Often dysplastic and/or in direct
connected with NS with tumor continuity with the carcinoma;
may be ulcerated
Extravasated mucin May be present May be present Absent
Necrosis of salivary May or may not be present Absent Absent
gland lobules
Inflammation May be prominent May be prominent with mucin May be present; associated
extravasation desmoplasia
Cytogenetics None known CRTC1-MAML2 translocation None known
MEC, Mucoepidermoid carcinoma; NS, necrotizing sialometaplasia; PEH, pseudoepitheliomatous hyperplasia; SCC, squamous cell
carcinoma.
SANS most often affects intraoral sites, including

the hard palate, soft palate, buccal mucosa, and
tonsils.
Lesions typically are nonulcerated swellings, develop
over a short period of time (7 to 10 days), and range
in size from 0.3 to 2.5cm in diameter.
Histopathologic features include:
m Diffuse involvement of minor salivary glands by
lymphocytes, histiocytes, neutrophils, and vari-

ably by eosinophils
m Loss of acinar cells, early acinar cell necrosis sur-
rounded by a dense polymorphous inflammatory

infiltrate, and atrophy of ductal cells
m Squamous metaplasia is not usually seen.
Appears to be a self-limiting process with most A

cases resolving 2 to 3 weeks after biopsy without
recurrences
Main differences between SANS and NS include:
m SANS is usually a smaller-sized lesion than lesions
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 Oncocytoma; oncocytic carcinoma
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.
Oncocytosis (Fig. 19-8)

Oncocytosis (also referred to as oncocytic [adenoma-
tous] hyperplasia) represents a non-neoplastic mass
forming proliferation of oncocytic cells within the
salivary gland.
Typically appear as nodular foci, referred to as nod
ular oncocytic hyperplasia or nodular oncocytosis
Less commonly, may represent a diffuse alteration in
the affected salivary gland referred to as diffuse
oncocytosis
In either nodular or diffuse form may present as a
clinically detectable mass lesion presenting difficul-
ties in differentiation from oncocytoma
Histologically, oncocytotic foci: A
m Include multiple (often two or more) separate
nodules
m Unencapsulated
m Gradual merge with and/or contain residual
(nononcocytic) salivary gland parenchyma,

including ductular epithelium and serous acinar
cells
Such histologic findings assist in differentiating
oncocytosis from oncocytoma, the latter
entirely composed of oncocytes without identi-
fiable residual normal parenchyma.
m May show clear cell change
Differentiation of oncocytosis from oncocytoma

may not be possible due to overlapping histologic
features, and this differentiation may be more of an B
academic than practical issue because treatment
and prognosis are essentially similar (i.e., cured by
excision).
Intercalated Duct Lesions (IDL)

(Fig. 19-9)
Definition: Rare lesions that include hyperplasia,
adenoma, or both (hybrid) that may be a precursor
lesion of salivary gland neoplasms:
m Proposal that IDL may represent precursor lesion
to salivary gland neoplasms based on presence of

small foci of IDL in cases of basal cell adenoma,
epithelial-myoepithelial carcinoma, pleomorphic
adenoma, mucoepidermoid carcinoma, basal cell
C
adenocarcinoma, Warthin tumor, acinic cell car-
cinoma, others
m Role as a precursor lesion not definitively proven Fig. 19-8. Oncocytosis.
Clinical A, Mass-forming oncocytic nodule that is circumscribed

but not encapsulated gradually merging with (arrowheads)
Rare lesion and incorporating (arrows) residual salivary gland
More common in females than in males; occur over parenchyma. Higher magnification shows the (B) absence
a wide age range from second to ninth decades with of a capsule and (C) presence of acini within oncocytic
a mean in the sixth decade cells characterized by the presence of cells with granular
Majority occur in the parotid gland > oral cavity > eosinophilic cytoplasm.
submandibular gland.
A B
C D
Fig. 19-9. Intercalated duct hyperplasia.

A and B, Intraparotid relatively circumscribed but unencapsulated cellular proliferation composed of closely packed ducts
that includes acinar cells along the periphery as well as within the lesion; stromal hyalinization focally around ducts is
present. C, Closely packed ducts and incorporation of acinar cells within and along the periphery of the proliferation.
D, Ducts are lined by cuboidal cells with small round nuclei and eosinophilic cytoplasm. There is an absence of nuclear
pleomorphism or increased mitotic activity; acinar cells characterized by intracytoplasm basophilic (zymogen) granules are
seen.
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.
Other uncommon features may include:

m Perilesional follicular lymphoid hyperplasia
TRUE CYSTS OF MAJOR
m Clear myoepithelial cells SALIVARY GLANDS
m Entrapment of nerve within the lesion (SIALOCYSTS)
m Presence of focal luminal eosinophilic secretions
m Cystic change Most cystic lesions of major salivary glands repre-

m Basal lamina-like material with a cribriform sent cystic neoplasms.
pattern True cysts differ from pseudocysts by the presence of
m Absence of fat cells or intralesional inflammatory an epithelial lining.
infiltrates Most true cysts of major salivary gland arise in the
parotid gland and are divided into three general
Intercalated Duct Adenoma categories:
Presence of discrete, rounded, partially to com m Lymphoepithelial cyst
pletely encapsulated nodules with well-defined m Salivary duct cyst
contours m Polycystic (dysgenetic) disease
m Fibrous capsule may vary in thickness and

may contain entrapped, irregular-appearing Lymphoepithelial Cyst (LEC)
ducts.
(Fig. 19-10)
Composed of intercalated ducts lined by a single
layer of cuboidal to columnar cells with small Definition: Benign true cystic lesion of the parotid gland
round nuclei and eosinophilic to amphophilic of uncertain origin with characteristic histology and
cytoplasm: unrelated to human immunodeficiency virus (HIV)
m There is an absence of nuclear pleomorphism or infection.
increased mitotic activity.
m Minimal intervening stroma present Clinical
Occasionally acinar cells may be interspersed among Uncommon acquired parotid gland cyst
the ductular structures. Slightly more common in men than in women;
occurs over a wide age range including at birth to
Hybrid Intercalated Duct Lesion the eighth decade of life; the average age is in the
Least common type of IDL fifth decade of life
m Partially round, encapsulated adenoma-like m May be present at birth but the clinical manifesta-
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-
CK14 vary duct cysts and dysgenetic or congenital cysts,

arise from salivary ducts and have no relation
Treatment and Prognosis with the branchial apparatus.
No specific treatment required
Given their usual small size typically cured in the Pathology
excision without known untoward biology Gross
More critical issues relative to treatment and prog- Cyst is usually sharply circumscribed, fluctulent and
nosis relate to associated neoplasms some of which unilocular, rubbery to firm ranging in size from 0.5
include malignant salivary gland neoplasms (see to 6cm in greatest dimension
under definition earlier). Multilocular cysts are uncommon.
A B
C D
Fig. 19-10. Parotid gland lymphoepithelial cyst.

A, The cystic proliferation is sharply delineated from the parotid parenchyma (lower left). B and C, Cyst is lined by benign
squamous epithelium and the cyst wall includes a dense lymphoid cell proliferation including germinal centers.
D, Intraepithelial mucous cells (arrow) can be found.
On cut section, small intracystic protrusions may Immunohistochemistry:

be present, imparting a granular appearance to m Lymphoid component shows expression for B-cell
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-
later). ization for Epstein-Barr encoded RNA)

Usually contain caseous material with a yellow-white m Absence of p24 staining (marker for HIV
appearance infection)
Histology Differential Diagnosis

Sharply circumscribed from the surrounding parotid Other salivary gland true cysts, as well as cystic
parenchyma and is separated from the parotid tissue neoplasms:
by fibrous tissue m LECs may be mistaken for cystic lymphoepithe-
Lined by a variety of epithelial cell types, including lial sialadenitis (LESA):

squamous, cuboidal, columnar, and pseudostratified In contrast to LECs, the cystic LESA has:
types; mucous (goblet) cells, sebaceous cells, and Characteristic lymphoepithelial cell lesions
oncocytic metaplasia may be present. Tendency of the lymphocytes to migrate
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.
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
seen in lymphoepithelial cysts is not seen in sali-

Treatment and Prognosis vary duct cysts.
Surgical excision is curative. Cystic neoplasms in particular mucoepidermoid
carcinoma:
m In contrast to cystic mucoepidermoid carci
noma (MEC), salivary duct cysts lack the prolif-
Salivary Duct Cyst (Fig. 19-11) erative (hyperplastic) cellular features as well as
Definition: Acquired cyst believed to develop due to combination of cell types (i.e., epidermoid
ductal obstruction with marked cystic dilation of a sali- cells, mucocytes and intermediate cells) seen in
vary gland duct. MEC:
Synonyms: Acquired, simple, and retention cyst Infiltrative growth would further support
a diagnosis of a malignant neoplasm but a
Clinical number of malignant salivary gland neoplasms
Most common salivary gland cysts including MEC may not be infiltrative and still
m Represent approximately 2% to 3% of all parotid represent a carcinoma (see Chapter 20 for
gland lesions more complete discussion).
No gender predilection; occur over a wide age range
from early childhood to older adults but most Treatment and Prognosis
patients are over 30 years of age Surgical excision is curative.
Clinical presentation includes unilateral painless Rarely, salivary gland neoplasms have been associ-
swelling. ated with salivary duct cysts.
A B
C D
Fig. 19-11. Salivary duct cyst.

A, Unilocular cyst with fibrotic wall delineated from atrophic-appearing parotid parenchyma (bottom). The cyst is variably
lined by (B) flattened (attenuated) epithelium, (C) cuboidal epithelium; (D) single to multilayered columnar epithelium;
(E) mucous cells usually interspersed with nonmucous cells.
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
Fig. 19-12. Polycystic dysgenetic disease.

A and B, The involved gland is diffusely replaced by multiple varying-sized epithelial-lined cysts creating a honeycomb or
lattice-like appearance. C, Cysts are lined by flattened to cuboidal to columnar-appearing epithelium; intraluminal
proteinaceous and eosinophilic concretions with concentric laminations resembling microliths are present. D, Apocrine-like
snouting may be present; entrapped salivary gland acini and ducts can be seen in between the cysts. Minimal
inflammation is present.
blood cells, and small clusters of ductal epithelial

cells Treatment and Prognosis
Characteristic eosinophilic laminated spheroliths lie Polycystic disease can be managed conservatively
in many of the cystic spaces. without surgical resection; however, surgical inter-
vention may be required to establish a diagnosis or
Gross for cosmesis.
On cut section the enlarged gland is spongy in con- This is a benign disorder with excellent long-term
sistency with apparent variable-sized cysts. prognosis.
To date, there is no evidence to suggest that polycys-
Histology tic salivary gland disease is associated with cystic
Dominated by the presence of multiple varying-sized lesions of other organs.
epithelial-lined cysts diffusely involving the affected
gland(s):
m Cysts have honeycomb, lattice-like appearances.
NONDEVELOPMENTAL CYSTS
Cysts are lined by flattened to cuboidal to columnar-
appearing epithelium with apocrine-like snouting, Salivary gland mucocele is a general term used to
and cytoplasmic eosinophilia. describe minor salivary gland lesions resulting from
Some cells may contain lipid, creating a vacuolated obstruction secondary to a mucous plug or intralu-
or microvesicular appearance to the cytoplasm. minal sialolith resulting in a mucus retention cyst, or
Cysts vary in size and may be empty or contain due to trauma resulting in mucus extravasation
inspissated proteinaceous material, as well as eosino- phenomenon.
philic concretions that may demonstrate concentric
laminations resembling microliths: Mucus Extravasation Phenomenon
m Eosinophilic concretions are diastase-resistant
periodic acid Schiff positive.
(Figs. 19-13 and 19-14)
m Concretions may also stain for amyloid. Definition: Dilatation of minor salivary glands with
Cysts replace the parenchyma, creating a honeycomb accumulated mucus secretion often associated with
appearance. mucus extravasation into the connective tissue without
Despite parenchymal replacement, the overall lobular an associated epithelial lining.
architecture of the gland is retained. Synonyms: Mucus escape phenomenon; extravasa-
Cysts often interconnect with incomplete fibrous tion mucocele
septa.
Parenchyma in between the cysts is fibrous but resid- Clinical
ual (entrapped) salivary gland acini and ducts can be Relatively common lesion
seen. No gender predilection; occur in all age groups but
Inflammation is minimal to absent; no association are most common in the second to third decades of
with acute or chronic sialadenitis. life
Most common site of occurrence is lower lip,
Differential Diagnosis although other sites may be affected, including the
Sclerosing polycystic adenosis (see Chapter 20): buccal mucosa, floor of mouth, palate, tongue, ret-
m Unilateral well-circumscribed and partially encap- romolar fossa, tonsillar region, and upper lip.
sulated lesion considered to be a neoplasm based Clinical presentation varies but most common pre-
on evidence of clonality and capability to harbor sentation is that of a painless swelling developing
dysplasia and carcinoma in situ of ductal from days to week, then ruptures and disappears
epithelium only to recur within several weeks.
Cystic salivary gland neoplasms, including cystade- Superficial lesions present as raised swelling that is
noma, cystadenocarcinoma, mucoepidermoid fluctuant on palpation.
carcinoma: If the lesion is close to the surface, the overlying
m In contrast to a neoplastic proliferation where the epithelium may be thin and the lesion has a translu-
disease process is localized, the changes associ- cent, bluish appearance; deeper-seated lesions located
ated with polycystic disease diffusely involve the in soft tissues are more nodular and depending on
affected gland(s). the depth:
m Absence of the constituent cells of mucoepider- m Superficial lesions are movable, smooth, soft to
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.
Differential Diagnosis
Diagnosis is usually straightforward and given the
absence of epithelial lining essentially excludes all
epithelial-lined cystic lesions (non-neoplastic and
neoplastic).

Surgical excision is the preferred treatment to include
excision of the associated salivary gland acini to
prevent recurrence.
Except in cases treated by inadequate surgery (inci-
A sion), recurrences rarely occur.
Mucus Retention Cyst (Fig. 19-15)

Definition: Obstructive disorder of salivary glands
resulting in ductal dilatation with increased intralumi-
nal pressure; mucus retention cyst represents a true cyst
in that an epithelial lining is present.
Synonyms: Retention mucocele; oral sialocyst
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
mucus extravasation phenomenon.

Pathology m Others consider it as a separate unique entity.
Histology m Given differences in clinical and histologic find-
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
positive. layer of cuboidal, columnar, or nonkeratinizing

These stains are useful for identifying residual squamous epithelium; occasional mucus-secreting
mucus in the lesion. cells can be found.
A C
D E
Fig. 19-14. Mucus extravasation phenomenon.

A, Mucus extravasation phenomenon characterized by a well-circumscribed submucosal mucin-filled cystic lesion. Cyst
lining includes (B) granulation tissue and/or (C) inflammatory cells; intraluminal and intramural mucinous material is positive
for (D) mucicarmine (weakly) and (E) PAS with diastase.
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.
Ranula (Fig. 19-16)

Definition: Form of mucus retention cyst or mucus
extravasation phenomenon specifically occurring in the
floor of the mouth in association with the ducts of the
sublingual or submaxillary gland.
In Latin, ranula means frog-like and is so named
due to its bluish appearance, likened to a frogs belly.
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:
Considered a true cyst based on the presence

Cyst filled with eosinophilic material that stains with of an epithelial lining
mucicarmine and PAS with diastase m Plunging ranula:
Significant associated inflammatory cell infiltrate is Considered a pseudocyst based on absence of

not typically present. an associated epithelial lining
Differential Diagnosis Simple Ranula (Sublingual Ranula)

Diagnosis of mucus retention cyst is usually straight- Occurs in lateral aspect of the floor of the mouth
forward, although in any given case the differential Most frequently associated with sublingual gland:
diagnosis includes a salivary gland neoplasm such as m Occasionally may be associated with subman-
a mucoepidermoid carcinoma. dibular gland

m Absence of identifying the cellular components of Presenting symptoms include loud snoring and a
mucoepidermoid carcinoma (i.e., mucous cells, painless mass; if large, deviation of the tongue may
epidermoid cells and intermediate cells) plus the occur.
absence of invasive growth exclude this diagnos-
tic consideration. Pathology
Gross
Treatment and Prognosis Fluctuant masses measuring up to several
Surgical excision is curative. centimeters
Superficial lesions may impart a bluish color; more

commonly, the lesions are deep-seated with the color
of the overlying intact mucosa.
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.
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.

Surgical excision, including removal of the entire
associated salivary gland, is the treatment of choice;
some authorities prefer to simply unroof the lesion
(marsupialization of the cyst wall) rather than per-
forming total excision.
Inadequate excision occasionally results in
recurrence.
Plunging Ranula (Deep Ranula)

(Figs. 19-17 and 19-18)
Extends beyond mucous membranes with herniation
through the mylohyoid muscle into the neck result-
ing from mucus extravasation
Clinical presentation is that of a painless neck mass
in the submental or submandibular triangle with or
without an associated lesion in the floor of the
mouth.
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.
the function of the gland secondary to physiologic

dysfunction or to an anatomic barrier.
Microorganisms may gain access to the gland via
retrograde extension through the ductal system, lym-
phatic spread to intraglandular lymph nodes, or by
hematogenous routes.
Acute sialadenitis most commonly affects the parotid
and submandibular glands.
Acute sialadenitis may be bacterial or viral in origin:
m Staphylococcus aureus and Streptococcus viri-
dans are the most commonly cultured bacteria,

but anaerobic bacteria have also been implicated
in a significant number of cases.
m Most common viral illness infecting the salivary
glands is epidemic parotitis, also referred to as

Fig. 19-18. Plunging ranula. mumps, the causative organism being an RNA
Left, Histologically, plunging ranulas appear as mucinous virus in the Paramyxovirus group:
material surrounded by fibrous tissue, chronic Patients who are serologically negative for
inflammatory cells including histiocytes without an mumps may have infection caused by other
associated epithelial lining. Right, Mucicarmine staining viruses including Coxsackie A, ECHO, Epstein-
shows the presence of weakly positive mucin material Barr virus, cytomegalovirus, parainfluenza
within the fibroinflammatory tissue. virus type C, and lymphocytic choriomeningitis
virus.
m In addition, the salivary glands represent a site of
Treatment and Prognosis involvement for human immune virus (HIV)
Meticulous excision of the lesion including excision infection with subsequent development of HIV-
of the associated salivary gland of origin is the pre- associated salivary gland disease.
ferred treatment. m Opportunistic infections such as cytomegalovi-
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.
Fig. 19-20. HIV salivary gland disease.

Fig. 19-19. Mumps.
This HIV-infected patient has enlargement of his right
This child had rapid and painful enlargement of both
parotid gland area, which represents the clinical
parotid glands over days.
presentation of HIV salivary gland disease. Note the
scar of the left neck representing prior resection of
an enlarged left parotid gland, which also shows HIV-
related changes.
Other glands may be affected, including the lacrimal
gland, thyroid gland.
Systemic manifestations due to viremia may include:
m Hepatosplenomegaly, pancreatitis, abdominal Complications of infection are rare and include:
pain, lymphadenopathy, polyarthritis, (aseptic) m Sterility in men secondary to testicular atrophy
meningitis, and encephalitis: after orchitis

Systemic manifestations are more likely to m Deafness as a sequelae to encephalitis
occur in adults. Fatalities are rare and are related to encephalitis,

Orchitis and epididymitis can occur in approxi- myocarditis, and nephritis.
mately one third of postpubescent males.
Swelling and systemic symptoms gradually
subside in 3 to 7 days. Human Immunodeficiency Virus
Diagnosis usually made on clinical grounds, which Salivary Gland Disease (HIV-SGD)
may include serum antibody titers and serum iso-
(Figs. 19-20 through 19-26)
amylase fractions; surgical resection rarely occurs.
Patients who are serologically negative for mumps Definition: HIV-SGD is defined as those HIV-infected
may have infection caused by other viruses, includ- individuals with xerostomia, enlargement of one or
ing Coxsackie A, ECHO, Epstein-Barr virus, cyto- more major salivary glands, or both.
megalovirus, parainfluenza virus type C, and Synonyms: AIDS-related parotid cyst (ARPC); cystic
lymphocytic choriomeningitis virus. lymphoid hyperplasia (CLH)
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.
Fig. 19-21. Imaging findings in HIV-SGD.

CT scan imaging in HIV-SGD showing the presence of
bilateral, multicentric, variable-sized cysts.
Primarily affects adult men aged 20 to 60 years with

greater than 90% of cases occurring in men:
m May occur in children born of HIV-infected
mothers; under these circumstances there is no

gender predilection B
Symptoms include painless swelling of one or
more salivary glands, xerostomia, dry eyes, and Fig. 19-22. Cytology in HIV-SGD.
arthralgias.
Fine-needle aspiration biopsy of HIV-SGD.
Salivary gland involvement is almost always the
A, Heterogeneous lymphoid population is present,
parotid gland (98%) and less often the submandibu- including the presence of scattered plasma cells,
lar gland (2%): macrophages, and a multinucleated giant cell (lower).
m In approximately 60% of the cases there is bilat- B, Higher magnification showing the multinucleated giant
eral disease. cells. In the appropriate clinical setting, these cytologic
Salivary gland involvement typically occurs in the findings would be consistent with HIV infection.
early stages of HIV disease prior to the development
of AIDS. Represents an uncommon manifestation of HIV
m
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.
A A
B B
Fig. 19-23. HIV-SGD. Fig. 19-25. HIV-SGD.

A, B, Multiple epithelial-lined cysts with associated A, Findings include an epithelial lining infiltrated by mature
lymphoid cell proliferation, including florid follicular lymphocytes (so-called lymphoepithelium) with a subjacent
hyperplasia with attenuated to absent mantle lymphocytes. small lymphoid aggregate. B, Lymphoepithelial lesion
(left of center) within the cyst wall. Such features in
conjunction with other findings, the presence of
multinucleated giant cells (right of center) would support
the diagnostic consideration of HIV-SGD but requires
clinical and serologic correlation.
This infiltrative process resembles in many

aspects a Sjgren-like syndrome, owing to the
visceral lymphocytic infiltration.
Pulmonary process associated with DILS may
mimic clinically and radiographically the pneu-
monic process caused by Pneumocystis jiroveci
(formerly carinii).
m Other manifestations of DILS to consider include
a severe form of peripheral neuropathy, lympho-

cytic infiltration of the liver, evident as hepatitis,
myositis, and lymphocytic interstitial nephritis.
m DILS may progress to development of parotid
Fig. 19-24. HIV-SGD. cysts.
m DILS in HIV has similarities to classic Sjgren
In addition to the epithelial-lined cysts and the lymphoid
changes, the histology of HIV-SGD also includes the syndrome, manifested by distinctive clinical,
presence of lymphoepithelial islands (identical to those serologic, immunologic, and immunogenetic
seen in lymphoepithelial sialadenitis). characteristics:
Interfollicular mixed (benign) inflammatory-cell

infiltrate with mature lymphocytes, histiocytes, neu-
trophils, and plasma cells are also present.
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
Cytology (Fine-Needle Aspiration be found in the germinal centers (follicular den-

Biopsy [FNAB]) dritic cells), scattered lymphoid cells and in the
Simple and cost-effective procedure for the multinucleated giant cells:
diagnosis Multinucleated giant cells may also show the
Diagnosis of HIV-SGD can be considered in cystic presence of S100 protein and p55 (actin bun-
parotid gland lesion(s) showing a combination of: dling protein).
m Heterogeneous lymphoid population Cytogenetics and molecular genetics:
m Scattered single and/or clustered foamy m In two related settings, diffuse infiltrative lym-
macrophages phocytosis syndrome (DILS) and HIV-associated

m Numerous multinucleated giant cells CD8+ lymphocytosis syndrome, monoclonal
m Superficial and/or anucleated squamous cells TCR gene has been reported:
Despite the finding of monoclonal TCR gene,
Histology there is evidence that the CD8+ expansions are
Lymphoid-Related Changes reactive populations capable of mediating non-
Histologic alterations similar to changes seen in cytotoxic inhibition of HIV replication that
lymph nodes in early phases of HIV infection, includ- is believed to represent an immune response
ing florid follicular hyperplasia, attenuated to absent to viral infection rather than a malignant
mantle lymphocytes, disruption of the germinal disorder.
centers (follicle lysis), and the presence of multinu-
cleated giant cells (MGCs) localized to interfollicu- Differential Diagnosis
lar, intrafollicular, and periepithelial areas Other infectious diseases
Monomorphic round cells with clear cytoplasm Salivary gland lesions with morphologic changes
(monocytoid B-cells) can be found in clusters. that overlap with HIV-SGD collectively referred to
as lymphoepithelial lesion (LEL) occurring in lym-

phoepithelial sialadenitis (see later).
Chronic Sialadenitis
Sjgren syndrome: Definition: Chronic inflammation of salivary glands that
m Serologic markers that are present in Sjgren may result from a variety of causes, including nonob-
syndrome, including polyclonal hypergamma- structive diseases and obstructive lesions.
globulinemia and production of organ-specific Causes include:
autoantibodies (antisalivary duct antibodies m Mechanical obstruction, infectious disease, and
autoantibodies), nonorgan-specific (rheumatoid autoimmune diseases

factor, anti-nuclear antibodies [ANA], anti-RO m In many patients the cause of chronic sialadenitis
[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
comparable morphologically and molecularly to Clinical

those arising after solid organ transplantation Worldwide sarcoidosis is most common in young to
also occur in association with HIV infection, middle-aged women.
although their biologic significance and malig- In the United States, sarcoidosis is ten times more
nant status remains unclear. common in African Americans with a female
diagnosis of Sjgren syndrome (see Differential

Diagnosis later)
No laboratory findings specific for or diagnostic of
sarcoidosis:
m Elevated serum levels of angiotensin-converting
enzyme (ACE) are found in patients with active

pulmonary sarcoidosis; however, ACE levels are
elevated in other (nonsarcoid) diseases including
liver disease and leprosy.
m Cutaneous anergy to skin test (sarcoid) anti-
gens referred to as the Kveim test is positive in a

majority of patients with recently diagnosed (sub-
acute) sarcoidosis; the Kveim test reaction may
be low or absent in patients with inactive or
chronic sarcoidosis.
Although a known cause has not be elucidated to
Fig. 19-27. Sarcoidosis.
date, speculation remains that sarcoidosis is an infec-
tious disease possibly caused by a mycobacterial
Sarcoidosis in the parotid gland. Intraparenchymal infection (i.e., mycobacteria other than M. tubercu-
noncaseating granulomas are identified. Special stains for losis [MOTT]).
microorganisms were negative. The patient was known to
have sarcoidosis. Pathology
Cytology
Collections of epithelioid histiocytes with or without
multinucleated giant cells without accompanying
predominance; there is a higher prevalence among necrosis or acute inflammation
people in the southeast United States. Salivary gland acini with varying degrees of degen-
Pulmonary symptoms are present in approximately erative changes
60% of cases and consist of dyspnea, cough, and Efficacy, utility, and cost savings of fine-needle aspi-
nonpleuritic chest pain. ration biopsy in the diagnosis and differential diag-
Nonspecific symptoms may include fever, malaise, nosis of granulomatous sialadenitis to include
weight loss, and lymphadenopathy, the latter includ- sarcoidosis has been demonstrated in numerous
ing (but not limited to) hilar and paratracheal lymph studies.
nodes.
Cutaneous lesions may occur in up to one third of Microscopic
patients and red- or purple-appearing papules. Histologic hallmark is presence of well-formed,
In head and neck, more common sites of involve- noncaseating granulomas consisting of epithelioid
ment include: histiocytes surrounded by a mixed inflammatory
m Cervical neck lymph nodes (anterior and poste- infiltrate and multinucleated (Langhans type) giant
rior cervical lymph nodes), eye, salivary glands, cells.
and mucosal sites of the upper aerodigestive tract Intracytoplasmic inclusions including star-shaped,
m Salivary gland involvement usually includes the referred to as asteroid bodies, and calcific laminated
parotid gland and submandibular gland, but bodies, called Schaumann bodies, can be seen.
minor salivary glands may be affected. No polarizable, pigmented foreign material or dis-
Parotid gland involvement may occur as an isolated solvable material is identified.
process or as part of a syndrome termed uveoparotid Histochemistry:
fever, also known as Heerfordt syndrome, character- m All special stains for microorganisms, including
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:
Occurs in 6% of patients with systemic sar- Differential Diagnosis

coidosis and may be bilateral in a majority of NOTE: The noncaseating granulomas of sarcoidosis are
cases not pathognomonic. The pathologic features of sarcoid-
May occur in association with Sjgren disease osis are characteristic but they are not specific; the diag-
May present with sicca complex (xerophthal- nosis of sarcoidosis can only be considered in the
mia and xerostomia), suggesting a clinical absence of identifying an infectious agent.
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
Sjgren syndrome: in association with or independent of nodal

m Patients with sarcoidosis of the salivary glands disease, including major salivary glands.
may present with sicca complex (xerophthalmia m Salivary gland involvement is uncommon and
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
or central nervous system involvement. m Congenital duct malformations
m Ascending infections
Extranodal Sinus Histiocytosis with m Kussmaul disease (fibromucinous plugs in the col-
lecting system of dehydrated patients)

Massive Lymphadenopathy m Trauma
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:
Fig. 19-28. Sialolithiasis.

Oral cavity showing a white stone situated within the
orifice of the parotid (Stensen) duct causing an obstructive
sialadenitis.
m Recurrent, acute exacerbations of inflammation

resulting in a slowly progressive destruction of
the parotid gland.
Chronic sialadenitis may or may not be associated B
with stone formation; however, calculi are seen
in nearly two thirds of patients with chronic
sialadenitis. Fig. 19-29. Sialolithiasis.
Chronic sialadenitis more commonly affects the A, A calculus is seen within a large duct as concentric
parotid gland, probably resulting from the anatomy laminations of calcification peripherally surrounded by
of Stenson duct, which is long and narrow making compressed ductal epithelium and fibrotic change within
it more susceptible to any alterations in the composi- adjacent salivary gland parenchyma; minimal inflammation
tion of its saliva. is present. B, In this example a calculus is present
within a duct surrounded by the presence of a marked
inflammatory cell infiltrate.
Sialolithiasis (Figs. 19-28
through 19-31)
Definition: Occurrence of calcerous concretions within
salivary gland ducts and/or parenchyma as a result Salivary calculi occur slightly more often in men than
of mineralization of debris accumulated within duct in women; occur at any age but are most frequently
lumens. seen in middle-aged adults; pediatric sialolithiasis is
uncommon.
Clinical Symptoms depend on size and location of calculi:
Calculi may be seen in the ductal system of all sali- m Submandibular gland calculi are:
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
A B
C D
Fig. 19-30. Sialolithiasis.

A and B, Ectatic duct filled with reddish-appearing crystalline stone material with associated neutrophils and blue-
appearing bacterial colonization; cyst epithelial lining is attenuated and includes scattered cells with enlarged
hyperchromatic nuclei (arrowheads). The wall of the cyst shows fibrosis and scattered fibroblasts. The cyst lining may
variably include (C) oncocytic cells; (D) squamous cells. Mucous cells may be present (not shown). C, D, In some cases
there may be extracellular mucus extravasation (in cyst wall) that, in conjunction with squamous-appearing cells and
mucocytes, may suggest a diagnosis of mucoepidermoid carcinoma (MEC). The absence of a proliferative (thickened)
epithelial component, including an admixture of epidermoid cells, mucocytes, and intermediate cells as well as presence
of identifiable intraductal stone material, would weigh against a diagnosis of MEC.
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
Calculi may be palpated or even visualized in the visualized by routine radiography.

distal duct system; because of its deeper anatomic m Majority of parotid gland calculi are radiolucent
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.
When crystalloids/stone fragments identified in aspi-

rated material, these cases pose little diagnostic
difficulty.
When crystalloids/stone fragments not present, epi-
thelial changes and mucus accumulation may be dif-
ficult to distinguish from low-grade mucoepidermoid
carcinoma or other neoplasms.
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.

Small stones can be treated conservatively by
increased intake of fluids, moist heat, analgesics, and
massage; such therapy may result in the passage of
the stone with restoration of salivary flow; calculi
may pass spontaneously.
Failure by conservative means or if the stone is large
necessitates surgical removal of the obstruction,
which varies from excisional biopsy to shock wave
lithotripsy to removal of the entire submandibular
B or parotid gland.
Antibiotics are administered in those cases second-
arily infected. Recurrent infections may occur if the
Fig. 19-31. Sialolithiasis. cause of the obstruction is not removed.
A, B, Over time, the surrounding parenchymal changes in
sialolithiasis may include fibrosis, parenchymal atrophy
with loss of acini, chronic inflammation, and scarring. Chronic Recurrent
Sialadenitis (Fig. 19-32)
Definition: Represents a group of lesions primarily
Cause: affecting the parotid gland characterized by recurrent
m Remains uncertain attacks of swelling associated with pain involving one
m Suggested correlation with smoking history, or both glands.
diuretic use
Clinical
Pathology No gender predilection; may affect children or
Gross adults
Affected gland is enlarged, firm, and nonfluctuating. Clinically, characterized by recurrent attacks of
Sialoliths are round to oval, white to yellow-brown, swelling of affected gland with associated pain
measuring from a few millimeters to several centime- Primarily involves parotid gland
ters in diameter. m One or both parotid glands may be affected
m Anatomically, parotid gland duct (Stensen duct)
Cytology is long and narrow as compared with the shorter

Abundant polyhedral, multifaceted (nontyrosine) and wider submandibular gland duct (Wharton
crystalloids may be seen in the background of scanty duct), predisposing parotid gland to abnormali-
cellular specimens composed predominantly of onco- ties of secretions that may result in recurrent
cytic cells. sialadenitis.
Advanced stages characterized by a marked increase

of periductal inflammatory cell infiltrate eventually
resulting in near complete obliteration of the affected
gland with destruction of the lobular formation and
effacement of the salivary gland parenchyma.
Lymphoid follicles may be present and in some cases
lymphepithelial islands similar in appearance to
those identified in benign lymphoepithelial lesions
may be present.

May spontaneously resolve with puberty; however,
A spontaneous resolution in the adult population is not
common
Because cause and pathogenesis remains unknown,
no causal therapy is available.
Therapy may vary from conservative treatment to
surgery and a variety of therapeutic modalities
have been used, including gland massage, infrared
light, antibiotics, injection of a sclerosing agent (e.g.,
methyl violet), antiphlogistics, Trasylol, duct occlu-
sion, ductal ligation, ductoplasty, gland denervation,
tympanic neurectomy, and radiotherapy.
Conservative management often fails necessitating
surgery (e.g., parotidectomy):
B m For patients unresponsive to conservative
measures, superficial parotidectomy with preser-
vation of the main duct is safe and effective in
Fig. 19-32. Chronic recurrent sialadenitis. the treatment of chronic sialadenitis, and in
A, B, Duct ectasia with retention of the lobular architecture some patients allows for some preservation of
of the gland; a mild inflammatory cell infiltrate (composed function.
of mature lymphocytes and plasma cells) is present within
the parenchyma.
Sialadenosis
Cause: Definition: Non-neoplastic, noninflammatory enlarge-
m Remains uncertain but predisposing factors ment of salivary glands (in particular parotid), which is
associated with alterations of saliva (decreased almost always associated with an underlying systemic
secretion, stasis, and changes in its chemical com- disorder or a secretory dysfunction.
position) creating an environment conducive for Synonym: Sialosis
infection with induction of ductal epithelial meta-
plasia resulting in obstruction and recurrent Clinical
inflammation(s) No gender predilection; occurs most commonly in
Sialography remains the preferred investigation. adults
Diagnostic siladenoscopy may complement or even Salivary gland enlargement most often affects parotid
supersede sialography as the diagnostic procedure gland:
of choice, but at present more experience is needed m Is usually bilateral
in this technique and its use becomes more m Is an indolent process
widespread. m May be chronic and recurrent
m May be associated with pain

Pathology Almost always associated with a systemic disorder,
Histology including:
In the initial stages the regular lobular architecture m Diabetes, thyroid insufficiency, alcoholism, mal-
of the gland is retained. nutrition, hepatic cirrhosis, drug reactions (e.g.,

Duct ectasia surrounded by a mild inflammatory cell antihypertensive medications), anorexia nervosa,
component composed of mature lymphocytes and and bulimia
plasma cells is present. m Patients are generally afebrile.
Pathogenesis: plasma cell infiltration in affected tissues, and elevated

m Major loss and thinning of myofilament compo- serum concentrations of IgG4.
nent of myoepithelial cells, resulting in loss of Diagnosis of IgG4-RD unifies many eponymous
mechanical support for the acini, proposed as fibroinflammatory conditions previously thought to
causative of sialadenosis: be confined to single organs.
Allows acinar cells to expand as secretory gran- Consensus on pathologic criteria for diagnosis in
ules accumulate intracellularly to produce great specific organs include:
acinar enlargement m Tendency to form tumefactive lesions in multiple
Functional myoepithelial insufficiency is pos- sites

sibly a consequence of an autonomic neuropa- m Characteristic histopathologic appearance,
thy secondary to severe metabolic or hormonal including:
disorders. Dense lymphoplasmacytic infiltrate
Storiform pattern of fibrosis
Pathology Obliterative phlebitis
Cytology Increased numbers of IgG4+ plasma cell
Smears show clusters of swollen acini and numerous m Often but not always elevated serum IgG4
naked nuclei of acinar origin in the background and concentrations
an absence of inflammatory cells. m Tissue IgG4 counts and IgG4:IgG ratios are sec-
m Features are considered distinctive enough to ondary in importance.

enable its diagnosis on fine-needle aspiration. m Pathologic findings do not supplant careful
clinicopathologic correlation and sound clinical
Histology judgment.
Acinar cell enlargement with absent inflammatory Recognition and diagnosis of IgG4-RD crucial
cell infiltrate. owing to the fact that there is a favorable response
m Acinar cell enlargement may take the form of to immunosuppression (e.g., glucocorticoids,
a granular-appearing cytoplasm with densely rituximab)
packed periodic acid Schiff positive material or Precise mechanisms leading to disease are unknown.
honeycomb with vacuolated-appearing cyto- Characteristically IgG4-RD affects the pancreas,
plasm or both. referred to as autoimmune pancreatitis (AIP), which
Histologic findings demonstrate little correlation to consists of two distinct pathologic entities:
specific underlying disorder. m Type 1 AIP:
As disease persists, atrophy of parenchymal tissues Manifestation of a systemic IgG4-related

are seen but the glands remain enlarged due to disease
compensatory increase in intraglandular adipose Affects older patients
tissue. Characterized by an elevated serum IgG4 level
and sites of extra-pancreatic disease
Differential Diagnosis Characteristic features include:
Inflammatory and infectious disease of salivary Increased serum IgG4 levels
glands: Lymphoplasmacytic sclerosing pancreatitis
m A careful and detailed history should allow for including:

the diagnosis and differentiating sialadenosis Abundant infiltration of IgG4+ plasmacytes
from other lesions. and lymphocytes

Storiform fibrosis
Treatment and Prognosis Obliterative phlebitis
Treatment directed toward treating the underlying Extra-pancreatic manifestations (e.g., scle-
systemic disorder rosing cholangitis, sclerosing sialadenitis, ret-

Patients with sialadenosis secondary to systemic roperitoneal fibrosis, others)
endocrine disorders, hepatic cirrhosis, or neurogenic Steroid responsiveness
abnormalities tend to be resistant to treatment. m Type 2 AIP
Not associated with elevated IgG4 levels or

extra-pancreatic disease
Disease process confined to the pancreas
IgG4-Related Diseases (IgG4-RD) Affects younger patients
Definition: Multiorgan autoimmune disorder that can Associated with inflammatory bowel disease
affect any organ, has heterogenous presentation, and is m Both subtypes can mimic malignancy, particularly
characterized by fibrous inflammation, IgG4-positive pancreatic cancer.

Possible pathogenesis: IgG4-related sialadenitis may include:

m IgG4-RD lesions infiltrated by T helper cells, m Chronic sclerosing sialadenitis (CSS):
which likely cause progressive fibrosis and organ Synonyms: Kttner tumor, punctate parotitis
damage m Mikulicz disease (MD):
m IgG4 antibodies are generally regarded as Was considered to be subtype of Sjgren

noninflammatory: syndrome (SS) based on histopathologic
Autoreactive IgG4 antibodies are observed in similarities
IgG4-RD but there is no evidence that they are Recent studies indicated that patients with MD
directly pathogenic. show high serum IgG4 concentration
m Rituximab-induced B-cell depletion in IgG4-RD MD considered as an IgG4-related disease dis-
leads to rapid clinical and histologic improve- tinguishable from SS
ment accompanied by swift declines in serum To establish a definitive diagnosis of IgG4-related
IgG4 concentrations. sialadenitis in the clinical and pathologic settings
m Although IgG autoantibodies against various that correlate to CSS and MD, immunohistochemi-
exocrine gland antigens have been described, in cal staining should be performed to determine the
IgG4-RD remains unknown whether they are number and fraction of plasma cells with IgG4:
members of IgG4 subclass m Not all cases of CSS (Kttner tumor) and MD
m Contribution of autoantibodies to IgG4-RD show requisite IgG4 to IgG plasma cells to

remains unclear. establish a definitive diagnosis of IgG4-related
After the pancreatobiliary system, head and neck is sialadenitis.
next most common site for involvement by IgG4-
related disease. Clinical
Head and neck manifestations of IgG4-RD include Incidence of IgG4-associated sialadenitis unknown
involvement of: More common in men than in women; usually occurs
m Salivary gland(s) from the fourth to seventh decades of life
IgG4-related sialadenitis, see later. Primarily involves submandibular gland:
Mikulicz disease, see later. m Typically one gland
Sclerosing mucoepidermoid carcinoma, see m Rarely multiple glands (major and minor) may be
Chapter 20: affected in a single patient

Suggested relationship to IgG4-RD but has m In Mikulicz disease (MD), in addition to salivary
not definitively been proven gland involvement, there is persistent swelling of

m Thyroid gland (see Section 8): lacrimal glands
Conflicting information in the literature Symptoms include pain and swelling often associated
whether the fibrous variant of Hashimoto thy- with ingestion of food
roiditis represents an IgG4-RD m Patients may present with asymptomatic swelling
Reidel thyroiditis of affected gland.

Sclerosing mucoepidermoid carcinoma: Disease process may be localized to salivary glands
Suggested relationship to IgG4-RD but has or may be associated with sclerosing lesions in
not definitively been proven extrasalivary gland tissues (i.e., systemic IgG4-
m Sinonasal tract: related disease)
Eosinophilic angiocentric fibrosis Laboratory findings:
m Other head and neck sites of involvement may m Elevated serum levels of IgG4, IgG, IgG4/IgG
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
IgG4-Related Sialadenitis elevated.

m Eosinophilia, hypergammaglobulinemia, and
(Figs. 19-33 and 19-34) antinuclear antibodies (ANA) may be present in
Definition: Chronic fibroinflammatory salivary gland systemic disease but are not typically elevated in
disease with characteristic morphology included within localized disease.
the spectrum of systemic IgG4-related diseases that
includes autoimmune pancreatitis and involvement of Pathology
extrapancreatic organs (e.g., kidney, lung, retroperito- Cytology
neum, liver, gallbladder, lymph nodes, breast, salivary In combination with the clinical findings, the fine-
glands, lacrimal glands, aorta). needle aspiration biopsy (FNAB) findings can
A B
C D
Fig. 19-33. IgG4-related sialadenitis.

IgG4-related sialadenitis of the submandibular gland. Two different cases showing varying degree of fibrosis, creating a
lobular appearance including (A) storiform type and (B) nonstoriform type; irregular-shaped germinal centers are evident.
Storiform-type fibrosis is less common in relationship to salivary (submandibular) glands; (C) lobular architecture is
preserved with lobules separated by fibrosis; acinar atrophy is evident; (D) dense lymphoplasmacytic infiltrate within
lobules and extended into fibrosis; a prominent germinal center is present; (E) sheets of mature plasma cells.
Histology
Histopathologic features of IgG4-related sialadenitis
include:
m Preservation of lobular architecture
m Lobules separated by fibrosis:
Typical storiform-type fibrosis seen in other

organs (e.g., pancreas) may not be as frequently
present in salivary glands
m Dense lymphoplasmacytic infiltrate within lobules
and extended into fibrosis

m Large, irregular lymphoid follicles with expanded
germinal centers (florid lymphoid hyperplasia)

m Sheets of mature plasma cells
A m Acinar atrophy
m Obliterative phlebitis may or may not be

present:
Venous channels are obliterated by dense lym-
phoplasmacytic infiltrate
Not as frequently seen as in other organ sites
(e.g., pancreas)
Not required for diagnosis
Elastic stains may assist in confirming presence
of phlebitis.
Additional findings may include:
m Squamous metaplasia of ducts
m Mucous metaplasia of ducts
May include ciliated cells and goblet cells

m Noncaseating granulomas may be seen:
B Likely results from mucus extravasation from

ducts in association with sialolithiasis
Immunohistochemistry:
Fig. 19-34. IgG4-related sialadenitis. m IgG4 immunostaining essential test for pathologi-
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
IgG4+/IgG+ plasma cell ratio more powerful tool

m Rituximab-induced B-cell depletion in IgG4-RD
m
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
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):
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
m Pain may be present in up to 40% of cases.
High proportion of cases (approximately 50% to

85%) have clinical and laboratory evidence of
Sjgren syndrome (see later).
Represents a risk factor for development of salivary
gland lymphoma especially when associated with
Sjgren syndrome or other connective tissue diseases
(e.g., rheumatoid arthritis):
m Estimated risk to be 44 fold
m Majority (80%) are extranodal marginal zone
(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-
lial lesions may occur:

Cysts may vary in size from small to large, the
latter resulting in a prominent cystic lesion
(cystic LESA).
Findings may simulate those seen in lympho-
epithelial cyst and in HIV-related salivary gland
disease.
In early stage of disease glandular lumens of the
lymphoepithelial lesions are preserved; with progres-
sion of disease there is near total or total effacement
of the normal architecture with replacement of
acinar tissue of the gland lobules with the lymphoid
infiltrate as well as obliteration of the glandular
lumens of the lymphoepithelial lesions, which appear
B as irregular-shaped nests of polygonal and spindle-
shaped cells containing a variable amount of eosino-
Fig. 19-35. Lymphoepithelial sialadenitis. philic hyaline material.
Overall lobular architecture of affected gland is
A, Lymphoepithelial sialadenitis (LESA) presenting as a preserved.
markedly enlarged left parotid gland along the mandible
Early changes include multiple scattered foci of peri-
and lateral neck region. B, Radiographic findings depict the
presence of an enhancing, well-delineated, solid lesion
ductal lymphoid proliferation.
with diffuse enlargement of the parotid gland. Germinal center formation within the lymphoid infil-
trate varies from rare to extensive; reactive follicles
often have irregular outlines and do not show expan-
sion of the mantle or marginal zones.
A B
C D
Fig. 19-36. LESA.

A, Enlarged parotid gland with diffuse nodularity and tan-white to fleshy appearance. B, Replacement of parotid gland
parenchyma by lymphocytic infiltrate with identifiable germinal centers; the proliferation is well-demarcated from adjacent
salivary gland parenchyma (extreme left side of illustration). C and D, Characteristic appearance of lymphoepithelial lesion
(island) in which there is lymphocytic infiltration of proliferating ductal epithelium with obliteration of ductal lumina
surrounded by a mixed chronic inflammatory cell infiltrate. E, Cystic alteration of the lymphoepithelial lesion may occur
ranging from an incidental finding (as depicted here) to examples in which the cysts are markedly dilated appearing as a
predominantly cystic lesion (not shown).
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:
Monotypic cell population may not be invasive

and may remain localized.
m Epithelial component:
Cytokeratins positive
Molecular biology:
m Lymphoid infiltrates may reveal heavy- and light-
chain Ig gene rearrangement.

m Presence of molecular evidence of B-cell clonality
may be seen in the absence of histologic features,

diagnostic for a lymphoma; the meaning and
importance of this finding remains controversial:
Most cases with monoclonal populations have
A B an uneventful course.
Significance of clonality in LESA without
morphologic evidence of lymphoma remains
controversial.
Most important differential diagnosis of LESA is
malignant lymphoma:
m Lymphomas of the major salivary glands may or
may not be associated with LESA.

m Irrespective of the setting, most lymphomas
of salivary glands are B-cell non-Hodgkin
lymphomas:
Mucosa-associated lymphoid tissue (MALT)
C D lymphomas most common > diffuse large B-
cell lymphoma and follicular lymphoma
m See Chapter 20 for more complete coverage of
Fig. 19-37. LESA.
salivary gland malignant lymphomas.
A, The epithelial cells of the lymphoepithelial lesions are m MALT lymphomas:
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
Absence of additional histologic findings sup- MALT lymphoma

portive of a malignant lymphoma Normal lobular architecture is altered with
Absence of clinical evidence supportive of a replacement of acini and ducts and invasion
malignant lymphoma of the neoplastic cells into surrounding
An overall indolent biologic course structures.
Some of these examples may evolve into a Immunohistochemical stains show:
malignant lymphoma (extranodal marginal Light chain restriction
zone B-cell lymphoma). Diffuse sheets of CD20+ B cells
In later stages of disease, plasma cells are more B-cells show aberrant coexpression of CD43
conspicuous. t(14;18) translocation with IgH/MALT1 fusion

Immunohistochemistry: and trisomies 3 and 18 present in a proportion
m Lymphoid component: of cases and assist in differentiating malignancy
Polyclonality including reactivity for B-cell and from benign or borderline case
T-cell markers: Monocytoid B-cell lymphomas rarely have
B-cells > T-cells t(14;18) translocations as frequently found

Lymphoid infiltrates in LESA may contain in MALT lymphoma of stomach and lung (as
monotypic cells that have restricted immuno- determined by immunologic studies for the
globulin pattern bcl-2 protein)
Lymphoepithelial cyst Diffuse swelling of the salivary glands that may be

HIV-salivary gland disease nontender or tender and is usually bilateral; the sub-
mandibular gland may be affected before the parotid
Treatment and Prognosis gland.
Treatment for LESA is symptomatic relief and/or Extra-glandular manifestations include:
directed at specific associated disease (see Box 19-2): m Raynaud phenomenon
m However, owing to increased risk for developing m Primary biliary cirrhosis
lymphoma, parotidectomy may be performed. m Diffuse interstitial lung disease
m Interstitial nephritis
m Atrophic gastritis
Sjgren Syndrome (SS) m Hepatobiliary diseases
Definition: Chronic autoimmune disease characterized m Neuropathies
by lymphocytic infiltration of exocrine glands and epi- m Inflammatory vascular disease
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-
involvement. ciation with rheumatoid arthritis is much more

Synonym: Autoimmune epithelitis common than other collagen vascular diseases,
including systemic lupus erythematosus, sclero-
History derma, polymyositis/dermatomyositis, mixed con
m Henrik Sjgren observed that many patients with nective tissue disease, and polyarteritis nodosa.
a particular form of dry eyes (keratoconjunctivits m Previously, patients were classified into two cat-
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,
Ocular manifestations (keratoconjunctivitis sicca) with high sensitivity and specificity.

are quantitative and qualitative changes of tear film.
Oral manifestations include dry, sticky oral mucosal Laboratory Findings
surfaces, no or cloudy saliva, primary or recurrent Most commonly used test in diagnosis is Schirmer
dental carries, angular cheilitis, or patchy or general- test:
ized oral mucosal erythema with dorsal tongue fis- m Measures wetting of standardized tear test strips
suring and papillary atrophy. applied between eyeball and lateral inferior eyelid
m Performed without anesthetic eye drops Antibodies to mitochondria reported in SS:

m Score of 5mm in 5 minutes considered m Found only in patients with primary biliary
positive test and objective evidence of ocular cirrhosis

involvement: Plasma interleukin-6 (IL-6) elevated in primary SS:
This test may be reduced in normal subjects m Primary SS patients with celiac disease,
older than 60 years so should be excluded from pulmonary fibrosis or alveolitis, or peripheral
the criteria or not considered for a diagnosis of nervous system symptoms had significantly
SS in elderly subjects. higher IL-6 levels than patients without these
Ocular staining score (OSS): manifestations.
m Sum of 0 to 6 score for fluorescein staining of m IL-6 levels increase in parallel with the histologic
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:
junctivae, yielding a total score ranging from 0 to Lymphocyte-mediated destruction of exocrine

12 glands; possibly a graft-versus host disease-
OSS score of 3 considered positive test and like process in which the histocompatibility
objective evidence of ocular involvement antigens of the ductal epithelium or lymphoid
Assuming that individual is not currently cells changes, leading to a loss of self-
using daily eye drops for glaucoma and has recognition
not had corneal surgery or cosmetic eyelid
surgery in the last 5 years Diagnostic Criteria/Classification
Laboratory evaluation includes sialochemistry with Criteria for the classification and diagnosis of SS
increased sodium, chloride, IgA, IgG, lactoferrin, have been suggested without universal acceptance.
and albumin, and decreased phosphates; mild Classification criteria for SS representing a revision
anemia, leukopenia, eosinophilia, elevated ESR, and of the European criteria have been proposed
elevated serum immunoglobulins. by the American-European Consensus Group
Sjgren syndrome is characterized serologically by (AECG):
presence of autoantibodies against Ro/SSA and La/ m This group proposed revised international clas-
SSB: sification criteria for SS (Box 19-3) and the revised

m Mechanisms by which these autoantibodies arise
are not clear.

m Most commonly detected autoantibodies are
those directed against the ribonucleoproteins Ro/
SSA and La/SSB, and presence of antibodies in SS BOX 19-3 Revised International Classification
is associated with early disease onset, longer Criteria for SS
disease duration, parotid gland enlargement,
I. Ocular symptoms
higher frequency of extraglandular manifesta- II. Oral symptoms
tions, and more intense lymphocytic infiltration III. Ocular signs
of the minor salivary glands. a. Schirmer test (5mm in 5min)
m Organ-specific autoantibodies present in SS b. Rose Bengal score or other ocular dry eye score
include anti-salivary duct antibodies (4 according to van Bijsterveld scoring system)
IV. Histopathology:
m Nonorgan-specific antibodies present in SS a. Focus score of 1 (see later)
include: V. Salivary gland involvement:
Rheumatoid factor (70% to 90% frequency) a. Unstimulated whole salivary flow (1.5ml in 15min)
Antinuclear antibodies (ANA) b. Parotid sialography showing diffuse sialectasia
Antibodies to centromere (<5%) (punctuate, globular, cavitary, destructive patterns)
c. Salivary scintigraphy showing delayed uptake,
Antineutrophil cytoplasmic antibodies (ANCA) pos- reduced concentration, and/or delayed excretion of
itivity can be found in patients with primary SS, and tracer
its detection is associated with the presence of clini- VI. Autoantibodies in serum to:
cal manifestations attributable to vascular involve- Ro (SSA) antigen
ment (cutaneous vasculitis, peripheral neuropathy, Lo (SSB) antigen
Both Ro (SSA) and Lo (SSB) antigens
and Raynaud phenomenon).
Patients with SS develop antibodies to three autoan- Modified from Vitali C etal: European study group on
classification criteria for Sjgrens syndrome. Classification
tigens called IFI16, KLHL12, and KLHL7:
criteria for Sjgrens syndrome: a revised version of the
m These autoantigens represent family of transcrip-
European criteria proposed by the American-European
tion regulators. Consensus Group, Ann Rheum Dis 61:554-558, 2002, Table 2.
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
or biologic perspective m Likely possibility is autoimmune with an abnor-
m More recent studies based exclusively on objec- mal response to one or more unidentified
tive tests, stringency of AECG criteria, and antigens:
In support of this consideration, and as detailed

previously, there are several autoimmune- Pathology
related diseases (e.g., autoimmune thyroiditis, Histology
inflammatory bowel disease, primary biliary SS is characterized by the spectrum of histomor-
cirrhosis, others), in which there is significant phologic changes associated with LESA (see
involvement of salivary glands. above).
m Another possible cause is viral, with numerous
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
Fig. 19-38. Lip biopsy in Sjgren syndrome.

A, The biopsy includes overlying squamous mucosa (arrowhead) with greater than five lobules of minor salivary glands
within the submucosa; within the minor salivary glands there are multiple lymphocytic foci (arrows). B and C, The
lymphocytic cell clusters number greater than 50 lymphocytes so each cluster represents a focus score and in this
example the focus score is more than 1 focus/4mm2; note lymphocytic clusters are occurring in the background of
normal-appearing minor salivary glands. D, The cellular components of each cluster are predominantly composed of
mature lymphocytes as well as scattered plasma cells. These overall histologic findings support a diagnosis of Sjgren
syndrome but are not 100% reliable, requiring additional confirmation. In this patients case there was clinical evidence
and elevated of Ro/SSA and La/SSB antibodies.
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-
severity. vary glands are rare tumors, these carcinomas

most likely develop as de novo neoplasms
Treatment and Prognosis unrelated to other conditions (e.g., lymphoepithe-
Treatment is symptomatic relief. lial sialadenitis) (see Chapter 20).
Disease course is generally one of chronicity with m Histologic setting is similar to benign lymphoepi-
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-
period. quently occur in the fifth decade of life

In SS patients with immune-mediated extraglandular m Among Eskimos, the parotid gland is the most
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.
CHAPTER 19 Non-Neoplastic Diseases of Salivary Glands 860.e1
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CH 19 Non-Neoplastic Diseases of Salivary Glands

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CH 19 Non-Neoplastic Diseases of Salivary Glands

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Chapter

CLASSIFICATION OF NON-NEOPLASTIC SALIVARY

Developmental Lesions Infectious, Inflammatory, and Autoimmune Disease

Salivary gland tissue has been reported in thyroglos-

thelial ductal proliferations

Represent primary intranodal neoplasms with

neoplasm from an adjacent salivary gland,

Heterotopic Salivary Gland Tissue

m Represents an admixture of seromucinous glands m Pleomorphic adenoma, monomorphic adenomas

may originate within periparotid nodal salivary

plasm from an adjacent salivary gland, these Adenomatoid Hyperplasia of

single cell type (i.e., mucinous acini) should allow

Treatment and Prognosis

Necrotizing Sialometaplasia (NS)

Fig. 19-3. Necrotizing sialometaplasia. Fig. 19-4. Necrotizing sialometaplasia.

burning sensation and dysphagia

Fig. 19-5. Necrotizing sialometaplasia.

with uniform nuclei and abundant eosinophilic

determined by reactivity for myoepithelial so that the designation of sialometaplasia without

necrotizing would be more appropriate in such

m PEH results when the metaplastic lobules present healing process.

may be identified. included within the spectrum of necrotizing sialo-

Squamous cell carcinoma early or minimal form of NS.

TABLE 19-1 Necrotizing Sialometaplasia: Differential Diagnosis

NS MEC, Low-Grade SCC

SANS most often affects intraoral sites, including

lymphocytes, histiocytes, neutrophils, and vari-

rounded by a dense polymorphous inflammatory

Appears to be a self-limiting process with most A

m Oncocytoma; oncocytic carcinoma

Oncocytosis (Fig. 19-8)

m Gradual merge with and/or contain residual

(nononcocytic) salivary gland parenchyma,

Differentiation of oncocytosis from oncocytoma

Intercalated Duct Lesions (IDL)

to salivary gland neoplasms based on presence of

Clinical A, Mass-forming oncocytic nodule that is circumscribed

Fig. 19-9. Intercalated duct hyperplasia.

Other uncommon features may include:

m Cystic change Most cystic lesions of major salivary glands repre-

pletely encapsulated nodules with well-defined m Salivary duct cyst

contours m Polycystic (dysgenetic) disease

m Fibrous capsule may vary in thickness and

CK14 vary duct cysts and dysgenetic or congenital cysts,

Fig. 19-10. Parotid gland lymphoepithelial cyst.

On cut section, small intracystic protrusions may Immunohistochemistry:

later). ization for Epstein-Barr encoded RNA)

Histology Differential Diagnosis

Lined by a variety of epithelial cell types, including lial sialadenitis (LESA):

oncocytic metaplasia may be present. Tendency of the lymphocytes to migrate

seen in lymphoepithelial cysts is not seen in sali-

Fig. 19-11. Salivary duct cyst.

Fig. 19-12. Polycystic dysgenetic disease.

blood cells, and small clusters of ductal epithelial

Treatment and Prognosis

Mucus Retention Cyst (Fig. 19-15)

mucus extravasation phenomenon.

Histology m Given differences in clinical and histologic find-

positive. layer of cuboidal, columnar, or nonkeratinizing

Fig. 19-14. Mucus extravasation phenomenon.

Ranula (Fig. 19-16)

Considered a true cyst based on the presence

Significant associated inflammatory cell infiltrate is Considered a pseudocyst based on absence of